- About this Journal
- Abstracting and Indexing
- Aims and Scope
- Article Processing Charges
- Articles in Press
- Author Guidelines
- Bibliographic Information
- Citations to this Journal
- Contact Information
- Editorial Board
- Editorial Workflow
- Free eTOC Alerts
- Publication Ethics
- Reviewers Acknowledgment
- Submit a Manuscript
- Subscription Information
- Table of Contents
International Journal of Vascular Medicine
Volume 2012 (2012), Article ID 274381, 6 pages
The Influence of Endothelial Function and Myocardial Ischemia on Peak Oxygen Consumption in Patients with Coronary Artery Disease
1Montreal Behavioural Medicine Centre, H####^~^~^~^~^~^####xf4;pital du Sacr####^~^~^~^~^~^####xe9;-Coeur de Montr####^~^~^~^~^~^####xe9;al, A University of Montreal Affiliated Hospital, Montr####^~^~^~^~^~^####xe9;al, QC, Canada H4J 1C5
2Department of Exercise Science, Concordia University, Montreal, QC, Canada H4B 1R6
3Research Centre, H####^~^~^~^~^~^####xf4;pital du Sacr####^~^~^~^~^~^####xe9;-Coeur de Montr####^~^~^~^~^~^####xe9;al, A University of Montreal Affiliated Hospital, Montr####^~^~^~^~^~^####xe9;al, QC, Canada H4J 1C5
4Research Centre, Montreal Heart Institute, A University of Montreal Affiliated Hospital, Montr####^~^~^~^~^~^####xe9;al, QC, Canada H1T 1C8
5Department of Psychiatry and Behavioral Science, Duke University Medical Center, Durham, NC 27708, USA
6Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
7Department of Psychology, Universit####^~^~^~^~^~^####xe9; du Qu####^~^~^~^~^~^####xe9;bec ####^~^~^~^~^~^####xe0; Montr####^~^~^~^~^~^####xe9;al, Montr####^~^~^~^~^~^####xe9;al, QC, Canada H3C 3P8
Received 11 June 2012; Revised 16 August 2012; Accepted 8 September 2012
Academic Editor: Linda Pescatello
Copyright © 2012 Simon L. Bacon 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.
Impaired endothelial function has been shown to limit exercise in coronary artery disease (CAD) patients and has been implicated in myocardial ischemia. However, the association of endothelial function and ischemia on peak exercise oxygen consumption (VO2) has not been previously reported. A total of 116 CAD patients underwent standard exercise stress testing, during which VO2 was measured. On a separate day, endothelial-dependent and -independent function were assessed by ultrasound using flow-mediated arterial vasodilation (FMD) and sublingual glyceryl trinitrate administration (GTNMD) of the brachial artery. Patients with exercise-induced myocardial ischemia had lower FMD than nonischemic patients ( versus , ), but there was no difference in GTNMD ( versus , ). Analyses revealed that both FMD () and GTNMD () were related to peak VO2. However, neither the presence of ischemia () nor the interaction of ischemia with FMD () and GTNMD () was related to peak VO2. These data suggest that poor endothelial function, potentially via impaired NO production and smooth muscle dysfunction, may be an important determinant of exercise capacity in patients with CAD, independent of myocardial ischemia.
Under normal physiological conditions, exercise-induced increases in myocardial oxygen demand are met by coronary vasodilation and increased oxygen delivery, thus preventing ischemia or perfusion defects . Vasodilation during exercise is, in part, contingent upon the vascular endothelium [2, 3] and endothelial dysfunction may limit skeletal muscle oxygen delivery and exercise capacity. For example, impaired endothelial function has been associated with poorer exercise treadmill time in CAD patients  and in postcardiac transplant patients .
Endothelial dysfunction is widely implicated in cardiovascular disease and its complications . Compared to matched controls, patients with coronary artery disease (CAD) have a greater degree of endothelial dysfunction [7, 8]. In addition, patients with exercise-induced myocardial ischemia have impaired endothelial function compared to nonischemic patients . It is possible that endothelial dysfunction may result in failure of arterial vasodilation during exercise , thus compromising oxygen supply and precipitating ischemia in a CAD population .
The primary aim of the current study was to assess impact of exercise-induced myocardial ischemia on the relationship between endothelial function, as measured by flow mediated dilatation in the brachial artery (FMD) and peak oxygen consumption (VO2) during symptom limited exercise testing in stable CAD patients. It was hypothesized that endothelial function would be positively correlated to VO2, that patients who experienced ischemia during exercise would have greater degrees of endothelial dysfunction, and that there would be a significant interaction between ischemia and endothelial function in the prediction of VO2, such that the relationship between endothelial function and VO2 would be strongest in patients without ischemia.
2. Materials and Methods
Patients were participants in a randomized controlled trial, the results of which have been previously reported [11####^~^~^~^~^~^####x2013;13]. Patients were included in the current secondary analyses if they had complete endothelial function and exercise testing data at baseline. As such, of the 145 patients recruited, a total of 116 patients were used in the current analyses. Patients not included in the analyses did not differ from those included on age, sex, medication status, or medical comorbidities. All patients that were recruited had documented coronary artery disease with prior evidence of inducible exercise ischemia. Patients were excluded from the study if they had baseline blood pressure ####^~^~^~^~^~^####x3e;200/120####^~^~^~^~^~^####x2009;mm####^~^~^~^~^~^####x2009;Hg, LVEF ####^~^~^~^~^~^####x3c;30####^~^~^~^~^~^####x25;, history of MI, CABG, or PCI in the last 3 months, or had severe electrophysiological disorders. The study was approved by the Institutional Review Boards of both Duke University Medical Center and the Durham Veterans Affairs Medical Center. Signed informed consent was obtained from all patients prior to their participation. None of the authors have any conflict of interests or competing interests with the content of the paper.
2.2. Measurement of Endothelial Function
Participants were removed from all antianginal medications at least 48####^~^~^~^~^~^####x2009;hrs prior to testing, with the exception of 23 patients who remained on medications (21 beta-blockers, 9 long-acting nitrates, and 7 calcium channel blockers) due to adverse cardiac profiles. To control for this potential confounder, being on or off medications during the endothelial function test was included in the analyses as a covariate. During the morning following at least an 8 hour fast, endothelial function was assessed in participants using flow-mediated arterial vasodilation (for further details see ). The technique, which conforms to published guidelines , involves the digital capture and storage of high-resolution end-diastolic (ECG R-wave synchronized) longitudinal B-mode images of the brachial artery. Images were obtained at rest, during reactive hyperemia induced by 5 minutes of forearm ischemia, and following sublingual glyceryl trinitrate administration (GTNMD) using an ultrasound imaging system with a 7####^~^~^~^~^~^####x2013;11####^~^~^~^~^~^####x2009;MHz linear-array transducer and an Aspen acquisition system (Acuson, Mountain View, California).
2.3. Graded Exercise Test
On a separate visit and after resumption of all antianginal medications (for which 16 participants were not taking antianginal medications), participants performed a maximal graded exercise test on a motor-driven treadmill (Quinton, model Q5000) using the Duke-Wake Forrest protocol . The electrocardiogram was continuously monitored at rest, during exercise, and throughout recovery with a 12-lead trace being printed at 1-minute intervals. Blood pressure was measured at rest and during each workload with an automated BP monitor (Accutracker model 4240; Suntech). Oxygen consumption (VO2) was measured during exercise by respiratory gas exchange analysis with a calibrated metabolic cart (Sensormedics, model 2900; Yorba Linda, CA), using a breath-by-breath technique. VO2 data were averaged over 20 second intervals, and peak VO2 was taken as the highest 20 second average during the last three minutes of the test. Every minute during exercise patients were asked to rate chest pain (1####^~^~^~^~^~^####x2013;10 scale) and perceived exertion (Borg 6####^~^~^~^~^~^####x2013;20 scale), by pointing to hand held charts. Ischemia was determined by a senior cardiologist and was defined as ST depression ####^~^~^~^~^~^####x3e;1.0####^~^~^~^~^~^####x2009;mm for at least 3 beats. All electrocardiogram readings were made by an experienced senior cardiologist.
2.4. Data Analysis
Student -tests, analyses, and general linear models (used when covariates were required) were used to assess differences in demographic and exercise variables between patients who had exercise-inducible ischemia and those who did not exhibit ischemia during the exercise test. Current hypertensive status was defined by use of antihypertensive medication. All significantly different demographic and exercise variables were used as covariates in the multivariate analyses. As BMI was significantly different between the groups and was entered into the main models, absolute peak VO2 (L/min) and not peak VO2 relative to body weight (mL/kg/min) were used for statistical purposes. This was done to prevent body weight being adjusted for twice. Conventional general linear models were used to test the relationships between endothelial function, exercise performance, and ischemia. In total four models were estimated: model 1 tested the independent effects of FMD and ischemia on peak VO2 during the exercise test; model 2 tested the joint effect of FMD and ischemia on peak VO2; model 3 tested the independent effects of GTNMD and ischemia on peak VO2 during the exercise test; model 4 tested the joint effect of GTNMD and ischemia on peak VO2. All models used brachial artery vessel size, age, medication status during the FMD test, and BMI as covariates. All statistical analyses were performed using SAS (version 8.2, Cary, NC), with significance set at .
3. Results and Discussion
3.1. Clinical Characteristics
The clinical characteristics of the 34 patients who exhibited exercise inducible ischemia and the 84 patients who were not ischemic are summarized in Table 1. The ischemic group was significantly older and had a significantly lower BMI compared to the nonischemic group. There were no differences in any other characteristics, including resting blood pressure and heart rate, as measured in a seated position prior to the start of the stress test. FMD, controlling for vessel size, was significantly lower in the ischemic group, whereas there was no significant difference in GTNMD between the groups. Table 2 shows that there were no significant differences in exercise treadmill time, chest pain, or level of perceived exertion between the two groups.
3.2. Relationship between Endothelial Function, Ischemia, and Peak VO2
The results of the sequence of general linear models for peak VO2 are presented in Table 3, with the parameter estimate b (analogous to unstandardized regression coefficients) and -values shown for each model. The results for Models 1 and 2 revealed that of the covariates, age and brachial artery vessel size were related to peak VO2 during exercise. From Model 1, we observed a main effect for FMD, but not ischemia, on peak VO2 levels, such that lower levels of FMD were related to lower peak VO2 values. Figure 1 shows the main effect of FMD (split by quartiles) on VO2. The FMD ####^~^~^~^~^~^####xd7; ischemia interaction in Model 2 was not significant, indicating that there was no evidence for a joint effect of these variables on peak VO2. A similar pattern of results were seen in Models 3 and 4. Age, BMI, and brachial artery vessel size were all related to peak VO2. Model 3 revealed a main effect for GTNMD, and not ischemia, on peak VO2, and a nonsignificant interaction between GTNMD and ischemia in Model 4. These results found that reductions in GTNMD were associated with reduced peak VO2, and that there were no main or interaction effects of ischemia on peak VO2. Of note, these results did not substantially change when those patients who were taking medications during the FMD test were removed from the analyses.
The current study found that both endothelial-dependent and -independent vascular reactivity were associated with lower levels of peak VO2 in CAD patients undergoing exercise treadmill testing. This relationship remained significant after adjusting for age, BMI, and brachial artery vessel size. However, neither the presence of ischemia during the exercise test nor the interaction of ischemia with FMD or GTNMD was related to peak VO2. As such, the major new finding of this study is that endothelial-dependent and -independent vasodilator function is related to exercise capacity independently of whether a patient experiences myocardial ischemia. In line with previous studies [4, 10, 17], we did find that, as a group, ischemic patients had lower FMD values than nonischemic patients.
Both exercise capacity and endothelial function have been shown to predict clinical events in patients with CAD [18, 19]. Additionally, both have been shown to improve with exercise training [20####^~^~^~^~^~^####x2013;24]. Reviews of the previous research in this area has shown that endothelial dysfunction seems to limit exercise capacity and that this may be through multiple mechanisms [2, 3, 25], including altered production of NO , prostanoids , or endothelin . However, it should be noted that the vast majority of this work has come from healthy participants and animal studies. Our finding that both FMD and GTNMD were related to VO2 is consistent with the idea of a multimechanistic process. Previous research has suggested that a significant response or relationship seen with both endothelial-dependent (FMD) and -independent (GTNMD) stimuli, as in the current study, is indicative of both impaired endothelial function and smooth muscle dysregulation [28, 29], and thus, may contribute to the relationship between vasoreactivity and exercise capacity.
It has been suggested that endothelial dysfunction can lead to paradoxical coronary vasoconstriction during exercise, thus helping to precipitate ischemia . Endothelial dysfunction is associated with reduced exercise treadmill time in CAD patients  and in postcardiac transplant patients . Therefore, we had anticipated that the relationship between endothelial function and VO2 would be weaker or even nonexistent in those patients with ischemia. However, the lack of an interaction between FMD or GTNMD and ischemia indicated that this was not true in the current study.
One inherent limitation of cross-sectional research, as in the current study, is that we are unable to infer directionality of the endothelial function-oxygen consumption relationship. Previous research has suggested that endothelial dysfunction precedes oxygen consumption limitation. For example, an exercise intervention in heart failure patients found that improvements in exercise capacity were proportional to the beneficial changes seen in agonist-mediated endothelial dilation . However, more work is needed to elucidate the true nature of the FMD-VO2 relationship. It is possible that some underlying factor, which was not measured in the current study, directly influences both the endothelium and oxygen requirements such that the relationship seen is an artifact of the third variable. For example, elevated C-reactive protein or homocysteinemia have both been shown to influence vasoreactivity [31, 32] and neither were assessed in the current population. Also, we were not able to assess the potential effect of shear rate as this data was not recorded and this may account for some of the observed relationship.
Patients in the present study were withdrawn from their anti-ischemic medications prior to and during the endothelial function testing but remained on medications during the exercise test. This is likely to account for the relatively low incidence of exercise-induced ischemia seen during the exercise test. It is impossible to truly estimate the residual effects of medications on the outcome measures. However, a previous study found that endothelial function was not altered in patients when they took their normal regimen of cardiac medications compared to when they were medication-free . This study suggests that medication utilization has small effects on endothelial function. Of course, it is also possible that the taking of medications during the exercise stress test may have had a beneficial effect on exercise performance and myocardial perfusion, which may have influenced the results. However, this does reflect what a patient would normally experience during daily living.
Finally, given that men and women seem to have different CAD courses and patterns of CAD outcomes [34, 35] and that endothelial function has been postulated as one reason for such differences , it would have been interesting to include further analyses which had a sex interaction or were sex-specific. However, it should be noted that only around 30####^~^~^~^~^~^####x25; of the sample were women, which did not provide enough power for us to conduct such analyses. The need for such future studies in this area is further strengthened by the fact that when we included sex as an additional covariate there was a reduction in the estimates for the effects of FMD (change from 0.04 to 0.02) and GTNMD (change from 0.02 to 0.01). Though it is possible that this reduction in effect seen when sex was added to the model could be a consequence of over-fitting , there are other potential physiological explanations, such as the fact that women are thought to have greater microvascular dysfunction relative to men [38, 39]. As the current study did not have the capacity to disentangle such issues further work to assess the sex-specific nature of this relationship should be conducted.
Endothelial-dependent and -independent vascular dysfunction were associated with reduced oxygen consumption in CAD patients, and these relationships were independent of myocardial ischemia. These data suggest that impaired vascular reactivity via reduced NO production and smooth muscle dysfunction may be an important determinant of exercise capacity in patients with CAD. Further research is needed to delineate the exact mechanisms of these relationships.
This study was supported by Grant HL 59672 from the National Institutes of Health, Bethesda, MD and Grant M01-RR-30 from the General Clinical Research Center program, National Center for Research Resources, National Institutes of Health. Dr. Bacon is currently supported by a Chercher-boursier award from the Fonds de Recherche du Qu####^~^~^~^~^~^####xe9;bec####^~^~^~^~^~^####x2013;Sant####^~^~^~^~^~^####xe9; and a New Investigator Award from the Canadian Institutes of Health Research.
- J. D. Tune, K. N. Richmond, M. W. Gorman, and E. O. Feigl, “Control of coronary blood flow during exercise,” Experimental Biology and Medicine, vol. 227, no. 4, pp. 238–250, 2002.
- D. J. Duncker, R. J. Bache, and D. Merkus, “Regulation of coronary resistance vessel tone in response to exercise,” Journal of Molecular and Cellular Cardiology, vol. 52, pp. 802–813, 2012.
- D. J. Duncker and R. J. Bache, “Regulation of coronary blood flow during exercise,” Physiological Reviews, vol. 88, no. 3, pp. 1009–1086, 2008.
- J. T. Kuvin, A. R. Patel, K. A. Sliney et al., “Peripheral vascular endothelial function testing as a noninvasive indicator of coronary artery disease,” Journal of the American College of Cardiology, vol. 38, no. 7, pp. 1843–1849, 2001.
- A. R. Patel, J. T. Kuvin, D. DeNofrio et al., “Peripheral vascular endothelial function correlates with exercise capacity in cardiac transplant recipients,” American Journal of Cardiology, vol. 91, no. 7, pp. 897–899, 2003.
- A. Lerman and A. M. Zeiher, “Endothelial function: cardiac events,” Circulation, vol. 111, no. 3, pp. 363–368, 2005.
- H. Brunner, J. R. Cockcroft, J. Deanfield et al., “Endothelial function and dysfunction. Part II: association with cardiovascular risk factors and diseases. A statement by the Working Group on Endothelins and Endothelial Factors of the European Society of Hypertension,” Journal of Hypertension, vol. 23, no. 2, pp. 233–246, 2005.
- Z. Jambrik, L. Venneri, A. Varga, F. Rigo, A. Borges, and E. Picano, “Peripheral vascular endothelial function testing for the diagnosis of coronary artery disease,” American Heart Journal, vol. 148, no. 4, pp. 684–689, 2004.
- A. M. Zeiher, “Endothelial vasodilator dysfunction: pathogenetic link to myocardial ischaemia or epiphenomenon?” The Lancet, vol. 348, supplement 1, pp. S10–S12, 1996.
- A. M. Zeiher, T. Krause, V. Schachinger, J. Minners, and E. Moser, “Impaired endothelium-dependent vasodilation of coronary resistance vessels is associated with exercise-induced myocardial ischemia,” Circulation, vol. 91, no. 9, pp. 2345–2352, 1995.
- S. L. Bacon, L. L. Watkins, M. Babyak et al., “Effects of daily stress on autonomic cardiac control in patients with coronary artery disease,” American Journal of Cardiology, vol. 93, no. 10, pp. 1292–1294, 2004.
- J. A. Blumenthal, A. Sherwood, M. Babyak et al., “Mental stress and coronary disease. The Smart-Heart Study,” North Carolina Medical Journal, vol. 60, no. 2, pp. 95–99, 1999.
- J. A. Blumenthal, A. Sherwood, M. A. Babyak et al., “Effects of exercise and stress management training on markers of cardiovascular risk in patients with ischemic heart disease: a randomized controlled trial,” Journal of the American Medical Association, vol. 293, no. 13, pp. 1626–1634, 2005.
- A. Sherwood, K. Johnson, J. A. Blumenthal, and A. L. Hinderliter, “Endothelial function and hemodynamic responses during mental stress,” Psychosomatic Medicine, vol. 61, no. 3, pp. 365–370, 1999.
- M. C. Corretti, T. J. Anderson, E. J. Benjamin et al., “Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the international brachial artery reactivity task force,” Journal of the American College of Cardiology, vol. 39, no. 2, pp. 257–265, 2002.
- J. A. Blumenthal, W. J. Rejeski, M. Walsh-Riddle et al., “Comparison of high- and low-intensity exercise training early after acute myocardial infarction,” American Journal of Cardiology, vol. 61, no. 1, pp. 26–30, 1988.
- T. H. Schindler, E. Nitzsche, N. Magosaki et al., “Regional myocardial perfusion defects during exercise, as assessed by three dimensional integration of morphology and function, in relation to abnormal endothelium dependent vasoreactivity of the coronary microcirculation,” Heart, vol. 89, no. 5, pp. 517–526, 2003.
- J. F. McNeer, J. R. Margolis, and K. L. Lee, “The role of the exercise test in the evaluation of patients for ischemic heart disease,” Circulation, vol. 57, no. 1, pp. 64–70, 1978.
- S. Fichtlscherer, S. Breuer, and A. M. Zeiher, “Prognostic value of systemic endothelial dysfunction in patients with acute coronary syndromes: further evidence for the existence of the “vulnerable” patient,” Circulation, vol. 110, no. 14, pp. 1926–1932, 2004.
- American College of Sports Medicine (ACSM), Guidelines for Exercise Testing and Prescription, Lippincott Williams & Wilkins, Baltimore, Md, USA, 6th edition, 2000.
- A. Linke, N. Schoene, S. Gielen et al., “Endothelial dysfunction in patients with chronic heart failure: systemic effects of lower-limb exercise training,” Journal of the American College of Cardiology, vol. 37, no. 2, pp. 392–397, 2001.
- C. Walther, S. Gielen, and R. Hambrecht, “The effect of exercise training on endothelial function in cardiovascular disease in humans,” Exercise and Sport Sciences Reviews, vol. 32, no. 4, pp. 129–134, 2004.
- C. A. DeSouza, L. F. Shapiro, C. M. Clevenger et al., “Regular aerobic exercise prevents and restores age-related declines in endothelium-dependent vasodilation in healthy men,” Circulation, vol. 102, no. 12, pp. 1351–1357, 2000.
- T. S. Hermann, C. H. Dall, S. B. Christensen, J. P. Goetze, E. Prescott, and F. Gustafsson, “Effect of high intensity exercise on peak oxygen uptake and endothelial function in long-term heart transplant recipients,” American Journal of Transplantation, vol. 11, no. 3, pp. 536–541, 2011.
- M. E. Tschakovsky and M. J. Joyner, “Nitric oxide and muscle blood flow in exercise,” Applied Physiology, Nutrition and Metabolism, vol. 33, no. 1, pp. 151–160, 2008.
- S. J. Duffy, S. F. Castle, R. W. Harper, and I. T. Meredith, “Contribution of vasodilator prostanoids and nitric oxide to resting flow, metabolic vasodilation, and flow-mediated dilation in human coronary circulation,” Circulation, vol. 100, no. 19, pp. 1951–1957, 1999.
- V. J. de Beer, S. B. Bender, Y. J. Taverne et al., “Exercise limits the production of endothelin in the coronary vasculature,” American Journal of Physiology, vol. 300, no. 5, pp. H1950–H1959, 2011.
- M. R. Adams, J. Robinson, R. McCredie et al., “Smooth muscle dysfunction occurs independently of impaired endothelium- dependent dilation in adults at risk of atherosclerosis,” Journal of the American College of Cardiology, vol. 32, no. 1, pp. 123–127, 1998.
- O. T. Raitakari, J. P. Seale, and D. S. Celermajer, “Impaired vascular responses to nitroglycerin in subjects with coronary atherosclerosis,” American Journal of Cardiology, vol. 87, no. 2, pp. 217–219, 2001.
- J. P. J. Halcox, W. H. Schenke, G. Zalos et al., “Prognostic value of coronary vascular endothelial dysfunction,” Circulation, vol. 106, no. 6, pp. 653–658, 2002.
- J. C. Chambers, P. M. Ueland, O. A. Obeid, J. Wrigley, H. Refsum, and J. S. Kooner, “Improved vascular endothelial function after oral B vitamins: an effect mediated through reduced concentrations of free plasma homocysteine,” Circulation, vol. 102, no. 20, pp. 2479–2483, 2000.
- S. Fichtlscherer, G. Rosenberger, D. H. Walter, S. Breuer, S. Dimmeler, and A. M. Zeiher, “Elevated C-reactive protein levels and impaired endothelial vasoreactivity in patients with coronary artery disease,” Circulation, vol. 102, no. 9, pp. 1000–1006, 2000.
- N. Gokce, M. Holbrook, L. M. Hunter et al., “Acute effects of vasoactive drug treatment on brachial artery reactivity,” Journal of the American College of Cardiology, vol. 40, no. 4, pp. 761–765, 2002.
- V. Vaccarino, L. Badimon, R. Corti et al., “Ischaemic heart disease in women: are there sex differences in pathophysiology and risk factors?” Cardiovascular Research, vol. 90, no. 1, pp. 9–17, 2011.
- C. S. P. Lam and W. C. Little, “Sex and cardiovascular risk,” Circulation, vol. 126, pp. 913–915, 2012.
- S. Bacon, K. Lavoie, A. Arsenault, et al., “The research on endothelial function in women and men at risk for cardiovascular disease (REWARD) study: methodology,” BMC Cardiovascular Disorders, vol. 11, article 50, 2011.
- M. A. Babyak, “What you see may not be what you get: a brief, nontechnical introduction to overfitting in regression-type models,” Psychosomatic Medicine, vol. 66, no. 3, pp. 411–421, 2004.
- O. C. Marroquin, R. Holubkov, D. Edmundowicz et al., “Heterogeneity of microvascular dysfunction in women with chest pain not attributable to coronary artery disease: implications for clinical practice,” American Heart Journal, vol. 145, no. 4, pp. 628–635, 2003.
- S. E. Reis, R. Holubkov, A. J. C. Smith et al., “Coronary microvascular dysfunction is highly prevalent in women with chest pain in the absence of coronary artery disease: results from the NHLBI WISE study,” American Heart Journal, vol. 141, no. 5, pp. 735–741, 2001.