BioMed Research International: Cardiology The latest articles from Hindawi Publishing Corporation © 2016 , Hindawi Publishing Corporation . All rights reserved. Prevalence and Prognosis of Anemia in Dogs with Degenerative Mitral Valve Disease Thu, 20 Oct 2016 06:37:23 +0000 In humans, heart failure (HF) and renal insufficiency (RI) have negative reciprocal effects, and anemia can exacerbate their progression. In this retrospective study, the prevalence and prognostic significance of anemia in 114 dogs with degenerative mitral valve disease (DMVD) was investigated. Pretreatment clinical parameters, prevalence of anemia and azotemia, and survival time were analyzed in relation to HF severity. The prevalence of anemia was highest in dogs with the modified New York Heart Association (NYHA) class IV HF (33.3%), followed by classes III (15.2%) and II (0%; p < 0.001). The presence of anemia was associated with HF severity and blood creatinine > 1.6 mg/dL (both p < 0.001). Anemic dogs had a shorter median survival [13 months; 95% confidence interval (CI): 0.7–19.1] than nonanemic dogs (28 months; 95% CI: 15.3–40.7; p < .001). NYHA class IV (hazard ratio (HR): 3.1, 95% CI: 2.2–4.3; p < 0.001), left atrium/aorta ratio > 1.7 (HR: 2.7, 95% CI: 1.7–4.2; p = 0.001), and presence of anemia (HR: 1.43, 95% CI: 1.1–1.9; p = 0.004) emerged as predictors of mortality. A cardiorenal-anemia syndrome-like triangle was observed and anemia was a prognostic factor for survival in dogs with DMVD. Ivarosa Bing-Ye Yu and Hui-Pi Huang Copyright © 2016 Ivarosa Bing-Ye Yu and Hui-Pi Huang. All rights reserved. Does Physical Fitness Buffer the Relationship between Psychosocial Stress, Retinal Vessel Diameters, and Blood Pressure among Primary Schoolchildren? Tue, 04 Oct 2016 06:58:11 +0000 Background. Strong evidence exists showing that psychosocial stress plays an important part in the development of cardiovascular diseases. Because physical inactivity is associated with less favourable retinal vessel diameter and blood pressure profiles, this study explores whether physical fitness is able to buffer the negative effects of psychosocial stress on retinal vessel diameters and blood pressure in young children. Methods. 325 primary schoolchildren (51% girls, years) took part in this cross-sectional research project. Retinal arteriolar diameters, retinal venular diameters, arteriolar to venular ratio, and systolic and diastolic blood pressure were assessed in all children. Interactions terms between physical fitness (performance in the 20 m shuttle run test) and four indicators of psychosocial stress (parental reports of critical life events, family, peer and school stress) were tested in a series of hierarchical regression analyses. Results. Critical life events and family, peer, and school-related stress were only weakly associated with retinal vessel diameters and blood pressure. No support was found for a stress-buffering effect of physical fitness. Conclusion. More research is needed with different age groups to find out if and from what age physical fitness can protect against arteriolar vessel narrowing and the occurrence of other cardiovascular disease risk factors. Markus Gerber, Katharina Endes, Christian Herrmann, Flora Colledge, Serge Brand, Lars Donath, Oliver Faude, Uwe Pühse, Henner Hanssen, and Lukas Zahner Copyright © 2016 Markus Gerber et al. All rights reserved. The Effects of Diabetes Mellitus in Patients Undergoing Off-Pump Coronary Artery Bypass Grafting Thu, 29 Sep 2016 12:49:03 +0000 Objective. To investigate the effects of diabetes mellitus (DM) in patients undergoing off-pump coronary artery bypass grafting (OPCAB). Method. A total of 728 patients with DM and 1380 patients without DM who underwent OPCAB treatment from March 2012 to April 2015 were reviewed. The effects of DM on intraoperative variables and postoperative complications were determined using propensity score analysis. Results. Two well-matched subgroups were selected using propensity score analysis (DM = 728, no-DM = 728) to compare the perioperative outcome. The duration of the ICU stay, in hours (55.2 ± 53.0 versus 49.29 ± 51.30, ), postoperative new-onset atrial fibrillation (20.9% versus 14.97%, ), and postoperative infection (9.2% versus 4.67%, ) were greater in DM patients, as indicated by univariate analysis. Conclusion. OPCAB was found to be effective in DM patients, but postoperative infection and postoperative new-onset atrial fibrillation were found to be more likely to occur in DM patients than in other patients. DM was found to be a powerful risk factor for postoperative infection and postoperative new-onset atrial fibrillation. Yu Liu, Jinsong Han, Tao Liu, Zhonglu Yang, Hui Jiang, and Huishan Wang Copyright © 2016 Yu Liu et al. All rights reserved. Role of Histone Demethylases in Cardiomyocytes Induced to Hypertrophy Sun, 18 Sep 2016 10:58:36 +0000 Epigenetic changes induced by histone demethylases play an important role in differentiation and pathological changes in cardiac cells. However, the role of the jumonji family of demethylases in the development of cardiac hypertrophy remains elusive. In this study, the presence of different histone demethylases in cardiac cells was evaluated after hypertrophy was induced with neurohormones. A cell line from rat cardiomyocytes was used as a biological model. The phenotypic profiles of the cells, as well as the expression of histone demethylases, were studied through immunofluorescence, transient transfection, western blot, and qRT-PCR analysis after inducing hypertrophy by angiotensin II and endothelin-1. An increase in fetal gene expression (ANP, BNP, and β-MHC) was observed in cardiomyocytes after treatment with angiotensin II and endothelin-1. A significant increase in JMJD2A expression, but not in UTX or JMJD2C expression, was observed. When JMJD2A was overexpressed in cardiomyocytes through transient transfection, the effect of neurohormones on fetal cardiac gene expression was increased. We conclude that JMJD2A plays a principal role in the regulation of fetal cardiac genes, which increase in expression during the pathological hypertrophic process. Wendy Rosales, Juan Carulla, Jeison García, Diana Vargas, and Fernando Lizcano Copyright © 2016 Wendy Rosales et al. All rights reserved. Assessment of the Utility of the Septal Ratio and Tissue Doppler Index in Predicting Left Ventricular Remodeling after Acute Myocardial Infarction Thu, 15 Sep 2016 08:46:51 +0000 Background. The aim of this study is to show whether the septal ratio assessed by tissue Doppler echocardiography can predict left ventricular remodeling after first ST segment elevation myocardial infarction treated successfully with primary percutaneous intervention. Methods. Consecutive patients () presenting with acute anterior myocardial infarction for the first time in their life were enrolled. All patients underwent successful primary percutaneous coronary intervention. Standard and tissue Doppler echocardiography were performed in the first 24-36 hours of admission. Echocardiographic examination was repeated after 6 months to reassess left ventricular volumes. Septal ratio was assessed by pulsed Doppler echocardiography. Results. Group 1 consisted of 33 patients with left ventricular (LV) remodeling, and Group 2 had 78 patients without LV remodeling. was significantly higher in Group 1 ( versus , ). The optimal cutoff value for ratio was 2.34 with 87.0% sensitivity and 82.1% specificity. Conclusion. Septal values measured after the acute anterior myocardial infarction can strongly predict LV remodeling in the 6-month follow-up. In the risk assessment, the septal can be evaluated together with the conventional echocardiographic techniques. Selma Kenar Tiryakioglu, Hakan Ozkan, Hasan Ari, Kıvanc Yalin, Senol Coskun, and Osman Tiryakioglu Copyright © 2016 Selma Kenar Tiryakioglu et al. All rights reserved. Polymorphism of HDAC9 Gene Is Associated with Increased Risk of Acute Coronary Syndrome in Chinese Han Population Wed, 24 Aug 2016 07:26:35 +0000 Recent genome-wide association studies (GWAS) have indicated an association of histone deacetylase 9 (HDAC9) genetic variant with large-vessel stroke and coronary artery disease, among the European population. However, whether HDAC9 gene is associated with an increased susceptibility to acute coronary syndrome (ACS) in Chinese Han population is not known. A total of 472 patients, including patients with ACS (), and those with chest pain syndrome (controls, ) were enrolled. Genotyping for HDAC9 gene was performed using the ligation detection reaction assay. A series of statistical analyses were performed to investigate the correlation between HDAC9 gene SNPs and the susceptibility to ACS. The results revealed a significant association of rs2240419 with ACS risk in which the A allele (P = 0.047) and the A allele carriers (AA + AG) (P = 0.037) were more likely to be in ACS group as compared to those in the control group. None of two other SNPs, rs2389995 and rs2107595, were significantly associated with ACS risk (P > 0.05). Logistic regression analyses further revealed an increased risk for ACS in A allele carrier among rs2240419 genotypes, as compared to those with GG homozygotes (odds ratio: 1.869, 95% CI 1.143, 3.056, P = 0.013). A significant correlation between rs2240419 polymorphism of HDAC9 gene and the susceptibility to ACS in Chinese Han population was observed in this study. Zhenhua Han, Xin Dong, Chaoying Zhang, Yue Wu, Zuyi Yuan, and Xinhong Wang Copyright © 2016 Zhenhua Han et al. All rights reserved. Corrigendum to “Effects of Sevoflurane and Propofol on Organ Blood Flow in Left Ventricular Assist Devices in Pigs” Wed, 17 Aug 2016 07:29:20 +0000 Paloma Morillas-Sendín, Emilio Delgado-Baeza, María Jesús Delgado-Martos, Mónica Barranco, Juan Francisco Del Cañizo, Manuel Ruíz, and Begoña Quintana-Villamandos Copyright © 2016 Paloma Morillas-Sendín et al. All rights reserved. Role of miRNAs in Epicardial Adipose Tissue in CAD Patients with T2DM Sun, 14 Aug 2016 06:12:14 +0000 Background. Epicardial adipose tissue (EAT) is identified as an atypical fat depot surrounding the heart with a putative role in the involvement of metabolic disorders, including obesity, type-2 diabetes mellitus, and atherosclerosis. We profiled miRNAs in EAT of metabolic patients with coronary artery disease (CAD) and type-2 diabetes mellitus (T2DM) versus metabolically healthy patients by microarray. Compared to metabolically healthy patients, we identified forty-two miRNAs that are differentially expressed in patients with CAD and T2DM from Xinjiang, China. Eleven miRNAs were selected as potential novel miRNAs according to P value and fold change. Then the potential novel miRNAs targeted genes were predicted via TargetScan, PicTar, and miRTarbase, and the function of the target genes was predicted via Gene Ontology (GO) analysis while the enriched KEGG pathway analyses of the miRNAs targeted genes were performed by bioinformatics software DAVID. Then protein-protein interaction networks of the targeted gene were conducted by online software STRING. Finally, using microarray, bioinformatics approaches revealed the possible molecular mechanisms pathogenesis of CAD and T2DM. A total of 11 differentially expressed miRNAs were identified and among them, hsa-miR-4687-3p drew specific attention. Bioinformatics analysis revealed that insulin signaling pathway is the central way involved in the progression of metabolic disorders. Conclusions. The current findings support the fact that miRNAs are involved in the pathogenesis of metabolic disorders in EAT of CAD patients with T2DM, and validation of the results of these miRNAs by independent and prospective study is certainly warranted. Yang Liu, Wenbo Fu, Mu Lu, Shitao Huai, Yaqin Song, and Yutao Wei Copyright © 2016 Yang Liu et al. All rights reserved. Cilostazol Improves Proangiogenesis Functions in Human Early Endothelial Progenitor Cells through the Stromal Cell-Derived Factor System and Hybrid Therapy Provides a Synergistic Effect In Vivo Tue, 09 Aug 2016 10:24:18 +0000 This study investigated the effect of cilostazol on proangiogenesis functions in human early endothelial progenitor cells (EPCs) in vitro and the therapeutic implication of hybrid therapy with cilostazol and human early EPCs in vivo. Cilostazol significantly increased colony-forming units and enhanced differentiation of EPCs toward endothelial lineage. Treatments resulted in antiapoptotic effects and stimulated proliferation and migration and in vitro vascular tube formation through activation of stromal cell-derived factor-1 (SDF-1)/C-X-C chemokine receptor type 4 (CXCR4)/phosphatidylinositol-3 kinase (PI3K)/Akt signaling pathway. Blood flow recovery and capillary density in murine ischemic hindlimbs were significantly improved in cilostazol-treated, human early EPCs-treated, and cotreatment groups. The effects were attenuated with SDF-1α inhibition. Plasma SDF-1α levels were significantly higher in 3 active treatment groups after surgery, with greatest effects observed in hybrid therapy. The angiogenic effects of transplanted EPCs pretreated with cilostazol ex vivo were superior to untreated EPCs using in vivo Matrigel assay. Implanted EPCs were incorporated into the capillary, with pretreatment or cotreatment with cilostazol resulting in enhanced effects. Taken together, cilostazol promotes a large number of proangiogenic functions in human early EPCs through activation of SDF-1/CXCR4/PI3K/Akt signaling, and hybrid therapy provides a synergistic effect in vivo. Cotreatment may be beneficial in ischemic disease. Shih-Ya Tseng, Ting-Hsing Chao, Yi-Heng Li, and Chung-Lung Cho Copyright © 2016 Shih-Ya Tseng et al. All rights reserved. MicroRNA Expression Signature in Degenerative Aortic Stenosis Thu, 04 Aug 2016 08:09:47 +0000 Degenerative aortic stenosis, characterized by narrowing of the exit of the left ventricle of the heart, has become the most common valvular heart disease in the elderly. The aim of this study was to investigate the microRNA (miRNA) signature in degenerative AS. Through microarray analysis, we identified the miRNA expression signature in the tissue samples from healthy individuals () and patients with degenerative AS (). Six miRNAs (hsa-miR-193a-3p, hsa-miR-29b-1-5p, hsa-miR-505-5p, hsa-miR-194-5p, hsa-miR-99b-3p, and hsa-miR-200b-3p) were overexpressed and 14 (hsa-miR-3663-3p, hsa-miR-513a-5p, hsa-miR-146b-5p, hsa-miR-1972, hsa-miR-718, hsa-miR-3138, hsa-miR-21-5p, hsa-miR-630, hsa-miR-575, hsa-miR-301a-3p, hsa-miR-636, hsa-miR-34a-3p, hsa-miR-21-3p, and hsa-miR-516a-5p) were downregulated in aortic tissue from AS patients. GeneSpring 13.1 was used to identify potential human miRNA target genes by comparing a 3-way comparison of predictions from TargetScan, PITA, and microRNAorg databases. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed to identify potential pathways and functional annotations associated with AS. Twenty miRNAs were significantly differentially expressed between patients with AS samples and normal controls and identified potential miRNA targets and molecular pathways associated with this morbidity. This study describes the miRNA expression signature in degenerative AS and provides an improved understanding of the molecular pathobiology of this disease. Jing Shi, Hui Liu, Hui Wang, and Xiangqing Kong Copyright © 2016 Jing Shi et al. All rights reserved. Association between Serum Ferritin and Contrast-Induced Nephropathy in Patients with Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention Thu, 28 Jul 2016 09:56:49 +0000 Background and Aims. CIN is a major and serious complication following PCI in patients with ACS. It is unclear whether a higher serum ferritin level is associated with an increased risk of CIN in high-risk patients. Thus, we conducted this study to assess the predictive value of SF for the risk of CIN after PCI. Methods. We prospectively examined SF levels in 548 patients with ACS before undergoing PCI. Multivariate logistic regression analysis was used to analyze the independent risk factors for CIN. The ROC analysis was performed to evaluate the predictive value of SF for CIN. Results. CIN occurred in 96 patients. Baseline SF was higher in patients who developed CIN compared to those who did not ( versus ; ). Multivariate logistic regression analysis showed that SF was an independent predictor of CIN (OR, 1.008; 95% CI, 1.003–1.013; ). The area under ROC curve for SF was 0.629, and SF > 180.9 μg/L predicted CIN with sensitivity of 80.2% and specificity of 41.4%. Conclusion. Our data show that a higher SF level was significantly associated with an increased risk of CIN after PCI. Boqian Zhu, Jiantong Hou, Yaoyao Gong, Gaoliang Yan, Qingjie Wang, Dong Wang, Yong Qiao, Yifei Chen, and Chengchun Tang Copyright © 2016 Boqian Zhu et al. All rights reserved. Association of Aortic Compliance and Brachial Endothelial Function with Cerebral Small Vessel Disease in Type 2 Diabetes Mellitus Patients: Assessment with High-Resolution MRI Wed, 20 Jul 2016 09:30:31 +0000 Objective. To assess the possible association of aortic compliance and brachial endothelial function with cerebral small vessel disease in type 2 diabetes mellitus (DM2) patients by using 3.0 T high-resolution magnetic resonance imaging. Methods. Sixty-two clinically confirmed DM2 patients (25 women and 37 men; mean age: years) were prospectively enrolled for noninvasive MR examinations of the aorta, brachial artery, and brain. Aortic arch pulse wave velocity (PWV), flow-mediated dilation (FMD) of brachial artery, lacunar brain infarcts, and periventricular and deep white matter hyperintensities (WMHs) were assessed. Pearson and Spearman correlation analysis were performed to analyze the association between PWV and FMD with clinical data and biochemical test results. Univariable logistic regression analyses were used to analyze the association between PWV and FMD with cerebral small vessel disease. Multiple logistic regression analyses were used to find out the independent predictive factors of cerebral small vessel disease. Results. Mean PWV was  m/s and FMD was %. After adjustment for compounding factors, PWV was found significantly associated with lacunar brain infarcts (OR = 2.00; 95% CI: 1.14–3.2; ) and FMD was significantly associated with periventricular WMHs (OR = 0.82; 95% CI: 0.71–0.95; ). Conclusions. Quantitative evaluation of aortic compliance and endothelial function by using high-resolution MRI may be potentially useful to stratify DM2 patients with risk of cerebral small vessel disease. Yan Shan, Jiang Lin, Pengju Xu, Mengsu Zeng, Huandong Lin, and Hongmei Yan Copyright © 2016 Yan Shan et al. All rights reserved. NALP3-Inflammasome-Related Gene Polymorphisms in Patients with Prehypertension and Coronary Atherosclerosis Thu, 30 Jun 2016 12:40:45 +0000 Objectives. Prehypertension is an early stage of hypertension that is characterized by inflammatory factors. Inflammation also plays an essential role in the development of coronary atherosclerosis (CAS). The present study evaluated the NALP3-inflammasome and its related genes, NLRP3, NOD2, and CARD8, using SNP linkage and gene haplotypes in prehypertensive patients. Methods. A total of 576 patients with prehypertension and suspected coronary heart disease (CHD) were enrolled. According to coronary angiography, patients were divided into two groups: arterial stenosis <50% of the diameter (control) and arterial stenosis >50% of the diameter (case). Fifteen polymorphisms in the NOD2, NLRP3, and CARD8 genes were analyzed, and serum levels of C-reactive protein (CRP) were measured. Results. When comparing allele frequencies, none of these 15 SNPs in NOD2, CARD8, and NLPR3 genes showed a significant difference using multiple logistic regression. However, the CTACATAA () and CCACATAG () haplotypes of the NOD2 gene SNPs were significantly different between cases and controls. Conclusions. Although our study excludes a significant association of selected SNPs in these genes with CHD in prehypertension patients, this work suggests that the CTACATAA and CCACATAG haplotypes were associated with CHD in the NOD2 locus. This work suggests that the CTACATAA and CCACATAG haplotypes were associated with CHD in prehypertension patients in the NOD2 locus. Xin Zhao, Chonghuai Gu, Chenghui Yan, Xiaolin Zhang, Yi Li, Li Wang, Lili Ren, Yan Zhang, Junyin Peng, Zhiming Zhu, and Yaling Han Copyright © 2016 Xin Zhao et al. All rights reserved. Myocardial Diseases: Current Views on Etiopathogenesis, Diagnostic Modalities, and Therapeutic Options Thu, 16 Jun 2016 11:48:48 +0000 Tomas Palecek, Javier Ganame, and Giovanni Di Salvo Copyright © 2016 Tomas Palecek et al. All rights reserved. Inflammatory Cardiomyopathy: A Current View on the Pathophysiology, Diagnosis, and Treatment Sun, 12 Jun 2016 08:10:47 +0000 Inflammatory cardiomyopathy is defined as inflammation of the heart muscle associated with impaired function of the myocardium. In our region, its etiology is most often viral. Viral infection is a possible trigger of immune and autoimmune mechanisms which contributed to the damage of myocardial function. Myocarditis is considered the most common cause of dilated cardiomyopathy. Typical manifestation of this disease is heart failure, chest pain, or arrhythmias. The most important noninvasive diagnostic method is magnetic resonance imaging, but the gold standard of diagnostics is invasive examination, endomyocardial biopsy. In a significant proportion of cases with impaired left ventricular systolic function, recovery occurs spontaneously in several weeks and therefore it is appropriate to postpone critical therapeutic decisions about 3–6 months after start of the treatment. Therapy is based on standard heart failure treatment; immunosuppressive or antimicrobial treatment may be considered in some cases depending on the results of endomyocardial biopsy. If severe dysfunction of the left ventricle persists, device therapy may be needed. Jan Krejci, Dalibor Mlejnek, Dana Sochorova, and Petr Nemec Copyright © 2016 Jan Krejci et al. All rights reserved. Optimal Duration of Monitoring for Atrial Fibrillation in Cryptogenic Stroke: A Nonsystematic Review Sun, 29 May 2016 09:11:13 +0000 Atrial fibrillation (AF) is the most common form of cardiac arrhythmias and an independent risk factor for stroke. Despite major advances in monitoring strategies, clinicians tend to miss the diagnoses of AF and especially paroxysmal AF due mainly to its asymptomatic presentation and the rather limited duration dedicated for monitoring for AF after a stroke, which is 24 hours as per the current recommended guidelines. Hence, determining the optimal duration of monitoring for paroxysmal atrial fibrillation after acute ischemic stroke remains a matter of debate. Multiple trials were published in regard to this matter using both invasive and noninvasive monitoring strategies for different monitoring periods. The data provided by these trials showcase strong evidence suggesting a longer monitoring strategy beyond 24 hours is associated with higher detection rates of AF, with the higher percentage of patients detected consequently receiving proper secondary stroke prevention with anticoagulation and thus justifying the cost-effectiveness of such measures. Overall, we thus conclude that increasing the monitoring duration for AF after a cryptogenic stroke to at least 72 hours will indeed enhance the detection rates, but the cost-effectiveness of this monitoring strategy compared to longer monitoring durations is yet to be established. Essa Hariri, Ahmad Hachem, Georges Sarkis, and Samer Nasr Copyright © 2016 Essa Hariri et al. All rights reserved. The CYBA Gene 49A>G Polymorphism (rs7195830) Is Associated with Hypertension in Patients with Coronary Artery Disease Tue, 24 May 2016 11:18:16 +0000 Purpose. Single nucleotide polymorphisms of the CYBA gene may modify the risk of coronary artery disease (CAD). The aim of the present study was to investigate whether the 49A>G (rs7195830) polymorphism is associated with CAD. Materials and Methods. CYBA gene 49A>G polymorphism was determined in 481 subjects: 242 patients with premature CAD and 239 age and sex matched controls using the fluorescently labeled allele-specific oligonucleotides method. Results. The frequency of the 49G allele carrier state was significantly higher in patients than in controls (84.8% versus 76.6%, resp., ), as well as the frequency of the 49G allele (62.2% versus 54.0%, ). Both factors were associated with CAD in the analyzed population (OR = 1.70, 95% CI: 1.04–2.76 for GG+AG versus AA and OR = 1.40, 95% CI: 1.08–1.83 for 49G versus  49A). Carrier state of the 49G allele was a stronger and independent risk factor for CAD among women (OR = 4.35, 95% CI: 1.50–13.20, ), as well as the 49G allele (OR = 2.25, 95% CI: 1.34–3.77, ). The 49G allele carrier state was also associated with left ventricular hypertrophy in patients with coronary artery disease (). Conclusion. The CYBA gene 49A>G polymorphism modifies the risk of coronary artery disease. Tomasz Nowak, Paweł Niemiec, Sylwia Górczyńska-Kosiorz, Anna Balcerzyk, Tomasz Iwanicki, Jolanta Krauze, Wladyslaw Grzeszczak, Anna Ochalska-Tyka, Joanna Iwanicka, and Iwona Zak Copyright © 2016 Tomasz Nowak et al. All rights reserved. The Research of Improved Grey GM (1, 1) Model to Predict the Postprandial Glucose in Type 2 Diabetes Mon, 23 May 2016 08:33:24 +0000 Diabetes may result in some complications and increase the risk of many serious health problems. The purpose of clinical treatment is to carefully manage the blood glucose concentration. If the blood glucose concentration is predicted, treatments can be taken in advance to reduce the harm to patients. For this purpose, an improved grey GM (1, 1) model is applied to predict blood glucose with a small amount of data, and especially in terms of improved smoothness it can get higher prediction accuracy. The original data of blood glucose of type 2 diabetes is acquired by CGMS. Then the prediction model is established. Finally, 50 cases of blood glucose from the Henan Province People’s Hospital are predicted in 5, 10, 15, 20, 25, and 30 minutes, respectively, in advance to verify the prediction model. The prediction result of blood glucose is evaluated by the EGA, MSE, and MAE. Particularly, the prediction results of postprandial blood glucose are presented and analyzed. The result shows that the improved grey GM (1, 1) model has excellent performance in postprandial blood glucose prediction. Yannian Wang, Fenfen Wei, Changqing Sun, and Quanzhong Li Copyright © 2016 Yannian Wang et al. All rights reserved. Two-Year Follow-Up after Contact Force Sensing Radiofrequency Catheter and Second-Generation Cryoballoon Ablation for Paroxysmal Atrial Fibrillation: A Comparative Single Centre Study Sun, 22 May 2016 12:32:07 +0000 Background. There are little comparative data on catheter ablation of paroxysmal atrial fibrillation (AF) using the contact force radiofrequency (CF-RF) catheter versus the second-generation cryoballoon (CB2). Methods and results. This is a single center, retrospective, nonrandomized study of 98 patients with symptomatic, drug-refractory paroxysmal AF who underwent their first PVI ablation using either the CB2 () or CF-RF (). The mean age was 60 years with 63% men, a mean LA size of 42 mm. The procedure duration ( versus minutes ) was shorter for CB2 group; the fluoroscopy time ( versus minutes, ) was similar. Complete PVI was achieved in 96% of patients with RF-CF and 98% with CB2. Phrenic nerve palsies (2 transient and 1 persistent) occurred exclusively in the CB2 group and 1 severe, nonlethal complication (pericardial tamponade) occurred in the CF-RF group. At 24-month follow-up, the success rate, defined as freedom from AF/atrial tachycardia (AT) after a single procedure without antiarrhythmic drug, was comparable in CF-RF group and CB2 group (65.5% versus 67%, resp., log rank ). Conclusion. Both the CB2 and the RF-CF ablation appeared safe; the success rate at 2 years was comparable between both technologies. Attila Kardos, Zsuzsanna Kis, Zoltan Som, Zsofia Nagy, and Csaba Foldesi Copyright © 2016 Attila Kardos et al. All rights reserved. Sundarban Honey Confers Protection against Isoproterenol-Induced Myocardial Infarction in Wistar Rats Tue, 17 May 2016 09:58:29 +0000 The present study was designed to investigate the cardioprotective effects of Sundarban honey (SH) in rats with isoproterenol- (ISO-) induced myocardial infarction. Adult male Wistar Albino rats were pretreated with Sundarban honey (5 g/kg) daily for a period of 6 weeks. After the treatment period, ISO (85 mg/kg) was subcutaneously injected into the rats at 24 h intervals for 2 days. ISO-induced myocardial damage was indicated by increased serum cardiac specific troponin I levels and cardiac marker enzyme activities including creatine kinase-MB, lactate dehydrogenase, aspartate transaminase, and alanine transaminase. Significant increases in serum total cholesterol, triglycerides, and low-density lipoprotein-cholesterol levels were also observed, along with a reduction in the serum high-density lipoprotein-cholesterol level. In addition to these diagnostic markers, the levels of lipid peroxide products were significantly increased. The activities of antioxidant enzymes such as superoxide dismutase, glutathione peroxidase, and glutathione reductase were significantly decreased in the hearts after ISO-induced myocardial infarction. However, pretreatment of ischemic rats with Sundarban honey brought the biochemical parameters to near normalcy, indicating the protective effect of Sundarban honey against ISO-induced ischemia in rats. Histopathological findings of the heart tissues further confirmed the biochemical findings, indicating that Sundarban honey confers protection against ISO-induced oxidative stress in the myocardium. Rizwana Afroz, E. M. Tanvir, Nurul Karim, Md. Sabir Hossain, Nadia Alam, Siew Hua Gan, and Md. Ibrahim Khalil Copyright © 2016 Rizwana Afroz et al. All rights reserved. Extracorporeal Membrane Oxygenation as a Bridge for Heart Failure and Cardiogenic Shock Mon, 16 May 2016 06:12:24 +0000 Heart failure (HF) can be defined as cardiac structural or functional abnormality leading to a series of symptoms due to deficiency of oxygen delivery. In the clinical practice, acute heart failure (AHF) is usually performed as cardiogenic shock (CS), pulmonary edema, and single or double ventricle congestive heart failure. CS refers to depressed or insufficient cardiac output (CO) attributable to myocardial infarction, fulminant myocarditis, acute circulatory failure attributable to intractable arrhythmias or the exacerbation of chronic heart failure, postcardiotomy low CO syndrome, and so forth. Epidemiological studies have shown that CS has higher in-hospital mortality in patients with AHF. Besides, we call the induced, sustained circulatory failure even after administration of high doses of inotropes and vasopressors refractory cardiogenic shock. In handling these cases, mechanical circulatory support devices are usually needed. In this review, we discuss the current application status and clinical points in utilizing extracorporeal membrane oxygenation (ECMO). Zhao-peng Zhong, Hong Wang, and Xiao-tong Hou Copyright © 2016 Zhao-peng Zhong et al. All rights reserved. Obstructive Form of Hypertrophic Cardiomyopathy-Left Ventricular Outflow Tract Gradient: Novel Methods of Provocation, Monitoring of Biomarkers, and Recent Advances in the Treatment Tue, 10 May 2016 14:24:59 +0000 Dynamic (latent or/and labile) obstruction of left ventricular outflow (LVOT) was recognized from the earliest clinical descriptions of hypertrophic cardiomyopathy (HCM) and has proved to be a complex phenomenon, as well as arguably the most audible (“visible”) pathophysiological hallmark of this heterogeneous disease. The aim of the current review is focused on two novel issues in a subgroup of obstructive HCM. Firstly, the important methodological problem in HCM is the examination of a subgroup of patients with nonobstructive hypertrophy in resting conditions and hard, but possible provoking obstruction. Recently, investigators have proposed physiological stress test (with double combined stimuli) to disclose such type of patients. The upright exercise is described in the ESC guideline on hypertrophic cardiomyopathy from 2014 and may appear as a candidate for gold standard provocation test. The second novel area of interest is associated with elevated level of signaling biomarkers: hypercoagulation, hemolysis, acquired von Willebrand 2A disease, and enhanced oxidative stress. The accelerated and turbulent flow within narrow LVOT may be responsible for these biochemical disturbances. The most recent advances in the treatment of obstructive HCM are related to nonpharmacological methods of LVOT gradient reduction. This report extensively discusses novel methods. Pawel Petkow Dimitrow and Renata Rajtar-Salwa Copyright © 2016 Pawel Petkow Dimitrow and Renata Rajtar-Salwa. All rights reserved. Vagal Reactions during Cryoballoon-Based Pulmonary Vein Isolation: A Clue for Autonomic Nervous System Modulation? Tue, 03 May 2016 09:40:10 +0000 Although paroxysmal atrial fibrillation (AF) is known to be initiated by rapid firing of pulmonary veins (PV) and non-PV triggers, the crucial role of cardiac autonomic nervous system (ANS) in the initiation and maintenance of AF has long been appreciated in both experimental and clinical studies. The cardiac intrinsic ANS is composed of ganglionated plexi (GPs), located close to the left atrium-pulmonary vein junctions and a vast network of interconnecting neurons. Ablation strategies aiming for complete PV isolation (PVI) remain the cornerstone of AF ablation procedures. However, several observational studies and few randomized studies have suggested that GP ablation, as an adjunctive strategy, might achieve better clinical outcomes in patients undergoing radiofrequency-based PVI for both paroxysmal and nonparoxysmal AF. In these patients, vagal reactions (VR) such as vagally mediated bradycardia or asystole are thought to reflect intrinsic cardiac ANS modulation and/or denervation. Vagal reactions occurring during cryoballoon- (CB-) based PVI have been previously reported; however, little is known on resulting ANS modulation and/or prevalence and significance of vagal reactions during PVI with the CB technique. We conducted a review of prevalence, putative mechanisms, and significance of VR during CB-based PVI. Michaël Peyrol, Jérémie Barraud, Linda Koutbi, Baptiste Maille, Lory Trevisan, Elisa Martinez, Samuel Lévy, Franck Paganelli, and Frederic Franceschi Copyright © 2016 Michaël Peyrol et al. All rights reserved. HSP27 Inhibits Homocysteine-Induced Endothelial Apoptosis by Modulation of ROS Production and Mitochondrial Caspase-Dependent Apoptotic Pathway Sun, 17 Apr 2016 14:04:41 +0000 Objectives. Elevated plasma homocysteine (Hcy) could lead to endothelial dysfunction and is viewed as an independent risk factor for atherosclerosis. Heat shock protein 27 (HSP27), a small heat shock protein, is reported to exert protective effect against atherosclerosis. This study aims to investigate the protective effect of HSP27 against Hcy-induced endothelial cell apoptosis in human umbilical vein endothelial cells (HUVECs) and to determine the underlying mechanisms. Methods. Apoptosis, reactive oxygen species (ROS), and mitochondrial membrane potential (MMP) of normal or HSP27-overexpressing HUVECs in the presence of Hcy were analyzed by flow cytometry. The mRNA and protein expression levels were measured by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. Results. We found that Hcy could induce cell apoptosis with corresponding decrease of nitric oxide (NO) level, increase of endothelin-1 (ET-1), intracellular adhesion molecule-1 (ICAM-1), vascular cellular adhesion molecule-1 (VCAM-1), and monocyte chemoattractant protein-1 (MCP-1) levels, elevation of ROS, and dissipation of MMP. In addition, HSP27 could protect the cell against Hcy-induced apoptosis and inhibit the effect of Hcy on HUVECs. Furthermore, HSP27 could increase the ratio of Bcl-2/Bax and inhibit caspase-3 activity. Conclusions. Therefore, we concluded that HSP27 played a protective role against Hcy-induced endothelial apoptosis through modulation of ROS production and the mitochondrial caspase-dependent apoptotic pathway. Xin Tian, Lei Zhao, Xianjing Song, Youyou Yan, Ning Liu, Tianyi Li, Bingdi Yan, and Bin Liu Copyright © 2016 Xin Tian et al. All rights reserved. Incidence and Predictors of Catheterization-Related Cerebral Infarction on Diffusion-Weighted Magnetic Resonance Imaging Tue, 05 Apr 2016 11:25:09 +0000 Introduction. The aim of this study was to examine the incidence and risk factors of catheterization-related CI in the contemporary era, using diffusion-weighted magnetic resonance imaging. Methods. We retrospectively analyzed consecutive 84 patients who underwent MRI (magnetic resonance imaging) after days of catheterization via aortic arch. We categorized the patients by the presence or absence of acute CI determined by diffusion-weighted MRI and analyzed the incidence and predictors. Results. Of 84 patients that underwent MRI after catheterization, acute CI was determined in 27 (32.1%) patients. In univariate analysis, dyslipidemia, age, coronary artery disease, antiplatelet agents, number of catheters used, urgent settings, and interventional procedures were significantly different. Multivariate analysis revealed dyslipidemia (odds ratio [OR], 4.46; 95% confidence interval [CI], 1.41–16.03; ), higher age (OR, 1.09; 95% CI, 1.007–1.19; ), and the number of catheters used (OR, 2.21; 95% CI, 1.21–4.36; ) as independent predictors of the incidence of catheterization-related acute CI. Conclusions. Dyslipidemia, higher age, and number of catheters used were independent predictors for acute CI after catheterization. These findings imply that managing dyslipidemia and comprehensive planning to minimize the numbers of catheters are important. Yusuke Morita, Takao Kato, Mitsumasa Okano, Kanae Suu, Masahiro Kimura, Eri Minamino-Muta, Eisaku Nakane, Toshiaki Izumi, Shoichi Miyamoto, Tetsuya Haruna, Koji Ueyama, and Moriaki Inoko Copyright © 2016 Yusuke Morita et al. All rights reserved. Curcumin Downregulates Phosphate Carrier and Protects against Doxorubicin Induced Cardiomyocyte Apoptosis Tue, 05 Apr 2016 09:39:55 +0000 Aim. To explore the effects of curcumin on phosphate carrier (PiC) and its role in protection against doxorubicin induced myocyte toxicity. Methods. Using H9c2 cell line, the cardiotoxic effect of doxorubicin and its mitigation by curcumin were studied. H9c2 cells were cultured with doxorubicin and/or curcumin at various concentrations. Analysis for apoptosis of H9c2 was done using flow cytometry. Confocal laser scanning microscopy was used to record the fluorescence intensity ratios and to determine the mitochondrial permeability transition pore (MPTP) opening state. Oxidative stress was measured using glutathione level, superoxide dismutase activities, and malondialdehyde content. The effect of doxorubicin and curcumin on PiC gene expression was measured by real-time PCR. Results. Curcumin decreased mRNA of PiC and was partly protective against oxidative stress, loss of mitochondrial transmembrane potential, and apoptosis induced by doxorubicin. Interestingly, the effect was not clearly dose dependent and the concentration of 12 mg/L was more efficient than 15 and 10 mg/L. Conclusion. Curcumin downregulates PiC and partly protects against doxorubicin induced oxidative stress and myocyte apoptosis. Lu Junkun, Chu Erfu, Hasahya Tony, Li Xin, K. C. Sudeep, Zhang Mingliang, Wang Yanqin, and Qi XiangQian Copyright © 2016 Lu Junkun et al. All rights reserved. Cardiovascular Function in Intensive Care Medicine or Homo Mensura Est Mon, 04 Apr 2016 08:19:58 +0000 Mitja Lainscak, Zsolt Molnar, Xavier Monnet, and Gorazd Voga Copyright © 2016 Mitja Lainscak et al. All rights reserved. In Patients with Coronary Artery Disease and Type 2 Diabetes, SIRT1 Expression in Circulating Mononuclear Cells Is Associated with Levels of Inflammatory Cytokines but Not with Coronary Lesions Thu, 31 Mar 2016 10:11:54 +0000 While SIRT1 is significantly associated with atherosclerosis and diabetic complications, its relevance to coronary lesions in patients with coronary artery disease and type 2 diabetes has not been specifically investigated. Thus, we assessed SIRT1 expression in peripheral blood mononuclear cells in these patients. We found that SIRT1 expression did not significantly correlate with syntax scores from coronary angiography (). Notably, plasma levels of the inflammatory cytokines tumor necrosis factor-α, monocyte chemoattractant protein-1, and high-sensitivity C-reactive protein were markedly higher in diabetic patients (). In addition, SIRT1 expression was negatively correlated with levels of these cytokines, as well as that of interleukin-6 (). In summary, the data indicate that SIRT1 expression in peripheral blood mononuclear cells is significantly correlated with inflammatory cytokines levels in patients with coronary artery disease and type 2 diabetes but not with the severity of coronary lesions. Yuanmin Li, Jing Ni, Rong Guo, and Weiming Li Copyright © 2016 Yuanmin Li et al. All rights reserved. The NLRP3 rs10754558 Polymorphism Is Associated with the Occurrence and Prognosis of Coronary Artery Disease in the Chinese Han Population Thu, 24 Mar 2016 13:14:06 +0000 The objective of this study is to investigate the potential association of the NLRP3 rs10754558 and CARD8 rs2043211 polymorphisms with the occurrence and prognosis of CAD. Gene polymorphisms were analyzed using the ABI PRISM-Snapshot multiplex method in 515 CAD patients and 401 control subjects. The serum level of IL-1β was investigated by ELISA assays. The clinical endpoints were evaluated during a median follow-up period of 32 months. The NLRP3 rs10754558 gene polymorphism was significantly associated with the occurrence of CAD, while the CARD8 rs2043211 gene polymorphism was not involved. Patients carrying G allele of NLRP3 rs10754558 had more severe coronary artery stenosis. Multivariable analysis revealed a significant association of the G allele with major adverse cardiac event. The serum IL-1β concentrations in patients with GG genotype were significantly increased compared with those in the patients with CC genotype. Our findings for the first time show that the NLRP3 rs10754558 polymorphism is involved in the occurrence of CAD in the Chinese Han population; and G allele can effectively predict clinical outcome of CAD. The G allele susceptibility to CAD is maybe associated with the increased level of serum IL-1β. Dong Zhou, Xinhong Wang, Tao Chen, Wen Wen, Yang Liu, Yue Wu, and Zuyi Yuan Copyright © 2016 Dong Zhou et al. All rights reserved. Time-Dependent Regional Myocardial Strains in Patients with Heart Failure with a Preserved Ejection Fraction Thu, 03 Mar 2016 11:49:36 +0000 Objectives. To better understand the etiology of HFpEF in a controlled human population, regional time-varying strains were computed using echocardiography speckle tracking in patients with heart failure with a preserved ejection fraction and normal subjects. Methods. Eleven normal volunteers and ten patients with echo-graded diastolic dysfunction and symptoms of heart failure were imaged with echocardiography and longitudinal, circumferential, and rotational strains were determined using speckle-tracking. Diastolic strain rate was also determined. Patient demographics and echo-derived flows, volumes, and pressures were recorded. Results. Peak longitudinal and circumferential strain was globally reduced in patients (), when compared to controls. The patients attained peak longitudinal and circumferential strain at a consistently later point in systole than controls. Rotational strains were not different in most LV regions. Early diastolic strain rate was significantly reduced in the patients (). LV mass and wall thickness were significantly increased in the patients; however ejection fraction was preserved and stroke volume was diminished (). Conclusions. This study shows that patients with HFpEF have reduced early diastolic strain rate and reduced peak strain that is regionally homogeneous and that they also utilize a longer fraction of systole to achieve peak axial strains. Shane P. Smith, Timothy W. Secomb, Brian D. Hong, and Michael J. Moulton Copyright © 2016 Shane P. Smith et al. All rights reserved. Transcatheter Mitral Valve Repair in Surgical High-Risk Patients: Gender-Specific Acute and Long-Term Outcomes Wed, 02 Mar 2016 13:28:07 +0000 Background. Analyses emphasizing gender-related differences in acute and long-term outcomes following MitraClip therapy for significant mitral regurgitation (MR) are rare. Methods. 592 consecutive patients ( years, 362 men, 230 women) underwent clinical and echocardiographic follow-up for a median of 2.13 (0.99–4.02) years. Results. Significantly higher prevalence of cardiovascular comorbidities, renal failure, and adverse echocardiographic parameters in men resulted in longer device time and higher numbers of implanted clips , with equal procedural success . Rehospitalization for heart failure did not differ while survival was higher in women . Logarithmic increase of NT-proBNP was a common independent predictor of death. Hypercholesterolemia and peripheral artery disease were predictors of death only in men while ischemic and dilative cardiomyopathy (CM) and age were predictors in women. Independent predictors of rehospitalization for heart failure were severely reduced ejection fraction and success in men while both ischemic and dilative CM, logistic EuroSCORE, and MR severity were predictive in women. Conclusions. Higher numbers of implanted clips and longer device time are likely related to more comorbidities in men. Procedural success and acute and mid-term clinical outcomes were equal. Superior survival for women in long-term analysis is presumably attributable to a comparatively better preprocedural health. Eike Tigges, Daniel Kalbacher, Christina Thomas, Sebastian Appelbaum, Florian Deuschl, Niklas Schofer, Michael Schlüter, Lenard Conradi, Johannes Schirmer, Hendrik Treede, Hermann Reichenspurner, Stefan Blankenberg, Ulrich Schäfer, and Edith Lubos Copyright © 2016 Eike Tigges et al. All rights reserved. Effectiveness of Percutaneous Balloon Mitral Valvuloplasty for Rheumatic Mitral Stenosis with Mild to Severe Mitral Regurgitation Mon, 29 Feb 2016 18:50:19 +0000 This study is designed to test whether percutaneous balloon mitral valvuloplasty (PBMV) is effective for rheumatic mitral stenosis in Chinese patients with moderate to severe mitral regurgitation. Fifty-six patients with rheumatic mitral valve stenosis were divided into the mild, moderate, and severe regurgitation groups. Cardiac ultrasonography was measured before and 1 to 2 days after PBMV. Following PBMV, the mitral orifice was enlarged, and the left atrial diameter was reduced in the 3 patient groups. The enlargement of the mitral orifice in the mild regurgitation group was greater than that observed in the moderate and severe regurgitation groups. The size of the regurgitation area increased in the mild regurgitation group and decreased in the moderate and severe regurgitation groups, with the decrease in the severe regurgitation group being greater than that in the moderate regurgitation group. Therefore, PBMV is effective for treating rheumatic mitral stenosis in Chinese patients with mild to severe mitral regurgitation. LinXiang Lu, Lang Hong, Jun Fang, and LiangLong Chen Copyright © 2016 LinXiang Lu et al. All rights reserved. The Correlation of Serum Myeloid-Related Protein-8/14 and Eosinophil Cationic Protein in Patients with Coronary Artery Disease Sun, 28 Feb 2016 09:29:23 +0000 Objective. To investigate the changes in serum Myeloid-Related Protein 8/14 (MRP8/14) and Eosinophil Cationic Protein (ECP) levels in patients with different types of coronary artery diseases (CAD) and assess the value of MRP8/14 and ECP detection in predicting CAD. Methods. 178 patients were divided into CAD group including unstable angina pectoris (UAP), acute myocardial infarction (AMI), and stable angina pectoris (SAP). Thirty-six individuals with normal coronary artery served as the control group. Serum MRP8/14 and ECP were measured by ELISA. The severity of coronary artery stenosis was assessed by the numbers of involved coronary artery branches and the sum of Gensini scores. Results. The MRP8/14 levels were significantly higher in AMI and UAP group than SAP and control group (). The levels of MRP8/14 in AMI group were also obviously higher than UAP group (). The ECP levels were obviously increased in AMI group, but there was no difference between SAP and UAP group (). The ECP was significantly increased in three impaired coronary arteries and obviously correlated with Gensini score (), whereas the MRP8/14 was obviously positively correlated with CRP (). Conclusions. Increased MRP8/14 levels suggest the instability of the atherosclerotic plaque. ECP reflects the severity of coronary arteries stenosis, predicting atherosclerosis burden. They may become the new biomarkers of CAD. Guo-lian Xia, Yun-kai Wang, and Zhao-quan Huang Copyright © 2016 Guo-lian Xia et al. All rights reserved. Serum Amyloid a Promotes Visfatin Expression in Macrophages Wed, 24 Feb 2016 15:17:54 +0000 Visfatin has been reported to exert an important role in the development of atherosclerosis. However, the mechanism that regulated the expression of Visfatin has not been elucidated yet. This study aimed to investigate the effect of SAA on the regulation of Visfatin, as well as the potential pathway. After RAW264.7 macrophages and primary monocytes were stimulated with SAA, the mRNA and protein expression of Visfatin was detected with real-time PCR and western blot, respectively. The concentration of Visfatin in the supernatant was measured with ELISA. Formyl peptide receptor 2 (FPR2) agonist (WKYMVm) and inhibitor (WRW4), extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor (PD98059), and peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist (Rosiglitazone) and inhibitor (GW9662) were used to investigate the mechanism of regulation of Visfatin. The results demonstrated that SAA upregulated Visfatin expression in cultured RAW264.7 macrophages and in the primary monocytes. WRW4 decreased SAA-induced Visfatin production, while WKYMVm could induce Visfatin expression. PD98059 reduced SAA-induced Visfatin production. What is more, GW9662 inhibited SAA-induced Visfatin production, while Rosiglitazone promoted Visfatin expression. These results demonstrate that SAA upregulates Visfatin expression via a FPR2/ERK1/2/PPAR-γ signaling pathway. Shixun Wang, Xincai Zhang, and Lei Tan Copyright © 2016 Shixun Wang et al. All rights reserved. Novel Biomarkers and Treatments of Cardiac Diseases Wed, 17 Feb 2016 11:39:17 +0000 Hua Zhu, Renzhi Han, and Dayue Darrel Duan Copyright © 2016 Hua Zhu et al. All rights reserved. Associations of Polymorphisms in HRH2, HRH3, DAO, and HNMT Genes with Risk of Chronic Heart Failure Wed, 17 Feb 2016 11:33:46 +0000 The pathophysiological functions of cardiac histamine level and related histamine receptors during the development of chronic heart failure (CHF) were intensively investigated previously. However, the relevance of polymorphisms in histamine-related genes, such as HRH2, HRH3, DAO, and HNMT, with CHF remains largely neglected. This study herein aims to analyze the clinical associations of polymorphisms in those genes with CHF risk. A total of 333 unrelated Chinese Han CHF patients and 354 ethnicity-matched healthy controls were recruited and 11 single nucleotide polymorphisms (SNPs) were genotyped. We found that the HRH3 rs3787429 polymorphism was associated with CHF risk (). The T allele of rs3787429 exhibited protective effect against CHF under the dominant (ORs = 0.455; 95% CIs = 0.322–0.642) and additive models (ORs = 0.662; 95% CIs = 0.523–0.838), while, for SNPs in HRH2, DAO, and HNMT, no significant associations were observed in the present study. These findings for the first time screen out one SNP (rs3787429) of HRH3 gene that was significantly associated with CHF in Chinese Han population, which may be a novel biomarker for personal prevention and treatment of CHF and provides novel highlights for investigating the contribution of this disease. Gong-Hao He, Wen-Ke Cai, Jia-Bin Zhang, Chao-Yu Ma, Feng Yan, Jun Lu, and Gui-Li Xu Copyright © 2016 Gong-Hao He et al. All rights reserved. Assessment of Structural and Functional Abnormalities of the Myocardium and the Ascending Aorta in Fetus with Hypoplastic Left Heart Syndrome Mon, 15 Feb 2016 07:59:00 +0000 Aims. To detect anatomical and intrinsic histopathological features of the ascending aorta and left ventricular (LV) myocardium and evaluate right ventricular (RV) function in fetuses with hypoplastic left heart syndrome (HLHS). Methods. Twenty-five fetuses diagnosed with HLHS were followed up in the antenatal and postpartum periods. 12 necropsy heart specimens were analyzed for morphological and histological changes. Results. Prenatal echocardiography and pathologic anatomy displayed the typical characteristics of HLHS as a severe underdevelopment of the LV in the form of mitral stenosis or atresia or as aortic atresia or stenosis, with a decreased ratio of aortic diameter to pulmonary artery diameter (median of 0.49 with a range of 0.24 to 0.69, ) and a higher ratio of RV diameter to LV diameter (median of 2.44 with a range of 1.33 to 6.25, ). The RV volume, stroke volume, and cardiac output in HLHS fetuses were increased compared with the gestational age-matched normal controls (). Histological changes in the 12 HLHS specimens included LV myocardial fibrosis, aortic elastic fragmentation, and fibrosis. Conclusions. In addition to severe anatomical deformity, distinct histological abnormalities in the LV myocardium and aortic wall were identified in the fetuses with HLHS. RV function damage may be potentially exists. Yan Jiang, Yali Xu, Jinliang Tang, and Hongmei Xia Copyright © 2016 Yan Jiang et al. All rights reserved. Substance P Receptor Signaling Mediates Doxorubicin-Induced Cardiomyocyte Apoptosis and Triple-Negative Breast Cancer Chemoresistance Thu, 11 Feb 2016 11:20:36 +0000 Doxorubicin (DOX), an anthracycline, is broadly considered the most active single agent available for treating breast cancer but has been known to induce cardiotoxicity. Although DOX is highly effective in treating triple-negative breast cancer (TNBC), DOX can have poor outcomes owing to induction of chemoresistance. There is an urgent need to develop new therapies for TNBC aimed at improving DOX outcome and DOX-induced cardiotoxicity. Substance P (SP), a neuropeptide involved in pain transmission is known to stimulate production of reactive oxygen species (ROS). Elevated cardiac ROS is linked with heart injury and failure. We investigated the role of SP in chemotherapy-associated death of cardiomyocytes and chemoresistance. We showed that pretreating a cardiomyocyte cell line (H9C2) and a TNBC cell line (MDA-MB 231) with aprepitant, a SP receptor antagonist that is routinely used to treat chemotherapy-associated associated nausea, decreased DOX-induced reduction of cell viability, apoptotic cell death, and ROS production in cardiomyocytes and increased DOX-induced reduction of cell viability, apoptotic cell death, and ROS production in TNBC cells compared with cells treated with DOX alone. Our findings demonstrate the ability of aprepitant to decrease DOX-induced killing of cardiomyocytes and to increase cancer cell sensitivity to DOX, which has tremendous clinical significance. Prema Robinson, Moses Kasembeli, Uddalak Bharadwaj, Nikita Engineer, Kris T. Eckols, and David J. Tweardy Copyright © 2016 Prema Robinson et al. All rights reserved. Two-Dimensional Speckle Tracking Echocardiography Detects Subclinical Left Ventricular Systolic Dysfunction among Adult Survivors of Childhood, Adolescent, and Young Adult Cancer Thu, 28 Jan 2016 13:25:51 +0000 Two-dimensional speckle tracking echocardiography (2DSTE) provides a sensitive measure of left ventricular (LV) systolic function and may aid in the diagnosis of cardiotoxicity. 2DSTE was performed in a cross-sectional study of 134 patients (mean age: years; 55% male; mean time since diagnosis: years) previously treated with anthracyclines (mean cumulative dose:  mg/m2), with () or without () mediastinal radiotherapy. The prevalence of LV systolic dysfunction, defined as fractional shortening < 27%, LV ejection fraction (LVEF) < 55%, and global longitudinal strain (GLS) ≤ 16%, was 5.2%, 6.0%, and 23.1%, respectively. Abnormal GLS was observed in 24 (18%) patients despite a normal LVEF. Indices of LV systolic function were similar regardless of anthracycline dose. However, GLS was worse (18.0 versus 19.0, ) and prevalence of abnormal GLS was higher (36.5% versus 14.6%, ) in patients treated with mediastinal radiotherapy. Mediastinal radiotherapy was associated with reduced GLS () after adjusting for sex, age, and cumulative anthracycline dose. In adult survivors of childhood, adolescent, and young adult cancer, 2DSTE frequently detects LV systolic dysfunction despite a normal LVEF and may be useful for the long-term cardiac surveillance of adult cancer survivors. Anthony F. Yu, Jayant Raikhelkar, Emily C. Zabor, Emily S. Tonorezos, Chaya S. Moskowitz, Roberto Adsuar, Elton Mara, Kevin Huie, Kevin C. Oeffinger, Richard M. Steingart, and Jennifer E. Liu Copyright © 2016 Anthony F. Yu et al. All rights reserved. Potential Diagnostic and Prognostic Biomarkers of Epigenetic Drift within the Cardiovascular Compartment Thu, 28 Jan 2016 11:04:33 +0000 Biomarkers encompass a wide range of different measurable indicators, representing a tangible link to physiological changes occurring within the body. Accessibility, sensitivity, and specificity are significant factors in biomarker suitability. New biomarkers continue to be discovered, and questions over appropriate selection and assessment of their usefulness remain. If traditional markers of inflammation are not sufficiently robust in their specificity, then perhaps alternative means of detection may provide more information. Epigenetic drift (epigenetic modifications as they occur as a direct function with age), and its ancillary elements, including platelets, secreted microvesicles (MVs), and microRNA (miRNA), may hold enormous predictive potential. The majority of epigenetic drift observed in blood is independent of variations in blood cell composition, addressing concerns affecting traditional blood-based biomarker efficacy. MVs are found in plasma and other biological fluids in healthy individuals. Altered MV/miRNA profiles may also be found in individuals with various diseases. Platelets are also highly reflective of physiological and lifestyle changes, making them extremely sensitive biomarkers of human health. Platelets release increased levels of MVs in response to various stimuli and under a plethora of disease states, which demonstrate a functional effect on other cell types. Robert G. Wallace, Laura C. Twomey, Marc-Antoine Custaud, Niall Moyna, Philip M. Cummins, Marco Mangone, and Ronan P. Murphy Copyright © 2016 Robert G. Wallace et al. All rights reserved. Predominance of Abdominal Visceral Adipose Tissue Reflects the Presence of Aortic Valve Calcification Sun, 24 Jan 2016 13:38:45 +0000 Background. Aortic valve calcification (AVC) is a common feature of aging and is related to coronary artery disease. Although abdominal visceral adipose tissue (VAT) plays fundamental roles in coronary artery disease, the relationship between abdominal VAT and AVC is not fully understood. Methods. We investigated 259 patients who underwent cardiac and abdominal computed tomography (CT). AVC was defined as calcified lesion on the aortic valve by CT. %abdominal VAT was calculated as abdominal VAT area/total adipose tissue area. Results. AVC was detected in 75 patients, and these patients showed higher %abdominal VAT (44% versus 38%, ) compared to those without AVC. When the cutoff value of %abdominal VAT was set at 40.9%, the area under the curve to diagnose AVC was 0.626. Multivariable logistic regression analysis showed that age (OR 1.120, 95% CI 1.078–1.168, ), diabetes (OR 2.587, 95% CI 1.323–5.130, ), and %abdominal VAT (OR 1.032, 95% CI 1.003–1.065, ) were independent risk factors for AVC. The net reclassification improvement value for detecting AVC was increased when %abdominal VAT was added to the model: 0.5093 (95% CI 0.2489–0.7697, ). Conclusion. We determined that predominance of VAT is associated with AVC. Masayoshi Oikawa, Takashi Owada, Hiroyuki Yamauchi, Tomofumi Misaka, Hirofumi Machii, Takayoshi Yamaki, Koichi Sugimoto, Hiroyuki Kunii, Kazuhiko Nakazato, Hitoshi Suzuki, Shu-ichi Saitoh, and Yasuchika Takeishi Copyright © 2016 Masayoshi Oikawa et al. All rights reserved. Current Diagnostic and Therapeutic Aspects of Eosinophilic Myocarditis Sun, 17 Jan 2016 16:19:34 +0000 Eosinophilic myocarditis (EM) represents a rare form of myocardial inflammation with very heterogeneous aetiology. In developed countries, the most prevalent causes of EM are hypersensitivity or allergic reactions, as well as hematological diseases leading to eosinophilia. The disease may have a variable clinical presentation, ranging from asymptomatic forms to life-threatening conditions. Most patients with EM have marked eosinophilia in peripheral blood. Endomyocardial biopsy needs to be performed in most cases in order to establish a definitive diagnosis of EM. The therapy depends on the underlying aetiology. Immunosuppressive therapy represents the treatment mainstay in the majority of EM forms. Petr Kuchynka, Tomas Palecek, Martin Masek, Vladimir Cerny, Lukas Lambert, Ivana Vitkova, and Ales Linhart Copyright © 2016 Petr Kuchynka et al. All rights reserved. The Causes of HIV-Associated Cardiomyopathy: A Tale of Two Worlds Sun, 17 Jan 2016 13:49:50 +0000 Antiretroviral therapy (ART) has transformed the clinical profile of human immunodeficiency virus (HIV) from an acute infection with a high mortality into a treatable, chronic disease. As a result, the clinical sequelae of HIV infection are changing as patients live longer. HIV-associated cardiomyopathy (HIVAC) is a stage IV, HIV-defining illness and remains a significant cause of morbidity and mortality among HIV-infected individuals despite ART. Causes and clinical manifestations of HIVAC depend on the degree of host immunosuppression. Myocarditis from direct HIV toxicity, opportunistic infections, and nutritional deficiencies are implicated in causing HIVAC when HIV viral replication is unchecked, whereas cardiac autoimmunity, chronic inflammation, and ART cardiotoxicity contribute to HIVAC in individuals with suppressed viral loads. The initiation of ART has dramatically changed the clinical manifestation of HIVAC in high income countries from one of severe, left ventricular systolic dysfunction to a pattern of subclinical cardiac dysfunction characterized by abnormal diastolic function and strain. In low and middle income countries, however, HIVAC is the most common HIV-associated cardiovascular disease. Clear diagnostic and treatment guidelines for HIVAC are currently lacking but should be prioritized given the global burden of HIVAC. Rebecca H. Lumsden and Gerald S. Bloomfield Copyright © 2016 Rebecca H. Lumsden and Gerald S. Bloomfield. All rights reserved. Experimental Heart Failure Models and Their Pathophysiological Characterization Wed, 13 Jan 2016 07:21:53 +0000 Peter Moritz Becher, Bodh I. Jugdutt, John Baugh, and Bastian Schmack Copyright © 2016 Peter Moritz Becher et al. All rights reserved. Vascular Endothelial Growth Factor Is Associated with the Morphologic and Functional Parameters in Patients with Hypertrophic Cardiomyopathy Thu, 31 Dec 2015 07:10:28 +0000 Background. Hypertrophic cardiomyopathy (HCM) is mostly autosomal dominant disease of the myocardium, which is characterized by myocardial hypertrophy. Vascular endothelial growth factor (VEGF) is involved in myocyte function, growth, and survival. The aim of study was to analyze the clinical significance of VEGF in structural and functional changes in patient with HCM. Methods. In a group of 21 patients with nonobstructive HCM, we assessed serum VEGF and analyzed its association with morphological and functional parameters. Compared to healthy controls, serum VEGF was increased: 199 (IQR: 120.4–260.8) ng/L versus 20 (IQR: 14.8–37.7) ng/L, . VEGF levels were associated with left atrium diameter (, ), left ventricle ejection fraction (, ), fractional shortening (, ), left ventricular mass (, ), LV mass index (, ), vena cava inferior diameter (, ), and peak gradient of tricuspid regurgitation (, ). Conclusions. Increased VEGF level is associated with structural and functional parameters in patients with HCM and serves as a potential tool for diagnostic process of these patients. Radek Pudil, Martina Vasatova, Alena Fucikova, Helena Rehulkova, Pavel Rehulka, Vladimir Palicka, and Jiri Stulik Copyright © 2015 Radek Pudil et al. All rights reserved. Fluid Therapy: Double-Edged Sword during Critical Care? Tue, 22 Dec 2015 09:29:52 +0000 Fluid therapy is still the mainstay of acute care in patients with shock or cardiovascular compromise. However, our understanding of the critically ill pathophysiology has evolved significantly in recent years. The revelation of the glycocalyx layer and subsequent research has redefined the basics of fluids behavior in the circulation. Using less invasive hemodynamic monitoring tools enables us to assess the cardiovascular function in a dynamic perspective. This allows pinpointing even distinct changes induced by treatment, by postural changes, or by interorgan interactions in real time and enables individualized patient management. Regarding fluids as drugs of any other kind led to the need for precise indication, way of administration, and also assessment of side effects. We possess now the evidence that patient centered outcomes may be altered when incorrect time, dose, or type of fluids are administered. In this review, three major features of fluid therapy are discussed: the prediction of fluid responsiveness, potential harms induced by overzealous fluid administration, and finally the problem of protocol-led treatments and their timing. Jan Benes, Mikhail Kirov, Vsevolod Kuzkov, Mitja Lainscak, Zsolt Molnar, Gorazd Voga, and Xavier Monnet Copyright © 2015 Jan Benes et al. All rights reserved. An Upgrade on the Rabbit Model of Anthracycline-Induced Cardiomyopathy: Shorter Protocol, Reduced Mortality, and Higher Incidence of Overt Dilated Cardiomyopathy Wed, 16 Dec 2015 09:39:37 +0000 Current protocols of anthracycline-induced cardiomyopathy in rabbits present with high premature mortality and nephrotoxicity, thus rendering them unsuitable for studies requiring long-term functional evaluation of myocardial function (e.g., stem cell therapy). We compared two previously described protocols to an in-house developed protocol in three groups: Group DOX2 received doxorubicin 2 mg/kg/week (8 weeks); Group DAU3 received daunorubicin 3 mg/kg/week (10 weeks); and Group DAU4 received daunorubicin 4 mg/kg/week (6 weeks). A cohort of rabbits received saline (control). Results of blood tests, cardiac troponin I, echocardiography, and histopathology were analysed. Whilst DOX2 and DAU3 rabbits showed high premature mortality (50% and 33%, resp.), DAU4 rabbits showed 7.6% premature mortality. None of DOX2 rabbits developed overt dilated cardiomyopathy; 66% of DAU3 rabbits developed overt dilated cardiomyopathy and quickly progressed to severe congestive heart failure. Interestingly, 92% of DAU4 rabbits showed overt dilated cardiomyopathy and 67% developed congestive heart failure exhibiting stable disease. DOX2 and DAU3 rabbits showed alterations of renal function, with DAU3 also exhibiting hepatic function compromise. Thus, a shortened protocol of anthracycline-induced cardiomyopathy as in DAU4 group results in high incidence of overt dilated cardiomyopathy, which insidiously progressed to congestive heart failure, associated to reduced systemic compromise and very low premature mortality. Jesús Talavera, Alejandro Giraldo, María Josefa Fernández-Del-Palacio, Obdulio García-Nicolás, Juan Seva, Gavin Brooks, and Jose M. Moraleda Copyright © 2015 Jesús Talavera et al. All rights reserved. Effect of Left Ventricular Outflow Tract Obstruction on Left Atrial Mechanics in Hypertrophic Cardiomyopathy Wed, 16 Dec 2015 07:15:35 +0000 Left atrial (LA) volumes are known to be increased in hypertrophic cardiomyopathy (HCM) and are a predictor of adverse outcome. In addition, LA function is impaired and is presumed to be due to left ventricular (LV) diastolic dysfunction as a result of hypertrophy and myocardial fibrosis. In the current study, we assess the incremental effect of outflow tract obstruction (and concomitant mitral regurgitation) on LA function as assessed by LA strain. Patients with HCM (50 obstructive, 50 nonobstructive) were compared to 50 normal controls. A subset of obstructive patients who had undergone septal myectomy was also studied. Utilising feature-tracking software applied to cardiovascular magnetic resonance images, LA volumes and functional parameters were calculated. LA volumes were significantly elevated and LA ejection fraction and strain were significantly reduced in patients with HCM compared with controls and were significantly more affected in patients with obstruction. LA volumes and function were significantly improved after septal myectomy. LVOT obstruction and mitral regurgitation appear to further impair LA mechanics. Septal myectomy results in a significant reduction in LA volumes, paralleled by an improvement in function. Lynne K. Williams, Raymond H. Chan, Shemy Carasso, Miranda Durand, Jimmy Misurka, Andrew M. Crean, Anthony Ralph-Edwards, Christiane Gruner, Anna Woo, John R. Lesser, Barry J. Maron, Martin S. Maron, and Harry Rakowski Copyright © 2015 Lynne K. Williams et al. All rights reserved. Effects of Physical Exercise on Cardiovascular Diseases: Biochemical, Cellular, and Organ Effects Tue, 15 Dec 2015 09:38:46 +0000 Antonio Crisafulli, Pasquale Pagliaro, Alain Cohen-Solal, and Andrew J. Coats Copyright © 2015 Antonio Crisafulli et al. All rights reserved. Pressor Response to Noradrenaline in the Setting of Septic Shock: Anything New under the Sun—Dexmedetomidine, Clonidine? A Minireview Sun, 13 Dec 2015 06:48:49 +0000 Progress over the last 50 years has led to a decline in mortality from ≈70% to ≈20% in the best series of patients with septic shock. Nevertheless, refractory septic shock still carries a mortality close to 100%. In the best series, the mortality appears related to multiple organ failure linked to comorbidities and/or an intense inflammatory response: shortening the period that the subject is exposed to circulatory instability may further lower mortality. Treatment aims at reestablishing circulation within a “central” compartment (i.e., brain, heart, and lung) but fails to reestablish a disorganized microcirculation or an adequate response to noradrenaline, the most widely used vasopressor. Indeed, steroids, nitric oxide synthase inhibitors, or donors have not achieved overwhelming acceptance in the setting of septic shock. Counterintuitively, α2-adrenoceptor agonists were shown to reduce noradrenaline requirements in two cases of human septic shock. This has been replicated in rat and sheep models of sepsis. In addition, some data show that α2-adrenoceptor agonists lead to an improvement in the microcirculation. Evidence-based documentation of the effects of alpha-2 agonists is needed in the setting of human septic shock. A. Géloën, C. Pichot, S. Leroy, C. Julien, M. Ghignone, C. N. May, and L. Quintin Copyright © 2015 A. Géloën et al. All rights reserved. Relevance of the Carotid Body Chemoreflex in the Progression of Heart Failure Tue, 08 Dec 2015 06:44:04 +0000 Chronic heart failure (CHF) is a global health problem affecting millions of people. Autonomic dysfunction and disordered breathing patterns are commonly observed in patients with CHF, and both are strongly related to poor prognosis and high mortality risk. Tonic activation of carotid body (CB) chemoreceptors contributes to sympathoexcitation and disordered breathing patterns in experimental models of CHF. Recent studies show that ablation of the CB chemoreceptors improves autonomic function and breathing control in CHF and improves survival. These exciting findings indicate that alterations in CB function are critical to the progression of CHF. Therefore, better understanding of the physiology of the CB chemoreflex in CHF could lead to improvements in current treatments and clinical management of patients with CHF characterized by high chemosensitivity. Accordingly, the main focus of this brief review is to summarize current knowledge of CB chemoreflex function in different experimental models of CHF and to comment on their potential translation to treatment of human CHF. David C. Andrade, Claudia Lucero, Camilo Toledo, Carlos Madrid, Noah J. Marcus, Harold D. Schultz, and Rodrigo Del Rio Copyright © 2015 David C. Andrade et al. All rights reserved. Kidney Injury Molecule-1 and Cardiovascular Diseases: From Basic Science to Clinical Practice Mon, 30 Nov 2015 13:30:51 +0000 Despite the recent findings concerning pathogenesis and novel therapeutic strategies, cardiovascular disease (CVD) still stays the leading cause of morbidity and mortality in patients with renal dysfunction, especially acute kidney injury (AKI). Early detection of patients with impaired renal function with cardiovascular risk may help ensure more aggressive treatment and improve clinical outcome. Kidney injury molecule-1 (KIM-1) is a new, promising marker of kidney damage which is currently the focus of countless studies worldwide. Some recent animal and human studies established KIM-1 as an important marker of acute tubular necrosis (ATN) and reliable predictor of development and prognosis of AKI. Food and Drug Administration (FDA) in USA acclaimed KIM-1 as an AKI biomarker for preclinical drug development. Recent data suggest the importance of monitoring of KIM-1 for early diagnosis and clinical course not only in patients with various forms of AKI and other renal diseases but also in patients with cardiorenal syndrome, heart failure, cardiopulmonary bypass, cardiothoracic surgical interventions in the pediatric emergency setting, and so forth. The aim of this review article is to summarize the literature data concerning KIM-1 as a potential novel marker in the early diagnosis and prediction of clinical outcome of certain cardiovascular diseases. Branislava Medić, Branislav Rovčanin, Gordana Basta Jovanović, Sanja Radojević-Škodrić, and Milica Prostran Copyright © 2015 Branislava Medić et al. All rights reserved. QT Interval Variability Index and QT Interval Duration in Different Sleep Stages: Analysis of Polysomnographic Recordings in Nonapneic Male Patients Sun, 29 Nov 2015 13:58:40 +0000 The aim of the study was to determine whether different sleep stages, especially REM sleep, affect QT interval duration and variability in male patients without obstructive sleep apnea (OSA). Polysomnographic recordings of 30 patients were analyzed. Beat-to-beat QT interval variability was calculated using QTV index (QTVI) formula. For QTc interval calculation, in addition to Bazett’s formula, linear and parabolic heart rate correction formulas with two separate α values were used. QTVI and QTc values were calculated as means of 2 awake, 3 NREM, and 3 REM sleep episodes; the duration of each episode was 300 sec. Mean QTVI values were not statistically different between sleep stages. Therefore, elevated QTVI values found in patients with OSA cannot be interpreted as physiological sympathetic impact during REM sleep and should be considered as a risk factor for potentially life-threatening ventricular arrhythmias. The absence of difference of the mean QTc interval values between NREM and REM stages seems to confirm our conclusion that sympathetic surges during REM stage do not induce repolarization variability. In patients without notable structural and electrical remodeling of myocardium, physiological elevation in sympathetic activity during REM sleep remains subthreshold concerning clinically significant increase of myocardial electrical instability. Moonika Viigimae, Deniss Karai, Peeter Pirn, Kristjan Pilt, Kalju Meigas, and Jyri Kaik Copyright © 2015 Moonika Viigimae et al. All rights reserved. Alternatives to Transplantation in the Treatment of Heart Failure: New Diagnostic and Therapeutic Insights Sun, 29 Nov 2015 11:16:39 +0000 Francesco Nicolini, Massimo F. Piepoli, Giulio Agnetti, and Giuseppe Siniscalchi Copyright © 2015 Francesco Nicolini et al. All rights reserved. Disease Classification and Biomarker Discovery Using ECG Data Tue, 24 Nov 2015 06:54:20 +0000 In the recent decade, disease classification and biomarker discovery have become increasingly important in modern biological and medical research. ECGs are comparatively low-cost and noninvasive in screening and diagnosing heart diseases. With the development of personal ECG monitors, large amounts of ECGs are recorded and stored; therefore, fast and efficient algorithms are called for to analyze the data and make diagnosis. In this paper, an efficient and easy-to-interpret procedure of cardiac disease classification is developed through novel feature extraction methods and comparison of classifiers. Motivated by the observation that the distributions of various measures on ECGs of the diseased group are often skewed, heavy-tailed, or multimodal, we characterize the distributions by sample quantiles which outperform sample means. Three classifiers are compared in application both to all features and to dimension-reduced features by PCA: stepwise discriminant analysis (SDA), SVM, and LASSO logistic regression. It is found that SDA applied to dimension-reduced features by PCA is the most stable and effective procedure, with sensitivity, specificity, and accuracy being 89.68%, 84.62%, and 88.52%, respectively. Rong Huang and Yingchun Zhou Copyright © 2015 Rong Huang and Yingchun Zhou. All rights reserved. Haemodynamic Effects of Lung Recruitment Manoeuvres Sun, 22 Nov 2015 06:22:14 +0000 Atelectasis caused by lung injury leads to increased intrapulmonary shunt, venous admixture, and hypoxaemia. Lung recruitment manoeuvres aim to quickly reverse this scenario by applying increased airway pressures for a short period of time which meant to open the collapsed alveoli. Although the procedure can improve oxygenation, but due to the heart-lung and right and left ventricle interactions elevated intrathoracic pressures can inflict serious effects on the cardiovascular system. The purpose of this paper is to give an overview on the pathophysiological background of the heart-lung interactions and the best way to monitor these changes during lung recruitment. András Lovas and Tamás Szakmány Copyright © 2015 András Lovas and Tamás Szakmány. All rights reserved. Anatomical Basis for the Cardiac Interventional Electrophysiologist Thu, 19 Nov 2015 13:48:18 +0000 The establishment of radiofrequency catheter ablation techniques as the mainstay in the treatment of tachycardia has renewed new interest in cardiac anatomy. The interventional arrhythmologist has drawn attention not only to the gross anatomic details of the heart but also to architectural and histological characteristics of various cardiac regions that are relevant to the development or recurrence of tachyarrhythmias and procedural related complications of catheter ablation. In this review, therefore, we discuss some anatomic landmarks commonly used in catheter ablations including the terminal crest, sinus node region, Koch’s triangle, cavotricuspid isthmus, Eustachian ridge and valve, pulmonary venous orifices, venoatrial junctions, and ventricular outflow tracts. We also discuss the anatomical features of important structures in the vicinity of the atria and pulmonary veins, such as the esophagus and phrenic nerves. This paper provides basic anatomic information to improve understanding of the mapping and ablative procedures for cardiac interventional electrophysiologists. Damián Sánchez-Quintana, Manuel Doblado-Calatrava, José Angel Cabrera, Yolanda Macías, and Farhood Saremi Copyright © 2015 Damián Sánchez-Quintana et al. All rights reserved. Increased Circulating Advanced Oxidation Protein Products and High-Sensitive Troponin T in Cirrhotic Patients with Chronic Hepatitis C: A Preliminary Report Thu, 19 Nov 2015 09:40:43 +0000 Aim. To investigate the relationship between advanced oxidation protein products (AOPPs) and myocardial injury by comparing the selected biomarker for detecting myocardial injury [high-sensitive troponin T (hs-TnT)] in patients with chronic HCV infection. Methods and Results. Eighty-eight patients with cirrhosis and 40 healthy control subjects were enrolled in the study. Circulating levels of AOPPs-albumin (the ratio of AOPPs to albumin content), hs-TnT, tumor necrosis factor α (TNF-α), and high-sensitivity C-reactive protein (hs-CRP) were assessed. Compared with healthy controls, the cirrhotic patients with chronic HCV infection had higher levels of AOPPs-albumin, which were associated with increased hs-TnT. When the presence of ascites was considered, the plasma levels of AOPPs-albumin were higher, as well as TNF-α. AOPPs-albumin positively correlated with hs-TnT level in all cirrhotic patients with chronic HCV infection and this correlation was stronger in decompensated cirrhotic patients. In multivariate logistic regression analysis, the independent factors associated with the presence of ascites were high AOPPs-albumin levels and elevated hs-TnT levels. Conclusion. The simultaneous monitoring of plasma AOPPs and hs-TnT can be helpful for the alterations in myocardial function control in cirrhotic patients with chronic HCV infection. Jolanta Zuwala-Jagiello, Eugenia Murawska-Cialowicz, and Monika Pazgan-Simon Copyright © 2015 Jolanta Zuwala-Jagiello et al. All rights reserved. Outcomes of Cryoballoon Ablation in High- and Low-Volume Atrial Fibrillation Ablation Centres: A Russian Pilot Survey Thu, 12 Nov 2015 06:06:44 +0000 Purpose. The results of cryoballoon ablation (CBA) procedure have been mainly derived from studies conducted in experienced atrial fibrillation (AF) ablation centres. Here, we report on CBA efficacy and complications resulting from real practice of this procedure at both high- and low-volume centres. Methods. Among 62 Russian centres performing AF ablation, 15 (24%) used CBA technology for pulmonary vein isolation. The centres were asked to provide a detailed description of all CBA procedures performed and complications, if encountered. Results. Thirteen sites completed interviews on all CBAs in their centres (>95% of CBAs in Russia). Six sites were high-volume AF ablation (>100 AF cases/year) centres, and 7 were low-volume AF ablation. There was no statistical difference in arrhythmia-free rates between high- and low-volume centres (64.6 versus 60.8% at 6 months). Major complications developed in 1.5% of patients and were equally distributed between high- and low-volume centres. Minor procedure-related events were encountered in 8% of patients and were more prevalent in high-volume centres. Total event and vascular access site event rates were higher in women than in men. Conclusions. CBA has an acceptable efficacy profile in real practice. In less experienced AF ablation centres, the major complication rate is equal to that in high-volume centres. Evgeny N. Mikhaylov, Dmitry S. Lebedev, Evgeny A. Pokushalov, Karapet V. Davtyan, Eduard A. Ivanitskii, Anatoly A. Nechepurenko, Alexey Ya. Kosonogov, Grigory V. Kolunin, Igor A. Morozov, Sergey A. Termosesov, Evgeny B. Maykov, Dmitry N. Khomutinin, Sergey A. Eremin, Igor M. Mayorov, Alexander B. Romanov, Vitaliy V. Shabanov, Victoria Shatakhtsyan, Viktor Tsivkovskii, Amiran Sh. Revishvili, and Evgeny V. Shlyakhto Copyright © 2015 Evgeny N. Mikhaylov et al. All rights reserved. Transcriptome and Molecular Endocrinology Aspects of Epicardial Adipose Tissue in Cardiovascular Diseases: A Systematic Review and Meta-Analysis of Observational Studies Mon, 09 Nov 2015 07:26:38 +0000 The objective of this study was to perform a systematic review of published literature on differentially expressed genes (DEGs) in human epicardial adipose tissue (EAT) to identify molecules associated with CVDs. A systematic literature search was conducted in PubMed, SCOPUS, and ISI Web of Science literature databases for papers published before October 2014 that addressed EAT genes and cardiovascular diseases (CVDs). We included original papers that had performed gene expressions in EAT of patients undergoing open-heart surgery. The Reporting Recommendations for Tumor Marker Prognostic Studies (PRIMARK) assessment tool was also used for methodological quality assessment. From the 180 papers identified by our initial search strategy, 40 studies met the inclusion criteria and presented DEGs in EAT samples from patients with and without CVDs. The included studies reported 42 DEGs identified through comparison of EAT-specific gene expression in patients with and without CVDs. Among the 42 DEGs, genes involved in regulating apoptosis had higher enrichment scores. Notably, interleukin-6 (IL-6) and tumor protein p53 (TP53) were the main hub genes in the network. The results suggest that regulation of apoptosis in EAT is critical for CVD development. Moreover, IL-6 and TP53 as hub genes could serve as biomarkers and therapeutic targets for CVDs. Zhila Maghbooli and Arash Hossein-nezhad Copyright © 2015 Zhila Maghbooli and Arash Hossein-nezhad. All rights reserved. New Insight in the Assessment of Atrial Size and Function Sun, 08 Nov 2015 09:49:58 +0000 Giovanni Di Salvo Copyright © 2015 Giovanni Di Salvo. All rights reserved. Endogenous Ouabain: An Old Cardiotonic Steroid as a New Biomarker of Heart Failure and a Predictor of Mortality after Cardiac Surgery Sun, 01 Nov 2015 11:22:05 +0000 Cardiovascular diseases remain the main cause of mortality and morbidity worldwide; primary prevention is a priority for physicians. Biomarkers are useful tools able to identify high-risk individuals, guide treatments, and determine prognosis. Our aim is to investigate Endogenous Ouabain (EO), an adrenal stress hormone with hemodynamic effects, as a valuable biomarker of heart failure. In a population of 845 patients undergoing elective cardiac surgery, we have investigated the relationships between EO and echocardiography parameters/plasmatic biomarker of cardiac function. EO was found to be correlated negatively with left ventricular EF (), positively with Cardiac End-Diastolic Diameter (), and positively with plasmatic NT-proBNP level (). Moreover, a different plasmatic EO level (both preoperative and postoperative) was found according to NYHA class (). All these results have been replicated on an independent cohort of patients (147 subjects from US). Finally, a higher EO level in the immediate postoperative time was indicative of a more severe cardiological condition and it was associated with increased perioperative mortality risk ( for 30-day morality). Our data suggest that preoperative and postoperative plasmatic EO level identifies patients with a more severe cardiovascular presentation at baseline. These patients have a higher risk of morbidity and mortality after cardiac surgery. Marco Simonini, Simona Pozzoli, Elena Bignami, Nunzia Casamassima, Elisabetta Messaggio, Chiara Lanzani, Elena Frati, Irene Maria Botticelli, Francesco Rotatori, Ottavio Alfieri, Alberto Zangrillo, and Paolo Manunta Copyright © 2015 Marco Simonini et al. All rights reserved. Renal Doppler Resistive Index as a Marker of Oxygen Supply and Demand Mismatch in Postoperative Cardiac Surgery Patients Thu, 29 Oct 2015 11:53:22 +0000 Background and Objective. Renal Doppler resistive index (RDRI) is a noninvasive index considered to reflect renal vascular perfusion. The aim of this study was to identify the independent hemodynamic determinants of RDRI in mechanically ventilated patients after cardiac surgery. Methods. RDRI was determined in 61 patients by color and pulse Doppler ultrasonography of the interlobar renal arteries. Intermittent thermodilution cardiac output measurements were obtained and blood samples taken from the tip of pulmonary artery catheter to measure hemodynamics and mixed venous oxygen saturation (SvO2). Results. By univariate analysis, RDRI was significantly correlated with SvO2, oxygen extraction ratio, left ventricular stroke work index, and cardiac index, but not heart rate, central venous pressure, mean artery pressure, pulmonary capillary wedge pressure, systemic vascular resistance index, oxygen delivery index, oxygen consumption index, arterial lactate concentration, and age. However, by multivariate analysis RDRI was significantly correlated with SvO2 only. Conclusions. The present data suggests that, in mechanically ventilated patients after cardiac surgery, RDRI increases proportionally to the decrease in SvO2, thus reflecting an early vascular response to tissue hypoxia. Francesco Corradi, Claudia Brusasco, Francesco Paparo, Tullio Manca, Gregorio Santori, Filippo Benassi, Alberto Molardi, Alan Gallingani, Andrea Ramelli, Tiziano Gherli, and Antonella Vezzani Copyright © 2015 Francesco Corradi et al. All rights reserved. Corrigendum to “Sleep-Disordered Breathing in Patients with Heart Failure: New Trends in Therapy” Wed, 28 Oct 2015 11:06:28 +0000 Anna Kazimierczak, Paweł Krzesiński, Krystian Krzyżanowski, and Grzegorz Gielerak Copyright © 2015 Anna Kazimierczak et al. All rights reserved. The Role of Focused Echocardiography in Pediatric Intensive Care: A Critical Appraisal Wed, 28 Oct 2015 06:57:28 +0000 Echocardiography is a key tool for hemodynamic assessment in Intensive Care Units (ICU). Focused echocardiography performed by nonspecialist physicians has a limited scope, and the most relevant parameters assessed by focused echocardiography in Pediatric ICU are left ventricular systolic function, fluid responsiveness, cardiac tamponade and pulmonary hypertension. Proper ability building of pediatric emergency care physicians and intensivists to perform focused echocardiography is feasible and provides improved care of severely ill children and thus should be encouraged. Heloisa Amaral Gaspar and Samira Saady Morhy Copyright © 2015 Heloisa Amaral Gaspar and Samira Saady Morhy. All rights reserved. Bridging the Gap between Translational and Outcome Research in Cardiovascular Disease Tue, 27 Oct 2015 06:41:22 +0000 Giacomo Frati, Umberto Benedetto, Giuseppe Biondi-Zoccai, and Sebastiano Sciarretta Copyright © 2015 Giacomo Frati et al. All rights reserved. ECG-Based Detection of Early Myocardial Ischemia in a Computational Model: Impact of Additional Electrodes, Optimal Placement, and a New Feature for ST Deviation Mon, 26 Oct 2015 08:44:12 +0000 In case of chest pain, immediate diagnosis of myocardial ischemia is required to respond with an appropriate treatment. The diagnostic capability of the electrocardiogram (ECG), however, is strongly limited for ischemic events that do not lead to ST elevation. This computational study investigates the potential of different electrode setups in detecting early ischemia at 10 minutes after onset: standard 3-channel and 12-lead ECG as well as body surface potential maps (BSPMs). Further, it was assessed if an additional ECG electrode with optimized position or the right-sided Wilson leads can improve sensitivity of the standard 12-lead ECG. To this end, a simulation study was performed for 765 different locations and sizes of ischemia in the left ventricle. Improvements by adding a single, subject specifically optimized electrode were similar to those of the BSPM: 2–11% increased detection rate depending on the desired specificity. Adding right-sided Wilson leads had negligible effect. Absence of ST deviation could not be related to specific locations of the ischemic region or its transmurality. As alternative to the ST time integral as a feature of ST deviation, the K point deviation was introduced: the baseline deviation at the minimum of the ST-segment envelope signal, which increased 12-lead detection rate by 7% for a reasonable threshold. Axel Loewe, Walther H. W. Schulze, Yuan Jiang, Mathias Wilhelms, Armin Luik, Olaf Dössel, and Gunnar Seemann Copyright © 2015 Axel Loewe et al. All rights reserved. New Insights in the Diagnosis and Treatment of Heart Failure Mon, 26 Oct 2015 08:18:33 +0000 Cardiovascular disease is the leading cause of mortality in the US and in westernized countries with ischemic heart disease accounting for the majority of these deaths. Paradoxically, the improvements in the medical and surgical treatments of acute coronary syndrome are leading to an increasing number of “survivors” who are then developing heart failure. Despite considerable advances in its management, the gold standard for the treatment of end-stage heart failure patients remains heart transplantation. Nevertheless, this procedure can be offered only to a small percentage of patients who could benefit from a new heart due to the limited availability of donor organs. The aim of this review is to evaluate the safety and efficacy of innovative approaches in the diagnosis and treatment of patients refractory to standard medical therapy and excluded from cardiac transplantation lists. Giulio Agnetti, Massimo F. Piepoli, Giuseppe Siniscalchi, and Francesco Nicolini Copyright © 2015 Giulio Agnetti et al. All rights reserved. Filament Dynamics during Simulated Ventricular Fibrillation in a High-Resolution Rabbit Heart Mon, 26 Oct 2015 08:17:32 +0000 The mechanisms underlying ventricular fibrillation (VF) are not well understood. The electrical activity on the heart surface during VF has been recorded extensively in the experimental setting and in some cases clinically; however, corresponding transmural activation patterns are prohibitively difficult to measure. In this paper, we use a high-resolution biventricular heart model to study three-dimensional electrical activity during fibrillation, focusing on the driving sources of VF: “filaments,” the organising centres of unstable reentrant scroll waves. We show, for the first time, specific 3D filament dynamics during simulated VF in a whole heart geometry that includes fine-scale anatomical structures. Our results suggest that transmural activity is much more complex than what would be expected from surface observations alone. We present examples of complex intramural activity, including filament breakup and reattachment, anchoring to the thin right ventricular apex; rapid transitions among various filament shapes; and filament lengths much greater than wall thickness. We also present evidence for anatomy playing a major role in VF development and coronary vessels and trabeculae influencing filament dynamics. Overall, our results indicate that intramural activity during simulated VF is extraordinarily complex and suggest that further investigation of 3D filaments is necessary to fully comprehend recorded surface patterns. Pras Pathmanathan and Richard A. Gray Copyright © 2015 Pras Pathmanathan and Richard A. Gray. All rights reserved. A Computer Simulation Study of Anatomy Induced Drift of Spiral Waves in the Human Atrium Mon, 26 Oct 2015 07:42:57 +0000 The interaction of spiral waves of excitation with atrial anatomy remains unclear. This simulation study isolates the role of atrial anatomical structures on spiral wave spontaneous drift in the human atrium. We implemented realistic and idealised 3D human atria models to investigate the functional impact of anatomical structures on the long-term (∼40 s) behaviour of spiral waves. The drift of a spiral wave was quantified by tracing its tip trajectory, which was correlated to atrial anatomical features. The interaction of spiral waves with the following idealised geometries was investigated: (a) a wedge-like structure with a continuously varying atrial wall thickness; (b) a ridge-like structure with a sudden change in atrial wall thickness; (c) multiple bridge-like structures consisting of a bridge connected to the atrial wall. Spiral waves drifted from thicker to thinner regions and along ridge-like structures. Breakthrough patterns caused by pectinate muscles (PM) bridges were also observed, albeit infrequently. Apparent anchoring close to PM-atrial wall junctions was observed. These observations were similar in both the realistic and the idealised models. We conclude that spatially altering atrial wall thickness is a significant cause of drift of spiral waves. PM bridges cause breakthrough patterns and induce transient anchoring of spiral waves. Sanjay R. Kharche, Irina V. Biktasheva, Gunnar Seemann, Henggui Zhang, and Vadim N. Biktashev Copyright © 2015 Sanjay R. Kharche et al. All rights reserved. Application of Mathematical Modeling for Simulation and Analysis of Hypoplastic Left Heart Syndrome (HLHS) in Pre- and Postsurgery Conditions Sun, 25 Oct 2015 12:38:16 +0000 This paper is concerned with the mathematical modeling of a severe and common congenital defect called hypoplastic left heart syndrome (HLHS). Surgical approaches are utilized for palliating this heart condition; however, a brain white matter injury called periventricular leukomalacia (PVL) occurs with high prevalence at or around the time of surgery, the exact cause of which is not known presently. Our main goal in this paper is to study the hemodynamic conditions under which HLHS physiology may lead to the occurrence of PVL. A lumped parameter model of the HLHS circulation has been developed integrating diffusion modeling of oxygen and carbon dioxide concentrations in order to study hemodynamic variables such as pressure, flow, and blood gas concentration. Results presented include calculations of blood pressures and flow rates in different parts of the circulation. Simulations also show changes in the ratio of pulmonary to systemic blood flow rates when the sizes of the patent ductus arteriosus and atrial septal defect are varied. These changes lead to unbalanced blood circulations and, when combined with low oxygen and carbon dioxide concentrations in arteries, result in poor oxygen delivery to the brain. We stipulate that PVL occurs as a consequence. Ali Jalali, Gerard F. Jones, Daniel J. Licht, and C. Nataraj Copyright © 2015 Ali Jalali et al. All rights reserved. Simulation of Ectopic Pacemakers in the Heart: Multiple Ectopic Beats Generated by Reentry inside Fibrotic Regions Sun, 25 Oct 2015 12:37:00 +0000 The inclusion of nonconducting media, mimicking cardiac fibrosis, in two models of cardiac tissue produces the formation of ectopic beats. The fraction of nonconducting media in comparison with the fraction of healthy myocytes and the topological distribution of cells determines the probability of ectopic beat generation. First, a detailed subcellular microscopic model that accounts for the microstructure of the cardiac tissue is constructed and employed for the numerical simulation of action potential propagation. Next, an equivalent discrete model is implemented, which permits a faster integration of the equations. This discrete model is a simplified version of the microscopic model that maintains the distribution of connections between cells. Both models produce similar results when describing action potential propagation in homogeneous tissue; however, they slightly differ in the generation of ectopic beats in heterogeneous tissue. Nevertheless, both models present the generation of reentry inside fibrotic tissues. This kind of reentry restricted to microfibrosis regions can result in the formation of ectopic pacemakers, that is, regions that will generate a series of ectopic stimulus at a fast pacing rate. In turn, such activity has been related to trigger fibrillation in the atria and in the ventricles in clinical and animal studies. Bruno Gouvêa de Barros, Rodrigo Weber dos Santos, Marcelo Lobosco, and Sergio Alonso Copyright © 2015 Bruno Gouvêa de Barros et al. All rights reserved. Recent Advances on Pathophysiology, Diagnostic and Therapeutic Insights in Cardiac Dysfunction Induced by Antineoplastic Drugs Sun, 25 Oct 2015 11:41:50 +0000 Along with the improvement of survival after cancer, cardiotoxicity due to antineoplastic treatments has emerged as a clinically relevant problem. Potential cardiovascular toxicities due to anticancer agents include QT prolongation and arrhythmias, myocardial ischemia and infarction, hypertension and/or thromboembolism, left ventricular (LV) dysfunction, and heart failure (HF). The latter is variable in severity, may be reversible or irreversible, and can occur soon after or as a delayed consequence of anticancer treatments. In the last decade recent advances have emerged in clinical and pathophysiological aspects of LV dysfunction induced by the most widely used anticancer drugs. In particular, early, sensitive markers of cardiac dysfunction that can predict this form of cardiomyopathy before ejection fraction (EF) is reduced are becoming increasingly important, along with novel therapeutic and cardioprotective strategies, in the attempt of protecting cardiooncologic patients from the development of congestive heart failure. Marilisa Molinaro, Pietro Ameri, Giancarlo Marone, Mario Petretta, Pasquale Abete, Fabio Di Lisa, Sabino De Placido, Domenico Bonaduce, and Carlo G. Tocchetti Copyright © 2015 Marilisa Molinaro et al. All rights reserved. Transcriptional Changes Associated with Long-Term Left Ventricle Volume Overload in Rats: Impact on Enzymes Related to Myocardial Energy Metabolism Sun, 25 Oct 2015 11:38:57 +0000 Patients with left ventricle (LV) volume overload (VO) remain in a compensated state for many years although severe dilation is present. The myocardial capacity to fulfill its energetic demand may delay decompensation. We performed a gene expression profile, a model of chronic VO in rat LV with severe aortic valve regurgitation (AR) for 9 months, and focused on the study of genes associated with myocardial energetics. Methods. LV gene expression profile was performed in rats after 9 months of AR and compared to sham-operated controls. LV glucose and fatty acid (FA) uptake was also evaluated in vivo by positron emission tomography in 8-week AR rats treated or not with fenofibrate, an activator of FA oxidation (FAO). Results. Many LV genes associated with mitochondrial function and metabolism were downregulated in AR rats. FA β-oxidation capacity was significantly impaired as early as two weeks after AR. Treatment with fenofibrate, a PPARα agonist, normalized both FA and glucose uptake while reducing LV dilation caused by AR. Conclusion. Myocardial energy substrate preference is affected early in the evolution of LV-VO cardiomyopathy. Maintaining a relatively normal FA utilization in the myocardium could translate into less glucose uptake and possibly lesser LV remodeling. Elise Roussel, Marie-Claude Drolet, Elisabeth Walsh-Wilkinson, Wahiba Dhahri, Dominic Lachance, Suzanne Gascon, Otman Sarrhini, Jacques A. Rousseau, Roger Lecomte, Jacques Couet, and Marie Arsenault Copyright © 2015 Elise Roussel et al. All rights reserved. Simulating Cardiac Electrophysiology Using Unstructured All-Hexahedra Spectral Elements Sun, 25 Oct 2015 11:24:18 +0000 We discuss the application of the spectral element method to the monodomain and bidomain equations describing propagation of cardiac action potential. Models of cardiac electrophysiology consist of a system of partial differential equations coupled with a system of ordinary differential equations representing cell membrane dynamics. The solution of these equations requires solving multiple length scales due to the ratio of advection to diffusion that varies among the different equations. High order approximation of spectral elements provides greater flexibility in resolving multiple length scales. Furthermore, spectral elements are extremely efficient to model propagation phenomena on complex shapes using fewer degrees of freedom than its finite element equivalent (for the same level of accuracy). We illustrate a fully unstructured all-hexahedra approach implementation of the method and we apply it to the solution of full 3D monodomain and bidomain test cases. We discuss some key elements of the proposed approach on some selected benchmarks and on an anatomically based whole heart human computational model. Gianmauro Cuccuru, Giorgio Fotia, Fabio Maggio, and James Southern Copyright © 2015 Gianmauro Cuccuru et al. All rights reserved. Design and Evaluation of a Fully Implantable Control Unit for Blood Pumps Sun, 25 Oct 2015 09:23:06 +0000 As the number of donor hearts is limited while more and more patients suffer from end stage biventricular heart failure, Total Artificial Hearts become a promising alternative to conventional treatment. While pneumatic devices sufficiently supply the patients with blood flow, the patient’s quality of life is limited by the percutaneous pressure lines and the size of the external control unit. This paper describes the development of the control unit of the ReinHeart, a fully implantable Total Artificial Heart. General requirements for any implantable control unit are defined from a technical and medical point of view: necessity of a Transcutaneous Energy Transmission, autonomous operation, safety, geometry, and efficiency. Based on the requirements, a prototype is designed; it incorporates a LiFePo4 battery pack with charger, a rectifier for transcutaneous energy transmission, the motor’s driver electronics, and a microcontroller which monitors and controls all functions. In validation tests, the control unit demonstrated a stable operation on TET and battery supply and a safe switching from one supply to the other. The overall mean efficiency is 14% on TET and 22% on battery supply. The control unit is suitable for chronic animal trials of the ReinHeart. Kristin Unthan, Felix Gräf, Marco Laumen, Thomas Finocchiaro, Christoph Sommer, Hermann Lanmüller, and Ulrich Steinseifer Copyright © 2015 Kristin Unthan et al. All rights reserved. Durable Mechanical Circulatory Support versus Organ Transplantation: Past, Present, and Future Sun, 25 Oct 2015 09:20:59 +0000 For more than 30 years, heart transplantation has been a successful therapy for patients with terminal heart failure. Mechanical circulatory support (MCS) was developed as a therapy for end-stage heart failure at a time when cardiac transplantation was not yet a useful treatment modality. With the more successful outcomes of cardiac transplantation in the 1980s, MCS was applied as a bridge to transplantation. Because of donor scarcity and limited long-term survival, heart transplantation has had a trivial impact on the epidemiology of heart failure. Surgical implementation of MCS, both for short- and long-term treatment, affords physicians an opportunity for dramatic expansion of a meaningful therapy for these otherwise mortally ill patients. This review explores the evolution of mechanical circulatory support and its potential for providing long-term therapy, which may address the limitations of cardiac transplantation. Jatin Anand, Steve K. Singh, David G. Antoun, William E. Cohn, O. H. (Bud) Frazier, and Hari R. Mallidi Copyright © 2015 Jatin Anand et al. All rights reserved. A 2D Electromechanical Model of Human Atrial Tissue Using the Discrete Element Method Sun, 25 Oct 2015 09:19:34 +0000 Cardiac tissue is a syncytium of coupled cells with pronounced intrinsic discrete nature. Previous models of cardiac electromechanics often ignore such discrete properties and treat cardiac tissue as a continuous medium, which has fundamental limitations. In the present study, we introduce a 2D electromechanical model for human atrial tissue based on the discrete element method (DEM). In the model, single-cell dynamics are governed by strongly coupling the electrophysiological model of Courtemanche et al. to the myofilament model of Rice et al. with two-way feedbacks. Each cell is treated as a viscoelastic body, which is physically represented by a clump of nine particles. Cell aggregations are arranged so that the anisotropic nature of cardiac tissue due to fibre orientations can be modelled. Each cell is electrically coupled to neighbouring cells, allowing excitation waves to propagate through the tissue. Cell-to-cell mechanical interactions are modelled using a linear contact bond model in DEM. By coupling cardiac electrophysiology with mechanics via the intracellular Ca2+ concentration, the DEM model successfully simulates the conduction of cardiac electrical waves and the tissue’s corresponding mechanical contractions. The developed DEM model is numerically stable and provides a powerful method for studying the electromechanical coupling problem in the heart. Paul Brocklehurst, Ismail Adeniran, Dongmin Yang, Yong Sheng, Henggui Zhang, and Jianqiao Ye Copyright © 2015 Paul Brocklehurst et al. All rights reserved. Characterizing Spatial Dynamics of Bifurcation to Alternans in Isolated Whole Rabbit Hearts Based on Alternate Pacing Sun, 25 Oct 2015 09:02:17 +0000 Sudden cardiac death instigated by ventricular fibrillation (VF) is the largest cause of natural death in the USA. Alternans, a beat-to-beat alternation in the action potential duration, has been implicated as being proarrhythmic. The onset of alternans is mediated via a bifurcation, which may occur through either a smooth or a border-collision mechanism. The objective of this study was to characterize the mechanism of bifurcation to alternans based on experiments in isolated whole rabbit hearts. High resolution optical mapping was performed and the electrical activity was recorded from the left ventricle (LV) epicardial surface of the heart. Each heart was paced using an “alternate pacing protocol,” where the basic cycle length (BCL) was alternatively perturbed by ±δ. Local onset of alternans in the heart, , was measured in the absence of perturbations () and was defined as the BCL at which 10% of LV exhibited alternans. The influences of perturbation size were investigated at two BCLs: one prior to ( ms) and one preceding ( ms). Our results demonstrate significant spatial correlation of the region exhibiting alternans with smooth bifurcation characteristics, indicating that transition to alternans in isolated rabbit hearts occurs predominantly through smooth bifurcation. Kanchan Kulkarni, Ramjay Visweswaran, Xiaopeng Zhao, and Elena G. Tolkacheva Copyright © 2015 Kanchan Kulkarni et al. All rights reserved. Novel Therapeutic Strategies for Reducing Right Heart Failure Associated Mortality in Fibrotic Lung Diseases Sun, 25 Oct 2015 08:59:35 +0000 Fibrotic lung diseases carry a significant mortality burden worldwide. A large proportion of these deaths are due to right heart failure and pulmonary hypertension. Underlying contributory factors which appear to play a role in the mechanism of progression of right heart dysfunction include chronic hypoxia, defective calcium handling, hyperaldosteronism, pulmonary vascular alterations, cyclic strain of pressure and volume changes, elevation of circulating TGF-β, and elevated systemic NO levels. Specific therapies targeting pulmonary hypertension include calcium channel blockers, endothelin (ET-1) receptor antagonists, prostacyclin analogs, phosphodiesterase type 5 (PDE5) inhibitors, and rho-kinase (ROCK) inhibitors. Newer antifibrotic and anti-inflammatory agents may exert beneficial effects on heart failure in idiopathic pulmonary fibrosis. Furthermore, right ventricle-targeted therapies, aimed at mitigating the effects of functional right ventricular failure, include β-adrenoceptor (β-AR) blockers, angiotensin-converting enzyme (ACE) inhibitors, antioxidants, modulators of metabolism, and 5-hydroxytryptamine-2B (5-HT2B) receptor antagonists. Newer nonpharmacologic modalities for right ventricular support are increasingly being implemented. Early, effective, and individualized therapy may prevent overt right heart failure in fibrotic lung disease leading to improved outcomes and quality of life. Ayodeji Adegunsoye, Matthew Levy, and Olusegun Oyenuga Copyright © 2015 Ayodeji Adegunsoye et al. All rights reserved. Effects of Sevoflurane and Propofol on Organ Blood Flow in Left Ventricular Assist Devices in Pigs Sun, 25 Oct 2015 08:56:59 +0000 The aim of this study was to assess the effect of sevoflurane and propofol on organ blood flow in a porcine model with a left ventricular assist device (LVAD). Ten healthy minipigs were divided into 2 groups (5 per group) according to the anesthetic received (sevoflurane or propofol). A Biomedicus centrifugal pump was implanted. Organ blood flow (measured using colored microspheres), markers of tissue injury, and hemodynamic parameters were assessed at baseline (pump off) and after 30 minutes of partial support. Blood flow was significantly higher in the brain (both frontal lobes), heart (both ventricles), and liver after 30 minutes in the sevoflurane group, although no significant differences were recorded for the lung, kidney, or ileum. Serum levels of alanine aminotransferase and total bilirubin were significantly higher after 30 minutes in the propofol group, although no significant differences were detected between the groups for other parameters of liver function, kidney function, or lactic acid levels. The hemodynamic parameters were similar in both groups. We demonstrated that, compared with propofol, sevoflurane increases blood flow in the brain, liver, and heart after implantation of an LVAD under conditions of partial support. Paloma Morillas-Sendín, Emilio Delgado-Baeza, María Jesús Delgado-Martos, Mónica Barranco, Juan Francisco del Cañizo, Manuel Ruíz, and Begoña Quintana-Villamandos Copyright © 2015 Paloma Morillas-Sendín et al. All rights reserved. Computational Approaches to Understanding the Role of Fibroblast-Myocyte Interactions in Cardiac Arrhythmogenesis Sun, 25 Oct 2015 08:55:46 +0000 The adult heart is composed of a dense network of cardiomyocytes surrounded by nonmyocytes, the most abundant of which are cardiac fibroblasts. Several cardiac diseases, such as myocardial infarction or dilated cardiomyopathy, are associated with an increased density of fibroblasts, that is, fibrosis. Fibroblasts play a significant role in the development of electrical and mechanical dysfunction of the heart; however the underlying mechanisms are only partially understood. One widely studied mechanism suggests that fibroblasts produce excess extracellular matrix, resulting in collagenous septa. These collagenous septa slow propagation, cause zig-zag conduction paths, and decouple cardiomyocytes resulting in a substrate for arrhythmia. Another emerging mechanism suggests that fibroblasts promote arrhythmogenesis through direct electrical interactions with cardiomyocytes via gap junctions. Due to the challenges of investigating fibroblast-myocyte coupling in native cardiac tissue, computational modeling and in vitro experiments have facilitated the investigation into the mechanisms underlying fibroblast-mediated changes in cardiomyocyte action potential morphology, conduction velocity, spontaneous excitability, and vulnerability to reentry. In this paper, we summarize the major findings of the existing computational studies investigating the implications of fibroblast-myocyte interactions in the normal and diseased heart. We then present investigations from our group into the potential role of voltage-dependent gap junctions in fibroblast-myocyte interactions. Tashalee R. Brown, Trine Krogh-Madsen, and David J. Christini Copyright © 2015 Tashalee R. Brown et al. All rights reserved. Adaptive Mesh Refinement and Adaptive Time Integration for Electrical Wave Propagation on the Purkinje System Sun, 25 Oct 2015 08:36:12 +0000 A both space and time adaptive algorithm is presented for simulating electrical wave propagation in the Purkinje system of the heart. The equations governing the distribution of electric potential over the system are solved in time with the method of lines. At each timestep, by an operator splitting technique, the space-dependent but linear diffusion part and the nonlinear but space-independent reactions part in the partial differential equations are integrated separately with implicit schemes, which have better stability and allow larger timesteps than explicit ones. The linear diffusion equation on each edge of the system is spatially discretized with the continuous piecewise linear finite element method. The adaptive algorithm can automatically recognize when and where the electrical wave starts to leave or enter the computational domain due to external current/voltage stimulation, self-excitation, or local change of membrane properties. Numerical examples demonstrating efficiency and accuracy of the adaptive algorithm are presented. Wenjun Ying and Craig S. Henriquez Copyright © 2015 Wenjun Ying and Craig S. Henriquez. All rights reserved. Characterization of Electrograms from Multipolar Diagnostic Catheters during Atrial Fibrillation Sun, 25 Oct 2015 08:16:25 +0000 Atrial fibrillation (AF) is the most common arrhythmia in USA with more than 2.3 million people affected annually. Catheter ablation procedure is a method for treatment of AF, which involves 3D electroanatomic mapping of the patient's left atrium (LA) by maneuvering a conventional multipolar diagnostic catheter (MPDC) along the LA endocardial surface after which pulmonary vein (PV) isolation is performed, thus eliminating the AF triggers originating from the PVs. However, it remains unclear how to effectively utilize the information provided by the MPDC to locate the AF-sustaining sites, known as sustained rotor-like activities (RotAs). In this study, we use computer modeling to investigate the variations in the characteristics of the MPDC electrograms, namely, total conduction delay (TCD) and average cycle length (CL), as the MPDC moves towards a RotA source. Subsequently, a study with a human subject was performed in order to verify the predictions of the simulation study. The conclusions from this study may be used to iteratively direct an MPDC towards RotA sources thus allowing the RotAs to be localized for customized and improved AF ablation. Prasanth Ganesan, Elizabeth M. Cherry, Arkady M. Pertsov, and Behnaz Ghoraani Copyright © 2015 Prasanth Ganesan et al. All rights reserved. Image-Based Structural Modeling of the Cardiac Purkinje Network Sun, 25 Oct 2015 07:16:13 +0000 The Purkinje network is a specialized conduction system within the heart that ensures the proper activation of the ventricles to produce effective contraction. Its role during ventricular arrhythmias is less clear, but some experimental studies have suggested that the Purkinje network may significantly affect the genesis and maintenance of ventricular arrhythmias. Despite its importance, few structural models of the Purkinje network have been developed, primarily because current physical limitations prevent examination of the intact Purkinje network. In previous modeling efforts Purkinje-like structures have been developed through either automated or hand-drawn procedures, but these networks have been created according to general principles rather than based on real networks. To allow for greater realism in Purkinje structural models, we present a method for creating three-dimensional Purkinje networks based directly on imaging data. Our approach uses Purkinje network structures extracted from photographs of dissected ventricles and projects these flat networks onto realistic endocardial surfaces. Using this method, we create models for the combined ventricle-Purkinje system that can fully activate the ventricles through a stimulus delivered to the Purkinje network and can produce simulated activation sequences that match experimental observations. The combined models have the potential to help elucidate Purkinje network contributions during ventricular arrhythmias. Benjamin R. Liu and Elizabeth M. Cherry Copyright © 2015 Benjamin R. Liu and Elizabeth M. Cherry. All rights reserved. Pentraxin-3 Predicts Long-Term Cardiac Events in Patients with Chronic Heart Failure Thu, 22 Oct 2015 14:05:03 +0000 The aim of this study was to investigate the long-term prognostic value of pentraxin-3 (PTX3) in patients with chronic heart failure (CHF). 377 patients were prospectively followed up for 3 years to determine cardiac events including cardiac death or rehospitalization for worsening heart failure. The plasma PTX3 levels were significantly higher in CHF patients than in healthy subjects (), and they increased with advancing New York Heart Association (NYHA) Functional Classification (). Plasma PTX3 levels in CHF patients with cardiac events were significantly higher than in event-free patients (). We determined the normal upper limit of plasma PTX3 levels from the mean + 2 SD value of 64 control subjects (3.64 ng/mL). A Kaplan-Meier analysis revealed that patients with increased PTX3 (≥3.64 ng/mL) were at a higher risk for cardiac events than those without increased PTX3 (). A multifactorial Cox proportional hazards model showed that increased PTX3 (≥3.64 ngImL) was an independent risk factor for cardiac events in CHF patients (hazard ratio (HR) = 4.224, ; 95% CI: 1.130–15.783). Plasma PTX3 levels are a long-term independent predictor of prognosis in patients with CHF. Haibo Liu, Xiaofang Guo, Kang Yao, Chunming Wang, Guozhong Chen, Wei Gao, Jie Yuan, Wangjun Yu, and Junbo Ge Copyright © 2015 Haibo Liu et al. All rights reserved. Effects of Physical (In)activity on Platelet Function Sun, 18 Oct 2015 13:32:23 +0000 As platelet activation is closely related to the liberation of growth factors and inflammatory mediators, platelets play a central role in the development of CVD. Virtually all cardiovascular risk factors favor platelet hyperreactivity and, accordingly, also physical (in)activity affects platelet function. Within this paper, we will summarize and discuss the current knowledge on the impact of acute and habitual exercise on platelet function. Although there are apparent discrepancies regarding the reported effects of acute, strenuous exercise on platelet activation, a deeper analysis of the available literature reveals that the applied exercise intensity and the subjects’ cardiorespiratory fitness represent critical determinants for the observed effects. Consideration of these factors leads to the summary that (i) acute, strenuous exercise can lead to platelet activation, (ii) regular physical activity and/or physical fitness diminish or prevent platelet activation in response to acute exercise, and (iii) habitual physical activity and/or physical fitness also favorably modulate platelet function at physical rest. Notably, these effects of exercise on platelet function show obvious similarities to the well-recognized relation between exercise and the risk for cardiovascular events where vigorous exercise transiently increases the risk for myocardial infarction and a physically active lifestyle dramatically reduces cardiovascular mortality. Stefan Heber and Ivo Volf Copyright © 2015 Stefan Heber and Ivo Volf. All rights reserved. Impaired Circulating Angiogenic Cells Mobilization and Metalloproteinase-9 Activity after Dynamic Exercise in Early Metabolic Syndrome Sun, 18 Oct 2015 11:36:30 +0000 Increased levels of adhesion molecules or metalloproteinases (MMPs) may indicate endothelial dysfunction. Exercise mobilizes circulating angiogenic cells (CACs) from bone marrow in healthy subjects, improving vascular function. However, it is unclear whether this mechanism is preserved in the early stages of metabolic syndrome (early MetS). We aimed to evaluate the acute effects of exercise on adhesion molecules, angiogenic factors, MMPs, and CACs in early MetS. Fifteen subjects with early MetS and nine healthy controls underwent an exercise session and a nonexercise session, randomly. Adhesion molecules, angiogenic factors, CACs, and MMPs were evaluated before and after exercise or nonexercise sessions. At baseline, levels of sE-selectin, sICAM-1, and MMP-9 were higher in early MetS than in controls (). After exercise, sE-selectin, sICAM-1, and MMP-9 levels were still higher in early MetS (). Subjects with early MetS presented less CACs () and higher MMP-9 activity (), while healthy controls presented higher MMP-2 activity after exercise. There was no difference between moments in nonexercise session (). In conclusion, subjects with early MetS already presented impaired endothelial function at rest along with a decrease in CACs and an increase in MMP-9 activity in response to exercise. Natalia G. Rocha, Allan R. K. Sales, Leticia A. Penedo, Felipe S. Pereira, Mayra S. Silva, Renan L. Miranda, Jemima F. R. Silva, Bruno M. Silva, Aline A. Santos, and Antonio C. L. Nobrega Copyright © 2015 Natalia G. Rocha et al. All rights reserved. Cardiovascular Reflexes Activity and Their Interaction during Exercise Sun, 18 Oct 2015 09:26:17 +0000 Cardiac output and arterial blood pressure increase during dynamic exercise notwithstanding the exercise-induced vasodilation due to functional sympatholysis. These cardiovascular adjustments are regulated in part by neural reflexes which operate to guarantee adequate oxygen supply and by-products washout of the exercising muscles. Moreover, they maintain adequate perfusion of the vital organs and prevent excessive increments in blood pressure. In this review, we briefly summarize neural reflexes operating during dynamic exercise with particular emphasis on their interaction. Antonio Crisafulli, Elisabetta Marongiu, and Shigehiko Ogoh Copyright © 2015 Antonio Crisafulli et al. All rights reserved. Effects of Exercise Training on Autonomic Function in Chronic Heart Failure: Systematic Review Mon, 12 Oct 2015 11:30:01 +0000 Objectives. Cardiac autonomic imbalance accompanies the progression of chronic heart failure (CHF). It is unclear whether exercise training could modulate autonomic control in CHF. This study aimed to review systematically the effects of exercise training on heart rate recovery (HRR) and heart rate variability (HRV) in patients with CHF. Methods. Literatures were systematically searched in electronic databases and relevant references. Only published randomized controlled trials (RCTs) focusing on exercise training for CHF were eligible for inclusion. Outcome measurements included HRR and HRV parameters. Results. Eight RCTs were eligible for inclusion and provided data on 280 participants (186 men). The participants were 52–70 years of age with New York Heart Association functional class II-III of CHF. Each study examined either aerobic or resistance exercise. Two trials addressed outcome of HRR and six HRV among these studies. Two RCTs showed that moderate aerobic exercise could improve HRR at 2 minutes after exercise training in CHF. Five of six RCTs demonstrated positive effects of exercise training on HRV which revealed the increments in high frequency (HF) and decrements in LF (low frequency)/HF ratio after training. Conclusion. Participation in an exercise training program has positive effects on cardiac autonomic balance in patients with CHF. Chung-Yin Hsu, Ping-Lun Hsieh, Shu-Fang Hsiao, and Meng-Yueh Chien Copyright © 2015 Chung-Yin Hsu et al. All rights reserved. Goal-Directed Resuscitation Aiming Cardiac Index Masks Residual Hypovolemia: An Animal Experiment Mon, 12 Oct 2015 10:57:30 +0000 The aim of this study was to compare stroke volume (SVI) to cardiac index (CI) guided resuscitation in a bleeding-resuscitation experiment. Twenty six pigs were randomized and bled in both groups till baseline SVI () dropped by 50% (), followed by resuscitation with crystalloid solution until initial SVI or CI was reached (). Similar amount of blood was shed but animals received significantly less fluid in the CI-group as in the SVI-group: median = 900 (interquartile range: 850–1780) versus 1965 (1584–2165) mL, , respectively. In the SVI-group all variables returned to their baseline values, but in the CI-group animals remained underresuscitated as indicated by SVI, heart rate (HR) and stroke volume variation (SVV), and central venous oxygen saturation () at as compared to : SVI = 23.8 ± 5.9 versus 31.4 ± 4.7 mL, HR: 117 ± 35 versus 89 ± 11/min SVV: 17.4 ± 7.6 versus 11.5 ± 5.3%, and : 64.1 ± 11.6 versus 79.2 ± 8.1%, , respectively. Our results indicate that CI-based goal-directed resuscitation may result in residual hypovolaemia, as bleeding caused stress induced tachycardia “normalizes” CI, without restoring adequate SVI. As the SVI-guided approach normalized most hemodynamic variables, we recommend using SVI instead of CI as the primary goal of resuscitation during acute bleeding. Krisztián Tánczos, Márton Németh, Domonkos Trásy, Ildikó László, Péter Palágyi, Zsolt Szabó, Gabriella Varga, and József Kaszaki Copyright © 2015 Krisztián Tánczos et al. All rights reserved. Effects of Light Intensity Activity on CVD Risk Factors: A Systematic Review of Intervention Studies Mon, 12 Oct 2015 07:23:24 +0000 The effects of light intensity physical activity (LIPA) on cardiovascular disease (CVD) risk factors remain to be established. This review summarizes the effects of LIPA on CVD risk factors and CVD-related markers in adults. A systematic search of four electronic databases (PubMed, Academic Search Complete, SPORTDiscus, and CINAHL) examining LIPA and CVD risk factors (body composition, blood pressure, glucose, insulin, glycosylated hemoglobin, and lipid profile) and CVD-related markers (maximal oxygen uptake, heart rate, C-reactive protein, interleukin-6, tumor necrosis factor-alpha, and tumor necrosis factor receptors 1 and 2) published between 1970 and 2015 was performed on 15 March 2015. A total of 33 intervention studies examining the effect of LIPA on CVD risk factors and markers were included in this review. Results indicated that LIPA did not improve CVD risk factors and CVD-related markers in healthy individuals. LIPA was found to improve systolic and diastolic blood pressure in physically inactive populations with a medical condition. Reviewed studies show little support for the role of LIPA to reduce CVD risk factors. Many of the included studies were of low to fair study quality and used low doses of LIPA. Further studies are needed to establish the value of LIPA in reducing CVD risk. Romeo B. Batacan Jr., Mitch J. Duncan, Vincent J. Dalbo, Patrick S. Tucker, and Andrew S. Fenning Copyright © 2015 Romeo B. Batacan Jr. et al. All rights reserved. Prognostic Significance of NT-proBNP Levels in Patients over 65 Presenting Acute Myocardial Infarction Treated Invasively or Conservatively Sun, 11 Oct 2015 13:59:48 +0000 Objectives. Assessment of prognostic significance of NT-proBNP level and the effects of invasive (I) and conservative (C) treatment of acute myocardial infarction (AMI) in patients over 65. Materials and Methods. One-year survival was assessed in 286 consecutive patients with AMI aged 65–100 (79 ± 8) subjected to I or C treatment (136 and 150 individuals), respectively. Results. 245 (85%) patients survived in-hospital stay: 124 (91.1%) received I treatment and 121 (80.6%) received C treatment. Heart failure (HF) was diagnosed in 30 patients receiving I treatment (22.6%) and in 71 subjected to C treatment (47.3%), p < 0,0001. NT-proBNP levels in the latter group were significantly higher than in the 185 patients without HF (12311 ± 13560 pg/mL versus 4773 ± 8807 pg/mL, p < 0.0001). NT-proBNP levels after coronary angioplasty were lower than in patients receiving C treatment (5922 ± 10250 pg/mL versus 8718 ± 12024 pg/mL, p = 0.0002). Left ventricular ejection fraction was significantly higher in I patients than in C patients (47 ± 13% versus 42 ± 11.6%, p = 0.004). During the one-year follow-up, 82.3% of I patients and 61.2% of the C patients survived (p < 0.0003). There was a significantly lower probability of death at NT-proBNP below 8548.5 pg/mL. Conclusions. The NT-proBNP level in the first day of AMI is a good prognosticator. One-year follow-up prognosis for patients who received I treatment in the AMI is better than that for C patients. I patients exhibit superior left ventricular function after angioplasty and in the follow-up. Wojciech Drewniak, Wojciech Szybka, Dariusz Bielecki, Michal Malinowski, Joanna Kotlarska, Agnieszka Krol-Jaskulska, Agata Popielarz-Grygalewicz, Aleksandra Konwicka, and Marek Dąbrowski Copyright © 2015 Wojciech Drewniak et al. All rights reserved. Kinetics of Highly Sensitive Troponin T after Cardiac Surgery Sun, 11 Oct 2015 13:57:48 +0000 Perioperative myocardial infarction (PMI) confers a considerable risk in cardiac surgery settings; finding the ideal biomarker seems to be an ideal goal. Our aim was to assess the diagnostic accuracy of highly sensitive troponin T (hsTnT) in cardiac surgery settings and to define a diagnostic level for PMI diagnosis. This was a single-center prospective observational study analyzing data from all patients who underwent cardiac surgeries. The primary outcome was the diagnosis of PMI through a specific level. The secondary outcome measures were the lengths of mechanical ventilation (LOV), stay in the intensive care unit (LOSICU), and hospitalization. Based on the third universal definition of PMI, patients were divided into two groups: no PMI (Group I) and PMI (Group II). Data from 413 patients were analyzed. Nine patients fulfilled the diagnostic criteria of PMI, while 41 patients were identified with a 5-fold increase in their CK-MB (≥120 U/L). Using ROC analysis, a hsTnT level of 3,466 ng/L or above showed 90% sensitivity and 90% specificity for the diagnosis of PMI. Secondary outcome measures in patients with PMI were significantly prolonged. In conclusion, the hsTnT levels detected here paralleled those of CK-MB and a cut-off level of 3466 ng/L could be diagnostic of PMI. Amr S. Omar, Suraj Sudarsanan, Samy Hanoura, Hany Osman, Praveen C. Sivadasan, Yasser Shouman, Alejandro Kohn Tuli, Rajvir Singh, and Abdulaziz Al Khulaifi Copyright © 2015 Amr S. Omar et al. All rights reserved. Inflammatory Biomarkers in Refractory Congestive Heart Failure Patients Treated with Peritoneal Dialysis Sun, 11 Oct 2015 13:54:04 +0000 Proinflammatory cytokines play a pathogenic role in congestive heart failure. In this study, the effect of peritoneal dialysis treatment on inflammatory cytokines levels in refractory congestive heart failure patients was investigated. During the treatment, the patients reached a well-tolerated edema-free state and demonstrated significant improvement in NYHA functional class. Brain natriuretic peptide decreased significantly after 3 months of treatment and remained stable at 6 months. C-reactive protein, a plasma marker of inflammation, decreased significantly following the treatment. Circulating inflammatory cytokines TNF-α and IL-6 decreased significantly after 3 months of peritoneal dialysis treatment and remained low at 6 months. The reduction in circulating inflammatory cytokines levels may be partly responsible for the efficacy of peritoneal dialysis for refractory congestive heart failure. Margarita Kunin, Vered Carmon, Michael Arad, Nomy Levin-Iaina, Dov Freimark, Eli J. Holtzman, and Dganit Dinour Copyright © 2015 Margarita Kunin et al. All rights reserved. Amelioration of Isoproterenol-Induced Oxidative Damage in Rat Myocardium by Withania somnifera Leaf Extract Sun, 11 Oct 2015 13:42:04 +0000 We investigated the protective role of Withania somnifera leaf extract (WSLEt) on isoproterenol- (ISO-) induced myocardial infarction (MI) in rats. Subcutaneous injection of ISO (85 mg/kg body weight (b.w.)) administered to rats for two consecutive days caused a significant increase in cardiac troponin I (cTnI) levels and serum lipid profiles, as well as the activities of some marker enzymes. In addition to these diagnostic markers, there were increased levels of lipid peroxidation (LPO) and decreased activities of enzymatic antioxidants (superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GRx), and glutathione-S-transferase (GST)) in the myocardium. However, oral pretreatment (100 mg/kg b.w.) with WSLEt for 4 weeks elicited a significant cardioprotective activity by lowering the levels of cTnI, lipid profiles, and marker enzymes. The levels of LPO products were also significantly decreased. Elevated activities of antioxidant enzymes were also observed in rats pretreated with WSLEt. As further confirmed histopathologically, our findings strongly suggest that the cardioprotective effect of WSLEt on myocardium experiencing ISO-induced oxidative damage may be due to an augmentation of the endogenous antioxidant system and an inhibition of LPO in the myocardial membrane. We conclude that WSLEt confers some protection against oxidative damage in ISO-induced MI in rats. Md. Ibrahim Khalil, Istiyak Ahmmed, Romana Ahmed, E. M. Tanvir, Rizwana Afroz, Sudip Paul, Siew Hua Gan, and Nadia Alam Copyright © 2015 Md. Ibrahim Khalil et al. All rights reserved. Serum Caveolin-1 as a Novel Biomarker in Idiopathic Pulmonary Artery Hypertension Sun, 11 Oct 2015 13:36:51 +0000 Pulmonary arterial hypertension (PAH) is a rare disease but with significant morbidity and high mortality. There is no specific way to diagnose PAH. Thus, an easy used with good sensitivity and specificity biomarker of PAH is highly desirable to aid in the screening, diagnosis, and follow-up. Caveolin-1 (Cav1) is the structural protein of caveolae and is highly expressed in type I pneumocytes. Lungs tissues from idiopathic PAH (IPAH) patients showed decreased expression of Cav1 in vascular endothelial cells. Therefore, we developed a direct sandwich immunoassay for the determination of Cav1 in IAPH patient’s serum. The result disclosed serum Cav1 level was significantly lower in IPAH than control groups. Using serum Cav1, 17.17 pg/mL as a cutoff value, the sensitivity was 0.59 and the specificity was 1.0. There were two major findings in our results. First, serum Cav1 might be a novel biomarker in the diagnosis of IPAH with fare sensitivity and good specificity. Second, Cav1 might be used to make differential diagnosis between COPD-PH and IPAH group. Kuo-Yang Wang, Mey-Fann Lee, Hung-Chin Ho, Kae-Woei Liang, Chia-Chi Liu, Wan-Jane Tsai, and Wei-Wen Lin Copyright © 2015 Kuo-Yang Wang et al. All rights reserved. Myeloperoxidase-Related Chlorination Activity Is Positively Associated with Circulating Ceruloplasmin in Chronic Heart Failure Patients: Relationship with Neurohormonal, Inflammatory, and Nutritional Parameters Sun, 11 Oct 2015 13:34:07 +0000 Rationale. Heart failure (HF) is accompanied by the development of an imbalance between oxygen- and nitric oxide-derived free radical production leading to protein nitration. Both chlorinating and peroxidase cycle of Myeloperoxidase (MPO) contribute to oxidative and nitrosative stress and are involved in tyrosine nitration of protein. Ceruloplasmin (Cp) has antioxidant function through its ferroxidase I (FeOxI) activity and has recently been proposed as a physiological defense mechanism against MPO inappropriate actions. Objective. We investigated the relationship between plasma MPO-related chlorinating activity, Cp and FeOxI, and nitrosative stress, inflammatory, neurohormonal, and nutritional biomarkers in HF patients. Methods and Results. In chronic HF patients (, 76 9 years, NYHA Class II (26); Class III (29); Class IV (26)) and age-matched controls (, 75 11 years, CTR), plasma MPO chlorinating activity, Cp, FeOxI, nitrated protein, free Malondialdehyde, BNP, norepinephrine, hsCRP, albumin, and prealbumin were measured. Plasma MPO chlorinating activity, Cp, BNP, norepinephrine, and hsCRP were increased in HF versus CTR. FeOxI, albumin, and prealbumin were decreased in HF. MPO-related chlorinating activity was positively related to Cp (, ), nitrated protein, hsCRP, and BNP and inversely to albumin. Conclusions. Plasma MPO chlorinated activity is increased in elderly chronic HF patients and positively associated with Cp, inflammatory, neurohormonal, and nitrosative parameters suggesting a role in HF progression. Aderville Cabassi, Simone Maurizio Binno, Stefano Tedeschi, Gallia Graiani, Cinzia Galizia, Michele Bianconcini, Pietro Coghi, Federica Fellini, Livia Ruffini, Paolo Govoni, Massimo Piepoli, Stefano Perlini, Giuseppe Regolisti, and Enrico Fiaccadori Copyright © 2015 Aderville Cabassi et al. All rights reserved. Activation of Endocannabinoid System Is Associated with Persistent Inflammation in Human Aortic Aneurysm Sun, 11 Oct 2015 11:51:46 +0000 Human aortic aneurysms have been associated with inflammation and vascular remodeling. Since the endocannabinoid system modulates inflammation and tissue remodeling, we investigated its components in human aortic aneurysms. We obtained anterior aortic wall samples from patients undergoing elective surgery for aortic aneurysm or coronary artery disease as controls. Histological and molecular analysis (RT-qPCR) was performed, and endocannabinoid concentration was determined using LC-MRM. Patient characteristics were comparable between the groups except for a higher incidence of arterial hypertension and diabetes in the control group. mRNA level of cannabinoid receptors was significantly higher in aneurysms than in controls. Concentration of the endocannabinoid 2-arachidonoylglycerol was significantly higher, while the second endocannabinoid anandamide and its metabolite arachidonic acid and palmitoylethanolamide were significantly lower in aneurysms. Histology revealed persistent infiltration of newly recruited leukocytes and significantly higher mononuclear cell density in adventitia of the aneurysms. Proinflammatory environment in aneurysms was shown by significant upregulation of M-CSF and PPARγ but associated with downregulation of chemokines. We found comparable collagen-stained area between the groups, significantly decreased mRNA level of CTGF, osteopontin-1, and MMP-2, and increased TIMP-4 expression in aneurysms. Our data provides evidence for endocannabinoid system activation in human aortic aneurysms, associated with persistent low-level inflammation and vascular remodeling. Christopher Gestrich, Georg D. Duerr, Jan C. Heinemann, Anne Meertz, Chris Probst, Wilhelm Roell, Wolfgang Schiller, Andreas Zimmer, Laura Bindila, Beat Lutz, Armin Welz, and Oliver Dewald Copyright © 2015 Christopher Gestrich et al. All rights reserved. Drift of Scroll Wave Filaments in an Anisotropic Model of the Left Ventricle of the Human Heart Sun, 11 Oct 2015 08:31:37 +0000 Scroll waves are three-dimensional vortices which occur in excitable media. Their formation in the heart results in the onset of cardiac arrhythmias, and the dynamics of their filaments determine the arrhythmia type. Most studies of filament dynamics were performed in domains with simple geometries and generic description of the anisotropy of cardiac tissue. Recently, we developed an analytical model of fibre structure and anatomy of the left ventricle (LV) of the human heart. Here, we perform a systematic study of the dynamics of scroll wave filaments for the cases of positive and negative tension in this anatomical model. We study the various possible shapes of LV and different degree of anisotropy of cardiac tissue. We show that, for positive filament tension, the final position of scroll wave filament is mainly determined by the thickness of the myocardial wall but, however, anisotropy attracts the filament to the LV apex. For negative filament tension, the filament buckles, and for most cases, tends to the apex of the heart with no or slight dependency on the thickness of the LV. We discuss the mechanisms of the observed phenomena and their implications for cardiac arrhythmias. Sergei Pravdin, Hans Dierckx, Vladimir S. Markhasin, and Alexander V. Panfilov Copyright © 2015 Sergei Pravdin et al. All rights reserved. Initial In Vivo Evaluation of a Novel Left Ventricular Assist Device Sun, 11 Oct 2015 08:30:31 +0000 The aim of the study was to use the ovine model to evaluate the hemocompatibility and end-organ effects of a newly developed magnetic suspension centrifugal left ventricular assist device (LVAD) by CH Biomedical Inc., Jiangsu, China. The LVADs were implanted in 6 healthy sheep, where inflow was inserted into the left ventricular apex and outflow was anastomosed to the descending aorta. All sheep received anticoagulation and antiaggregation therapy during the study. Hematologic and biochemical tests were performed to evaluate anemia, hepatorenal function, and the extent of hemolysis. The experiments lasted for up to 30 days on the beating hearts. All sheep were humanely killed at the termination of the experiments, and the end-organs were examined macroscopically and histopathologically. Autopsy was performed in all animals and there was no thrombus formation observed inside the pump. The pump’s inflow and outflow conduits were also free of thrombus. Hematologic and biochemical test results were within normal limits during the study period. Postmortem examination of the explanted organs revealed no evidence of ischemia or infarction. Based on the in vivo study, this LVAD is suitable for implantation and can provide efficient support with good biocompatibility. The encouraging results in this study suggest that it is feasible to evaluate the device’s long-term durability and stability. Guanghui Wu, Changyan Lin, Haiyang Li, Xiaotong Hou, Chen Chen, Xiujian Liu, Chuangye Xu, Jing Wang, Peng Yang, and Wenbo Qu Copyright © 2015 Guanghui Wu et al. All rights reserved. Detection of Differentially Expressed MicroRNAs in Rheumatic Heart Disease: miR-1183 and miR-1299 as Potential Diagnostic Biomarkers Sun, 11 Oct 2015 07:59:46 +0000 This study compared microRNA (miRNA) expression profiles between rheumatic heart disease (RHD) patients and healthy controls to investigate their differential expression and help elucidate their mechanisms of action. Microarray analysis was used to measure miRNA expression, and a total of 133 miRNAs were shown to be significantly upregulated in RHD patients compared with controls, including miR-1183 and miR-1299. A total of 137 miRNAs, including miR-4423-3p and miR-218-1-3p, were significantly downregulated in RHD patients. Quantitative real-time-PCR confirmed microarray findings for miR-1183 and miR-1299 in both tissue and plasma. Bioinformatic predictions were also made of differentially expressed miRNAs as biomarkers in RHD by databases and GO/pathway analysis. Furthermore, we investigated miR-1183 and miR-1299 expression in RHD patients with secondary pulmonary hypertension (PAH). Our findings identified an important role for miR-1299 as a direct regulator of RHD, while the observed difference in expression of miR-1183 between RHD-PAH patients with high or low pulmonary artery pressure suggests that miR-1183 overexpression may reflect pulmonary artery remodeling. miR-1183 and miR-1299 appear to play distinct roles in RHD pathogenesis accompanied by secondary PAH and could be used as potential biological markers for disease development. Ni Li, Jiangfang Lian, Sheng Zhao, Dawei Zheng, Xi Yang, Xiaoyan Huang, Xinbao Shi, Lebo Sun, Qingyun Zhou, Huoshun Shi, Guodong Xu, Enchill KoJo Incoom, Jianqing Zhou, and Guofeng Shao Copyright © 2015 Ni Li et al. All rights reserved. Evolution of Coronary Flow in an Experimental Slow Flow Model in Swines: Angiographic and Pathological Insights Sun, 11 Oct 2015 07:12:14 +0000 Objective. Pathomechanism of coronary slow flow phenomenon remains largely unclear now. Present study observed the pathological and angiographic evolution in a pig model of coronary slow flow. Methods. Coronary slow flow was induced by repeat coronary injection of small doses of 40 µm microspheres in 18 male domestic pigs and angiographic and pathological changes were determined at 3 hours, 7 days, and 28 days after microspheres injection. Results. Compared to control group treated with coronary saline injection and baseline level, coronary flow was significantly reduced at 3 hours and 7 days but completely recovered at 28 days after coronary microsphere injection in slow flow group. Despite normal coronary flow at 28 days after microsphere injection, enhanced myocardial cytokine expression, left ventricular dysfunction, adverse remodelling, and ischemia/microembolism related pathological changes still persisted or even progressed from 3 hours to 28 days after coronary microsphere injection. Conclusions. Our results show that this large animal slow flow model could partly reflect the chronic angiographic, hemodynamic, and pathological changes of coronary slow flow and could be used to test new therapy strategies against the slow flow phenomenon. Yupeng Bai, Liqun Hu, Delong Yu, Sheng Peng, Xiaogang Liu, Mingjing Zhang, and Ye Gu Copyright © 2015 Yupeng Bai et al. All rights reserved. Recent Developments in Minimally Invasive Cardiac Surgery: Evolution or Revolution? Thu, 08 Oct 2015 14:23:28 +0000 Intraluminal aortic clamping has been achieved until now by means of a sophisticated device consisting of a three-lumen catheter named Endoclamp, which allows at the same time occlusion of the aorta, antegrade delivering of cardioplegia, and venting through the aortic root. This tool has shown important advantages allowing aortic occlusion and perfusate delivering without a direct contact with ascending aorta reducing meanwhile the risk of traumatic and/or iatrogenic injuries. Recently, a new device (Intraclude catheter) with the same characteristics and properties has been proposed and introduced in clinical practice. The aim of this paper is to investigate the differences between Endoclamp and Intraclude catheters and to analyze the advantages advocated by this new device for intraluminal aortic occlusion since it is noticeable as these new technological tools are gaining more and more attractiveness due to their appraised clinical efficacy. Antonino G. M. Marullo, Francesco G. Irace, Piergiusto Vitulli, Mariangela Peruzzi, David Rose, Riccardo D’Ascoli, Alessandra Iaccarino, Angelo Pisani, Carlotta De Carlo, Giuseppe Mazzesi, Antonio Barretta, and Ernesto Greco Copyright © 2015 Antonino G. M. Marullo et al. All rights reserved. Role and Function of MicroRNAs in Extracellular Vesicles in Cardiovascular Biology Thu, 08 Oct 2015 07:05:59 +0000 Intercellular communication mediated by extracellular vesicles is crucial for preserving vascular integrity and in the development of cardiovascular disease. Extracellular vesicles consist of apoptotic bodies, microvesicles, and exosomes that can be found in almost every fluid compartment of the body like blood, saliva, and urine. In the recent years, a lot of reports came up suggesting that major cardiovascular and metabolic pathologies like atherogenesis, heart failure, or diabetes are highly influenced by transfer of microRNAs via extracellular vesicles leading to altered protein expression and phenotypes of recipient cells. The following review will summarize the fast developing field of intercellular signaling in cardiovascular biology by microRNA-containing extracellular vesicles. Philipp Pfeifer, Nikos Werner, and Felix Jansen Copyright © 2015 Philipp Pfeifer et al. All rights reserved. Evidential Value That Exercise Improves BMI -Score in Overweight and Obese Children and Adolescents Mon, 05 Oct 2015 11:54:12 +0000 Background. Given the cardiovascular disease (CVD) related importance of understanding the true effects of exercise on adiposity in overweight and obese children and adolescents, this study examined whether there is evidential value to rule out excessive and inappropriate reporting of statistically significant results, a major problem in the published literature, with respect to exercise-induced improvements in BMI -score among overweight and obese children and adolescents. Methods. Using data from a previous meta-analysis of 10 published studies that included 835 overweight and obese children and adolescents, a novel, recently developed approach (-curve) was used to test for evidential value and rule out selective reporting of findings. Chi-squared tests () were used to test for statistical significance with alpha () values <0.05 considered statistically significant. Results. Six of 10 findings (60%) were statistically significant. Statistically significant right-skew to rule out selective reporting was found ( = 38.8, = 0.0001). Conversely, studies neither lacked evidential value ( = 6.8, = 0.87) nor lacked evidential value and were intensely -hacked ( = 4.3, = 0.98). Conclusion. Evidential value results confirm that exercise reduces BMI -score in overweight and obese children and adolescents, an important therapeutic strategy for treating and preventing CVD. George A. Kelley and Kristi S. Kelley Copyright © 2015 George A. Kelley and Kristi S. Kelley. All rights reserved. Are Endothelial Progenitor Cells the Real Solution for Cardiovascular Diseases? Focus on Controversies and Perspectives Mon, 05 Oct 2015 09:42:42 +0000 Advanced knowledge in the field of stem cell biology and their ability to provide a cue for counteracting several diseases are leading numerous researchers to focus their attention on “regenerative medicine” as possible solutions for cardiovascular diseases (CVDs). However, the lack of consistent evidence in this arena has hampered the clinical application. The same condition affects the research on endothelial progenitor cells (EPCs), creating more confusion than comprehension. In this review, this aspect is discussed with particular emphasis. In particular, we describe biology and physiology of EPCs, outline their clinical relevance as both new predictive, diagnostic, and prognostic CVD biomarkers and therapeutic agents, discuss advantages, disadvantages, and conflicting data about their use as possible solutions for vascular impairment and clinical applications, and finally underline a very crucial aspect of EPCs “characterization and definition,” which seems to be the real cause of large heterogeneity existing in literature data on this topic. Carmela R. Balistreri, Silvio Buffa, Calogera Pisano, Domenico Lio, Giovanni Ruvolo, and Giuseppe Mazzesi Copyright © 2015 Carmela R. Balistreri et al. All rights reserved. Biological Niches within Human Calcified Aortic Valves: Towards Understanding of the Pathological Biomineralization Process Mon, 05 Oct 2015 08:33:04 +0000 Despite recent advances, mineralization site, its microarchitecture, and composition in calcific heart valve remain poorly understood. A multiscale investigation, using scanning electron microscopy (SEM), transmission electron microscopy (TEM), and energy dispersive X-ray spectrometry (EDS), from micrometre up to nanometre, was conducted on human severely calcified aortic and mitral valves, to provide new insights into calcification process. Our aim was to evaluate the spatial relationship existing between bioapatite crystals, their local growing microenvironment, and the presence of a hierarchical architecture. Here we detected the presence of bioapatite crystals in two different mineralization sites that suggest the action of two different growth processes: a pathological crystallization process that occurs in biological niches and is ascribed to a purely physicochemical process and a matrix-mediated mineralized process in which the extracellular matrix acts as the template for a site-directed nanocrystals nucleation. Different shapes of bioapatite crystallization were observed at micrometer scale in each microenvironment but at the nanoscale level crystals appear to be made up by the same subunits. Valentina Cottignoli, Michela Relucenti, Giovanna Agrosì, Elena Cavarretta, Giuseppe Familiari, Loris Salvador, and Adriana Maras Copyright © 2015 Valentina Cottignoli et al. All rights reserved. Angiotensinase C mRNA and Protein Downregulations Are Involved in Ethanol-Deteriorated Left Ventricular Systolic Dysfunction in Spontaneously Hypertensive Rats Mon, 05 Oct 2015 08:04:20 +0000 The influences of angiotensinase C on ethanol-induced left ventricular (LV) systolic function were assessed in spontaneously hypertensive rats (SHRs). SHRs were fed by a liquid diet with or without ethanol for 49 days. The normotensive Wistar Kyoto rats (WKY) were fed by the liquid diet without ethanol and used as control. We evaluated LV systolic function, angiotensinase C mRNA and protein expressions, activation of the renin-angiotensin system (RAS), and the gene expressions of LV collagen (Col) III a1 and matrix metalloproteinases- (MMP-) 9. Compared to the WKY, LV systolic dysfunction (expressed by decreased fractional shortening and ejection fraction) was observed in the SHRs before ethanol treatment and further deteriorated by ethanol treatment. In the ethanol-treated SHRs, the following were observed: downregulations of angiotensinase C mRNA and protein, increased RAS activity with low collagen production as evidenced by angiotensin II and angiotensin type 1 receptor (AT1R) protein upregulation, R mRNA downregulation, and an MMP-9 mRNA expression upregulation trend with the downregulation of Col III a1 mRNA expression in LV. We conclude that chronic ethanol regimen is sufficient to promote the enhanced RAS activity-induced decrease in the production of cardiac collagen via downregulated angiotensinase C, leading to the further deterioration of LV systolic dysfunction in SHRs. Jinyao Liu, Ayako Hakucho, and Tatsuya Fujimiya Copyright © 2015 Jinyao Liu et al. All rights reserved. Molecular Characterization of Reactive Oxygen Species in Myocardial Ischemia-Reperfusion Injury Mon, 05 Oct 2015 07:25:14 +0000 Myocardial ischemia-reperfusion (I/R) injury is experienced by individuals suffering from cardiovascular diseases such as coronary heart diseases and subsequently undergoing reperfusion treatments in order to manage the conditions. The occlusion of blood flow to the tissue, termed ischemia, can be especially detrimental to the heart due to its high energy demand. Several cellular alterations have been observed upon the onset of ischemia. The danger created by cardiac ischemia is somewhat paradoxical in that a return of blood to the tissue can result in further damage. Reactive oxygen species (ROS) have been studied intensively to reveal their role in myocardial I/R injury. Under normal conditions, ROS function as a mediator in many cell signaling pathways. However, stressful environments significantly induce the generation of ROS which causes the level to exceed body’s antioxidant defense system. Such altered redox homeostasis is implicated in myocardial I/R injury. Despite the detrimental effects from ROS, low levels of ROS have been shown to exert a protective effect in the ischemic preconditioning. In this review, we will summarize the detrimental role of ROS in myocardial I/R injury, the protective mechanism induced by ROS, and potential treatments for ROS-related myocardial injury. Tingyang Zhou, Chia-Chen Chuang, and Li Zuo Copyright © 2015 Tingyang Zhou et al. All rights reserved. A Review of Computational Methods to Predict the Risk of Rupture of Abdominal Aortic Aneurysms Mon, 05 Oct 2015 07:15:51 +0000 Computational methods have played an important role in health care in recent years, as determining parameters that affect a certain medical condition is not possible in experimental conditions in many cases. Computational fluid dynamics (CFD) methods have been used to accurately determine the nature of blood flow in the cardiovascular and nervous systems and air flow in the respiratory system, thereby giving the surgeon a diagnostic tool to plan treatment accordingly. Machine learning or data mining (MLD) methods are currently used to develop models that learn from retrospective data to make a prediction regarding factors affecting the progression of a disease. These models have also been successful in incorporating factors such as patient history and occupation. MLD models can be used as a predictive tool to determine rupture potential in patients with abdominal aortic aneurysms (AAA) along with CFD-based prediction of parameters like wall shear stress and pressure distributions. A combination of these computer methods can be pivotal in bridging the gap between translational and outcomes research in medicine. This paper reviews the use of computational methods in the diagnosis and treatment of AAA. Tejas Canchi, S. D. Kumar, E. Y. K. Ng, and Sriram Narayanan Copyright © 2015 Tejas Canchi et al. All rights reserved. The Power of Phase I Studies to Detect Clinical Relevant QTc Prolongation: A Resampling Simulation Study Mon, 05 Oct 2015 07:01:34 +0000 Concentration-effect (CE) models applied to early clinical QT data from healthy subjects are described in the latest E14 Q&A document as promising analysis to characterise QTc prolongation. The challenges faced if one attempts to replace a TQT study by thorough ECG assessments in Phase I based on CE models are the assurance to obtain sufficient power and the establishment of a substitute for the positive control to show assay sensitivity providing protection against false negatives. To demonstrate that CE models in small studies can reliably predict the absence of an effect on QTc, we investigated the role of some key design features in the power of the analysis. Specifically, the form of the CE model, inclusion of subjects on placebo, and sparse sampling on the performance and power of this analysis were investigated. In this study, the simulations conducted by subsampling subjects from 3 different TQT studies showed that CE model with a treatment effect can be used to exclude small QTc effects. The number of placebo subjects was also shown to increase the power to detect an inactive drug preventing false positives while an effect can be underestimated if time points around are missed. Georg Ferber, Ulrike Lorch, and Jörg Täubel Copyright © 2015 Georg Ferber et al. All rights reserved. Two-Step Pseudomaximum Amplitude-Based Confidence Interval Estimation for Oscillometric Blood Pressure Measurements Sun, 04 Oct 2015 14:02:33 +0000 Blood pressure (BP) is an important vital sign to determine the health of an individual. Although the estimation of average arterial blood pressure using oscillometric methods is possible, there are no established methods for obtaining confidence intervals (CIs) for systolic blood pressure (SBP) and diastolic blood pressure (DBP). In this paper, we propose a two-step pseudomaximum amplitude (TSPMA) as a novel approach to obtain improved CIs of SBP and DBP using a double bootstrap approach. The weighted median (WM) filter is employed to reduce impulsive and Gaussian noises in the step of preprocessing. Application of the proposed method provides tighter CIs and smaller standard deviation of CIs than the pseudomaximum amplitude-envelope and maximum amplitude algorithms with Student’s -method. Soojeong Lee, Gwanggil Jeon, and Seokhoon Kang Copyright © 2015 Soojeong Lee et al. All rights reserved. MicroRNAs Based Therapy of Hypertrophic Cardiomyopathy: The Road Traveled So Far Sun, 04 Oct 2015 14:02:11 +0000 Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disease characterized by variable expressivity, age penetrance, and a high heterogeneity. The transcriptional profile (miRNAs, mRNAs), epigenetic modifications, and posttranslational modifications seem to be highly relevant for the onset of the disease. miRNAs, small noncoding RNAs with 22 nucleotides, have been implicated in the regulation of cardiomyocyte function, being differentially expressed in several heart diseases, including HCM. Moreover, a different miRNA expression profile in the various stages of HCM development is also observed. This review summarizes the current knowledge of the profile of miRNAs characteristic of asymptomatic to overt HCM patients, discussing alongside their potential use for diagnosis and therapy. Indeed, the stability and specificity of miRNAs make them suitable targets for use as biomarkers for diagnosis and prognosis and as therapeutical targets. Catarina Roma-Rodrigues, Luís R. Raposo, and Alexandra R. Fernandes Copyright © 2015 Catarina Roma-Rodrigues et al. All rights reserved. Hypoglycaemia, Abnormal Lipids, and Cardiovascular Disease among Chinese with Type 2 Diabetes Sun, 04 Oct 2015 13:58:07 +0000 We recruited a group of 6713 consecutive Chinese patients with T2D but normal renal and liver function who were admitted to one of 81 top tertiary care hospitals in China. Mild hypoglycaemia was defined as having symptomatic hypoglycaemia in one month before hospitalization. Severe hypoglycaemia was defined as having hypoglycaemia that needed assistance from other people in three months before hospitalization. Prior cardiovascular disease (CVD) was defined as having coronary heart disease, stroke, or peripheral arterial disease. Of 6713 patients, 80 and 304 had severe and mild hypoglycaemia episodes, respectively, and 561 had CVD. Patients with severe and mild hypoglycaemia episodes were more likely to have prior CVD (32.5% versus 16.5% versus 7.7%, ). Both mild and severe hypoglycaemia were associated with increased risk of CVD (adjusted odds ratios (ORs): 2.64, 95% CI: 1.85–3.76 for mild hypoglycaemia; 6.59, 95% CI: 3.79–11.45 for sever hypoglycaemia) than those patients free of hypoglycaemia. Further adjustment for lipid profile did not change these two ORs. In the same way, the ORs of lipid profile for CVD were similar before and after adjustment for hypoglycaemia. We concluded that hypoglycaemia and lipid profile were independently associated with increased risk of CVD. Yijun Li, Yiming Mu, Qiuhe Ji, Qin Huang, Hongyu Kuang, Linong Ji, and Xilin Yang Copyright © 2015 Yijun Li et al. All rights reserved. Resting Heart Rate and Auditory Evoked Potential Sun, 04 Oct 2015 13:56:01 +0000 The objective of this study was to evaluate the association between rest heart rate (HR) and the components of the auditory evoked-related potentials (ERPs) at rest in women. We investigated 21 healthy female university students between 18 and 24 years old. We performed complete audiological evaluation and measurement of heart rate for 10 minutes at rest (heart rate monitor Polar RS800CX) and performed ERPs analysis (discrepancy in frequency and duration). There was a moderate negative correlation of the N1 and P3a with rest HR and a strong positive correlation of the P2 and N2 components with rest HR. Larger components of the ERP are associated with higher rest HR. Simone Fiuza Regaçone, Daiane Damaris Baptista de Lima, Vitor Engrácia Valenti, and Ana Cláudia Figueiredo Frizzo Copyright © 2015 Simone Fiuza Regaçone et al. All rights reserved. Renin-Angiotensin Activation and Oxidative Stress in Early Heart Failure with Preserved Ejection Fraction Sun, 04 Oct 2015 13:47:38 +0000 Animal models have suggested a role of renin-angiotensin system (RAS) activation and subsequent cardiac oxidation in heart failure with preserved ejection fraction (HFpEF). Nevertheless, RAS blockade has failed to show efficacy in treatment of HFpEF. We evaluated the role of RAS activation and subsequent systemic oxidation in HFpEF. Oxidative stress markers were compared in 50 subjects with and without early HFpEF. Derivatives of reactive oxidative metabolites (DROMs), F2-isoprostanes (IsoPs), and ratios of oxidized to reduced glutathione ( GSH) and cysteine ( CyS) were measured. Angiotensin converting enzyme (ACE) levels and activity were measured. On univariate analysis, HFpEF was associated with male sex , higher body mass index (BMI) , less oxidized CyS , lower DROMs , and lower IsoP . Higher BMI (OR: 1.3; 95% CI: 1.1–1.6) and less oxidized CyS (OR: 1.2; 95% CI: 1.1–1.4) maintained associations with HFpEF on multivariate analysis. Though ACE levels were higher in early HFpEF (OR: 1.09; 95% CI: 1.01–1.05), ACE activity was similar to that in controls. HFpEF is not associated with significant systemic RAS activation or oxidative stress. This may explain the failure of RAS inhibitors to alter outcomes in HFpEF. Smita I. Negi, Euy-Myoung Jeong, Irfan Shukrullah, Emir Veleder, Dean P. Jones, Tai-Hwang M. Fan, Sudhahar Varadarajan, Sergei M. Danilov, Tohru Fukai, and Samuel C. Dudley Jr. Copyright © 2015 Smita I. Negi et al. All rights reserved. Is Lipoprotein-Associated Phospholipase A2 a Link between Inflammation and Subclinical Atherosclerosis in Rheumatoid Arthritis? Sun, 04 Oct 2015 13:36:59 +0000 Objective. Lipoprotein-associated phospholipase A2 (Lp-PLA2), a marker of vascular inflammation, is associated with cardiovascular disease. This prospective study of an inception cohort aimed to investigate whether the level of Lp-PLA2 is associated with subclinical atherosclerosis in patients with rheumatoid arthritis (RA). Methods. Patients from northern Sweden diagnosed with early RA were consecutively recruited into an ongoing prospective study. From these, all patients ≤60 years () were included for measurements of subclinical atherosclerosis at inclusion (T0) and five years later (T5). Forty age- and sex-matched controls were included. The patients were clinically assessed, SCORE, Reynolds Risk Score, and Larsen score were calculated, and blood samples were drawn from all individuals at T0 and T5. Results. There was no significant difference in the level of Lp-PLA2 between patients with RA and controls (). In simple linear regression models among patients with RA, Lp-PLA2 at T0 was significantly associated with intima media thickness (IMT) at T0 and T5, flow mediated dilation (FMD) at T0 and T5, ever smoking, male sex, HDL-cholesterol (inversely), non-HDL-cholesterol, SCORE, Reynolds Risk Score, and Larsen score (). Conclusion. In this cohort of patients with early RA, the concentration of Lp-PLA2 was associated with both subclinical atherosclerosis and disease severity. Anna Södergren, Kjell Karp, Christine Bengtsson, Bozena Möller, Solbritt Rantapää-Dahlqvist, and Solveig Wållberg-Jonsson Copyright © 2015 Anna Södergren et al. All rights reserved. Neonatal Death and Heart Failure in Mouse with Transgenic HSP60 Expression Sun, 04 Oct 2015 13:02:07 +0000 Mitochondrial heat shock proteins, such as HSP60, are chaperones responsible for the folding, transport, and quality control of mitochondrial matrix proteins and are essential for maintaining life. Both prosurvival and proapoptotic roles have been proposed for HSP60, and HSP60 is reportedly involved in the initiation of autoimmune, metabolic, and cardiovascular diseases. The role of HSP60 in pathogenesis of these diseases remains unclear, partly because of the lack of mouse models expressing HSP60. In this study we generated HSP60 conditional transgenic mice suitable for investigating in vivo outcomes by expressing HSP60 at the targeted organ in disease models. Ubiquitous HSP60 induction in the embryonic stage caused neonatal death in mice at postnatal day 1. A high incidence of atrial septal defects was observed in HSP60-expressing mice, with increased apoptosis and myocyte degeneration that possibly contributed to massive hemorrhage and sponge-like cardiac muscles. Our results showed that neonatal heart failure through HSP60 induction likely involves developmental defects and excessive apoptosis. The conditional HSP60 mouse model is useful for studying crucial biological questions concerning HSP60. Tsung-Hsien Chen, Shan-Wen Liu, Mei-Ru Chen, Kuan-Hung Cho, Tzu-Yin Chen, Pao-Hsien Chu, Yu-Ying Kao, Ching-Han Hsu, and Kurt Ming-Chao Lin Copyright © 2015 Tsung-Hsien Chen et al. All rights reserved. Protective Effects of Cilastatin against Vancomycin-Induced Nephrotoxicity Sun, 04 Oct 2015 12:57:26 +0000 Vancomycin is a very effective antibiotic for treatment of severe infections. However, its use in clinical practice is limited by nephrotoxicity. Cilastatin is a dehydropeptidase I inhibitor that acts on the brush border membrane of the proximal tubule to prevent accumulation of imipenem and toxicity. The aim of this study was to investigate the potential protective effect of cilastatin on vancomycin-induced apoptosis and toxicity in cultured renal proximal tubular epithelial cells (RPTECs). Porcine RPTECs were cultured in the presence of vancomycin with and without cilastatin. Vancomycin induced dose-dependent apoptosis in cultured RPTECs, with DNA fragmentation, cell detachment, and a significant decrease in mitochondrial activity. Cilastatin prevented apoptotic events and diminished the antiproliferative effect and severe morphological changes induced by vancomycin. Cilastatin also improved the long-term recovery and survival of RPTECs exposed to vancomycin and partially attenuated vancomycin uptake by RPTECs. On the other hand, cilastatin had no effects on vancomycin-induced necrosis or the bactericidal effect of the antibiotic. This study indicates that cilastatin protects against vancomycin-induced proximal tubule apoptosis and increases cell viability, without compromising the antimicrobial effect of vancomycin. The beneficial effect could be attributed, at least in part, to decreased accumulation of vancomycin in RPTECs. Blanca Humanes, Juan Carlos Jado, Sonia Camaño, Virginia López-Parra, Ana María Torres, Luís Antonio Álvarez-Sala, Emilia Cercenado, Alberto Tejedor, and Alberto Lázaro Copyright © 2015 Blanca Humanes et al. All rights reserved. Osteoprotegerin and TRAIL in Acute Onset of Atrial Fibrillation Sun, 04 Oct 2015 12:48:44 +0000 Background. There is a growing amount of evidence that inflammatory processes are involved in the development of atrial fibrillation (AF) and its complications. We decided to investigate the behavior of osteoprotegerin (OPG) and TNF-related apoptosis inducing ligand (TRAIL) in terms of acute onset of AF. Methods and Results. We included 60 patients with acute onset of AF, candidates for pharmacological cardioversion. The presence of cardiovascular comorbidities was connected with higher concentration of OPG and lower level of TRAIL right from the first hours of AF paroxysm. The initial TRAIL level correlated also positively with left ventricle ejection fraction and negatively with left atrium diameter. We found subsequent increase of OPG in subgroups selected on the basis of CHA2DS2-VASc scoring. Although basal concentrations of studied markers did not allow prediction of the restoration of sinus rhythm, we observed important increase of TRAIL concentration in subgroup with sinus rhythm maintenance (94.11 ± 29.46 versus 111.39 ± 30.23 pg/mL; ). Conclusions. OPG and TRAIL are associated with the underlying cardiovascular damage in AF, but their balance is modulated by the fact of sinus rhythm restoration. Determining the suitability of OPG and TRAIL as predictive markers in AF requires further prospective studies. Krzysztof Rewiuk and Tomasz Grodzicki Copyright © 2015 Krzysztof Rewiuk and Tomasz Grodzicki. All rights reserved. Short-Term Effects of Verapamil and Diltiazem in the Treatment of No Reflow Phenomenon: A Meta-Analysis of Randomized Controlled Trials Sun, 04 Oct 2015 12:27:41 +0000 Currently, there is still a lack of an optimal treatment for no reflow phenomenon (NRP). We analyzed the efficacy and safety of using nondihydropyridine calcium channel antagonists (NDHP, verapamil/diltiazem) in patients suffering from NRP. Eight RCTs with 494 participants were eligible for analysis. The pooling analysis showed that intracoronary verapamil/diltiazem injection significantly decreased the occurrence of the coronary NRP (RR: 0.3, 95% CI: 0.16–0.57; ) and reduced corrected thrombolysis in myocardial infarction (TIMI) frame Count (WMD = −9.24, 95% CI −13.91–4.57; ) in patients with NRP. Moreover, verapamil/diltiazem treatment showed superiority in reducing wall motion index (WMI) compared to the control at day 1 (WMD = 0.11, 95% CI: 0.02–0.20; ) (). There was also a significantly greater decline at occurrence of the major adverse cardiac events between verapamil/diltiazem and control groups (WMD: 0.4, 95% CI: 0.19–0.84; ). However, using verapamil/diltiazem did not provide additional improvement of left ventricular ejection fraction post procedure (at 7 days, WMD, 0.1; 95% CI, −2.43–2.63; ; at 30 days, WMD, 0.42; 95% CI, −2.09–2.92; ). NDHP use is beneficial in attenuating NRP and reducing 6-month MACEs in patients with NRP. Lan Wang, Zhong Cheng, Ye Gu, and Dingfeng Peng Copyright © 2015 Lan Wang et al. All rights reserved. Monitoring Microcirculatory Blood Flow with a New Sublingual Tonometer in a Porcine Model of Hemorrhagic Shock Sun, 04 Oct 2015 11:48:51 +0000 Tissue capnometry may be suitable for the indirect evaluation of regional hypoperfusion. We tested the performance of a new sublingual capillary tonometer in experimental hemorrhage. Thirty-six anesthetized, ventilated mini pigs were divided into sham-operated () and shock groups (). Hemorrhagic shock was induced by reducing mean arterial pressure (MAP) to 40 mmHg for 60 min, after which fluid resuscitation started aiming to increase MAP to 75% of the baseline value (60–180 min). Sublingual carbon-dioxide partial pressure was measured by tonometry, using a specially coiled silicone rubber tube. Mucosal red blood cell velocity (RBCV) and capillary perfusion rate (CPR) were assessed by orthogonal polarization spectral (OPS) imaging. In the 60 min shock phase a significant drop in cardiac index was accompanied by reduction in sublingual RBCV and CPR and significant increase in the sublingual mucosal-to-arterial PCO2 gap ( gap), which significantly improved during the 120 min resuscitation phase. There was significant correlation between gap and sublingual RBCV (, ), CPR (, ), central venous oxygen saturation (, ), and central venous-to-arterial PCO2 difference (, ). This new sublingual tonometer may be an appropriate tool for the indirect evaluation of circulatory changes in shock. Péter Palágyi, József Kaszaki, Andrea Rostás, Dániel Érces, Márton Németh, Mihály Boros, and Zsolt Molnár Copyright © 2015 Péter Palágyi et al. All rights reserved. The Impact of Thrombocytopenia on Outcome in Patients with Acute Coronary Syndromes: A Single Center Retrospective Study Sun, 04 Oct 2015 10:32:00 +0000 Background. In acute coronary syndromes (ACS), treated by combined antithrombotic therapy and percutaneous coronary interventions (PCI), thrombocytopenia may occur. Our aim was to evaluate predictors and the impact of thrombocytopenia on mortality in high-risk ACS patients. Methods. We retrospectively evaluated high-risk ACS patients. Thrombocytopenia was defined as platelet count <140.000/mL or a drop in platelet count of >50% during in-hospital stay. We compared demographic, laboratory, clinical, and mortality data between nonthrombocytopenic and thrombocytopenic ACS patients and evaluated independent predictors of thrombocytopenia. Results. In 371 ACS patients, thrombocytopenia was observed in 21.3%. Thrombocytopenic patients were significantly older and, less likely treated by PCIs (72.1% versus 89.7%, ) and combined antithrombotic therapy, with increased incidence of in-hospital complications and the use of additional treatments, but with increased mortality at 30 days (27.8% versus 10.2%, ) and 6 months (35.4% versus 13.6%, ) when compared to nonthrombocytopenic patients. The use of antibiotics, transfusions, insertion of intra-aortic balloon pump (IABP), and prior stroke independently predicted thrombocytopenia. Conclusions. Thrombocytopenia, observed in about 20% of high-risk ACS patients, was associated significantly with in-hospital complications and mortality. Predictors of thrombocytopenia were the use of antibiotics, transfusions, insertion of IABP, and prior stroke. Andreja Sinkovič and Maja Majal Copyright © 2015 Andreja Sinkovič and Maja Majal. All rights reserved. Space-Time Analysis to Identify Areas at Risk of Mortality from Cardiovascular Disease Sun, 04 Oct 2015 09:21:37 +0000 This study aimed at identifying areas that were at risk of mortality due to cardiovascular disease in residents aged 45 years or older of the cities of Cuiabá and Várzea Grande between 2009 and 2011. We conducted an ecological study of mortality rates related to cardiovascular disease. Mortality rates were calculated for each census tract by the Local Empirical Bayes estimator. High- and low-risk clusters were identified by retrospective space-time scans for each year using the Poisson probability model. We defined the year and month as the temporal analysis unit and the census tracts as the spatial analysis units adjusted by age and sex. The Mann-Whitney test was used to compare the socioeconomic and environmental variables by risk classification. High-risk clusters showed higher income ratios than low-risk clusters, as did temperature range and atmospheric particulate matter. Low-risk clusters showed higher humidity than high-risk clusters. The Eastern region of Várzea Grande and the central region of Cuiabá were identified as areas at risk of mortality due to cardiovascular disease in individuals aged 45 years or older. High mortality risk was associated with socioeconomic and environmental factors. More high-risk clusters were observed at the end of the dry season. Poliany C. O. Rodrigues, Emerson S. Santos, Eliane Ignotti, and Sandra S. Hacon Copyright © 2015 Poliany C. O. Rodrigues et al. All rights reserved. Phytochemical Compounds and Protection from Cardiovascular Diseases: A State of the Art Sun, 04 Oct 2015 09:11:43 +0000 Cardiovascular diseases represent a worldwide relevant socioeconomical problem. Cardiovascular disease prevention relies also on lifestyle changes, including dietary habits. The cardioprotective effects of several foods and dietary supplements in both animal models and in humans have been explored. It was found that beneficial effects are mainly dependent on antioxidant and anti-inflammatory properties, also involving modulation of mitochondrial function. Resveratrol is one of the most studied phytochemical compounds and it is provided with several benefits in cardiovascular diseases as well as in other pathological conditions (such as cancer). Other relevant compounds are Brassica oleracea, curcumin, and berberine, and they all exert beneficial effects in several diseases. In the attempt to provide a comprehensive reference tool for both researchers and clinicians, we summarized in the present paper the existing literature on both preclinical and clinical cardioprotective effects of each mentioned phytochemical. We structured the discussion of each compound by analyzing, first, its cellular molecular targets of action, subsequently focusing on results from applications in both ex vivo and in vivo models, finally discussing the relevance of the compound in the context of human diseases. Beniamino Pagliaro, Caterina Santolamazza, Francesca Simonelli, and Speranza Rubattu Copyright © 2015 Beniamino Pagliaro et al. All rights reserved. Pressure Overload by Transverse Aortic Constriction Induces Maladaptive Hypertrophy in a Titin-Truncated Mouse Model Sun, 04 Oct 2015 09:09:12 +0000 Mutations in the giant sarcomeric protein titin (TTN) are a major cause for inherited forms of dilated cardiomyopathy (DCM). We have previously developed a mouse model that imitates a TTN truncation mutation we found in a large pedigree with DCM. While heterozygous Ttn knock-in mice do not display signs of heart failure under sedentary conditions, they recapitulate the human phenotype when exposed to the pharmacological stressor angiotensin II or isoproterenol. In this study we investigated the effects of pressure overload by transverse aortic constriction (TAC) in heterozygous (Het) Ttn knock-in mice. Two weeks after TAC, Het mice developed marked impairment of left ventricular ejection fraction , while wild-type (WT) TAC mice did not. Het mice also trended toward increased ventricular end diastolic pressure and volume compared to WT littermates. We found an increase in histologically diffuse cardiac fibrosis in Het compared to WT in TAC mice. This study shows that a pattern of DCM can be induced by TAC-mediated pressure overload in a TTN-truncated mouse model. This model enlarges our arsenal of cardiac disease models, adding a valuable tool to understand cardiac pathophysiological remodeling processes and to develop therapeutic approaches to combat heart failure. Qifeng Zhou, Scott Kesteven, Jianxin Wu, Parwez Aidery, Meinrad Gawaz, Michael Gramlich, Michael P. Feneley, and Richard P. Harvey Copyright © 2015 Qifeng Zhou et al. All rights reserved. Comparative Analysis of Methods to Induce Myocardial Infarction in a Closed-Chest Rabbit Model Sun, 04 Oct 2015 09:08:53 +0000 Objective. To develop a rabbit model of closed-chest catheter-induced myocardial infarction. Background. Limitations of rodent and large animal models justify the search for clinically relevant alternatives. Methods. Microcatheterization of the heart was performed in 47 anesthetized 3-4 kg New Zealand rabbits to test five techniques of myocardial ischemia: free coils (), interlocking coils (), thrombogenic gelatin sponge (), balloon occlusion (), and alcohol injection (). In order to limit ventricular fibrillation, an antiarrhythmic protocol was implemented, with beta-blockers/amiodarone before and xylocaine infusion during the procedure. Clinical, angiographic, and echographic data were gathered. End points included demonstration of vessel occlusion (TIMI flow grades 0 and 1 on the angiogram), impairment of left ventricular function at 2 weeks after procedure (by echocardiography), and pathologically confirmed myocardial infarction. Results. The best arterial access was determined to be through the right carotid artery. The internal mammary guiding catheter 4-Fr was selected as the optimal device for selective intracoronary injection. Free coils deployed prematurely and tended to prolapse into the aorta. Interlocking coils did not deploy completely and failed to provide reliable results. Gelatin sponge was difficult to handle, adhered to the catheter, and could not be clearly visualized by fluoroscopy. Balloon occlusion yielded inconsistent results. Alcohol injection was the most efficient and reproducible method for inducing myocardial infarction (4 out of 6 animals), the extent of which could be fine-tuned by using a coaxial balloon catheter as a microcatheter (0.52 mm) to achieve a superselective injection of 0.2 mL of alcohol. This approach resulted in a 20% decrease in LVEF and infarcted myocardium was confirmed histologically. Conclusions. By following a stepwise approach, a minimally invasive, effective, and reproducible rabbit model of catheter-induced myocardial infarction has been developed which addresses the limitations of rodent experiments while avoiding the logistical and cost issues associated with large animal models. Marc-Antoine Isorni, Amaury Casanova, Julie Piquet, Valérie Bellamy, Charly Pignon, Etienne Puymirat, and Philippe Menasche Copyright © 2015 Marc-Antoine Isorni et al. All rights reserved. Vascular Damage in Resistant Hypertension: TNF-Alpha Inhibition Effects on Endothelial Cells Sun, 04 Oct 2015 09:08:30 +0000 Inflammatory cytokines have been associated with the pathophysiology of hypertension and target organ damage (TOD). Resistant hypertensive patients (RHTN) are characterized by poor blood pressure control and higher prevalence of TOD. This study evaluated the relationship between plasma levels of TNF-α and arterial stiffness (pulse wave velocity—PWV) in 32 RHTN and 19 normotensive subjects. Moreover, we investigated the effect of TNF-α inhibition on human endothelial cells (HUVECs) incubated with serum from RHTN and normotensive subjects. HUVECs containing serum obtained from normotensive and hypertensive individuals were treated with TNF-α inhibitor (infliximab). Cell suspensions were used for measurement of DNA fragmentation and reactive oxygen species (ROS) content. RHTN patients showed higher levels of TNF-α compared to normotensive subjects, as well as higher PWV. Positive correlation was found between TNF-α levels and PWV measures in the whole group. HUVECs incubated with serum from RHTN showed increased cell apoptosis and higher ROS content compared to normotensive subjects. Infliximab attenuated the apoptosis of HUVECs incubated with serum from RHTN, but no effect in ROS production was observed. Our findings suggest that TNF-α might mediate, at least in part, vascular damage in resistant hypertension. Natália Ruggeri Barbaro, Thiago Matos de Araújo, José Eduardo Tanus-Santos, Gabriel Forato Anhê, Vanessa Fontana, and Heitor Moreno Copyright © 2015 Natália Ruggeri Barbaro et al. All rights reserved. Presence of Periodontopathic Bacteria DNA in Atheromatous Plaques from Coronary and Carotid Arteries Sun, 04 Oct 2015 09:07:23 +0000 Objectives. Interest in periodontitis as a potential risk factor for atherosclerosis and its complications resulted from the fact that the global prevalence of periodontal diseases is significant and periodontitis may induce a chronic inflammatory response. Many studies have analyzed the potential impact of the Porphyromonas gingivalis, major pathogen of periodontitis, on general health. The purpose of this study was to find the presence of the Porphyromonas gingivalis DNA in the atherosclerotic plaques of coronary and carotid arteries and in the periodontal pockets in patients with chronic periodontitis, who underwent surgery because of vascular diseases. Methods and Results. The study population consisted of 91 patients with coronary artery disease or scheduled for carotid endarterectomy. The presence of Porphyromonas gingivalis DNA in atheromatous plaques and in subgingival samples was determined by PCR. Bacterial DNA was found in 21 of 91 (23%) samples taken from vessels and in 47 of 63 (74.6%) samples from periodontal pockets. Conclusions. Porphyromonas gingivalis DNA is frequently found in atheromatous plaques of patients with periodontitis. That is why more research should be conducted to prove if this periopathogen may have an impact on endothelium of patients at risk of atherosclerosis. Malgorzata Szulc, Wojciech Kustrzycki, Dariusz Janczak, Dagmara Michalowska, Dagmara Baczynska, and Malgorzata Radwan-Oczko Copyright © 2015 Malgorzata Szulc et al. All rights reserved. Beyond the Limits: Clinical Utility of Novel Cardiac Biomarkers Sun, 04 Oct 2015 09:05:14 +0000 Preoperative assessment of cardiovascular risk is essential when it comes to extensive noncardiac surgery procedures. Therefore, accurate and timely diagnosis of myocyte damage is vital. In modern medical practice it is believed that the so-called “multimarker” approach is the most appropriate and most accurate, but new research points out that there are novel biomarkers which could be used independently. Studies that evaluate miRNA, H-FABP, and MR-PAMP give encouraging results. When it comes to miRNA clinical studies show high statistical significance, especially in the case of acute myocardial infarction (). Statistical significance of was found in acute coronary syndrome, when H-FABP was measured. Biochemical marker MR-PAMP showed statistical significance of in most clinical studies. Radmilo Janković, Danica Marković, Nenad Savić, and Vesna Dinić Copyright © 2015 Radmilo Janković et al. All rights reserved. Novel Model of Pulmonary Artery Banding Leading to Right Heart Failure in Rats Sun, 04 Oct 2015 08:59:23 +0000 Background. Congenital heart diseases often involve chronic pressure overload of the right ventricle (RV) which is a major cause of RV dysfunction. Pulmonary artery (PA) banding has been used to produce animal models of RV dysfunction. We have devised a new and easier method of constricting the PA and compared it directly with the partial ligation method. Methods. Eight-week-old male Sprague-Dawley rats (240–260 g) were divided into three groups: sham operation, partial pulmonary artery ligation (PAL) procedure, and pulmonary artery half-closed clip (PAC) procedure. RV function and remodeling were determined by echocardiography and histomorphometry. Results. Surgical mortality was significantly lower in the PAC group while echocardiography revealed significantly more signs of RV dysfunction. At the 8th week after surgery RV fibrosis rate was significantly higher in the PAC group. Conclusions. This procedure of pulmonary artery banding in rats is easier and more efficient than partial ligation. Masataka Hirata, Daiki Ousaka, Sadahiko Arai, Michihiro Okuyama, Suguru Tarui, Junko Kobayashi, Shingo Kasahara, and Shunji Sano Copyright © 2015 Masataka Hirata et al. All rights reserved. Prevalence, Risk Factors, and Genetic Traits in Metabolically Healthy and Unhealthy Obese Individuals Sun, 04 Oct 2015 06:49:17 +0000 Objective. To assess prevalence of metabolically healthy individuals among patients with abdominal obesity (AO) and to determine phenotype and potential genetic traits associated with a benign metabolic status. Methods. 503 AO patients without cardiovascular diseases were examined. Waist circumference (WC), BMI, blood pressure, plasma glucose and serum insulin levels, HOMA-IR, lipid profile, and adiponectin (AN) and leptin (LEP) concentrations in serum were measured. Polymorphisms A19G and Q223R of the LEP and LEP receptor gene, and G276T and T45G of the AN gene were investigated. Results. 91.3% of patients were metabolically unhealthy obese (MUO), and 8.7% metabolically healthy obese (MHO). MHO patients were younger, and had lesser BMI and WC, while duration of obesity, frequency, and duration of physical training were greater than MUO patients . In MHO and MUO patients distribution of the G19G, G19A, and A19A genotypes of the LEP gene and G276G, G276T, and T276T genotypes of AN gene did not differ. The Т45Т genotype was associated with increase of metabolic disorders’ risk for patients with АО (OR = 2.331; 95%  ). Conclusions. Prevalence of MHO individuals among patients with AO is low. Benign metabolic status was associated with younger age, lower waist circumference, and higher physical activity, shorter duration of obesity, and G45G adiponectin genotype carriage. A. Berezina, O. Belyaeva, O. Berkovich, E. Baranova, T. Karonova, E. Bazhenova, D. Brovin, E. Grineva, and E. Shlyakhto Copyright © 2015 A. Berezina et al. All rights reserved. Characteristics and Outcomes of Patients with Acute Myocardial Infarction at Non-PCI Capable Hospitals in 2007 and in 2014 Sun, 04 Oct 2015 06:47:48 +0000 Background. There is little known about whether characteristics and outcomes of patients with acute myocardial infarction (AMI) have changed over the years in non-PCI capable hospitals in real-life. Our aim was to assess them between 2007 and 2014. Methods. It was a retrospective cohort study. Characteristics and in-hospital mortality (standardized in cases of different characteristics between the groups by original simple method) were assessed for all patients with non-ST elevation myocardial infarction (NSTEMI) and ST elevation myocardial infarction (STEMI) at two non-PCI capable hospitals: one in 2007 () and another in 2014 (). Results. In 2014, females were older than in 2007 (80.18 ± 7.54 versus 76.15 ± 8.77, ), males were younger (71.61 ± 11.22 versus 79.20 ± 7.63, ), less had renal failure (RF) (19% versus 34.6%, ) and reinfarction (13.8% versus 35.6%, ), and the proportion of males (31% versus 43.3%, ) and the proportion of NSTEMI (60.3 versus 69.2, ) decreased. In cases of STEMI there were no differences in patient characteristics. STEMI (18.8% versus 21.7%) and standardized mortalities by gender, RF, and reinfarction NSTEMI (19.47%, 15.34%, and 17.5%, resp., versus 17.1%) showed no differences between 2007 and 2014. Conclusions. There were some differences in patient characteristics but not in mortality for AMI at non-PCI capable hospitals between 2007 and 2014. Egle Kalinauskiene, Dalia Gerviene, Inga Sabeckyte, and Albinas Naudziunas Copyright © 2015 Egle Kalinauskiene et al. All rights reserved. True Unipolar ECG Machine for Wilson Central Terminal Measurements Thu, 01 Oct 2015 13:07:20 +0000 Since its invention (more than 80 years ago), modern electrocardiography has employed a supposedly stable voltage reference (with little variation during the cardiac cycle) for half of the signals. This reference, known by the name of “Wilson Central Terminal” in honor of its inventor, is obtained by averaging the three active limb electrode voltages measured with respect to the return ground electrode. However, concerns have been raised by researchers about problems (biasing and misdiagnosis) associated with the ambiguous value and behavior of this reference voltage, which requires perfect and balanced contact of at least four electrodes to work properly. The Wilson Central Terminal has received scant research attention in the last few decades even though consideration of recent widespread medical practice (limb electrodes are repositioned closer to the torso for resting electrocardiography) has also sparkled concerns about the validity and diagnostic fitness of leads not referred to the Wilson Central Terminal. Using a true unipolar electrocardiography device capable of precisely measuring the Wilson Central Terminal, we show its unpredictable variability during the cardiac cycle and confirm that the integrity of cardinal leads is compromised as well as the Wilson Central Terminal when limb electrodes are placed close to the torso. Gaetano D. Gargiulo Copyright © 2015 Gaetano D. Gargiulo. All rights reserved. An Update on Renal Artery Denervation and Its Clinical Impact on Hypertensive Disease Thu, 01 Oct 2015 10:04:21 +0000 Hypertension is a globally prevalent condition, with a heavy clinical and economic burden. It is the predominant risk factor for premature cardiovascular and cerebrovascular disease, and is associated with a variety of clinical disorders including stroke, congestive cardiac failure, ischaemic heart disease, chronic renal failure, and peripheral arterial disease. A significant subset of hypertensive patients have resistant hypertensive disease. In this group of patients, catheter-based renal artery denervation has emerged as a potential therapy, with favourable clinical efficacy and safety in early trials. Additional benefits of this therapy are also being identified and include effects on left ventricular remodeling, cardiac performance, and symptom status in congestive cardiac failure. Utility of renal denervation for the management of resistant hypertension, however, has become controversial since the release of the Symplicity HTN-3 trial, the first large-scale blinded randomised study investigating the efficacy and safety of renal artery denervation. The aim of this paper is to evaluate the history, utility, and clinical efficacy of renal artery denervation technology, including an in-depth appraisal of the current literature and principal trials. Aditya Bhat, Ye Min Kuang, Gary C. H. Gan, David Burgess, and Alan Robert Denniss Copyright © 2015 Aditya Bhat et al. All rights reserved. Dissemination of Health-Related Research among Scientists in Three Countries: Access to Resources and Current Practices Thu, 01 Oct 2015 08:56:23 +0000 Objectives. In public health and clinical settings insufficient dissemination of evidence-based practices limits the reach of new discoveries to broad populations. This study aimed to describe characteristics of the dissemination process by researchers across three countries (Brazil, United Kingdom, and United States), explore how designing for dissemination practices has been used, and analyze factors associated with dissemination. Methods. A similar online survey was used to query researchers across the three countries; data were pooled to draw cross-country conclusions. Findings. This study identified similarities and differences between countries. Importance of dissemination to nonresearcher audiences was widely recognized as important; however, traditional academic venues were the main dissemination method. Several factors were associated with self-rated dissemination effort in the pooled sample, but these predictive factors (e.g., support and resources for dissemination) had low prevalence. Less than one-third of researchers rated their level of effort for dissemination as excellent. Respondents reported limited support and resources to make it easier for researchers who might want to disseminate their findings. Conclusion. Though intentions show the importance of dissemination, researchers across countries lack supports to increase dissemination efforts. Additional resources and training in designing for dissemination along with improved partnerships could help bridge the research-practice gap. Rachel G. Tabak, Rodrigo S. Reis, Paul Wilson, and Ross C. Brownson Copyright © 2015 Rachel G. Tabak et al. All rights reserved. Hemodynamic and Biologic Determinates of Arteriovenous Fistula Outcomes in Renal Failure Patients Thu, 01 Oct 2015 08:39:41 +0000 The outcome of patients with end-stage renal disease on hemodialysis depends on a functioning vascular access. Although a variety of access options are available, the arteriovenous fistula remains the best vascular access. Unfortunately the success rate of mature fistula use remains poor. The creation of an arteriovenous fistula is followed by altered hemodynamic and biological changes that may result in neointimal hyperplasia and eventual venous stenosis. This review provides an overview of these changes and the needed research to provide a long lasting vascular access and hence improve outcomes for patients with end-stage renal disease. Mary Hammes Copyright © 2015 Mary Hammes. All rights reserved. Guided Tissue Regeneration in Heart Valve Replacement: From Preclinical Research to First-in-Human Trials Thu, 01 Oct 2015 08:34:02 +0000 Heart valve tissue-guided regeneration aims to offer a functional and viable alternative to current prosthetic replacements. Not requiring previous cell seeding and conditioning in bioreactors, such exceptional tissue engineering approach is a very fascinating translational regenerative strategy. After in vivo implantation, decellularized heart valve scaffolds drive their same repopulation by recipient’s cells for a prospective autologous-like tissue reconstruction, remodeling, and adaptation to the somatic growth of the patient. With such a viability, tissue-guided regenerated conduits can be delivered as off-the-shelf biodevices and possess all the potentialities for a long-lasting resolution of the dramatic inconvenience of heart valve diseases, both in children and in the elderly. A review on preclinical and clinical investigations of this therapeutic concept is provided with evaluation of the issues still to be well deliberated for an effective and safe in-human application. L. Iop and G. Gerosa Copyright © 2015 L. Iop and G. Gerosa. All rights reserved. Does Defensive Medicine Change the Behaviors of Vascular Surgeons? A Qualitative Review Thu, 01 Oct 2015 07:29:16 +0000 Although in literature few successful claims have been shown in comparison with other medical specialties such as gynaecology and orthopaedics, vascular surgery is included among high-risk specialties. The high-risk of receiving medical claims may lead vascular surgeons to practice defensive medicine, as is normal in several other areas of clinical practice. No studies are available to our knowledge of the incidence of defensive medicine in the field of vascular surgery. Taking into consideration the scarce amount of information, the authors provide a critical discussion regarding the application of defensive medicine behaviour among vascular surgeons. Paola Frati, Francesco Paolo Busardò, Pasqualino Sirignano, Matteo Gulino, Simona Zaami, and Vittorio Fineschi Copyright © 2015 Paola Frati et al. All rights reserved. Full GMP-Compliant Validation of Bone Marrow-Derived Human CD133+ Cells as Advanced Therapy Medicinal Product for Refractory Ischemic Cardiomyopathy Thu, 01 Oct 2015 07:07:03 +0000 According to the European Medicine Agency (EMA) regulatory frameworks, Advanced Therapy Medicinal Products (ATMP) represent a new category of drugs in which the active ingredient consists of cells, genes, or tissues. ATMP-CD133 has been widely investigated in controlled clinical trials for cardiovascular diseases, making CD133+ cells one of the most well characterized cell-derived drugs in this field. To ensure high quality and safety standards for clinical use, the manufacturing process must be accomplished in certified facilities following standard operative procedures (SOPs). In the present work, we report the fully compliant GMP-grade production of ATMP-CD133 which aims to address the treatment of chronic refractory ischemic heart failure. Starting from bone marrow (BM), ATMP-CD133 manufacturing output yielded a median of 6.66 × 106 of CD133+ cells (range 2.85 × 106–30.84 × 106), with a viability ranged between 96,03% and 99,97% (median 99,87%) and a median purity of CD133+ cells of 90,60% (range 81,40%–96,20%). Based on these results we defined our final release criteria for ATMP-CD133: purity ≥ 70%, viability ≥ 80%, cellularity between 1 and 12 × 106 cells, sterile, and endotoxin-free. The abovementioned criteria are currently applied in our Phase I clinical trial (RECARDIO Trial). Daniela Belotti, Giuseppe Gaipa, Beatrice Bassetti, Benedetta Cabiati, Gabriella Spaltro, Ettore Biagi, Matteo Parma, Andrea Biondi, Laura Cavallotti, Elisa Gambini, and Giulio Pompilio Copyright © 2015 Daniela Belotti et al. All rights reserved. Heart Rate Variability in Shift Workers: Responses to Orthostatism and Relationships with Anthropometry, Body Composition, and Blood Pressure Thu, 01 Oct 2015 07:01:51 +0000 In order to investigate the response of heart rate variability (HRV) components to postural change and their association with cardiovascular risk factors in shift workers, a cross-sectional study with 438 Brazilian males rotating shift workers was done. Anthropometric, body composition, and clinical measures were collected. Electrocardiogram was recorded for 3 minutes, in the supine and orthostatic position, and HRV components were extracted. Descriptive analyses showed that mean values of body mass index, waist circumference (WC), waist-to-height ratio, visceral fat area (VFA), and blood pressure (BP) were higher than the reference values. In the regression model, age, WC, VFA, and systolic BP showed negative association with HRV components. These findings suggest the need for determining effective strategies for the evaluation and promotion of health among shift workers focused on the altered variables. Nayara Mussi Monteze, Breno Bernardes Souza, Henrique José de Paula Alves, Fernando Luiz Pereira de Oliveira, José Magalhães de Oliveira, Silvia Nascimento de Freitas, Raimundo Marques do Nascimento Neto, Maria Lilian Sales, and Gabriela Guerra Leal Souza Copyright © 2015 Nayara Mussi Monteze et al. All rights reserved. The Potential of GMP-Compliant Platelet Lysate to Induce a Permissive State for Cardiovascular Transdifferentiation in Human Mediastinal Adipose Tissue-Derived Mesenchymal Stem Cells Thu, 01 Oct 2015 06:53:56 +0000 Human adipose tissue-derived mesenchymal stem cells (ADMSCs) are considered eligible candidates for cardiovascular stem cell therapy applications due to their cardiac transdifferentiation potential and immunotolerance. Over the years, the in vitro culture of ADMSCs by platelet lysate (PL), a hemoderivate containing numerous growth factors and cytokines derived from platelet pools, has allowed achieving a safe and reproducible methodology to obtain high cell yield prior to clinical administration. Nevertheless, the biological properties of PL are still to be fully elucidated. In this brief report we show the potential ability of PL to induce a permissive state of cardiac-like transdifferentiation and to cause epigenetic modifications. RTPCR results indicate an upregulation of Cx43, SMA, c-kit, and Thy-1 confirmed by immunofluorescence staining, compared to standard cultures with foetal bovine serum. Moreover, PL-cultured ADMSCs exhibit a remarkable increase of both acetylated histones 3 and 4, with a patient-dependent time trend, and methylation at lysine 9 on histone 3 preceding the acetylation. Expression levels of p300 and SIRT-1, two major regulators of histone 3, are also upregulated after treatment with PL. In conclusion, PL could unravel novel biological properties beyond its routine employment in noncardiac applications, providing new insights into the plasticity of human ADMSCs. Camilla Siciliano, Isotta Chimenti, Antonella Bordin, Donatella Ponti, Paola Iudicone, Mariangela Peruzzi, Erino Angelo Rendina, Antonella Calogero, Luca Pierelli, Mohsen Ibrahim, and Elena De Falco Copyright © 2015 Camilla Siciliano et al. All rights reserved. Using Multicriteria Decision Analysis to Support Research Priority Setting in Biomedical Translational Research Projects Thu, 01 Oct 2015 06:24:48 +0000 Translational research is conducted to achieve a predefined set of economic or societal goals. As a result, investment decisions on where available resources have the highest potential in achieving these goals have to be made. In this paper, we first describe how multicriteria decision analysis can assist in defining the decision context and in ensuring that all relevant aspects of the decision problem are incorporated in the decision making process. We then present the results of a case study to support priority setting in a translational research consortium aimed at reducing the burden of disease of type 2 diabetes. During problem structuring, we identified four research alternatives (primary, secondary, tertiary microvascular, and tertiary macrovascular prevention) and a set of six decision criteria. Scoring of these alternatives against the criteria was done using a combination of expert judgement and previously published data. Lastly, decision analysis was performed using stochastic multicriteria acceptability analysis, which allows for the combined use of numerical and ordinal data. We found that the development of novel techniques applied in secondary prevention would be a poor investment of research funds. The ranking of the remaining alternatives was however strongly dependent on the decision maker’s preferences for certain criteria. Gimon de Graaf, Douwe Postmus, and Erik Buskens Copyright © 2015 Gimon de Graaf et al. All rights reserved. Comparison between Procalcitonin, Brain Natriuretic Peptide, and Uric Acid in Children with Cardiomyopathy and Controls Thu, 01 Oct 2015 05:55:33 +0000 Objective. This study was performed to determine the level of procalcitonin, Brain Natriuretic Peptide (BNP), and uric acid in children with cardiomyopathy in comparison with controls and the association with echocardiographic findings. Methods. The levels of BNP, procalcitonin, and serum uric acid were measured and the amounts of biomarkers compared with echocardiographic findings. Results. In this study mean age of participants was the same (). The majority of echocardiographic indices in left and right heart have different means in case and controls (). Means of BNP, procalcitonin, and uric acid were 213.814 ± 309.601, 9.326 ± 3.881, and 6.846 ± 1.814 for case group and 2.76 ± 1.013, 1.851 ± 1.466, and 3.317 ± 0.924 for control (), respectively. In the patients group there was relationship of Ross classification with BNP (χ2 = 15.845, ) and with age (χ2 = 8.946, ). For uric acid and procalcitonin no significant relationships were observed. Conclusions. procalcitonin, uric acid, and BNP had significant relationship with many echocardiographic findings in participants. For patients, procalcitonin did not show correlation. The severity of illness based on the Ross classification showed significant correlation with BNP level and age in patients. Noor Mohammad Noori, Maziar Mahjoubifard, Iraj Shahramian, Alireza Teimouri, and Alireza Jahangirifard Copyright © 2015 Noor Mohammad Noori et al. All rights reserved. Malnutrition and Gut Flora Dysbiosis: Specific Therapies for Emerging Comorbidities in Heart Failure Wed, 30 Sep 2015 11:58:40 +0000 Chronic heart failure is a complicated multifactorial disease with wide-spread social-economic consequences. In spite of the recent development of new drugs and therapeutic strategies, CHF-related mortality and morbidity remain high. Recent evidence suggests that changes in organs such as skeletal muscle and gut flora may play an important and independent role in CHF prognosis. This paper illustrates these phenomena, proposing how to identify them and presenting current therapies which treat organs all too often underestimated but which have a fundamental role in worsening CHF. Evasio Pasini, Roberto Aquilani, Giovanni Corsetti, and Francesco S. Dioguardi Copyright © 2015 Evasio Pasini et al. All rights reserved. Soluble Receptor for Advanced Glycation End Product: A Biomarker for Acute Coronary Syndrome Wed, 30 Sep 2015 09:41:43 +0000 The receptor of advanced glycation end products (RAGE) and its ligands are linked to the pathogenesis of coronary artery disease (CAD), and circulating soluble receptor of advanced glycation end products (sRAGE), reflecting the RAGE activity, is suggested as a potential biomarker. Elevated sRAGE levels are reported in relation to acute ischemia and this review focuses on the role of sRAGE as a biomarker for the acute coronary syndrome (ACS). The current studies demonstrated that sRAGE levels are elevated in relation to ACS, however during a very narrow time period, indicating that the time of sampling needs attention. Interestingly, activation of RAGE may influence the pathogenesis and reflection in sRAGE levels in acute and stable CAD differently. Louise J. N. Jensen, Allan Flyvbjerg, and Mette Bjerre Copyright © 2015 Louise J. N. Jensen et al. All rights reserved. Associations of C1q/TNF-Related Protein-9 Levels in Serum and Epicardial Adipose Tissue with Coronary Atherosclerosis in Humans Thu, 17 Sep 2015 06:20:36 +0000 Objective. To investigate the correlation of CTRP9 with coronary atherosclerosis. Methods. Coronary angiography confirmed CAD in 241 patients (62 received CABG) and non-CAD in 121 (55 received valve replacement). Results. Serum levels of LDL-C, CRP, TNF-α, IL-6, and leptin in CAD patients were significantly higher than those in non-CAD patients (), but APN and CTRP9 were lower (). Serum levels of CTRP9 and APN were negatively related to BMI, HOMA-IR, TNF-α, IL-6, and leptin but positively to HDL-C () in CAD patients. After adjustment of APN, CTRP9 was still related to the above parameters. Serum CTRP9 was a protective factor of CAD (). When compared with non-CAD patients, leptin mRNA expression increased dramatically, while CTRP9 mRNA expression reduced markedly in epicardial adipose tissue of CAD patients (). The leptin expression and macrophage count in CAD group were significantly higher than in non-CAD group, but CAD patients had a markedly lower CTRP9 expression (). Conclusions. Circulating and coronary CTRP9 plays an important role in the inflammation and coronary atherosclerosis of CAD patients. Serum CTRP9 is an independent protective factor of CAD. Jing Wang, Tao Hang, Xun-min Cheng, De-min Li, Qi-gao Zhang, Li-jun Wang, Yong-ping Peng, and Jian-bin Gong Copyright © 2015 Jing Wang et al. All rights reserved. Modulation of Immunity and Inflammation by the Mineralocorticoid Receptor and Aldosterone Thu, 10 Sep 2015 12:52:17 +0000 The mineralocorticoid receptor (MR) is a ligand dependent transcription factor. MR has been traditionally associated with the control of water and electrolyte homeostasis in order to keep blood pressure through aldosterone activation. However, there is growing evidence indicating that MR expression is not restricted to vascular and renal tissues, as it can be also expressed by cells of the immune system, where it responds to stimulation or antagonism, controlling immune cell function. On the other hand, aldosterone also has been associated with proinflammatory immune effects, such as the release of proinflammatory cytokines, generating oxidative stress and inducing fibrosis. The inflammatory participation of MR and aldosterone in the cardiovascular disease suggests an association with alterations in the immune system. Hypertensive patients show higher levels of proinflammatory mediators that can be modulated by MR antagonism. Although these proinflammatory properties have been observed in other autoimmune and chronic inflammatory diseases, the cellular and molecular mechanisms that mediate these effects remain unknown. Here we review and discuss the scientific work aimed at determining the immunological role of MR and aldosterone in humans, as well as animal models. N. Muñoz-Durango, A. Vecchiola, L. M. Gonzalez-Gomez, F. Simon, C. A. Riedel, C. E. Fardella, and A. M. Kalergis Copyright © 2015 N. Muñoz-Durango et al. All rights reserved. Sex Differences in Immunology: More Severe Development of Experimental Pulmonary Hypertension in Male Rats Exposed to Vascular Endothelial Growth Factor Receptor Blockade Tue, 01 Sep 2015 07:09:37 +0000 Background. The epidemiology of pulmonary hypertension (PH) is characterized by a female preponderance, whereas males share higher severity of the disease. Objective. To compare the severity of experimental PH between male and female athymic rats. Methods. PH was induced in 11 male and 11 female athymic rats (resp., SU_M and SU_F groups) using an inhibitor of VEGF-receptors I and II, semaxanib (40 mg/kg). After 28 days, right ventricular (RV) remodeling, systolic function, and hemodynamics were measured using echocardiography and a pressure-volume admittance catheter. Morphometric analyses of lung vasculature and RV myocardium were performed. Results. Four weeks after semaxanib injection, RV end-systolic pressure was higher in SU_M than in SU_F. Males developed marked RV enlargement and systolic dysfunction compared to females. Impairment of RV-PA coupling efficiency was observed only in SU_M. The smooth muscle cells of the pulmonary arteries switched from a contractile state to a dedifferentiated state only in males. Conclusions. Female athymic rats were protected against the development of severe PH. RV-PA coupling was preserved in females through limitation of pulmonary artery muscularization. Control of smooth muscle cells plasticity may be a promising therapeutic approach to reverse established vascular remodeling in PH patients. Julien Guihaire, Tobias Deuse, Dong Wang, Elie Fadel, Hermann Reichenspurner, and Sonja Schrepfer Copyright © 2015 Julien Guihaire et al. All rights reserved. The Role of Cardiolipin in Cardiovascular Health Sun, 02 Aug 2015 13:50:37 +0000 Cardiolipin (CL), the signature phospholipid of mitochondrial membranes, is crucial for both mitochondrial function and cellular processes outside of the mitochondria. The importance of CL in cardiovascular health is underscored by the life-threatening genetic disorder Barth syndrome (BTHS), which manifests clinically as cardiomyopathy, skeletal myopathy, neutropenia, and growth retardation. BTHS is caused by mutations in the gene encoding tafazzin, the transacylase that carries out the second CL remodeling step. In addition to BTHS, CL is linked to other cardiovascular diseases (CVDs), including cardiomyopathy, atherosclerosis, myocardial ischemia-reperfusion injury, heart failure, and Tangier disease. The link between CL and CVD may possibly be explained by the physiological roles of CL in pathways that are cardioprotective, including mitochondrial bioenergetics, autophagy/mitophagy, and mitogen activated protein kinase (MAPK) pathways. In this review, we focus on the role of CL in the pathogenesis of CVD as well as the molecular mechanisms that may link CL functions to cardiovascular health. Zheni Shen, Cunqi Ye, Keanna McCain, and Miriam L. Greenberg Copyright © 2015 Zheni Shen et al. All rights reserved. Application and Progress of Combined Mesenchymal Stem Cell Transplantation in the Treatment of Ischemic Cardiomyopathy Wed, 29 Jul 2015 08:20:18 +0000 Treatment of ischemic cardiomyopathy caused by myocardial infarction (MI) using mesenchymal stem cell (MSC) transplantation is a widely researched field, with promising clinical application. However, the low survival rate of transplanted cells has a severe impact on treatment outcome. Currently, research is focused on investigating the strategy of combining genetic engineering, tissue engineering materials, and drug/hypoxia preconditioning to improve ischemic cardiomyopathy treatment outcome using MSC transplantation treatment (MSCTT). This review discusses the application and progress of these techniques. Ping Hua, Jian-Yang Liu, Jun Tao, and Song-Ran Yang Copyright © 2015 Ping Hua et al. All rights reserved. Incidence and Predictors of New-Onset Silent Atrial Fibrillation after Coronary Artery Bypass Graft Surgery Tue, 28 Jul 2015 08:58:57 +0000 Aims. We investigated the incidence, risk factors, and prognostic impact of silent atrial fibrillation (AF) after coronary artery bypass graft (CABG) surgery. Methods. This observational study prospectively included 100 patients referred for CABG surgery. Holter ECG monitoring was used to record every arrhythmic event for 7 days. AF was defined as at least one episode >30 s. Episodes recorded on Holter ECG monitoring but not clinically identified were classified as silent AF. Results. Among 34 patients who developed new-onset AF, 13 had silent AF. Compared with patients with maintained sinus rhythm (SR), silent AF patients had a significantly higher logistic EuroSCORE (2.9 (1.5–5.2) versus 2.3 (1.4–3.7), ) and were more likely to have previous sleep apnea (31% versus 8%, ) and left atrial diameter >45 mm (36% versus 5%, ). At one-year follow-up, 30% of silent AF patients had developed symptomatic AF versus 7% in the SR group () and 11% in the clinical AF group (). Conclusion. After CABG surgery, silent AF is common and may be associated with a higher incidence of recurrences at one-year follow-up than clinical AF. Improved screening for silent AF may help to reduce thromboembolic events in this high-risk population. Charles Guenancia, Charline Pujos, Frederique Debomy, Ghislain Malapert, Gabriel Laurent, and Olivier Bouchot Copyright © 2015 Charles Guenancia et al. All rights reserved. MicroRNA and Cardiovascular Disease Tue, 21 Jul 2015 08:03:35 +0000 Xiao-Bo Liao, Vinicio A. de Jesus Perez, Magdalena Król, Chi-Hsiao Yeh, and Ling-Qing Yuan Copyright © 2015 Xiao-Bo Liao et al. All rights reserved. The Different Effects of BMI and WC on Organ Damage in Patients from a Cardiac Rehabilitation Program after Acute Coronary Syndrome Mon, 13 Jul 2015 06:28:18 +0000 One of the purposes of cardiac rehabilitation (CR) after acute coronary syndrome (ACS) is to monitor and control weight of the patient. Our study is to compare the different obesity indexes, body mass index (BMI), and waist circumference (WC), through one well-designed CR program (CRP) with ACS in Guangzhou city of Guangdong Province, China, in order to identify different effects of BMI and WC on organ damage. In our work, sixty-one patients between October 2013 and January 2014 fulfilled our study. We collected the vital signs by medical records, the clinical variables of body-metabolic status by fasting blood test, and the organ damage variables by submaximal exercise treadmill test (ETT) and ultrasonic cardiogram (UCG) both on our inpatient and four-to-five weeks of outpatient part of CRP after ACS. We mainly used two-tailed Pearson’s test and liner regression to evaluate the relationship of BMI/WC and organ damage. Our results confirmed that WC could be more accurate than BMI to evaluate the cardiac function through the changes of left ventricular structure on the CRP after ACS cases. It makes sense of early diagnosis, valid evaluation, and proper adjustment to ACS in CRP of the obesity individuals in the future. Lin Xu, Hui Zhao, Jian Qiu, Wei Zhu, Hongqiang Lei, Zekun Cai, Wan-Hua Lin, Wenhua Huang, Heye Zhang, and Yuan-Ting Zhang Copyright © 2015 Lin Xu et al. All rights reserved. Rank-One and Transformed Sparse Decomposition for Dynamic Cardiac MRI Sun, 12 Jul 2015 12:33:13 +0000 It is challenging and inspiring for us to achieve high spatiotemporal resolutions in dynamic cardiac magnetic resonance imaging (MRI). In this paper, we introduce two novel models and algorithms to reconstruct dynamic cardiac MRI data from under-sampled space data. In contrast to classical low-rank and sparse model, we use rank-one and transformed sparse model to exploit the correlations in the dataset. In addition, we propose projected alternative direction method (PADM) and alternative hard thresholding method (AHTM) to solve our proposed models. Numerical experiments of cardiac perfusion and cardiac cine MRI data demonstrate improvement in performance. Xianchao Xiu and Lingchen Kong Copyright © 2015 Xianchao Xiu and Lingchen Kong. All rights reserved. Atrial Fibrillation: Biophysics, Molecular Mechanisms, and Novel Therapies Thu, 09 Jul 2015 07:40:41 +0000 Alexey V. Glukhov, Leonid V. Rosenshtraukh, Anamika Bhargava, Michele Miragoli, and Bas J. D. Boukens Copyright © 2015 Alexey V. Glukhov et al. All rights reserved. The Utility of 3D Left Atrial Volume and Mitral Flow Velocities as Guides for Acute Volume Resuscitation Tue, 07 Jul 2015 12:41:58 +0000 Left ventricular end-diastolic pressure (LVEDP) is the foundation of cardiac function assessment. Because of difficulties and risks associated with its direct measurement, correlates of LVEDP derived by pulmonary artery (PA) catheterization or transesophageal echocardiography (TEE) are commonly adopted. TEE has the advantage of being less invasive; however TEE-based estimation of LVEDP using correlates such as left ventricular end-diastolic volume (LVEDV) has technical difficulties that limit its clinical usefulness. Using intraoperative acute normovolemic hemodilution (ANH) as a controlled hemorrhagic model, we examined various mitral flow parameters and three-dimensional reconstructions of left atrial volume as surrogates of LVEDP. Our results demonstrate that peak E wave velocity and left atrial end-diastolic volume (LAEDV) correlated with known changes in intravascular volume associated with ANH. Although left atrial volumetric analysis was done offline in our study, recent advances in echocardiographic software may allow for continuous display and real-time calculation of LAEDV. Along with the ease and reproducibility of acquiring Doppler images of flow across the mitral valve, these two correlates of LVEDP may justify a more widespread use of TEE to optimize intraoperative fluid management. The clinical applicability of peak E wave velocity and LAEDV still needs to be validated during uncontrolled resuscitation. Claudia M. Santosa, David D. Rose, and Neal W. Fleming Copyright © 2015 Claudia M. Santosa et al. All rights reserved. The Role of Magnetic Resonance Imaging and Cardiac Computed Tomography in the Assessment of Left Atrial Anatomy, Size, and Function Tue, 07 Jul 2015 12:34:54 +0000 In the last decade, there has been increasing evidence that comprehensive evaluation of the left atrium is of utmost importance. Numerous studies have clearly demonstrated the prognostic value of left atrial volume for long-term outcome. Furthermore, advances in catheter ablation procedures used for the treatment of drug-refractory atrial fibrillation require the need for detailed knowledge of left atrial and pulmonary venous morphology as well of atrial wall characteristics. This review article discusses the role of cardiac magnetic resonance and computed tomography in assessment of left atrial size, its normal and abnormal morphology, and function. Special interest is paid to the utility of these rapidly involving noninvasive imaging methods before and after atrial fibrillation ablation. Petr Kuchynka, Jana Podzimkova, Martin Masek, Lukas Lambert, Vladimir Cerny, Barbara Danek, and Tomas Palecek Copyright © 2015 Petr Kuchynka et al. All rights reserved. Echocardiographic Evaluation of Left Atrial Mechanics: Function, History, Novel Techniques, Advantages, and Pitfalls Tue, 07 Jul 2015 12:05:09 +0000 Left atrial (LA) functional analysis has an established role in assessing left ventricular diastolic function. The current standard echocardiographic parameters used to study left ventricular diastolic function include pulsed-wave Doppler mitral inflow analysis, tissue Doppler imaging measurements, and LA dimension estimation. However, the above-mentioned parameters do not directly quantify LA performance. Deformation studies using strain and strain-rate imaging to assess LA function were validated in previous research, but this technique is not currently used in routine clinical practice. This review discusses the history, importance, and pitfalls of strain technology for the analysis of LA mechanics. Roman Leischik, Henning Littwitz, Birgit Dworrak, Pankaj Garg, Meihua Zhu, David J. Sahn, and Marc Horlitz Copyright © 2015 Roman Leischik et al. All rights reserved. Left Atrial Appendage: Physiology, Pathology, and Role as a Therapeutic Target Tue, 07 Jul 2015 09:03:11 +0000 Atrial fibrillation (AF) is the most common clinically relevant cardiac arrhythmia. AF poses patients at increased risk of thromboembolism, in particular ischemic stroke. The CHADS2 and CHA2DS2-VASc scores are useful in the assessment of thromboembolic risk in nonvalvular AF and are utilized in decision-making about treatment with oral anticoagulation (OAC). However, OAC is underutilized due to poor patient compliance and contraindications, especially major bleedings. The Virchow triad synthesizes the pathogenesis of thrombogenesis in AF: endocardial dysfunction, abnormal blood stasis, and altered hemostasis. This is especially prominent in the left atrial appendage (LAA), where the low flow reaches its minimum. The LAA is the remnant of the embryonic left atrium, with a complex and variable morphology predisposing to stasis, especially during AF. In patients with nonvalvular AF, 90% of thrombi are located in the LAA. So, left atrial appendage occlusion could be an interesting and effective procedure in thromboembolism prevention in AF. After exclusion of LAA as an embolic source, the remaining risk of thromboembolism does not longer justify the use of oral anticoagulants. Various surgical and catheter-based methods have been developed to exclude the LAA. This paper reviews the physiological and pathophysiological role of the LAA and catheter-based methods of LAA exclusion. Damiano Regazzoli, Francesco Ancona, Nicola Trevisi, Fabrizio Guarracini, Andrea Radinovic, Michele Oppizzi, Eustachio Agricola, Alessandra Marzi, Nicoleta Carmen Sora, Paolo Della Bella, and Patrizio Mazzone Copyright © 2015 Damiano Regazzoli et al. All rights reserved. Surgical Left Atrial Appendage Exclusion Does Not Impair Left Atrial Contraction Function: A Pilot Study Tue, 07 Jul 2015 08:40:31 +0000 Background. In order to reduce stroke risk, left atrial appendage amputation (LAAA) is widely adopted in recent years. The effect of LAAA on left atrial (LA) function remains unknown. The objective of present study was to assess the effect of LAAA on LA function. Methods. Sixteen patients with paroxysmal AF underwent thoracoscopic, surgical PVI with LAAA (LAAA group), and were retrospectively matched with 16 patients who underwent the same procedure without LAA amputation (non-LAAA group). To objectify LA function, transthoracic echocardiography with 2D Speckle Tracking was performed before surgery and at 12 months follow-up. Results. Mean age was 57 ± 9 years, 84% were male. Baseline characteristics did not differ significantly except for systolic blood pressure (). In both groups, the contractile LA function and LA ejection fraction were not significantly reduced. However, the conduit and reservoir function were significantly decreased at follow-up, compared to baseline. The reduction of strain and strain rate was not significantly different between groups. Conclusions. In this retrospective, observational matched group comparison with a convenience sample size of 16 patients, findings suggest that LAAA does not impair the contractile LA function when compared to patients in which the appendage was unaddressed. However, the LA conduit and reservoir function are reduced in both the LAAA and non-LAAA group. Our data suggest that the LAA can be removed without late LA functional consequences. Gijs E. De Maat, Stefano Benussi, Yoran M. Hummel, Sebastien Krul, Alberto Pozzoli, Antoine H. G. Driessen, Massimo A. Mariani, Isabelle C. Van Gelder, Wim-Jan Van Boven, and Joris R. de Groot Copyright © 2015 Gijs E. De Maat et al. All rights reserved. Novel Anticoagulants in Atrial Fibrillation: Monitoring, Reversal and Perioperative Management Thu, 02 Jul 2015 09:09:22 +0000 Atrial fibrillation continues to be a significant source of morbidity and mortality worldwide. Effective anticoagulation remains the cornerstone of outpatient and inpatient treatment. The use of the new generation of anticoagulants (NOACs) continues to grow. Recently published data indicate their cost-effectiveness and overall safety in stroke prevention; compared to vitamin K antagonists, they can be prescribed in fixed doses for long-term therapy without the need for coagulation monitoring. Both United States and European Guidelines recommend NOACs for stroke prevention in patients with atrial fibrillation. This review discusses each of the NOACs, along with their efficacy and safety data. It explores the most recent guidelines regarding their perioperative use in atrial fibrillation patients. It also discusses bleeding complications, perioperative management, and reversal agents. Fadi Shamoun, Hiba Obeid, and Harish Ramakrishna Copyright © 2015 Fadi Shamoun et al. All rights reserved. Heartbeat Cycle Length Detection by a Ballistocardiographic Sensor in Atrial Fibrillation and Sinus Rhythm Wed, 01 Jul 2015 09:44:16 +0000 Background. Heart rate monitoring is especially interesting in patients with atrial fibrillation (AF) and is routinely performed by ECG. A ballistocardiography (BCG) foil is an unobtrusive sensor for mechanical vibrations. We tested the correlation of heartbeat cycle length detection by a novel algorithm for a BCG foil to an ECG in AF and sinus rhythm (SR). Methods. In 22 patients we obtained BCG and synchronized ECG recordings before and after cardioversion and examined the correlation between heartbeat characteristics. Results. We analyzed a total of 4317 heartbeats during AF and 2445 during SR with a correlation between ECG and BCG during AF of (95% CI 0.68–0.71, ) and (95% CI 0.73–0.77, ) during SR. By adding a quality index, artifacts could be reduced and the correlation increased for AF to 0.76 (95% CI 0.74–0.77, , ) and for SR to 0.85 (95% CI 0.83–0.86, , ). Conclusion. Heartbeat cycle length measurement by our novel algorithm for BCG foil is feasible during SR and AF, offering new possibilities of unobtrusive heart rate monitoring. This trial is registered with IRB registration number EK205/11. This trial is registered with clinical trials registration number NCT01779674. Matthias Daniel Zink, Christoph Brüser, Patrick Winnersbach, Andreas Napp, Steffen Leonhardt, Nikolaus Marx, Patrick Schauerte, and Karl Mischke Copyright © 2015 Matthias Daniel Zink et al. All rights reserved. Diagnosing Paroxysmal Atrial Fibrillation: Are Biomarkers the Solution to This Elusive Arrhythmia? Wed, 01 Jul 2015 08:46:50 +0000 Atrial fibrillation (AF) is the commonest sustained arrhythmia globally and results in significantly increased morbidity and mortality including a fivefold risk of stroke. Paroxysmal atrial fibrillation (PAF) constitutes approximately half of all AF cases and is thought to represent an early stage of the disease. This intermittent form of atrial arrhythmia can be a challenge to identify and as a result many affected individuals are not prescribed appropriate antithrombotic therapy and hence are at risk of stroke and thromboembolism. Despite these adverse outcomes there have been relatively few diagnostic advances in the field since the introduction of the Holter monitor in 1949. This review aims to establish the available evidence for electrophysiological, molecular, and morphological biomarkers to improve the detection of PAF with reference to the underlying mechanisms for the condition. P. J. Howlett, F. S. Hatch, V. Alexeenko, R. I. Jabr, E. W. Leatham, and C. H. Fry Copyright © 2015 P. J. Howlett et al. All rights reserved. Chronotropic Modulation of the Source-Sink Relationship of Sinoatrial-Atrial Impulse Conduction and Its Significance to Initiation of AF: A One-Dimensional Model Study Wed, 01 Jul 2015 07:34:00 +0000 Initiation and maintenance of atrial fibrillation (AF) is often associated with pharmacologically or pathologically induced bradycardic states. Even drugs specifically developed in order to counteract cardiac arrhythmias often combine their action with bradycardia and, in turn, with development of AF, via still largely unknown mechanisms. This study aims to simulate action potential (AP) conduction between sinoatrial node (SAN) and atrial cells, either arranged in cell pairs or in a one-dimensional strand, where the relative amount of SAN membrane is made varying, in turn, with junctional resistance. The source-sink relationship between the two membrane types is studied in control conditions and under different simulated chronotropic interventions, in order to define a safety factor for pacemaker-to-atrial AP conduction (SASF) for each treatment. Whereas antiarrhythmic-like interventions which involve downregulation of calcium channels or of calcium handling decrease SASF, the simulation of Ivabradine administration does so to a lesser extent. Particularly interesting is the increase of SASF observed when downregulation , which simulates the administration of class III antiarrhythmic agents and is likely sustained by an increase in . Also, the increase in SASF is accompanied by a decreased conduction delay and a better entrainment of repolarization, which is significant to anti-AF strategies. Francesca Cacciani and Massimiliano Zaniboni Copyright © 2015 Francesca Cacciani and Massimiliano Zaniboni. All rights reserved. Atrial Fibrillation and Fibrosis: Beyond the Cardiomyocyte Centric View Wed, 01 Jul 2015 07:27:49 +0000 Atrial fibrillation (AF) associated with fibrosis is characterized by the appearance of interstitial myofibroblasts. These cells are responsible for the uncontrolled deposition of the extracellular matrix, which pathologically separate cardiomyocyte bundles. The enhanced fibrosis is thought to contribute to arrhythmias “indirectly” because a collagenous septum is a passive substrate for propagation, resulting in impulse conduction block and/or zigzag conduction. However, the emerging results demonstrate that myofibroblasts in vitro also promote arrhythmogenesis due to direct implications upon cardiomyocyte electrophysiology. This electrical interference may be considered beneficial as it resolves any conduction blocks; however, the passive properties of myofibroblasts might cause a delay in impulse propagation, thus promoting AF due to discontinuous slow conduction. Moreover, low-polarized myofibroblasts reduce, via cell-density dependence, the fast driving inward current for cardiac impulse conduction, therefore resulting in arrhythmogenic uniformly slow propagation. Critically, the subsequent reduction in cardiomyocytes resting membrane potential in vitro significantly increases the likelihood of ectopic activity. Myofibroblast densities and the degree of coupling at cellular border zones also impact upon this likelihood. By considering future in vivo studies, which identify myofibroblasts “per se” as a novel targets for cardiac arrhythmias, this review aims to describe the implications of noncardiomyocyte view in the context of AF. Michele Miragoli and Alexey V. Glukhov Copyright © 2015 Michele Miragoli and Alexey V. Glukhov. All rights reserved. Results from the Registry of Atrial Fibrillation (AFABE): Gap between Undiagnosed and Registered Atrial Fibrillation in Adults—Ineffectiveness of Oral Anticoagulation Treatment with VKA Wed, 01 Jul 2015 07:25:14 +0000 Objective. This study aimed to examine the effectiveness of the use of oral anticoagulation (OAC) medication, recommended by national guidelines for stroke prevention but reportedly underused in AF patients with moderate to high stroke risk. Method. A multicentre and cross-sectional study of undiagnosed AF among out-of-hospital patients over 60 years old was carried out, visiting 3,638 patients at primary health centres or at home for AF diagnosis using the IDC-10 classification. The main outcome measures were , HAS-BLED scores, cardiovascular comorbidity, pharmacological information, TTR, and SAMe-TT2R2 scores. Results. The main findings were undiagnosed AF in 26.44% of cases; 31.04% registered with AF but not using OAC despite 95.6% having a score; a risk of bleeding in important subgroups using OAC without indication (37.50% score); the use of OAC with TTR < 60% (33.1%), of whom 47.6% had a HAS-BLED score ≥3. Thus, 35.4% of the expected AF prevalence achieved an optimal time in the therapeutic range. Conclusions. The expected AF prevalence was 10.9% ( 5267), but the registered prevalence was 7.5% ( 3638). Only 35.04% (CI = 95%, 33.7–36.3) of AF patients treated with vitamin K antagonists (VKAs) achieve the goal of TTR > 60%. Anna Panisello-Tafalla, Josep Lluís Clua-Espuny, Vicente F. Gil-Guillen, Antonia González-Henares, María Lluisa Queralt-Tomas, Carlos López-Pablo, Jorgina Lucas-Noll, Iñigo Lechuga-Duran, Rosa Ripolles-Vicente, Jesús Carot-Domenech, and Miquel Gallofré López Copyright © 2015 Anna Panisello-Tafalla et al. All rights reserved. Atorvastatin Treatment for Atrial Fibrillation Reduces Serum High-Sensitivity C-Reactive Protein Levels Wed, 01 Jul 2015 06:32:08 +0000 We investigated whether serum hs-CRP levels predict the efficacy of atrial fibrillation (AF) treated with atorvastatin. Bibliographic databases were exhaustively searched for studies relevant to the research topic. Newcastle-Ottawa Scale (NOS) criteria, combined with the Quality Assessment of Diagnostic Accuracy Studies (QUADAS), were applied for study quality assessment. Our meta-analysis identified seven cohort studies (2006~2013), providing information on the change in serum hs-CRP levels in AF patients receiving atorvastatin therapy. After atorvastatin treatment, hs-CRP level in AF patients decreased significantly (SMD = 1.02, 95% CI: 0.58–1.47, ). Subgroup analysis by country and hs-CRP detection methods suggested a negative relationship between atorvastatin treatment and hs-CRP levels among Chinese AF patients (SMD = 1.34, 95% CI: 1.00–1.69, ) and by using ELISA method (SMD = 1.11, 95% CI: 0.51–1.71, ), but not among Turkish population and using INA method (all ). Egger’s test showed no publication bias (). hs-CRP was clearly lowered in AF patients treated with atorvastatin, which may be helpful in the choice of statin agents for AF treatment. However, longer follow-ups are necessary to assess the clinical value of lowering hs-CRP in the clinical setting of AF treatment outcomes. Fang-Cheng Su, Xi-Dong Li, Shao-Xia Sun, Ming-Yu Shi, Feng-Hua Xue, Shi-Chao Teng, Li Jiang, Jing Zhu, Feng Yin, and Hong-Yue Gu Copyright © 2015 Fang-Cheng Su et al. All rights reserved. Impact of Dabigatran versus Phenprocoumon on ADP Induced Platelet Aggregation in Patients with Atrial Fibrillation with or without Concomitant Clopidogrel Therapy (the Dabi-ADP-1 and Dabi-ADP-2 Trials) Wed, 01 Jul 2015 06:28:43 +0000 Background. A relevant number of patients receive triple therapy with clopidogrel, aspirin, and oral anticoagulation. Clopidogrel’s efficacy on ADP induced platelet function may be influenced by concomitant antithrombotic therapies. Data regarding the effect of dabigatran on platelet function is limited to in vitro studies and healthy individuals. Methods. The “Dabi-ADP-1” and “Dabi-ADP-2” trials randomized patients with atrial fibrillation to either dabigatran or phenprocoumon for a 2-week period. In Dabi-ADP-1 () patients with clopidogrel therapy were excluded and in Dabi-ADP-2 () patients had to be treated concomitantly with clopidogrel. The primary endpoint was ADP-induced platelet aggregation between dabigatran and phenprocoumon at 14 days. Secondary endpoints were ADPtest HS-, TRAP-, and COL-induced platelet aggregation. Results. There was no significant difference regarding the primary endpoint between both groups in either trial (Dabi-ADP-1: Dabigatran: 846 [650–983] AU × min versus phenprocoumon: 839 [666–1039] AU × min, and Dabi-ADP-2: 326 [268–462] versus 350 [214–535], ) or regarding the secondary endpoints, ADPtest HS-, TRAP-, and COL-induced platelet aggregation. Conclusion. Dabigatran as compared to phenprocoumon has no impact on ADP-induced platelet aggregation in atrial fibrillation patients neither with nor without concomitant clopidogrel therapy. Amadea M. Martischnig, Julinda Mehilli, Janina Pollak, Tobias Petzold, Anette K. Fiedler, Katharina Mayer, Stefanie Schulz-Schüpke, Dirk Sibbing, Steffen Massberg, Adnan Kastrati, and Nikolaus Sarafoff Copyright © 2015 Amadea M. Martischnig et al. All rights reserved. Surgical Treatment of Concomitant Atrial Fibrillation: Focus onto Atrial Contractility Wed, 01 Jul 2015 06:25:18 +0000 Background. Maze procedure aims at restoring sinus rhythm (SR) and atrial contractility (AC). This study evaluated multiple aspects of AC recovery and their relationship with SR regain after ablation. Methods. 122 mitral and fibrillating patients underwent radiofrequency Maze. Rhythm check and echocardiographic control of biatrial contractility were performed at 3, 6, 12, and 24 months postoperatively. A multivariate Cox analysis of risk factors for absence of AC recuperation was applied. Results. At 2-years follow-up, SR was achieved in 79% of patients. SR-AC coexistence increased from 76% until 98%, while biatrial contraction detection augmented from 84 to 98% at late stage. Shorter preoperative arrhythmia duration was the only common predictor of SR-AC restoring, while pulmonary artery pressure (PAP) negatively influenced AC recuperation. Early AC restoration favored future freedom from arrhythmia recurrence. Minor LA dimensions correlated with improved future A/E value and vice versa. Right atrial (RA) contractility restoring favored better left ventricular (LV) performance and volumes. Conclusions. SR and left AC are two interrelated Maze objectives. Factors associated with arrhythmia “chronic state” (PAP and arrhythmia duration) are negative predictors of procedural success. Our results suggest an association between postoperative LA dimensions and “kick” restoring and an influence of RA contraction onto LV function. Claudia Loardi, Francesco Alamanni, Claudia Galli, Moreno Naliato, Fabrizio Veglia, Marco Zanobini, and Mauro Pepi Copyright © 2015 Claudia Loardi et al. All rights reserved. Cardiomyocyte Remodeling in Atrial Fibrillation and Hibernating Myocardium: Shared Pathophysiologic Traits Identify Novel Treatment Strategies? Mon, 29 Jun 2015 12:42:11 +0000 Atrial fibrillation (AF) is the most common arrhythmia and is associated with a high risk of morbidity and mortality. However, there are limited treatment strategies for prevention of disease onset and progression. Development of novel therapies for primary and secondary prevention of AF is critical and requires improved understanding of the cellular and molecular mechanisms underlying the AF disease process. Translational and clinical studies conducted over the past twenty years have revealed that atrial remodeling in AF shares several important pathophysiologic traits with the remodeling processes exhibited by hibernating myocardium that develop in response to chronic ischemia. These shared features, which include an array of structural, metabolic, and electrophysiologic changes, appear to represent a conserved adaptive myocyte response to chronic stress that involves dedifferentiation towards a fetal phenotype to promote survival. In this review, we discuss the pathophysiology of AF, summarize studies supporting a common remodeling program in AF and hibernating myocardium, and propose future therapeutic implications of this emerging paradigm. Ultimately, better understanding of the molecular mechanisms of atrial myocyte remodeling during the onset of AF and the transition from paroxysmal to persistent stages of the disease may facilitate discovery of new therapeutic targets. Brian R. Weil and Cevher Ozcan Copyright © 2015 Brian R. Weil and Cevher Ozcan. All rights reserved. Human miR-221/222 in Physiological and Atherosclerotic Vascular Remodeling Mon, 29 Jun 2015 07:31:44 +0000 A cluster of miR-221/222 is a key player in vascular biology through exhibiting its effects on vascular smooth muscle cells (VSMCs) and endothelial cells (ECs). These miRNAs contribute to vascular remodeling, an adaptive process involving phenotypic and behavioral changes in vascular cells in response to vascular injury. In proliferative vascular diseases such as atherosclerosis, pathological vascular remodeling plays a prominent role. The miR-221/222 cluster controls development and differentiation of ECs but inhibits their proangiogenic activation, proliferation, and migration. miR-221/222 are primarily implicated in maintaining endothelial integrity and supporting quiescent EC phenotype. Vascular expression of miR-221/222 is upregulated in initial atherogenic stages causing inhibition of angiogenic recruitment of ECs and increasing endothelial dysfunction and EC apoptosis. In contrast, these miRNAs stimulate VSMCs and switching from the VSMC “contractile” phenotype to the “synthetic” phenotype associated with induction of proliferation and motility. In atherosclerotic vessels, miR-221/222 drive neointima formation. Both miRNAs contribute to atherogenic calcification of VSMCs. In advanced plaques, chronic inflammation downregulates miR-221/222 expression in ECs that in turn could activate intralesion neoangiogenesis. In addition, both miRNAs could contribute to cardiovascular pathology through their effects on fat and glucose metabolism in nonvascular tissues such as adipose tissue, liver, and skeletal muscles. Dmitry A. Chistiakov, Igor A. Sobenin, Alexander N. Orekhov, and Yuri V. Bobryshev Copyright © 2015 Dmitry A. Chistiakov et al. All rights reserved. The Role of Epigenetics in Arterial Calcification Mon, 29 Jun 2015 07:28:05 +0000 Arterial calcification is highly prevalent and correlated with cardiovascular mortality, especially in patients with ESRD or diabetes. The pathogenesis of arterial calcification is multifactorial, with both genetic and environmental factors being implicated. In recent years, several mechanisms contributing to arterial calcification have been proposed. However, these can only explain a small proportion of the variability in arterial calcification, which is a major obstacle for its prevention and management. Epigenetics has emerged as one of the most promising areas that may fill in some of the gaps in our current knowledge of the interaction between the environmental insults with gene regulation in the development of diseases. Epigenetics refers to heritable and acquired changes in gene transcription that occur independently of the DNA sequence. Well-known components of epigenetic regulation include DNA methylation, histone modifications, and microRNAs. Epigenetics research in the regulation of arterial calcification has only recently been elucidated. In this review, we will summarise recent progress in epigenetic pathways involved in arterial calcification and discuss potential therapeutic interventions based on epigenetic mechanisms. Shan-Shan Wu, Xiao Lin, Ling-Qing Yuan, and Er-Yuan Liao Copyright © 2015 Shan-Shan Wu et al. All rights reserved. MicroRNA Clusters in the Adult Mouse Heart: Age-Associated Changes Sun, 28 Jun 2015 12:36:44 +0000 The microRNAs and microRNA clusters have been implicated in normal cardiac development and also disease, including cardiac hypertrophy, cardiomyopathy, heart failure, and arrhythmias. Since a microRNA cluster has from two to dozens of microRNAs, the expression of a microRNA cluster could have a substantial impact on its target genes. In the present study, the configuration and distribution of microRNA clusters in the mouse genome were examined at various inter-microRNA distances. Three important microRNA clusters that are significantly impacted during adult cardiac aging, the miR-17-92, miR-106a-363, and miR-106b-25, were also examined in terms of their genomic location, RNA transcript character, sequence homology, and their relationship with the corresponding microRNA families. Multiple microRNAs derived from the three clusters potentially target various protein components of the cdc42-SRF signaling pathway, which regulates cytoskeleton dynamics associated with cardiac structure and function. The data indicate that aging impacted the expression of both guide and passenger strands of the microRNA clusters; nutrient stress also affected the expression of the three microRNA clusters. The miR-17-92, miR-106a-363, and miR-106b-25 clusters are likely to impact the Cdc42-SRF signaling pathway and thereby affect cardiac morphology and function during pathological conditions and the aging process. Xiaomin Zhang, Gohar Azhar, Emmanuel D. Williams, Steven C. Rogers, and Jeanne Y. Wei Copyright © 2015 Xiaomin Zhang et al. All rights reserved. miR-126 Is Involved in Vascular Remodeling under Laminar Shear Stress Sun, 28 Jun 2015 12:15:09 +0000 Morphology and changes in gene expression of vascular endothelium are mainly due to shear stress and inflammation. Cell phenotype modulation has been clearly demonstrated to be controlled by small noncoding micro-RNAs (miRNAs). This study focused on the effect of laminar shear stress (LSS) on human endothelial cells (HUVECs), with an emphasis on the role of miRNA-126 (miR-126). Exposure of HUVECs in vitro to LSS modified the shape of HUVECs and concomitantly regulated the expression of miR-126, vascular cell adhesion molecule 1 (VCAM-1), and syndecan-4 (SDC-4). A significant upregulation of miR-126 during long-term exposure to flow was shown. Interestingly, LSS enhanced SDC-4 expression on the HUVEC membranes. Overexpression of miR-126 in HUVECs decreased the levels of targets stromal cell-derived factor-1 SDF-1/CXCL12 and VCAM-1 but increased the expression of RGS16, CXCR4, and SDC-4. No significant difference in terms of cell proliferation and apoptosis was observed between scramble, anti-miR-126, and pre-miR-126 transfected HUVECs. In Apo-E KO/CKD mice aortas expressing a high level of miR-126, SDC-4 was concomitantly increased. In conclusion, our results suggest that miR-126 (i) is overexpressed by long-term LSS, (ii) has a role in up- and downregulation of genes involved in atherosclerosis, and (iii) affects SDC-4 expression. Ana Mondadori dos Santos, Laurent Metzinger, Oualid Haddad, Eléonore M’baya-Moutoula, Fatiha Taïbi, Nathalie Charnaux, Ziad A. Massy, Hanna Hlawaty, and Valérie Metzinger-Le Meuth Copyright © 2015 Ana Mondadori dos Santos et al. All rights reserved. MicroRNAs: Novel Players in Aortic Aneurysm Sun, 28 Jun 2015 11:03:09 +0000 An aortic aneurysm (AA) is a common disease with potentially life-threatening complications. Despite significant improvements in the diagnosis and treatment of AA, the associated morbidity and mortality remain high. MicroRNAs (miRNAs, miR) are small noncoding ribonucleic acids that negatively regulate gene expression at the posttranscriptional level by inhibiting mRNA translation or promoting mRNA degradation. miRNAs are recently reported to be critical modulators for vascular cell functions such as cell migration, contraction, differentiation, proliferation, and apoptosis. Increasing evidences suggest crucial roles of miRNAs in the pathogenesis and progression of cardiovascular diseases such as coronary artery disease, heart failure, arterial hypertension, and cardiac arrhythmias. Recently, some miRNAs, such as miR-24, miR-155, miR-205, miR-712, miR-21, miR-26a, miR-143/145, miR-29, and miR-195, have been demonstrated to be differentially expressed in the diseased aortic tissues and strongly associated with the development of AA. In the present paper, we reviewed the recent available literature regarding the role of miRNAs in the pathogenesis of AA. Moreover, we discuss the potential use of miRNAs as diagnostic and prognostic biomarkers and novel targets for development of effective therapeutic strategies for AA. Xian-ming Fu, Yang-zhao Zhou, Zhao Cheng, Xiao-bo Liao, and Xin-min Zhou Copyright © 2015 Xian-ming Fu et al. All rights reserved. The Emerging Role of miR-223 in Platelet Reactivity: Implications in Antiplatelet Therapy Sun, 28 Jun 2015 08:50:47 +0000 Platelets are anuclear cells and are devoid of genomic DNA, but they are capable of de novo protein synthesis from mRNA derived from their progenitor cells, megakaryocytes. There is mounting evidence that microRNA (miRNA) plays an important role in regulating gene expression in platelets. miR-223 is the most abundant miRNAs in megakaryocytes and platelets. One of the miR-223-regulated genes is ADP P2Y12, a key target for current antiplatelet drug therapy. Recent studies showed that a blunted response to P2Y12 antagonist, that is, high on-treatment platelet reactivity (HTPR), is a strong predictor of major cardiovascular events (MACEs) in coronary heart disease (CHD) patients receiving antiplatelet treatment. Recent clinical cohort study showed that the level of circulating miR-223 is inversely associated with MACE in CHD patients. In addition, our recent data demonstrated that the level of both intraplatelet and circulating miR-223 is an independent predictor for HTPR, thus providing a link between miR-223 and MACE. These lines of evidence indicate that miR-223 may serve as a potential regulatory target for HTPR, as well as a diagnostic tool for identification of HTPR in clinical settings. Rui Shi, Xin Zhou, Wen-Jie Ji, Ying-Ying Zhang, Yong-Qiang Ma, Jian-Qi Zhang, and Yu-Ming Li Copyright © 2015 Rui Shi et al. All rights reserved. Update on the Pathogenic Implications and Clinical Potential of microRNAs in Cardiac Disease Sun, 28 Jun 2015 08:19:20 +0000 miRNAs, a unique class of endogenous noncoding RNAs, are highly conserved across species, repress gene translation upon binding to mRNA, and thereby influence many biological processes. As such, they have been recently recognized as regulators of virtually all aspects of cardiac biology, from the development and cell lineage specification of different cell populations within the heart to the survival of cardiomyocytes under stress conditions. Various miRNAs have been recently established as powerful mediators of distinctive aspects in many cardiac disorders. For instance, acute myocardial infarction induces cardiac tissue necrosis and apoptosis but also initiates a pathological remodelling response of the left ventricle that includes hypertrophic growth of cardiomyocytes and fibrotic deposition of extracellular matrix components. In this regard, recent findings place various miRNAs as unquestionable contributing factors in the pathogenesis of cardiac disorders, thus begging the question of whether miRNA modulation could become a novel strategy for clinical intervention. In the present review, we aim to expose the latest mechanistic concepts regarding miRNA function within the context of CVD and analyse the reported roles of specific miRNAs in the different stages of left ventricular remodelling as well as their potential use as a new class of disease-modifying clinical options. Mario Notari, Julián Pulecio, and Ángel Raya Copyright © 2015 Mario Notari et al. All rights reserved. miR-27 and miR-125 Distinctly Regulate Muscle-Enriched Transcription Factors in Cardiac and Skeletal Myocytes Sun, 28 Jun 2015 07:25:49 +0000 MicroRNAs are noncoding RNAs of approximately 22–24 nucleotides which are capable of interacting with the 3′ untranslated region of coding RNAs (mRNAs), leading to mRNA degradation and/or protein translation blockage. In recent years, differential microRNA expression in distinct cardiac development and disease contexts has been widely reported, yet the role of individual microRNAs in these settings remains largely unknown. We provide herein evidence of the role of miR-27 and miR-125 regulating distinct muscle-enriched transcription factors. Overexpression of miR-27 leads to impair expression of Mstn and Myocd in HL1 atrial cardiomyocytes but not in Sol8 skeletal muscle myoblasts, while overexpression of miR-125 resulted in selective upregulation of Mef2d in HL1 atrial cardiomyocytes and downregulation in Sol8 cells. Taken together our data demonstrate that a single microRNA, that is, miR-27 or miR-125, can selectively upregulate and downregulate discrete number of target mRNAs in a cell-type specific manner. Estefania Lozano-Velasco, Jennifer Galiano-Torres, Alvaro Jodar-Garcia, Amelia E. Aranega, and Diego Franco Copyright © 2015 Estefania Lozano-Velasco et al. All rights reserved. A MicroRNA-Transcription Factor Blueprint for Early Atrial Arrhythmogenic Remodeling Sun, 28 Jun 2015 06:52:43 +0000 Spontaneous self-terminating atrial fibrillation (AF) is one of the most common heart rhythm disorders, yet the regulatory molecular mechanisms underlying this syndrome are rather unclear. MicroRNA (miRNA) transcriptome and expression of candidate transcription factors (TFs) with potential roles in arrhythmogenesis, such as Pitx2, Tbx5, and myocardin (Myocd), were analyzed by microarray, qRT-PCR, and Western blotting in left atrial (LA) samples from pigs with transitory AF established by right atrial tachypacing. Induced ectopic tachyarrhythmia caused rapid and substantial miRNA remodeling associated with a marked downregulation of Pitx2, Tbx5, and Myocd expression in atrial myocardium. The downregulation of Pitx2, Tbx5, and Myocd was inversely correlated with upregulation of the corresponding targeting miRNAs (miR-21, miR-10a/10b, and miR-1, resp.) in the LA of paced animals. Through in vitro transient transfections of HL-1 atrial myocytes, we further showed that upregulation of miR-21 did result in downregulation of Pitx2 in cardiomyocyte background. The results suggest that immediate-early miRNA remodeling coupled with deregulation of TF expression underlies the onset of AF. Mario Torrado, Diego Franco, Estefanía Lozano-Velasco, Francisco Hernández-Torres, Ramón Calviño, Guillermo Aldama, Alberto Centeno, Alfonso Castro-Beiras, and Alexander Mikhailov Copyright © 2015 Mario Torrado et al. All rights reserved. Runx2/miR-3960/miR-2861 Positive Feedback Loop Is Responsible for Osteogenic Transdifferentiation of Vascular Smooth Muscle Cells Sun, 28 Jun 2015 06:48:56 +0000 We previously reported that Runx2/miR-3960/miR-2861 regulatory feedback loop stimulates osteoblast differentiation. However, the effect of this feedback loop on the osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs) remains unclear. Our recent study showed that miR-2861 and miR-3960 expression increases significantly during β-glycerophosphate-induced osteogenic transdifferentiation of VSMCs. Overexpression of miR-2861 or miR-3960 in VSMCs enhances β-glycerophosphate-induced osteoblastogenesis, whereas inhibition of miR-2861 or miR-3960 expression attenuates it. MiR-2861 or miR-3960 promotes osteogenic transdifferentiation of VSMCs by targeting histone deacetylase 5 or Homeobox A2, respectively, resulting in increased runt-related transcription factor 2 (Runx2) protein production. Furthermore, overexpression of Runx2 induces miR-2861 and miR-3960 transcription, and knockdown of Runx2 attenuates β-glycerophosphate-induced miR-2861 and miR-3960 transcription in VSMCs. Thus, our data show that Runx2/miR-3960/miR-2861 positive feedback loop plays an important role in osteogenic transdifferentiation of VSMCs and contributes to vascular calcification. Zhu-Ying Xia, Yin Hu, Ping-Li Xie, Si-Yuan Tang, Xiang-Hang Luo, Er-Yuan Liao, Fei Chen, and Hui Xie Copyright © 2015 Zhu-Ying Xia et al. All rights reserved. MicroRNA-143/-145 in Cardiovascular Diseases Sun, 28 Jun 2015 06:29:54 +0000 MicroRNAs (miRNAs) play an essential role in the onset and development of many cardiovascular diseases. Increasing evidence shows that miRNAs can be used as potential diagnostic biomarkers for cardiovascular diseases, and miRNA-based therapy may be a promising therapy for the treatment of cardiovascular diseases. The microRNA-143/-145 (miR-143/-145) cluster is essential for differentiation of vascular smooth muscle cells (VSMCs) and determines VSMC phenotypic switching. In this review, we summarize the recent progress in knowledge concerning the function of miR-143/-145 in the cardiovascular system and their role in cardiovascular diseases. We discuss the potential role of miR-143/-145 as valuable biomarkers for cardiovascular diseases and explore the potential strategy of targeting miR-143 and miR-145. Wang Zhao, Shui-Ping Zhao, and Yu-Hong Zhao Copyright © 2015 Wang Zhao et al. All rights reserved. Direct Cardiac Reprogramming: Advances in Cardiac Regeneration Mon, 15 Jun 2015 09:12:23 +0000 Heart disease is one of the lead causes of death worldwide. Many forms of heart disease, including myocardial infarction and pressure-loading cardiomyopathies, result in irreversible cardiomyocyte death. Activated fibroblasts respond to cardiac injury by forming scar tissue, but ultimately this response fails to restore cardiac function. Unfortunately, the human heart has little regenerative ability and long-term outcomes following acute coronary events often include chronic and end-stage heart failure. Building upon years of research aimed at restoring functional cardiomyocytes, recent advances have been made in the direct reprogramming of fibroblasts toward a cardiomyocyte cell fate both in vitro and in vivo. Several experiments show functional improvements in mouse models of myocardial infarction following in situ generation of cardiomyocyte-like cells from endogenous fibroblasts. Though many of these studies are in an early stage, this nascent technology holds promise for future applications in regenerative medicine. In this review, we discuss the history, progress, methods, challenges, and future directions of direct cardiac reprogramming. Olivia Chen and Li Qian Copyright © 2015 Olivia Chen and Li Qian. All rights reserved. State of the Art on the Evidence Base in Cardiac Regenerative Therapy: Overview of 41 Systematic Reviews Mon, 15 Jun 2015 09:09:02 +0000 Objectives. To provide a comprehensive appraisal of the evidence from secondary research on cardiac regenerative therapy. Study Design and Setting. Overview of systematic reviews of controlled clinical trials concerning stem cell administration or mobilization in patients with cardiovascular disease. Results. After a systematic database search, we short-listed 41 reviews (660 patients). Twenty-two (54%) reviews focused on acute myocardial infarction (AMI), 19 (46%) on chronic ischemic heart disease (IHD) or heart failure (HF), 29 (71%) on bone marrow-derived stem-cells (BMSC), and 36 (88%) to randomized trials only. Substantial variability among reviews was found for validity (AMSTAR score: median 9 [minimum 3]; 1st quartile 9; 3rd quartile 10; maximum 11), effect estimates (change in ejection fraction from baseline to follow-up: 3.47% [0.02%; 2.90%; 4.22%; 6.11%]), and citations (Web of Science yearly citations: 4.1 [0; 2.2; 6.5; 68.9]). No significant association was found between these three features. However, reviews focusing on BMSC therapy had higher validity scores () and showed more pronounced effect estimates (). Higher citations were associated with journal impact factor (), corresponding author from North America/Europe (), and inclusion of nonrandomized trials (). Conclusions. Substantial heterogeneity is apparent among these reviews in terms of quality and effect estimates. Mariangela Peruzzi, Elena De Falco, Antonio Abbate, Giuseppe Biondi-Zoccai, Isotta Chimenti, Marzia Lotrionte, Umberto Benedetto, Ronak Delewi, Antonino G. M. Marullo, and Giacomo Frati Copyright © 2015 Mariangela Peruzzi et al. All rights reserved. Stem Cell-Based Therapies in Chagasic Cardiomyopathy Mon, 15 Jun 2015 09:03:01 +0000 Chagas disease is caused by Trypanosoma cruzi and can lead to a dilated cardiomyopathy decades after the prime infection by the parasite. As with other dilated cardiomyopathies, conventional pharmacologic therapies are not always effective and as heart failure progresses patients need heart transplantation. Therefore alternative therapies are highly desirable and cell-based therapies have been investigated in preclinical and clinical studies. In this paper we review the main findings of such studies and discuss future directions for stem cell-based therapies in chronic chagasic cardiomyopathy. Antonio Carlos Campos de Carvalho and Adriana Bastos Carvalho Copyright © 2015 Antonio Carlos Campos de Carvalho and Adriana Bastos Carvalho. All rights reserved. Circulating MicroRNAs: Potential and Emerging Biomarkers for Diagnosis of Cardiovascular and Cerebrovascular Diseases Thu, 28 May 2015 06:03:33 +0000 MicroRNAs (miRNAs) are composed of a group of endogenous and noncoding small RNAs which control expression of complementary target mRNAs. The extended functions of miRNAs enhance the complexity of gene-regulatory processes in cardiovascular and cerebrovascular diseases. Indeed, recent studies have shown that miRNAs are closely related to myocardial infarction, heart failure, atrial fibrillation, cardiomyopathy, hypertension, angiogenesis, coronary artery disease, dyslipidaemia, stroke, and so forth. These findings suggest a new therapeutic pointcut for cardiovascular and cerebrovascular diseases and show the extensive therapeutic potential of miRNA regulation. Moreover, it has been shown that circulating extracellular miRNAs are stable in bodily fluids, which indicates circulating miRNAs as potential and emerging biomarkers for noninvasive diagnosis. This review highlights the most recent findings indicative of circulating miRNAs as potential clinical biomarkers for diagnosis of cardiovascular and cerebrovascular diseases. Meng Li and Junping Zhang Copyright © 2015 Meng Li and Junping Zhang. All rights reserved. Cardioprotective Effects of Tualang Honey: Amelioration of Cholesterol and Cardiac Enzymes Levels Sun, 03 May 2015 15:24:21 +0000 The present study was designed to investigate the cardioprotective effects of Malaysian Tualang honey against isoproterenol- (ISO-) induced myocardial infarction (MI) in rats by investigating changes in the levels of cardiac marker enzymes, cardiac troponin I (cTnI), triglycerides (TG), total cholesterol (TC), lipid peroxidation (LPO) products, and antioxidant defense system combined with histopathological examination. Male albino Wistar rats (n = 40) were pretreated orally with Tualang honey (3 g/kg/day) for 45 days. Subcutaneous injection of ISO (85 mg/kg in saline) for two consecutive days caused a significant increase in serum cardiac marker enzymes (creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), and aspartate transaminase (AST)), cTnI, serum TC, and TG levels. In addition, ISO-induced myocardial injury was confirmed by a significant increase in heart lipid peroxidation (LPO) products (TBARS) and a significant decrease in antioxidant enzymes (SOD, GPx, GRx, and GST). Pretreatment of ischemic rats with Tualang honey conferred significant protective effects on all of the investigated biochemical parameters. The biochemical findings were further confirmed by histopathological examination in both Tualang-honey-pretreated and ISO-treated hearts. The present study demonstrates that Tualang honey confers cardioprotective effects on ISO-induced oxidative stress by contributing to endogenous antioxidant enzyme activity via inhibition of lipid peroxidation. Md. Ibrahim Khalil, E. M. Tanvir, Rizwana Afroz, Siti Amrah Sulaiman, and Siew Hua Gan Copyright © 2015 Md. Ibrahim Khalil et al. All rights reserved. Changes of the eSheath Outer Dimensions Used for Transfemoral Transcatheter Aortic Valve Replacement Thu, 23 Apr 2015 11:01:35 +0000 Innovative catheter systems with lower-profile sheaths and a dynamic expansion mechanism (DEM) were recently introduced for transcatheter aortic valve replacement (TAVR). However, the labeling of 14 F and 16 F eSheaths denote the inner nominal diameter. Exact changes of the clinically relevant outer diameters during usage are not available. eSheaths were measured every 30 mm using a digital caliper. Unused 14 F and 16 F eSheaths served as controls. Maximum eSheath diameters were measured after insertion of the Edwards Commander Delivery System (ECDS) into 14 F and 16 F eSheaths.Finally, eSheaths were retrieved and measured after TAVR. Outer diameters of control 14 F eSheaths were 5.8 mm and 6.50 mm for the 16 F eSheath. Introduction of the 23 mm and 26 mm ECDS into 14 F eSheaths showed a maximum diameter of 7.65 mm and 7.64 mm (). Introduction of the 29 mm ECDS into the 16 F eSheath showed the greatest diameter of 8.18 mm (). After TAVR, diameters of the 14 F eSheaths were 7.14 mm (23 mm valve) and 7.26 mm (26 mm valve) (), while 16 F eSheaths were 8.10 mm (29 mm valve) (). Nominal 14 F and 16 F eSheaths showed a significant increase of the outer diameter during advancement of the ECDS and after TAVR implantation. Till Koehler, Michael Buege, Heinrich Schleiting, Melchior Seyfarth, Klaus Tiroch, and Marc Vorpahl Copyright © 2015 Till Koehler et al. All rights reserved. Cardioprotective Activity of Pongamia pinnata in Streptozotocin-Nicotinamide Induced Diabetic Rats Tue, 14 Apr 2015 14:21:31 +0000 Pongamia pinnata (L.) Pierre has been used in traditional medicine for the treatment for diabetes and metabolic disorder. The aim of this study was to investigate the effect of petroleum ether extract of the stem bark of P. pinnata (known as PPSB-PEE) on cardiomyopathy in diabetic rats. Diabetes was induced in overnight fasted Sprague-Dawley rats by using injection of streptozotocin (55 mg/kg, i.p.). Nicotinamide (100 mg/kg, i.p.) was administered 20 min before administration of streptozotocin. Rats were divided into group I: nondiabetic, group II: diabetic control (tween 80, 2%; 10 mL/kg, p.o.) as vehicle, and group III: PPSB-PEE (100 mg/kg, p.o.). The blood glucose level, ECG, hemodynamic parameters, cardiotoxic and antioxidant biomarkers, and histology of heart were carried out after 4 months after STZ with nicotinamide injection. PPSB-PEE treatment improved the electrocardiographic, hemodynamic changes; LV contractile function; biological markers; oxidative stress parameters; and histological changes in STZ induced diabetic rats. PPSB-PEE (100 mg/kg, p.o.) decreased blood glucose level, improved electrocardiographic parameters (QRS, QT, and QTc intervals) and hemodynamic parameters (SBP, DBP, EDP, max , contractility index, and heart rate), controlled levels of cardiac biomarkers (CK-MB, LDH, and AST), and improved oxidative stress (SOD, MDA, and GSH) in diabetic rats. PPSB-PEE is a promising remedy against cardiomyopathy in diabetic rats. Sachin L. Badole, Swapnil M. Chaudhari, Ganesh B. Jangam, Amit D. Kandhare, and Subhash L. Bodhankar Copyright © 2015 Sachin L. Badole et al. All rights reserved. A Preliminary Real-Time and Realistic Simulation Environment for Percutaneous Coronary Intervention Mon, 23 Mar 2015 13:49:54 +0000 Percutaneous coronary intervention (PCI) is a minimally invasive surgery procedure that is widely used in the treatment of coronary artery disease. This procedure requires interventional cardiologists to have high proficiency and therefore demands an extensive training period in order to ensure successful surgical outcome. In this paper, a realistic and real-time interactive simulator for training PCI procedure is presented. A set of new approaches for core simulation components is devised and integrated into the simulator. Trainees can interact with the virtual simulation environment with real instruments and essential maneuvers encountered in real PCI procedure. Although presently targeted at PCI, our simulator could be easily extended to mimic the necessities of any vascular interventional radiology procedures by updating vascular anatomy. Preliminary validation of the proposed physical model of instruments is conducted on vascular phantom to demonstrate its performance and effectiveness. Jianhuang Wu, Haoyu Wang, Peng Zhang, Xin Ma, and Qingmao Hu Copyright © 2015 Jianhuang Wu et al. All rights reserved. Wharton’s Jelly Derived Mesenchymal Stem Cells: Future of Regenerative Medicine? Recent Findings and Clinical Significance Sun, 15 Mar 2015 13:29:18 +0000 Around 5 million annual births in EU and 131 million worldwide give a unique opportunity to collect lifesaving Wharton’s jelly derived mesenchymal stem cells (WJ-MSC). Evidences that these cells possess therapeutic properties are constantly accumulating. Collection of WJ-MSC is done at the time of delivery and it is easy and devoid of side effects associated with collection of adult stem cells from bone marrow or adipose tissue. Likewise, their rate of proliferation, immune privileged status, lack of ethical concerns, nontumorigenic properties make them ideal for both autologous and allogeneic use in regenerative medicine applications. This review provides an outline of the recent findings related to WJ-MSC therapeutic effects and possible advantage they possess over MSC from other sources. Results of first clinical trials conducted to treat immune disorders are highlighted. Ilona Kalaszczynska and Katarzyna Ferdyn Copyright © 2015 Ilona Kalaszczynska and Katarzyna Ferdyn. All rights reserved. Preclinical Evaluation of the Immunomodulatory Properties of Cardiac Adipose Tissue Progenitor Cells Using Umbilical Cord Blood Mesenchymal Stem Cells: A Direct Comparative Study Tue, 10 Mar 2015 11:34:34 +0000 Cell-based strategies to regenerate injured myocardial tissue have emerged over the past decade, but the optimum cell type is still under scrutiny. In this context, human adult epicardial fat surrounding the heart has been characterized as a reservoir of mesenchymal-like progenitor cells (cardiac ATDPCs) with potential clinical benefits. However, additional data on the possibility that these cells could trigger a deleterious immune response following implantation are needed. Thus, in the presented study, we took advantage of the well-established low immunogenicity of umbilical cord blood-derived mesenchymal stem cells (UCBMSCs) to comparatively assess the immunomodulatory properties of cardiac ATDPCs in an in vitro allostimulatory assay using allogeneic mature monocyte-derived dendritic cells (MDDCs). Similar to UCBMSCs, increasing amounts of seeded cardiac ATDPCs suppressed the alloproliferation of T cells in a dose-dependent manner. Secretion of proinflammatory cytokines (IL6, TNFα, and IFNγ) was also specifically modulated by the different numbers of cardiac ATDPCs cocultured. In summary, we show that cardiac ATDPCs abrogate T cell alloproliferation upon stimulation with allogeneic mature MDDCs, suggesting that they could further regulate a possible harmful immune response in vivo. Additionally, UCBMSCs can be considered as valuable tools to preclinically predict the immunogenicity of prospective regenerative cells. Isaac Perea-Gil, Marta Monguió-Tortajada, Carolina Gálvez-Montón, Antoni Bayes-Genis, Francesc E. Borràs, and Santiago Roura Copyright © 2015 Isaac Perea-Gil et al. All rights reserved. Impact of Umbilical Cord Blood-Derived Mesenchymal Stem Cells on Cardiovascular Research Tue, 10 Mar 2015 11:25:15 +0000 Over the years, cell therapy has become an exciting opportunity to treat human diseases. Early enthusiasm using adult stem cell sources has been tempered in light of preliminary benefits in patients. Considerable efforts have been dedicated, therefore, to explore alternative cells such as those extracted from umbilical cord blood (UCB). In line, UCB banking has become a popular possibility to preserve potentially life-saving cells that are usually discarded after birth, and the number of UCB banks has grown worldwide. Thus, a brief overview on the categories of UCB banks as well as the properties, challenges, and impact of UCB-derived mesenchymal stem cells (MSCs) on the area of cardiovascular research is presented. Taken together, the experience recounted here shows that UCBMSCs are envisioned as attractive therapeutic candidates against human disorders arising and/or progressing with vascular deficit. Santiago Roura, Josep Maria Pujal, Carolina Gálvez-Montón, and Antoni Bayes-Genis Copyright © 2015 Santiago Roura et al. All rights reserved. Shengmai Injection Improved Doxorubicin-Induced Cardiomyopathy by Alleviating Myocardial Endoplasmic Reticulum Stress and Caspase-12 Dependent Apoptosis Mon, 09 Mar 2015 09:20:10 +0000 Background. Apoptosis plays vital roles in the progression of doxorubicin-induced cardiomyopathy (DOX-CM). Endoplasmic reticulum stress (ER stress) could induce specific apoptosis by caspase-12 dependent pathway. Shengmai Injection (SMI), a famous Traditional Chinese Medicine, could alleviate the heart damage via inhibiting myocardial apoptosis. However, it is unknown whether SMI can alleviate ER stress and its specific apoptosis in the setting of DOX-CM. Objective. To explore the effects of SMI on heart function, myocardial ER stress, and apoptosis of DOX-CM rats. Methods. Rats with DOX-CM were treated by SMI. Heart function was assessed by echocardiography and brain natriuretic peptide. Myocardial apoptosis was detected by TUNEL assay. ER stress was assessed by detecting the expressions of GRP78 and caspase-12. Results. At the end of eight-week, compared to control, significant heart dysfunction happened in DOX group. The ratio of apoptotic cardiomyocytes and the expressions of GRP78 and caspase-12 increased significantly (). Compared to DOX group, the apoptotic ratio and the expressions of GRP78 and caspase-12 significantly decreased in DOX + SMI group (), accompanied with improved heart function. Conclusion. SMI could alleviate myocardial ER stress and caspase-12 dependent apoptosis, which subsequently helped to improve the heart function of rats with DOX-CM. Yu Chen, Yong Tang, Yin Xiang, Yu-Quan Xie, Xiao-Hong Huang, and Ya-Chen Zhang Copyright © 2015 Yu Chen et al. All rights reserved. The Association between Serum LDL Cholesterol and Genetic Variation in Chromosomal Locus 1p13.3 among Coronary Artery Disease Patients Sun, 08 Mar 2015 07:55:49 +0000 Background. Several polymorphisms of a locus on chromosome 1p13.3 have a significant effect on low-density lipoprotein cholesterol (LDL-C), atherosclerosis, and acute coronary syndrome (ACS). Methods. We aimed to investigate the association between rs599839, rs646776, and rs4970834 of locus 1p13.3 and serum LDL-C and severity of coronary artery stenosis in ACS patients. Genotyping of the rs599839, rs646776, and rs4970834 polymorphisms was performed on Arab patients undergoing coronary angiography for ACS. Patients were divided into group A (ACS with insignificant stenosis (<50%)) and group B (with significant stenosis (≥50%)). Results. Patients carrying the minor G allele in rs599839 had significantly lower mean of LDL-C (2.58 versus 3.44 mM, ) than homozygous A allele carriers (GG versus AA). Carriers of minor C allele in rs64776 had significantly higher mean of HDL-C (2.16 versus 1.36 mM, ) than carriers of the T alleles (AA versus GG). The odd ratio and 95% confidence interval for dominant model for G allele carriers of rs599839 were 0.51 (0.30–0.92), , among patients with significant stenosis. Conclusions. Polymorphisms rs646776 and rs599839 of locus 1p13.3 were significantly associated with LDL-C and other lipid parameters. In addition, the G-allele carriers of variant rs599839 had a significant protective effect against the atherosclerosis. Nasser M. Rizk, Ayman El-Menyar, Huda Egue, Idil Souleman Wais, Hissa Mohamed Baluli, Khalid Alali, Fathi Farag, Noura Younes, and Jassim Al Suwaidi Copyright © 2015 Nasser M. Rizk et al. All rights reserved. Validation of New and Existing Decision Rules for the Estimation of Beat-to-Beat Pulse Transit Time Mon, 02 Mar 2015 07:05:54 +0000 Pulse transit time (PTT) is a pivotal marker of vascular stiffness. Because the actual PTT duration in vivo is unknown and the complicated variation in waveform may occur, the robust determination of characteristic point is still a very difficult task in the PTT estimation. Our objective is to devise a method for real-time estimation of PTT duration in pulse wave. It has an ability to reduce the interference caused by both high- and low-frequency noise. The reproducibility and performance of these methods are assessed on both artificial and clinical pulse data. Artificial data are generated to investigate the reproducibility with various signal-to-noise ratios. For all artificial data, the mean biases obtained from all methods are less than 1 ms; collectively, this newly proposed method has minimum standard deviation (SD, <1 ms). A set of data from 33 participants together with the synchronously recorded continuous blood pressure data are used to investigate the correlation coefficient (CC). The statistical analysis shows that our method has maximum values of mean CC (0.5231), sum of CCs (17.26), and median CC (0.5695) and has the minimum SD of CCs (0.1943). Overall, the test results in this study indicate that the newly developed method has advantages over traditional decision rules for the PTT measurement. Xiaolin Zhou, Rongchao Peng, Hongxia Ding, Ningling Zhang, and Pan Li Copyright © 2015 Xiaolin Zhou et al. All rights reserved. Comparative Myocardial Deformation in 3 Myocardial Layers in Mice by Speckle Tracking Echocardiography Mon, 02 Mar 2015 07:04:43 +0000 Background. Speckle tracking echocardiography (STE) using dedicated high-resolution ultrasound is a relatively new technique that is useful in assessing myocardial deformation in 3 myocardial layers in small animals. However, comparative studies of STE parameters acquired from murine are limited. Methods. A high-resolution rodent ultrasound machine (VSI Vevo 2100) and a clinically validated ultrasound machine (GE Vivid 7) were used to consecutively acquire echocardiography images from standardized parasternal long axis and short axis at midpapillary muscle level from 13 BALB/c mice. Speckle tracking strain (longitudinal, circumferential, and radial) from endocardial, myocardial, and epicardial layers was analyzed using vendor-specific offline analysis software. Results. Intersystem differences were not statistically significant in the global peak longitudinal strain (−16.8 ± 1.7% versus −18.7 ± 3.1%) and radial strain (46.8 ± 14.2% versus 41.0 ± 9.5%), except in the global peak circumferential strain (−16.9 ± 3.1% versus 27.0 ± 5.2%, ). This was corroborated by Bland Altman analysis that revealed a weak agreement in circumferential strain (mean bias ± 1.96 SD of −10.12 ± 6.06%) between endocardium and midmyocardium. However, a good agreement was observed in longitudinal strain between midmyocardium/endocardium (mean bias ± 1.96 SD of −1.88 ± 3.93%) and between midmyocardium/epicardium (mean bias ± 1.96 SD of 3.63 ± 3.91%). Radial strain (mean bias ± 1.96 SD of −5.84 ± 17.70%) had wide limits of agreement between the two systems that indicated an increased variability. Conclusions. Our study shows that there is good reproducibility and agreement in longitudinal deformation of the 3 myocardial layers between the two ultrasound systems. Directional deformation gradients at endocardium, myocardium, and epicardium observed in mice were consistent to those reported in human subjects, thus attesting the clinical relevance of STE findings in murine cardiovascular disease models. Nicole Tee, Yacui Gu, Murni, and Winston Shim Copyright © 2015 Nicole Tee et al. All rights reserved. Acute Myocardial Infarction: A Comparison of the Risk between Physicians and the General Population Mon, 23 Feb 2015 11:57:30 +0000 Physicians in Taiwan have a heavy workload and a stressful workplace, both of which may contribute to cardiovascular disease. However, the risk of acute myocardial infarction (AMI) in physicians is not clear. This population-based cohort study used Taiwan’s National Health Insurance Research Database. We identified 28,062 physicians as the case group and randomly selected 84,186 nonmedical staff patients as the control group. We used a conditional logistic regression to compare the AMI risk between physicians and controls. Subgroup analyses of physician specialty, age, gender, comorbidities, area, and hospital level were also done. Physicians have a higher prevalence of HTN (23.59% versus 19.06%, ) and hyperlipidemia (21.36% versus 12.93%, ) but a lower risk of AMI than did the controls (adjusted odds ratio (AOR): 0.57; 95% confidence interval (CI): 0.46–0.72) after adjusting for DM, HTN, hyperlipidemia, and area. Between medical specialty, age, and area subgroups, differences in the risk for having an AMI were nonsignificant. Medical center physicians had a lower risk (AOR: 0.42; 95% CI: 0.20–0.85) than did local clinic physicians. Taiwan’s physicians had higher prevalences of HTN and hyperlipidemia, but a lower risk of AMI than did the general population. Medical center physicians had a lower risk than did local clinic physicians. Physicians are not necessary healthier than the general public, but physicians, especially in medical centers, have a greater awareness of disease and greater access to medical care, which permits timely treatment and may prevent critical conditions such as AMI induced by delayed treatment. Yen-ting Chen, Chien-Cheng Huang, Shih-Feng Weng, Chien-Chin Hsu, Jhi-Joung Wang, Hung-Jung Lin, Shih-Bin Su, How-Ran Guo, and Chi-Wen Juan Copyright © 2015 Yen-ting Chen et al. All rights reserved. Cardiac Function in a Long-Term Follow-Up Study of Moderate and Severe Porcine Model of Chronic Myocardial Infarction Mon, 23 Feb 2015 08:52:31 +0000 Background. Novel therapies need to be evaluated in a relevant large animal model that mimics the clinical course and treatment in a reasonable time frame. To reliably assess therapeutic efficacy, knowledge regarding the translational model and the course of disease is needed. Methods. Landrace pigs were subjected to a transient occlusion of the proximal left circumflex artery (LCx) or mid-left anterior descending artery (LAD) for 150 min. Cardiac function was evaluated before by 2D echocardiography or 3D echocardiography and pressure-volume loop analysis. At 12 weeks of follow-up the heart was excised for histological analysis and infarct size calculations. Results. Directly following AMI, LVEF was severely reduced compared to baseline in the LAD group compared to only a moderate reduction in the LCx group and this effect remained unchanged during 12 weeks of follow-up. Conclusion. Two models of chronic MI, representative for different patient groups, can reproducibly be created through clinically relevant ischemia-reperfusion of the mid-LAD and proximal LCx. Renate de Jong, Gerardus P. J. van Hout, Jaco H. Houtgraaf, S. Takashima, Gerard Pasterkamp, Imo Hoefer, and Henricus J. Duckers Copyright © 2015 Renate de Jong et al. All rights reserved.