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Journal of Immunology Research
Volume 2019, Article ID 2164017, 9 pages
https://doi.org/10.1155/2019/2164017
Review Article

Role of Inflammatory Cell Subtypes in Heart Failure

1Cardiovascular Pulmonary Research Laboratory, University of Colorado Denver, Aurora CO, USA
2Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Denver, Aurora CO, USA
3Rocky Mountain Regional VA Medical Center, Aurora CO, USA
4Department of Pediatrics, University of Colorado Denver, Aurora CO, USA

Correspondence should be addressed to Derek Strassheim; ude.revnedcu@miehssarts.kered

Received 20 December 2018; Accepted 25 July 2019; Published 2 September 2019

Academic Editor: Ilaria Roato

Copyright © 2019 Derek Strassheim et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Inflammation is a well-known feature of heart failure. Studies have shown that while some inflammation is required for repair during injury and is protective, prolonged inflammation leads to myocardial remodeling and apoptosis of cardiac myocytes. Various types of immune cells are implicated in myocardial inflammation and include neutrophils, macrophages, eosinophils, mast cells, natural killer cells, T cells, and B cells. Recent clinical trials have targeted inflammatory cascades as therapy for heart failure with limited success. A better understanding of the temporal course of the infiltration of the different immune cells and their contribution to the inflammatory process may improve the success for therapy. This brief review outlines the major cell types involved in heart failure, and some of their actions are summarized in the supplementary figure.

1. Introduction

Heart failure develops secondary to left ventricular (LV) systolic and diastolic dysfunction. Systolic heart failure is also known as heart failure with reduced ejection fraction (HFrEF) and occurs when a decreased force of contractility of the left ventricle reduces the pumping capacity. Diastolic dysfunction, also known as heart failure with preserved ejection fraction (HFpEF), occurs when the muscle in the left ventricle becomes stiff, due to either change in contractile proteins of cardiac myocytes or effect of fibrosis on relaxation [14]. Right heart failure occurs in association with lung disease leading to pulmonary hypertension and as an end stage of left ventricular failure [5]. Risk factors that contribute to the development of heart failure include ischemic injury, hypertension, and metabolic syndrome and age [6]. Genetic cardiomyopathies occur in patients with autosomal dominant mutations in various sarcomeric proteins [7, 8]. Mechanical dysfunction, due to valve dysfunction, and aortic stenosis in the elderly cause pressure overload leading to cardiac hypertrophy and can progress into LV dysfunction [8]. Immune-based cardiomyopathies occur in autoimmune diseases and due to infectious agents (viral and bacterial) when the innate and adaptive immune systems are activated to coordinate a primary response [9].

The role of elevated inflammatory biomarkers in chronic HF and in disease progression is not clear [6]. Measurement of biomarkers in patients with systolic HF (either ischemic or nonischemic) and animal studies has demonstrated an elevation in proinflammatory cytokines (such as TNF-α, IL-1, IL-6, galectin 3, TNF receptor 1, and TNF receptor 2), during HF progression supporting the hypothesis that inflammation may contribute to HF.

Studies show that resident and recruited immune cells play a role in cardiac injury and are present in cardiac tissue early in disease [15, 9]. Initially, resident and infiltrating immune cells activate inflammatory/reparative pathways, and the relative balance between pathological inflammatory pathways and tissue reparative processes (physiological inflammation) defines the course of HF development [10]. Immune cells coordinate cardiomyocyte and noncardiomyocyte responses during maladaptive remodeling. These cells modulate not only cardiomyocyte function but also injury responses involving scar formation and interstitial fibrosis, which affect cardiac function. Therefore, modulating immune responses may be beneficial for therapy. In this review, we will discuss the role of different immune cells in noninfectious heart failure where activation of the immune system was a secondary response to dysfunction.

2. Immune Cells in the Heart

Immune cells identified in the heart either reside or infiltrate heart tissue and include macrophages, mast cells, monocytes, neutrophils, eosinophils, B cells, and T cells [11]. Inflammation in non-immune-mediated cardiac injury leads to secretion of inflammatory cytokines and chemokines such as IL-1, IL-6, TNF-α, and CC-chemokine ligand 2 (CCL2) and GM-CSF [11, 12]. An increase in levels of cytokines and chemokines leads to the recruitment of neutrophils and monocytes, from hematopoietic stem and progenitor cells (HSPCs) to the heart that scavenge dead cells [13]. Initially, the immune cells infiltrated the cells to scavenge dead and dying cardiomyocytes by digesting the tissue with proteolytic enzymes [14]. The inflammatory cascade is amplified by the dead cells causing further release of inflammatory cytokines which further amplify inflammation through their effects on leukocytes, endothelial cells, and cardiomyocytes [15]. Therefore, it is essential to identify the cytokines released by various cells and their role in the inflammatory cascade.

2.1. Neutrophils

Many studies show the involvement of neutrophils in the progression of cardiovascular diseases (CVD) including atherosclerosis, thrombosis, and ACS3 [16]. In ischemic cardiomyopathy, neutrophils infiltrate the infarcted myocardium and mediate tissue damage [17]. Neutrophils are short-lived and undergo apoptosis and shed the IL-6 receptor, which modulates the outcome of the inflammatory response by activating endothelial cells to recruit additional and a wider variety of leukocytes [14, 1820]. As regulators of both innate and adaptive immune responses, neutrophils can influence chronic immune response and affect the function of dendritic cells as well as lymphocytes. Neutrophils have shown to improve cardiac healing following myocardial infarction (MI), by promoting macrophage polarization towards a reparative phenotype through the release of neutrophil gelatinase-associated lipocalin [21, 22]. Depletion of neutrophils does not affect infarct size, but worsens cardiac function and heart failure, and increases cardiac fibrosis [21]. In a rat model, histology and staining for myeloperoxidase (MPO) activity revealed a significant accumulation of neutrophils in α-toxin A-challenged hearts concomitant with reduced cardiac contractility and endothelial dysfunction [23]. Plasma levels of MPO correlated with LVEF and LV end-diastolic volume in a model system of HF [24]. Atherosclerosis studies have shown hyperlipidemia-associated neutrophilia and a role for neutrophils in plaque destabilization [25]. Neutrophil blood count has shown to correlate with the severity of coronary damage in patients with coronary artery disease [26]. Perivascular accumulation of neutrophils and macrophages has been observed in murine lungs in association with hypoxic pulmonary hypertension (PH) and monocrotaline-induced PH in rats [27]. In right ventricular (RV) failure associated with experimental pulmonary hypertension, increased expression of IL-1β, IL-6, and IL-10, accompanied by infiltration of both neutrophils and macrophages, is observed [18]. Although the role of neutrophils in the pathogenesis of PAH has not been studied, an increase in a neutrophil-to-lymphocyte ratio is observed in PAH patients [28]. An increase in neutrophil elastase causes tissue damage. In clinical studies, a neutrophil-to-leukocyte ratio (NLR) showed a strong association with HF and death [29, 30]. NLR is shown to be associated with chronic kidney disease, major cardiovascular events, and hospitalizations for HF in elderly patients [20]. NLR was an independent predictor of outcome in patients with stable coronary artery disease (CAD) and a predictor of short- and long-term mortality in patients with acute coronary syndromes (ACS), ST-elevation myocardial infarction (STEMI), and cardiac transplantation [3133]. Despite the prominent role of neutrophils in inducing the chronic inflammatory response in the pathogenesis of many diseases, neutrophil-targeted treatments are still not available [34].

2.2. Macrophages

In the myocardium, different subsets of macrophages with different functions and origins have been identified, both protective and pathogenic [35]. Resident macrophages transition to a more reparative phenotype by dampening IL-6, TNF-α, and matrix metalloproteinase 9 (MMP9) expression and via extrinsic signals such as IL-10, which is produced by regulatory T (Treg) cells [11]. The consequence of this transition is the appearance of cardiac macrophages that produce TGF-β and VEGF thus promoting fibrosis and angiogenesis together with other factors such as myeloid-derived growth factor [22, 36]. Macrophages form 10% of noncardiomyocytes and maintain homeostasis by removing dying senescent cells and promoting angiogenesis [3739]. In response to injury, the release of cytokines and chemokines recruits monocytes which differentiate into Ly6C high macrophages characterized as an M1 phenotype and play an essential role in clearing dead cells by phagocytosis and regulating proinflammatory signals [40]. A decrease in neutrophils and the appearance of Ly6C low macrophages with decreased production of inflammatory cytokines marks the transition from inflammation to repair [41]. In a mouse model of myocardial infarction, a decrease in CSF-1R inhibition in M2 macrophages was associated with a loss in left ventricular contractile function, infarct enlargement, decreased collagen staining, and increased inflammatory cell infiltration into the infarct zone [41]. Clodronate liposome depletion of macrophages following infarction in mice increased mortality and impaired cardiac repair [42, 43]. A recent study showed that CCR2 monocyte-derived macrophages infiltrate the heart early following pressure overload-induced hemodynamic stress and that this macrophage population is responsible for the activation of T cells and transition to failure. Blocking this response either pharmacologically or with antibody-mediated CCR2 depletion protects the heart from pathological left ventricular remodeling and dysfunction, T cell expansion, and cardiac fibrosis [35]. In mice with macrophage-specific deletion of IL-10, there is an improvement in diastolic function. IL-10 may promote fibrosis, by activating fibroblasts, increasing collagen deposition, and impairing myocardial relaxation [43]. In HFpEF mouse models, inflammation is influential in promoting cardiac fibrosis [44, 45]. In coronary artery disease, resident macrophages that are different from monocyte-derived macrophages contribute to pathology [46].

In atherosclerosis, bone marrow- and spleen-derived macrophages are major contributors only at the early disease stage, and resident macrophages become dominant at later phases of the disease. Macrophage subtypes with different functions are identified in the development and progression of atherosclerotic lesions. Macrophage accumulation in human plaques is linked with lesion progression and destabilization as well as with symptomatic coronary artery disease. Numbers of circulating monocytes increase with atherosclerosis and predict clinical outcome [47]. Mox phenotype differentiation is stimulated by the exposure to oxidized phospholipids and by high-level expression of heme oxygenase-1 (HO-1), through the activation of nuclear factor (erythroid-derived-2)-like 2 (NEF2L2) transcription factor [4851]. In atherosclerotic plaques, macrophages adopt their phenotype under the influence of the degree of accumulated lipids and the production of specific mediators and immune factors and are responsible for the transition from a stable to an unstable plaque phenotype [52]. Mechanisms underlying the differentiation of macrophages by modulating the polarization of subpopulations would help to develop novel approaches aiming at slowing down the progression of atherosclerotic disease [53].

Macrophage accumulation in human plaques is linked with lesion progression and destabilization as well as with symptomatic coronary artery disease (CAD) [54]. Numbers of circulating monocytes is seen to be associated with atherosclerosis and to predict clinical outcome [33]. Increased numbers of macrophages were observed in myocardial biopsies from HFpEF patients and contribute to pathophysiology [43, 55]. Subsets of monocytes with different functions are identified in human patients [56]. Classical monocytes, Mon1, preferentially express cytokines IL-1β, IL-6, and MCP-1, intermediate monocytes, Mon2, produce anti-inflammatory IL-10, and nonclassical monocytes, Mon3, stimulate cytokine production in response to viral rather than bacterial load. Mon2 is shown to increase in heart failure and correlates with NYHA [57].

Macrophages have been implicated in the pathogenesis of experimental and human pulmonary hypertension [27]. Clodronate liposome depletion of macrophages prevented hypoxia-induced vascular remodeling. An increase in perivascular macrophages in vascular lesions of human patients with PH is observed [46, 47]. Notably, reduced right ventricle systolic pressure, right ventricle hypertrophy, and pulmonary vascular remodeling were noted in CX3CR12/2 mice, but not in CCL22/2 or CX3CR12/2/CCL22/2 mice, compared with wild-type mice [58]. In IPAH, CCL2 is thought to contribute to the inflammation process. Manipulating macrophages in both inflammatory diseases have been demonstrated to be beneficial in improving the outcome in preclinical mouse models, holding promise for the future design of therapeutic interventions [59].

2.3. Natural Killer Cells

NK cells comprise the most substantial subset of the innate lymphoid cell (ILC) family that lacks antigen receptors found in the classical T cells and B cells of the adaptive immune system [60]. They play a significant role in repairing damaged tissue and maintaining tissue homeostasis [61]. NK cells alter immune cell physiology either directly through receptor-ligand interactions or indirectly through cytokine secretion, direct contact-mediated lysis of autoaggressive T cells, and accelerated maturation of monocytes and dendritic cells. NK cells are essential in limiting cardiac viral infection and reducing cardiac eosinophilic infiltration in the mouse model of myocarditis [62]. NK cells are protective against the development of cardiac fibrosis both by directly limiting collagen formation in cardiac fibroblasts and by preventing the accumulation of specific inflammatory populations in the heart [62].

Multiple clinical studies have shown that coronary artery and ischemic heart disease patients have a decreased NK presence through either total numbers or phenotypic ability [62]. A chronic decrease in NK cells was correlated with low-grade cardiac inflammation, whereas patients that had restored circulating NK cells had little to no cardiac inflammation [62]. NK cell cytolytic impairment correlated with unstimulated levels of IL-6 in PBMCs of patients with heart failure. A decrease in NK cells was also observed in the coronary artery and ischemic heart disease [63].

NK cells prevent monocrotaline-induced endothelial damage [64, 65]. A study of fourteen patients with PAH (9 IPAH, 5 CTD) showed that deficiencies in NK cells might be associated with an increased risk of death in PAH patients [66]. NK cells from PAH patients showed functional impairment with a decrease in macrophage inflammatory protein 1b production and degranulation. Moreover, NK cells from PAH patients had higher levels of matrix metallopeptidase 9 and contribute to vascular remodeling [67]. These results indicated that NK cells have beneficial effects on the pathogenesis of PAH [62].

2.4. Platelets

Platelets play an essential role in cardiovascular disease both in the pathogenesis of atherosclerosis and in the development of acute thrombotic events [68]. Platelets modulate inflammatory response and produce proinflammatory mediators such as fibrosis-inducing PDGF and TGF-β antiangiogenic platelet factor 4 and B cell-activating CD40L [68, 69]. Occlusive intravascular platelet aggregates have been shown to cause ischemic myocardial damage both in the experimental animal and in patients [70]. Transgenic animals with decreased platelet aggregation were at reduced risk of coronary events. Risk factors for coronary artery disease, which include smoking, hypertension, and hypercholesterolemia, increase platelet hyperaggregability [71]. Patients with CHF have increased the risk of venous thromboembolism, stroke, and sudden death [72]. Thrombosis is the final pathogenic mechanism of acute ischemic events, including myocardial infarction, plaque rupture, and sudden cardiac arrest. Patients with acute myocardial infarction and unstable angina had increased platelet-derived thromboxane A2 and other prostaglandin metabolites [70]. CHF patients show increased whole blood aggregation and platelet-derived adhesion molecules as well as higher mean platelet volume. Although many studies have thus shown increased platelet activation in CHF, their role as inflammation-modulating cells is not well characterized [73]. A correlation between platelet-bound CD154 (CD40L) expression on platelets and serum levels of MCP-1 was observed [74]. Dual antiplatelet therapy (the cyclooxygenase inhibitor aspirin plus ADP receptor P2Y12 inhibitors) is the first-line treatment for STEMI.

Clinical studies show that patients with acute coronary syndromes have increased interactions between platelets and circulating leukocytes or neutrophils [58, 63]. Although not diagnostic, NLR and PLR were higher in HF patients than in age-sex-matched controls. PLR also was predictive of survivability after cardiac transplantation [75, 76]. Platelets have a significant role in the CTEPH type of pulmonary arterial hypertension [77]. In IPAH, thrombotic lesions and platelet dysfunction have been reported and may contribute to pathophysiology [36]. Abnormalities in the clotting cascade or platelets may contribute to thrombosis in pulmonary arteries. The von Willebrand factor, connected with endothelial dysfunction, plays a crucial role in platelet adhesion and aggregation in patients with IPAH [78].

2.5. Mast Cells

Mast cells are noncirculating immune cells that mature in target tissues in the presence of the c-kit ligand SCF from bone marrow-derived precursors [79]. Cardiac-resident mast cells increase in number in some disease conditions, including experimentally induced hypertension, myocardial infarction, and chronic cardiac volume overload, and promote cardiac remodeling and heart failure [79, 80]. They store and release a variety of active mediators, TNF-α and proteases such as tryptase, chymase, and stromelysin, implicated in the activation of MMPs, promoting fibrosis-stiffening-remodeling in cardiovascular disorders [42]. Inhibition of mast cell proteases was shown to prevent the development of cardiac fibrosis and improve LV dysfunction in experimental models of LV disease [70]. A role for mast cells in volume overload hypertrophy was established using c-kit-/- mice and drugs that prevent mast cell degranulation [71]. However, the role of mast cells was environment dependent. In homocysteine-induced cardiac fibrosis, mast cells had a protective role [81]. An increase in mast cell density was reported in the RV of the pulmonary banding model and chronic hypoxic rats. Mast cell density is also increased in the failing heart regardless of etiology. Patients with congestive heart failure with left ventricular assist devices had increased SCF and c-Kit gene expression and an increased number of mast cells after ventricular unloading [82]. It is found to contribute to atherosclerosis and plaque destabilization. Increased numbers of mast cells have been reported in explanted human hearts with dilated cardiomyopathy and heart failure [83].

2.6. Eosinophils

Cardiovascular manifestations of the hypereosinophilic syndrome are a common cause of morbidity and mortality in an otherwise uncommon disorder [84]. Pathological observations of the hearts of patients with prolonged eosinophilia have shown that both ventricles may be affected by thrombotic endocarditis associated with eosinophilic infiltration, vasculitis, and myocardial necrosis [8486]. Causes of eosinophilia include drug-induced hypersensitivity reaction, infections such as HIV and helminth infections, systemic diseases such as rheumatoid arthritis, Crohn’s disease, malignancies, and hypereosinophilic syndromes [86]. Binding of IgE antigen complexes and phagocytosis, release of granules with hydrolases, cationic and basic proteins toxic to the heart, and endothelial cells are capable of activating platelets by binding thrombomodulin [87]. In sustained eosinophilia, the accumulation of eosinophils in the interstitial compartment of the heart is deleterious to cardiac tissue and involves thrombus formation, thickening, and fibrosis of the endocardium [88]. There are some case reports of PAH in hypereosinophilic syndromes [89].

2.7. T Cells

Recent research has demonstrated that T lymphocyte-mediated immune response has a central role in CAD and the progression to heart failure [9093]. In congestive heart failure, activation of the immune system leads to increased production and release of several proinflammatory cytokines. Recent studies have shown that alterations of adaptive immunity are critical for CHF pathophysiology [93]. In chronic ischemic cardiomyopathy, systemic expansion of CD4+ and CD8+ T cells and CD4+ Th1, Th2, Th17, and Treg subsets is found in the failing heart, circulation, and lymphoid organs. Mice deficient in Rag2, not having functional B and T cells, were protected from the transition from hypertrophy to heart failure after transverse aortic constriction (TAC) [92]. TCRα-deficient mice or mice with T cells depleted by anti-CD3 antibodies had a preserved cardiac function after TAC [94]. Th1- and Th17-polarized T cells have been reported to induce cardiac fibrosis and adverse cardiac remodeling [95]. Various studies have shown a central role for T cells in the progression of cardiac remodeling after myocardial infarction, in atherosclerotic plaques in mice. Autoreactive T helper cells with specificity for an antigen expressed in cardiomyocytes can promote the progression from hypertrophy to heart failure in response to pressure overload [91, 92]. After myocardial infarction, CD4+ T cells were reported to stimulate collagen matrix formation and thereby improve wound healing and survival by reducing the risk of myocardial rupture [92].

CD4/CD28 null, a unique subset of CD4 cells, is present in low frequencies in healthy individuals and increased in patients with chronic inflammatory diseases such as autoimmunity. These cells were increased in coronary heart disease [96]. CD4/CD28-null T cells accumulate preferentially in unstable ruptured coronary plaques and have been suggested to promote plaque instability and predispose ACS patients to recurrent acute coronary events (myocardial infarction) and indicate a poor prognosis [97, 98]. Patients with CHF show increased frequencies of proinflammatory CD4+ T helper 1 (Th1) and Th17 cells and lower frequencies of regulatory T cells, and these features correlate with disease severity [99]. Reduction of T cell infiltration may thus be a novel translational target in HF. CD8+ lymphocyte depletion is independently associated with death, decreasing 6 min walk distance and increasing NYHA classification [100]. CD8+ T lymphocyte depletion is present in some PAH patients and develops as the disease process deteriorates [101, 102]. Treg cell deficiency is associated with the progression of PAH [65, 102].

2.8. B Cells

Recent experimental and clinical observations suggest a link between activation of humoral immune responses after myocardial heart failure [103]. Animal studies using RAG2-/- SCID mouse models with defective T and B cells demonstrate that pathways leading to the activation of B cells are important players in heart failure and disease progression. Mice lacking programmed cell death protein-1 (PD-1-/-), a key factor for B cell differentiation, develop a severe form of spontaneous dilated cardiomyopathy [104]. High levels of circulating IgG bind specifically to cardiac myocytes. An interaction of B cells with T helper (Th1) cells stimulates cytokine production that can affect contractility as well as adverse remodeling [105]. Activated B cells can cause apoptosis of myocytes by activation of complement-mediated cytotoxicity [106]. In cases of multiple episodes of myocardial infarction where the immune system encounters myocardial proteins such as troponin, the memory B cell response may lead to a persistent inflammatory state, enhancing myocardial cell death and injury [107, 108]. In mouse models of ischemic CMP, the expression of cytokines, IgM, and IgG was increased 3-fold in the post-ischemic state compared to controls [109]. Beta-1 adrenergic receptor autoantibodies can induce apoptosis in isolated myocytes and exert a similar effect in vivo, causing myocardial dysfunction [110, 111]. Antibodies against the Na+/K+-ATPase also have been demonstrated [112]. Their presence seems to contribute to electrical instability in the heart, possibly making it prone to arrhythmias. This adverse effect may be caused by binding of the antibody to the alpha subunit of the Na+/K+-ATPase. Finally, antibodies specifically targeting the Kv channel interacting protein (KChIP) also are associated with dilated CMP and can potentially cause cardiomyocyte death as shown in a rat model [113].

A role for B cells in the progression of HF in humans is indicated by the presence of immunoglobulin, IgG3, with an equal proportion among ischemic and nonischemic patients. Activated complement components are increased in the circulation of patients with advanced disease and, more importantly, present in the failing myocardium [114]. In humans with dilated CMP and ischemic heart disease, antibodies reported in the literature include anti-muscarinic receptor 2, anti-mitochondrial M7, anti-actin, and anti-HSP-60 [103, 106]. In heart failure, HSP-60 present in the mitochondrial matrix will undergo translocation to the plasma membrane, where antibodies will bind and cause increased rates of apoptosis [100]. Limited clinical observations suggest that strategies to remove antibodies may have an impact on the course of HF. Taken together, evidence suggests that after myocardial injury, B cell activation triggers downstream effects that result in anticardiac antibody formation, complement deposition, and further myocardial injury.

3. Conclusion

Despite advances in therapies in heart failure, the prognosis of patients is poor. The research focused on understanding the role of the immune system in CHF has shown that both innate and adaptive immune responses are activated in the heart both in ischemic and in hypertrophic cardiomyopathy mice. However, their pathophysiological roles in heart failure are poorly understood. It is still not clear whether circulating levels of inflammatory mediators like TNF-α in patients with CHF are secondary response to myocyte injury. Investigations with anakinra (anti-IL-1 signaling), as well as the recently published CANTOS trial, support a role for subclinical inflammation in the progression of atherosclerosis and atherosclerotic-related diseases such as CHF [115]. Beneficial treatments for heart failure with drugs like ACEI and beta-blockers decrease monocyte function in animal models [57, 116]. However, clinical trials in patients with CHF using immunomodulatory therapy had poor outcomes. This could be due to the limitation of translating observations in animal models to humans, therefore warranting more studies in human tissues. Markers, such as total neutrophil count and NLR, can be evaluated more routinely in the clinical setting and correlated with parameters of cardiac function [26]. Studies are needed to understand how cardiac dysfunction activates the immune system. Tissue damage in the heart could cause activation of damage-associated molecular patterns (DAMPs) by pattern recognition receptors (PRRs) resulting in the activation of proinflammatory mediators for tissue repair. Tissue damage can also release GPCR-purinergic receptor agonists, ATP and ADP, which are DAMPs, leading to sterile inflammation response, regulating monocytes, macrophages, and T and B cells among others [117119]. Finally, additional investigations are needed to better understand the role of immune cells in the heart in homeostasis and CHF to better define the therapeutic strategies targeting inflammation in patients with various forms of HF. Understanding their role in myocardial function and damage may be important not only in heart failure but also in preventing cardiac damage in patients undergoing immune-targeted therapies for cancer.

Conflicts of Interest

The authors declare that there is no conflict of interest regarding the publication of this paper.

Supplementary Materials

Abstract summary: role of inflammatory cells in heart failure. (Supplementary Materials)

References

  1. A. R. Bond, D. Iacobazzi, S. Abdul-Ghani et al., “Changes in contractile protein expression are linked to ventricular stiffness in infants with pulmonary hypertension or right ventricular hypertrophy due to congenital heart disease,” Open Heart, vol. 5, no. 1, article e000716, 2018. View at Publisher · View at Google Scholar · View at Scopus
  2. D. Iacobazzi, M. S. Suleiman, M. Ghorbel, S. J. George, M. Caputo, and R. M. Tulloh, “Cellular and molecular basis of RV hypertrophy in congenital heart disease,” Heart, vol. 102, no. 1, pp. 12–17, 2016. View at Publisher · View at Google Scholar · View at Scopus
  3. T. Liu, D. Song, J. Dong et al., “Current understanding of the pathophysiology of myocardial fibrosis and its quantitative assessment in heart failure,” Frontiers in Physiology, vol. 8, p. 238, 2017. View at Publisher · View at Google Scholar · View at Scopus
  4. P. G. Vikhorev and N. N. Vikhoreva, “Cardiomyopathies and related changes in contractility of human heart muscle,” International Journal of Molecular Sciences, vol. 19, no. 8, article 2234, 2018. View at Publisher · View at Google Scholar · View at Scopus
  5. M. Humbert, C. Guignabert, S. Bonnet et al., “Pathology and pathobiology of pulmonary hypertension: state of the art and research perspectives,” European Respiratory Journal, vol. 53, no. 1, article 1801887, 2019. View at Publisher · View at Google Scholar · View at Scopus
  6. P. K. Mehta, J. Wei, and N. K. Wenger, “Ischemic heart disease in women: a focus on risk factors,” Trends in Cardiovascular Medicine, vol. 25, no. 2, pp. 140–151, 2015. View at Publisher · View at Google Scholar · View at Scopus
  7. P. Teekakirikul, M. A. Kelly, H. L. Rehm, N. K. Lakdawala, and B. H. Funke, “Inherited cardiomyopathies: molecular genetics and clinical genetic testing in the postgenomic era,” The Journal of Molecular Diagnostics, vol. 15, no. 2, pp. 158–170, 2013. View at Publisher · View at Google Scholar · View at Scopus
  8. V. Lazzarini, R. J. Mentz, M. Fiuzat, M. Metra, and C. M. O'Connor, “Heart failure in elderly patients: distinctive features and unresolved issues,” European Journal of Heart Failure, vol. 15, no. 7, pp. 717–723, 2013. View at Publisher · View at Google Scholar · View at Scopus
  9. W. Bracamonte-Baran and D. Cihakova, “Cardiac autoimmunity: myocarditis,” Advances in Experimental Medicine and Biology, vol. 1003, pp. 187–221, 2017. View at Publisher · View at Google Scholar · View at Scopus
  10. A. J. Mouton, O. J. Rivera, and M. L. Lindsey, “Myocardial infarction remodeling that progresses to heart failure: a signaling misunderstanding,” American Journal of Physiology. Heart and Circulatory Physiology, vol. 315, no. 1, pp. H71–H79, 2018. View at Publisher · View at Google Scholar · View at Scopus
  11. F. K. Swirski and M. Nahrendorf, “Cardioimmunology: the immune system in cardiac homeostasis and disease,” Nature Reviews Immunology, vol. 18, no. 12, pp. 733–744, 2018. View at Publisher · View at Google Scholar · View at Scopus
  12. D. P. Ramji and T. S. Davies, “Cytokines in atherosclerosis: key players in all stages of disease and promising therapeutic targets,” Cytokine & Growth Factor Reviews, vol. 26, no. 6, pp. 673–685, 2015. View at Publisher · View at Google Scholar · View at Scopus
  13. D. A. Chistiakov, A. V. Grechko, V. A. Myasoedova, A. A. Melnichenko, and A. N. Orekhov, “The role of monocytosis and neutrophilia in atherosclerosis,” Journal of Cellular and Molecular Medicine, vol. 22, no. 3, pp. 1366–1382, 2018. View at Publisher · View at Google Scholar · View at Scopus
  14. D. Strassheim, J. S. Park, and E. Abraham, “Sepsis: current concepts in intracellular signaling,” The International Journal of Biochemistry & Cell Biology, vol. 34, no. 12, pp. 1527–1533, 2002. View at Publisher · View at Google Scholar · View at Scopus
  15. S. Epelman, P. P. Liu, and D. L. Mann, “Role of innate and adaptive immune mechanisms in cardiac injury and repair,” Nature Reviews. Immunology, vol. 15, no. 2, pp. 117–129, 2015. View at Publisher · View at Google Scholar · View at Scopus
  16. F. Cucu, C. Chiriloiu, M. Georgescu, C. Cucu, and A. Suciu, “The effect of exhaust gases on the serum lipids and on the arterial wall. Experimental study,” Medecine interne, vol. 13, no. 3, pp. 235–240, 1975. View at Google Scholar
  17. N. G. Frangogiannis, “The inflammatory response in myocardial injury, repair, and remodelling,” Nature Reviews Cardiology, vol. 11, no. 5, pp. 255–265, 2014. View at Publisher · View at Google Scholar · View at Scopus
  18. C. Dewachter, A. Belhaj, B. Rondelet et al., “Myocardial inflammation in experimental acute right ventricular failure: effects of prostacyclin therapy,” The Journal of Heart and Lung Transplantation, vol. 34, no. 10, pp. 1334–1345, 2015. View at Publisher · View at Google Scholar · View at Scopus
  19. V. Modur, Y. Li, G. A. Zimmerman, S. M. Prescott, and T. M. McIntyre, “Retrograde inflammatory signaling from neutrophils to endothelial cells by soluble interleukin-6 receptor alpha,” The Journal of Clinical Investigation, vol. 100, no. 11, pp. 2752–2756, 1997. View at Publisher · View at Google Scholar · View at Scopus
  20. B. Vulesevic, M. G. Sirois, B. G. Allen, S. de Denus, and M. White, “Subclinical inflammation in heart failure: a neutrophil perspective,” The Canadian Journal of Cardiology, vol. 34, no. 6, pp. 717–725, 2018. View at Publisher · View at Google Scholar · View at Scopus
  21. M. Horckmans, L. Ring, J. Duchene et al., “Neutrophils orchestrate post-myocardial infarction healing by polarizing macrophages towards a reparative phenotype,” European Heart Journal, vol. 38, no. 3, pp. 187–197, 2017. View at Google Scholar
  22. S. D. Prabhu and N. G. Frangogiannis, “The biological basis for cardiac repair after myocardial infarction: from inflammation to fibrosis,” Circulation Research, vol. 119, no. 1, pp. 91–112, 2016. View at Publisher · View at Google Scholar · View at Scopus
  23. M. Mollenhauer, K. Friedrichs, M. Lange et al., “Myeloperoxidase mediates postischemic arrhythmogenic ventricular remodeling,” Circulation Research, vol. 121, no. 1, pp. 56–70, 2017. View at Publisher · View at Google Scholar · View at Scopus
  24. T. Goto, K. Wakami, H. Fukuta, H. Fujita, T. Tani, and N. Ohte, “Patients with left ventricular ejection fraction greater than 58% have fewer incidences of future acute decompensated heart failure admission and all-cause mortality,” Heart and Vessels, vol. 31, no. 5, pp. 734–743, 2016. View at Publisher · View at Google Scholar · View at Scopus
  25. S. L. Hazen, “Neutrophils, hypercholesterolemia, and atherogenesis,” Circulation, vol. 122, no. 18, pp. 1786–1788, 2010. View at Publisher · View at Google Scholar · View at Scopus
  26. K. Sharma, A. K. Patel, K. H. Shah, and A. Konat, “Is neutrophil-to-lymphocyte ratio a predictor of coronary artery disease in Western Indians?” International Journal of Inflammation, vol. 2017, Article ID 4136126, 8 pages, 2017. View at Publisher · View at Google Scholar · View at Scopus
  27. H. Sawada, T. Saito, N. P. Nickel et al., “Reduced BMPR2 expression induces GM-CSF translation and macrophage recruitment in humans and mice to exacerbate pulmonary hypertension,” The Journal of Experimental Medicine, vol. 211, no. 2, pp. 263–280, 2014. View at Publisher · View at Google Scholar · View at Scopus
  28. L. Harbaum, K. M. Baaske, M. Simon et al., “Exploratory analysis of the neutrophil to lymphocyte ratio in patients with pulmonary arterial hypertension,” BMC Pulmonary Medicine, vol. 17, no. 1, article 72, 2017. View at Publisher · View at Google Scholar · View at Scopus
  29. A. J. Fowler and R. A. Agha, “Neutrophil/lymphocyte ratio is related to the severity of coronary artery disease and clinical outcome in patients undergoing angiography--the growing versatility of NLR,” Atherosclerosis, vol. 228, no. 1, pp. 44-45, 2013. View at Publisher · View at Google Scholar · View at Scopus
  30. Y. Arbel, A. Finkelstein, A. Halkin et al., “Neutrophil/lymphocyte ratio is related to the severity of coronary artery disease and clinical outcome in patients undergoing angiography,” Atherosclerosis, vol. 225, no. 2, pp. 456–460, 2012. View at Publisher · View at Google Scholar · View at Scopus
  31. I. Dogan, K. Karaman, B. Sonmez, S. Celik, and O. Turker, “Relationship between serum neutrophil count and infarct size in patients with acute myocardial infarction,” Nuclear Medicine Communications, vol. 30, no. 10, pp. 797–801, 2009. View at Publisher · View at Google Scholar · View at Scopus
  32. J. Budzianowski, K. Pieszko, P. Burchardt, J. Rzezniczak, and J. Hiczkiewicz, “The role of hematological indices in patients with acute coronary syndrome,” Disease Markers, vol. 2017, Article ID 3041565, 9 pages, 2017. View at Publisher · View at Google Scholar · View at Scopus
  33. J. A. L. Meeuwsen, M. Wesseling, I. E. Hoefer, and S. C. A. de Jager, “Prognostic value of circulating inflammatory cells in patients with stable and acute coronary artery disease,” Frontiers in Cardiovascular Medicine, vol. 4, p. 44, 2017. View at Publisher · View at Google Scholar
  34. C. K. Mårdh, J. Root, M. Uddin et al., “Targets of neutrophil influx and weaponry: therapeutic opportunities for chronic obstructive airway disease,” Journal of Immunology Research, vol. 2017, Article ID 5273201, 13 pages, 2017. View at Publisher · View at Google Scholar · View at Scopus
  35. B. Patel, S. S. Bansal, M. A. Ismahil et al., “CCR2(+) monocyte-derived infiltrating macrophages are required for adverse cardiac remodeling during pressure overload,” JACC: Basic to Translational Science, vol. 3, no. 2, pp. 230–244, 2018. View at Publisher · View at Google Scholar · View at Scopus
  36. M. Korf-Klingebiel, M. R. Reboll, S. Klede et al., “Myeloid-derived growth factor (C19orf10) mediates cardiac repair following myocardial infarction,” Nature Medicine, vol. 21, no. 2, pp. 140–149, 2015. View at Publisher · View at Google Scholar · View at Scopus
  37. H. B. Sager, T. Kessler, and H. Schunkert, “Monocytes and macrophages in cardiac injury and repair,” Journal of Thoracic Disease, vol. 9, Supplement 1, pp. S30–S35, 2017. View at Publisher · View at Google Scholar · View at Scopus
  38. S. Frantz and M. Nahrendorf, “Cardiac macrophages and their role in ischaemic heart disease,” Cardiovascular Research, vol. 102, no. 2, pp. 240–248, 2014. View at Publisher · View at Google Scholar · View at Scopus
  39. M. J. van Amerongen, M. C. Harmsen, N. van Rooijen, A. H. Petersen, and M. J. A. van Luyn, “Macrophage depletion impairs wound healing and increases left ventricular remodeling after myocardial injury in mice,” The American Journal of Pathology, vol. 170, no. 3, pp. 818–829, 2007. View at Publisher · View at Google Scholar · View at Scopus
  40. T. A. Wynn and K. M. Vannella, “Macrophages in tissue repair, regeneration, and fibrosis,” Immunity, vol. 44, no. 3, pp. 450–462, 2016. View at Publisher · View at Google Scholar · View at Scopus
  41. T. J. Koh and L. A. DiPietro, “Inflammation and wound healing: the role of the macrophage,” Expert Reviews in Molecular Medicine, vol. 13, article e23, 2011. View at Publisher · View at Google Scholar · View at Scopus
  42. A. L. Leblond, K. Klinkert, K. Martin et al., “Systemic and cardiac depletion of M2 macrophage through CSF-1R signaling inhibition alters cardiac function post myocardial infarction,” PLoS One, vol. 10, no. 9, article e0137515, 2015. View at Publisher · View at Google Scholar · View at Scopus
  43. M. Hulsmans, H. B. Sager, J. D. Roh et al., “Cardiac macrophages promote diastolic dysfunction,” The Journal of Experimental Medicine, vol. 215, no. 2, pp. 423–440, 2018. View at Publisher · View at Google Scholar · View at Scopus
  44. N. Glezeva and J. A. Baugh, “Role of inflammation in the pathogenesis of heart failure with preserved ejection fraction and its potential as a therapeutic target,” Heart Failure Reviews, vol. 19, no. 5, pp. 681–694, 2014. View at Publisher · View at Google Scholar · View at Scopus
  45. J. Tromp, B. D. Westenbrink, W. Ouwerkerk et al., “Identifying pathophysiological mechanisms in heart failure with reduced versus preserved ejection fraction,” Journal of the American College of Cardiology, vol. 72, no. 10, pp. 1081–1090, 2018. View at Publisher · View at Google Scholar · View at Scopus
  46. L. Honold and M. Nahrendorf, “Resident and monocyte-derived macrophages in cardiovascular disease,” Circulation Research, vol. 122, no. 1, pp. 113–127, 2018. View at Publisher · View at Google Scholar · View at Scopus
  47. F. De Paoli, B. Staels, and G. Chinetti-Gbaguidi, “Macrophage phenotypes and their modulation in atherosclerosis,” Circulation Journal, vol. 78, no. 8, pp. 1775–1781, 2014. View at Publisher · View at Google Scholar · View at Scopus
  48. S. C. Pugliese, J. M. Poth, M. A. Fini, A. Olschewski, K. C. El Kasmi, and K. R. Stenmark, “The role of inflammation in hypoxic pulmonary hypertension: from cellular mechanisms to clinical phenotypes,” American Journal of Physiology. Lung Cellular and Molecular Physiology, vol. 308, no. 3, pp. L229–L252, 2015. View at Publisher · View at Google Scholar · View at Scopus
  49. S. Vomund, A. Schafer, M. J. Parnham, B. Brune, and A. von Knethen, “Nrf2, the master regulator of anti-oxidative responses,” International Journal of Molecular Sciences, vol. 18, no. 12, article 2772, 2017. View at Publisher · View at Google Scholar · View at Scopus
  50. C. Biswas, N. Shah, M. Muthu et al., “Nuclear heme oxygenase-1 (HO-1) modulates subcellular distribution and activation of Nrf2, impacting metabolic and anti-oxidant defenses,” The Journal of Biological Chemistry, vol. 289, no. 39, pp. 26882–26894, 2014. View at Publisher · View at Google Scholar · View at Scopus
  51. V. Serbulea, C. M. Upchurch, M. S. Schappe et al., “Macrophage phenotype and bioenergetics are controlled by oxidized phospholipids identified in lean and obese adipose tissue,” Proceedings of the National Academy of Sciences, vol. 115, no. 27, pp. E6254–E6263, 2018. View at Publisher · View at Google Scholar · View at Scopus
  52. M. S. Gibson, N. Domingues, and O. V. Vieira, “Lipid and non-lipid factors affecting macrophage dysfunction and inflammation in atherosclerosis,” Frontiers in Physiology, vol. 9, p. 654, 2018. View at Publisher · View at Google Scholar · View at Scopus
  53. F. Abdolmaleki, S. M. Gheibi Hayat, V. Bianconi, T. P. Johnston, and A. Sahebkar, “Atherosclerosis and immunity: a perspective,” Trends in Cardiovascular Medicine, vol. 29, no. 6, pp. 363–371, 2019. View at Google Scholar
  54. E. A. L. Biessen and K. Wouters, “Macrophage complexity in human atherosclerosis: opportunities for treatment?” Current Opinion in Lipidology, vol. 28, no. 5, pp. 419–426, 2017. View at Publisher · View at Google Scholar · View at Scopus
  55. G. B. Lim, “Lifestyle offsets genetic risk of hypertension,” Nature Reviews Cardiology, vol. 15, no. 4, p. 196, 2018. View at Publisher · View at Google Scholar
  56. K. Urbanski, D. Ludew, G. Filip et al., “CD14(+)CD16(++) “nonclassical” monocytes are associated with endothelial dysfunction in patients with coronary artery disease,” Thrombosis and Haemostasis, vol. 117, no. 05, pp. 971–980, 2017. View at Publisher · View at Google Scholar · View at Scopus
  57. F. Shahid, G. Y. H. Lip, and E. Shantsila, “Role of monocytes in heart failure and atrial fibrillation,” Journal of the American Heart Association, vol. 7, no. 3, 2018. View at Publisher · View at Google Scholar · View at Scopus
  58. X. Q. Sun, A. Abbate, and H. J. Bogaard, “Role of cardiac inflammation in right ventricular failure,” Cardiovascular Research, vol. 113, no. 12, pp. 1441–1452, 2017. View at Publisher · View at Google Scholar · View at Scopus
  59. M. Ponzoni, F. Pastorino, D. Di Paolo, P. Perri, and C. Brignole, “Targeting macrophages as a potential therapeutic intervention: impact on inflammatory diseases and cancer,” International Journal of Molecular Sciences, vol. 19, no. 7, article 1953, 2018. View at Publisher · View at Google Scholar · View at Scopus
  60. D. R. Withers, “Innate lymphoid cell regulation of adaptive immunity,” Immunology, vol. 149, no. 2, pp. 123–130, 2016. View at Publisher · View at Google Scholar · View at Scopus
  61. A. Tosello-Trampont, F. A. Surette, S. E. Ewald, and Y. S. Hahn, “Immunoregulatory role of NK cells in tissue inflammation and regeneration,” Frontiers in Immunology, vol. 8, p. 301, 2017. View at Publisher · View at Google Scholar · View at Scopus
  62. S. Ong, N. R. Rose, and D. Cihakova, “Natural killer cells in inflammatory heart disease,” Clinical Immunology, vol. 175, pp. 26–33, 2017. View at Publisher · View at Google Scholar · View at Scopus
  63. K. Backteman, J. Ernerudh, and L. Jonasson, “Natural killer (NK) cell deficit in coronary artery disease: no aberrations in phenotype but sustained reduction of NK cells is associated with low-grade inflammation,” Clinical and Experimental Immunology, vol. 175, no. 1, pp. 104–112, 2014. View at Publisher · View at Google Scholar · View at Scopus
  64. M. L. Ormiston, Y. Deng, D. J. Stewart, and D. W. Courtman, “Innate immunity in the therapeutic actions of endothelial progenitor cells in pulmonary hypertension,” American Journal of Respiratory Cell and Molecular Biology, vol. 43, no. 5, pp. 546–554, 2010. View at Publisher · View at Google Scholar · View at Scopus
  65. R. Tamosiuniene, W. Tian, G. Dhillon et al., “Regulatory T cells limit vascular endothelial injury and prevent pulmonary hypertension,” Circulation Research, vol. 109, no. 8, pp. 867–879, 2011. View at Publisher · View at Google Scholar · View at Scopus
  66. A. L. Edwards, S. P. Gunningham, G. C. Clare et al., “Professional killer cell deficiencies and decreased survival in pulmonary arterial hypertension,” Respirology, vol. 18, no. 8, pp. 1271–1277, 2013. View at Publisher · View at Google Scholar · View at Scopus
  67. H. El Chami and P. M. Hassoun, “Immune and inflammatory mechanisms in pulmonary arterial hypertension,” Progress in Cardiovascular Diseases, vol. 55, no. 2, pp. 218–228, 2012. View at Publisher · View at Google Scholar · View at Scopus
  68. L. Badimon, T. Padro, and G. Vilahur, “Atherosclerosis, platelets and thrombosis in acute ischaemic heart disease,” European Heart Journal Acute Cardiovascular Care, vol. 1, no. 1, pp. 60–74, 2012. View at Publisher · View at Google Scholar
  69. C. N. Morrell, A. A. Aggrey, L. M. Chapman, and K. L. Modjeski, “Emerging roles for platelets as immune and inflammatory cells,” Blood, vol. 123, no. 18, pp. 2759–2767, 2014. View at Publisher · View at Google Scholar · View at Scopus
  70. E. Ricciotti and G. A. FitzGerald, “Prostaglandins and inflammation,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 31, no. 5, pp. 986–1000, 2011. View at Publisher · View at Google Scholar · View at Scopus
  71. S. Willoughby, A. Holmes, and J. Loscalzo, “Platelets and cardiovascular disease,” European Journal of Cardiovascular Nursing, vol. 1, no. 4, pp. 273–288, 2002. View at Publisher · View at Google Scholar
  72. W. Kim and E. J. Kim, “Heart failure as a risk factor for stroke,” Journal of Stroke, vol. 20, no. 1, pp. 33–45, 2018. View at Publisher · View at Google Scholar · View at Scopus
  73. M. E. Tsoumani, K. I. Kalantzi, I. A. Goudevenos, and A. D. Tselepis, “Platelet-mediated inflammation in cardiovascular disease. Potential role of platelet-endothelium interactions,” Current Vascular Pharmacology, vol. 10, no. 5, pp. 539–549, 2012. View at Publisher · View at Google Scholar · View at Scopus
  74. J. Sahler, S. Spinelli, R. Phipps, and N. Blumberg, “CD40 ligand (CD154) involvement in platelet transfusion reactions,” Transfusion Clinique et Biologique, vol. 19, no. 3, pp. 98–103, 2012. View at Publisher · View at Google Scholar · View at Scopus
  75. M. Yaprak, M. N. Turan, R. Dayanan et al., “Platelet-to-lymphocyte ratio predicts mortality better than neutrophil-to-lymphocyte ratio in hemodialysis patients,” International Urology and Nephrology, vol. 48, no. 8, pp. 1343–1348, 2016. View at Publisher · View at Google Scholar · View at Scopus
  76. A. Papa, M. Emdin, C. Passino, C. Michelassi, D. Battaglia, and F. Cocci, “Predictive value of elevated neutrophil-lymphocyte ratio on cardiac mortality in patients with stable coronary artery disease,” Clinica Chimica Acta, vol. 395, no. 1-2, pp. 27–31, 2008. View at Publisher · View at Google Scholar · View at Scopus
  77. A. Remkova, I. Simkova, and T. Valkovicova, “Platelet abnormalities in chronic thromboembolic pulmonary hypertension,” International Journal of Clinical and Experimental Medicine, vol. 8, no. 6, pp. 9700–9707, 2015. View at Google Scholar
  78. K. L. Lannan, R. P. Phipps, and R. J. White, “Thrombosis, platelets, microparticles and PAH: more than a clot,” Drug Discovery Today, vol. 19, no. 8, pp. 1230–1235, 2014. View at Publisher · View at Google Scholar · View at Scopus
  79. E. Z. M. da Silva, M. C. Jamur, and C. Oliver, “Mast cell function: a new vision of an old cell,” The Journal of Histochemistry and Cytochemistry, vol. 62, no. 10, pp. 698–738, 2014. View at Publisher · View at Google Scholar · View at Scopus
  80. J. S. Janicki, G. L. Brower, and S. P. Levick, “The emerging prominence of the cardiac mast cell as a potent mediator of adverse myocardial remodeling,” Methods in Molecular Biology, vol. 1220, pp. 121–139, 2015. View at Publisher · View at Google Scholar · View at Scopus
  81. J. Joseph, R. H. Kennedy, S. Devi, J. Wang, L. Joseph, and M. Hauer-Jensen, “Protective role of mast cells in homocysteine-induced cardiac remodeling,” American Journal of Physiology. Heart and Circulatory Physiology, vol. 288, no. 5, pp. H2541–H2545, 2005. View at Publisher · View at Google Scholar · View at Scopus
  82. J. Jahanyar, K. A. Youker, G. Torre-Amione et al., “Increased expression of stem cell factor and its receptor after left ventricular assist device support: a potential novel target for therapeutic interventions in heart failure,” The Journal of Heart and Lung Transplantation, vol. 27, no. 7, pp. 701–709, 2008. View at Publisher · View at Google Scholar · View at Scopus
  83. Y. Mina, S. Rinkevich-Shop, E. Konen et al., “Mast cell inhibition attenuates myocardial damage, adverse remodeling, and dysfunction during fulminant myocarditis in the rat,” Journal of Cardiovascular Pharmacology and Therapeutics, vol. 18, no. 2, pp. 152–161, 2013. View at Publisher · View at Google Scholar · View at Scopus
  84. P. U. Ogbogu, D. R. Rosing, and M. K. Horne 3rd., “Cardiovascular manifestations of hypereosinophilic syndromes,” Immunology and Allergy Clinics of North America, vol. 27, no. 3, pp. 457–475, 2007. View at Publisher · View at Google Scholar · View at Scopus
  85. N. L. Diny, G. C. Baldeviano, M. V. Talor et al., “Eosinophil-derived IL-4 drives progression of myocarditis to inflammatory dilated cardiomyopathy,” The Journal of Experimental Medicine, vol. 214, no. 4, pp. 943–957, 2017. View at Publisher · View at Google Scholar · View at Scopus
  86. C. C. Cheung, M. Constantine, A. Ahmadi, C. Shiau, and L. Y. C. Chen, “Eosinophilic myocarditis,” The American Journal of the Medical Sciences, vol. 354, no. 5, pp. 486–492, 2017. View at Publisher · View at Google Scholar · View at Scopus
  87. J. W. Yau, H. Teoh, and S. Verma, “Endothelial cell control of thrombosis,” BMC Cardiovascular Disorders, vol. 15, no. 1, article 130, 2015. View at Publisher · View at Google Scholar · View at Scopus
  88. N. Masaki, A. Issiki, M. Kirimura et al., “Echocardiographic changes in eosinophilic endocarditis induced by Churg-Strauss syndrome,” Internal Medicine, vol. 55, no. 19, pp. 2819–2823, 2016. View at Publisher · View at Google Scholar · View at Scopus
  89. T. Ibe, H. Wada, K. Sakakura et al., “A case of pulmonary hypertension associated with idiopathic hypereosinophilic syndrome,” International Heart Journal, vol. 59, no. 4, pp. 887–890, 2018. View at Publisher · View at Google Scholar · View at Scopus
  90. C. Li, X. N. Sun, M. R. Zeng et al., “Mineralocorticoid receptor deficiency in T cells attenuates pressure overload-induced cardiac hypertrophy and dysfunction through modulating T-cell activation,” Hypertension, vol. 70, no. 1, pp. 137–147, 2017. View at Publisher · View at Google Scholar · View at Scopus
  91. M. Kallikourdis, E. Martini, P. Carullo et al., “T cell costimulation blockade blunts pressure overload-induced heart failure,” Nature Communications, vol. 8, no. 1, article 14680, 2017. View at Publisher · View at Google Scholar · View at Scopus
  92. C. Gröschel, A. Sasse, S. Monecke et al., “CD8+-T Cells With Specificity for a Model Antigen in Cardiomyocytes Can Become Activated After Transverse Aortic Constriction but Do Not Accelerate Progression to Heart Failure,” Frontiers in Immunology, vol. 9, article 2665, 2018. View at Publisher · View at Google Scholar · View at Scopus
  93. T. Fukunaga, H. Soejima, A. Irie et al., “Relation between CD4+ T-cell activation and severity of chronic heart failure secondary to ischemic or idiopathic dilated cardiomyopathy,” The American Journal of Cardiology, vol. 100, no. 3, pp. 483–488, 2007. View at Publisher · View at Google Scholar · View at Scopus
  94. T. Nevers, A. M. Salvador, A. Grodecki-Pena et al., “Left ventricular T-cell recruitment contributes to the pathogenesis of heart failure,” Circulation. Heart Failure, vol. 8, no. 4, pp. 776–787, 2015. View at Publisher · View at Google Scholar · View at Scopus
  95. R. A. Frieler and R. M. Mortensen, “Immune cell and other noncardiomyocyte regulation of cardiac hypertrophy and remodeling,” Circulation, vol. 131, no. 11, pp. 1019–1030, 2015. View at Publisher · View at Google Scholar · View at Scopus
  96. I. E. Dumitriu, E. T. Araguas, C. Baboonian, and J. C. Kaski, “CD4+CD28null T cells in coronary artery disease: when helpers become killers,” Cardiovascular Research, vol. 81, no. 1, pp. 11–19, 2008. View at Publisher · View at Google Scholar · View at Scopus
  97. I. E. Dumitriu, “The life (and death) of CD4+CD28null T cells in inflammatory diseases,” Immunology, vol. 146, no. 2, pp. 185–193, 2015. View at Publisher · View at Google Scholar · View at Scopus
  98. A. Bajnok, M. Ivanova, J. Rigó, and G. Toldi, “The distribution of activation markers and selectins on peripheral T lymphocytes in preeclampsia,” Mediators of Inflammation, vol. 2017, Article ID 8045161, 7 pages, 2017. View at Publisher · View at Google Scholar · View at Scopus
  99. R.-x. Zhao, W.-j. Li, Y.-r. Lu et al., “Increased peripheral proinflammatory T helper subsets contribute to cardiovascular complications in diabetic patients,” Mediators of Inflammation, vol. 2014, Article ID 596967, 12 pages, 2014. View at Google Scholar
  100. A. Yazdanyar, M. M. Aziz, P. L. Enright et al., “Association between 6-minute walk test and all-cause mortality, coronary heart disease-specific mortality, and incident coronary heart disease,” Journal of Aging and Health, vol. 26, no. 4, pp. 583–599, 2014. View at Publisher · View at Google Scholar · View at Scopus
  101. E. D. Austin, M. T. Rock, C. A. Mosse et al., “T lymphocyte subset abnormalities in the blood and lung in pulmonary arterial hypertension,” Respiratory Medicine, vol. 104, no. 3, pp. 454–462, 2010. View at Publisher · View at Google Scholar · View at Scopus
  102. M. R. Nicolls and N. F. Voelkel, “The roles of immunity in the prevention and evolution of pulmonary arterial hypertension,” American Journal of Respiratory and Critical Care Medicine, vol. 195, no. 10, pp. 1292–1299, 2017. View at Publisher · View at Google Scholar · View at Scopus
  103. A. M. Cordero‐Reyes, K. A. Youker, A. R. Trevino et al., “Full Expression of Cardiomyopathy Is Partly Dependent on B‐Cells: A Pathway That Involves Cytokine Activation, Immunoglobulin Deposition, and Activation of Apoptosis,” Journal of the American Heart Association, vol. 5, no. 1, article e002484, 2016. View at Google Scholar
  104. D. Vdovenko and U. Eriksson, “Regulatory role of CD4(+) T cells in myocarditis,” Journal of Immunology Research, vol. 2018, Article ID 4396351, 11 pages, 2018. View at Publisher · View at Google Scholar · View at Scopus
  105. A. H. Sprague and R. A. Khalil, “Inflammatory cytokines in vascular dysfunction and vascular disease,” Biochemical Pharmacology, vol. 78, no. 6, pp. 539–552, 2009. View at Publisher · View at Google Scholar · View at Scopus
  106. A. M. Cordero-Reyes, K. A. Youker, and G. Torre-Amione, “The role of B-cells in heart failure,” Methodist DeBakey Cardiovascular Journal, vol. 9, no. 1, pp. 15–19, 2013. View at Publisher · View at Google Scholar
  107. W. Yan, Y. Song, L. Zhou et al., “Immune cell repertoire and their mediators in patients with acute myocardial infarction or stable angina pectoris,” International Journal of Medical Sciences, vol. 14, no. 2, pp. 181–190, 2017. View at Publisher · View at Google Scholar · View at Scopus
  108. K. L. Rock, J. J. Lai, and H. Kono, “Innate and adaptive immune responses to cell death,” Immunological Reviews, vol. 243, no. 1, pp. 191–205, 2011. View at Publisher · View at Google Scholar · View at Scopus
  109. S. Lachtermacher, B. L. B. Esporcatte, F. Montalvão et al., “Cardiac gene expression and systemic cytokine profile are complementary in a murine model of post-ischemic heart failure,” Brazilian Journal of Medical and Biological Research, vol. 43, no. 4, pp. 377–389, 2010. View at Publisher · View at Google Scholar · View at Scopus
  110. Y. Nagatomo and W. H. W. Tang, “Intersections between microbiome and heart failure: revisiting the gut hypothesis,” Journal of Cardiac Failure, vol. 21, no. 12, pp. 973–980, 2015. View at Publisher · View at Google Scholar · View at Scopus
  111. L. Wang, Y. Li, N. Ning et al., “Decreased autophagy induced by β1-adrenoceptor autoantibodies contributes to cardiomyocyte apoptosis,” Cell Death & Disease, vol. 9, no. 3, p. 406, 2018. View at Publisher · View at Google Scholar · View at Scopus
  112. A. Baba, T. Yoshikawa, and S. Ogawa, “Autoantibodies produced against sarcolemmal Na-K-ATPase: possible upstream targets of arrhythmias and sudden death in patients with dilated cardiomyopathy,” Journal of the American College of Cardiology, vol. 40, no. 6, pp. 1153–1159, 2002. View at Publisher · View at Google Scholar · View at Scopus
  113. S. Choudhury, M. Schnell, T. Bühler et al., “Antibodies against potassium channel interacting protein 2 induce necrosis in isolated rat cardiomyocytes,” Journal of Cellular Biochemistry, vol. 115, no. 4, pp. 678–689, 2014. View at Publisher · View at Google Scholar · View at Scopus
  114. N. Chun, A. S. Haddadin, J. Liu et al., “Activation of complement factor B contributes to murine and human myocardial ischemia/reperfusion injury,” PLoS One, vol. 12, no. 6, article e0179450, 2017. View at Publisher · View at Google Scholar · View at Scopus
  115. A. W. Aday and P. M. Ridker, “Antiinflammatory therapy in clinical care: the CANTOS trial and beyond,” Frontiers in Cardiovascular Medicine, vol. 5, p. 62, 2018. View at Publisher · View at Google Scholar
  116. M. Nahrendorf, M. J. Pittet, and F. K. Swirski, “Monocytes: protagonists of infarct inflammation and repair after myocardial infarction,” Circulation, vol. 121, no. 22, pp. 2437–2445, 2010. View at Publisher · View at Google Scholar · View at Scopus
  117. I. Garcia-Martinez, M. E. Shaker, and W. Z. Mehal, “Therapeutic opportunities in damage-associated molecular pattern-driven metabolic diseases,” Antioxidants & Redox Signaling, vol. 23, no. 17, pp. 1305–1315, 2015. View at Publisher · View at Google Scholar · View at Scopus
  118. E. Venereau, C. Ceriotti, and M. E. Bianchi, “DAMPs from cell death to new life,” Frontiers in Immunology, vol. 6, article 422, 2015. View at Publisher · View at Google Scholar · View at Scopus
  119. W. G. Junger, “Immune cell regulation by autocrine purinergic signalling,” Nature Reviews Immunology, vol. 11, no. 3, pp. 201–212, 2011. View at Publisher · View at Google Scholar · View at Scopus