Pulmonary function in patients with reduced left ventricular function: influence of smoking and cardiac surgery.

STUDY OBJECTIVE: The impact of stable, chronic heart failure on baseline pulmonary function remains controversial. Confounding influences include previous coronary artery bypass or valve surgery (CABG), history of obesity, stability of disease, and smoking history. DESIGN: To control for some of the variables affecting pulmonary function in patients with chronic heart failure, we analyzed data in four patient groups, all with left ventricular (LV) dysfunction (LV ejection fraction [LVEF] < or =35%): (1) chronic heart failure, nonsmokers, no CABG (n = 78); (2) chronic heart failure, nonsmokers, CABG (n = 46); (3) chronic heart failure, smokers, no CABG (n = 40); and (4) chronic heart failure, smokers, CABG (n = 48). Comparisons were made with age- and gender-matched patients with a history of coronary disease but no LV dysfunction or smoking history (control subjects, n = 112) and to age-predicted norms. RESULTS: Relative to control subjects and percent-predicted values, all groups with chronic heart failure had reduced lung volumes (total lung capacity [TLC] and vital capacity [VC]) and expiratory flows (p < 0.05). CABG had no influence on lung volumes and expiratory flows in smokers, but resulted in a tendency toward a reduced TLC and VC in nonsmokers. Smokers with chronic heart failure had reduced expiratory flows compared to nonsmokers (p < 0.05), indicating an additive effect of smoking. Diffusion capacity of the lung for carbon monoxide (DLCO) was reduced in smokers and in subjects who underwent CABG, but not in patients with chronic heart failure alone. There was no relationship between LV size and pulmonary function in this population, although LV function (cardiac index and stroke volume) was weakly associated with lung volumes and DLCO. CONCLUSIONS: We conclude that patients with chronic heart failure have primarily restrictive lung changes with smoking causing a further reduction in expiratory flows.

Novel risk factors for atherosclerosis.

In the past several years, evidence has accumulated that factors other than conventional risk factors may contribute to the development of atherosclerosis. Conventional risk factors predict less than one half of future cardiovascular events. Furthermore, conventional risk factors may not have the same causal effect in different ethnic groups in whom novel risk factors may have a role. These newer risk factors for atherosclerosis include homocysteine, fibrinogen, impaired fibrinolysis, increased platelet reactivity, hypercoagulability, lipoprotein(a), small dense low-density lipoprotein cholesterol, and inflammatory-infectious markers. Identification of other markers associated with an increased risk of atherosclerotic vascular disease may allow better insight into the pathobiology of atherosclerosis and facilitate the development of preventive and therapeutic measures. In this review, we discuss the evidence associating these factors in the pathogenesis of atherosclerosis, the mechanism of risk, and the clinical implications of this knowledge.

Ventilatory constraints during exercise in patients with chronic heart failure.

We examined the degree of ventilatory constraint in patients with a history of chronic heart failure (CHF; n = 11; mean +/- SE age, 62 +/- 4 years; cardiac index [CI], 2.0 +/- 0.1; and ejection fraction [EF], 24 +/- 2%) and in control subjects (CTLS; n = 8; age, 61 +/- 5 years; CI, 2.6 +/- 0.3) by plotting the tidal flow-volume responses to graded exercise in relationship to the maximal flow-volume envelope (MFVL). Inspiratory capacity (IC) maneuvers were performed to follow changes in end-expiratory lung volume (EELV) during exercise, and the degree of expiratory flow limitation was assessed as the percent of the tidal volume (VT) that met or exceeded the expiratory boundary of the MFVL. CHF patients had significantly (p < 0.05) reduced baseline pulmonary function (FVC, 76 +/- 4%; FEV(1), 78 +/- 4% predicted) relative to CTLS (FVC, 99 +/- 4%; FEV(1), 102 +/- 4% predicted). At peak exercise, oxygen consumption (VO(2)) and minute ventilation (V(E)) were lower in CHF patients than in CTLS (VO(2), 17 +/- 2 vs 32 +/- 2 mL/kg/min; VE, 56 +/- 4 vs 82 +/- 6 L/min, respectively), whereas VE/carbon dioxide output was higher (42 +/- 4 vs 29 +/- 5). In CTLS, EELV initially decreased with light exercise, but increased as VE and expiratory flow limitation increased. In contrast, the EELV in patients with CHF remained near residual volume (RV) throughout exercise, despite increasing flow limitation. At peak exercise, IC averaged 91 +/- 3% and 79 +/- 4% (p < 0.05) of the FVC in CHF patients and CTLS, respectively, and flow limitation was present over > 45% of the VT in CHF patients vs < 25% in CTLS (despite the higher VE in CTLS). The least fit and most symptomatic CHF patients demonstrated the lowest EELV, the greatest degree of flow limitation, and a limited response to increased inspired carbon dioxide during exercise, all consistent with VE constraint. We conclude that patients with CHF commonly breathe near RV during exertion and experience expiratory flow limitation. This results in VE constraint and may contribute to exertional intolerance.

Non-physician supervision of cardiopulmonary exercise testing in chronic heart failure: safety and results of a preliminary investigation.

PURPOSE: In the current era of efficient use of personnel and cost containment, the use of non-physicians in selected roles previously occupied exclusively by physicians has become increasingly prevalent. Traditionally, physicians have directly supervised graded exercise testing of patients with chronic heart failure. The purpose of this prospective pilot investigation was to determine the safety and results of non-physician supervised exercise testing of these high-risk patients. METHODS: Two hundred eighty-nine consecutive outpatients (211 men, 78 women) with left ventricular ejection fractions of < or = 35% were referred for cardiopulmonary exercise testing. Symptom-limited treadmill graded exercise tests were supervised by paramedical personnel with a physician immediately available, but not present in the lab. RESULTS: Nonsustained ventricular tachycardia was present during exercise in approximately 20% of patients. Test-limiting hypotension was documented in 5% of subjects. Only one serious event occurred during the 289 exercise tests, an episode of ventricular fibrillation with a successful resuscitation outcome. Peak exercise respiratory exchange ratio averaged 1.10 +/- 0.14, consistent with a near-maximal patient effort. Peak oxygen uptake was 18 +/- 5 ml/kg/min. CONCLUSIONS: Supervision of cardiopulmonary graded exercise testing in properly screened patients with severe systolic left ventricular dysfunction by experienced non-physicians appears to be reasonably safe and the results are suitable for clinical decision making. Such a practice is an attractive cost-containment strategy and deserves further investigation.

Achieving National Cholesterol Education Program goals for low-density lipoprotein cholesterol in cardiac patients: importance of diet, exercise, weight control, and drug therapy.

OBJECTIVE: To determine how frequently the National Cholesterol Education Program (NCEP) goal of a low-density lipoprotein (LDL) cholesterol level of 100 mg/dL or less is achieved in clinical practice in patients with coronary artery disease and what fraction of patients can achieve this goal without drug therapy. DESIGN: We examined the results of lipid management in 152 consecutive patients who had completed cardiac rehabilitation after an acute coronary event. Patients were randomized to follow-up by specially trained nurses or by preventive cardiologists, and they were not receiving lipid-lowering drugs at the start of the study. MATERIAL AND METHODS: Patients were given aggressive diet and exercise recommendations and lipid-lowering drugs in accordance with NCEP guidelines. Follow-up was continued for a mean of 526 days after the first lipid assessment subsequent to the coronary event. Multiple logistic regression analysis was used to identify independent predictors of a final LDL cholesterol level of 100 mg/dL or less. RESULTS: Of the study group, 39% achieved the NCEP goal LDL cholesterol level of 100 mg/dL or less. Characteristics of the patients with LDL cholesterol levels of 100 mg/dL or less in comparison with those with LDL cholesterol levels of more than 100 mg/dL included a greater frequency of drug therapy (65% versus 38%), more rigorous dietary compliance, longer follow-up (586 +/- 317 days versus 493 +/- 264 days), more favorable weight change (-0.3 +/- 4.9 kg versus +1.7 +/- 5.0 kg), and more extensive weekly exercise (183 +/- 118 minutes versus 127 +/- 107 minutes). CONCLUSION: The registered nurses managed the lipids of these patients as effectively as did the preventive cardiologists. Appropriate drug therapy was the most important factor in achieving an LDL cholesterol level of 100 mg/dL or less, but 35% of patients attaining this NCEP goal were not receiving drug therapy. Exercise, dietary compliance, and weight loss were also important factors.

Prognostic significance of exercise-induced systemic hypertension in healthy subjects.

Exercise hypertension has been suggested to predict future resting hypertension, but its significance in terms of cardiovascular risk has not been defined. To assess the prognostic significance of exercise hypertension, 150 healthy, asymptomatic subjects with normal resting blood pressures and exercise systolic blood pressures > or =214 mm Hg (i.e., >90th percentile) on Bruce treadmill tests were identified retrospectively and age- and gender-matched with subjects with exercise systolic blood pressures of 170 to 192 mm Hg (40th to 70th percentiles). Subjects were contacted by survey a mean of 7.7+/-2.9 years after the index treadmill test. The survey response rate was 93%. There were 12 deaths, including 8 in the exercise hypertension group. A major cardiovascular event, defined as cardiovascular death, myocardial infarction, stroke, coronary angioplasty, or coronary bypass graft surgery occurred in 5 controls and 10 subjects with exercise hypertension. At follow-up, 13 controls and 37 subjects with exercise hypertension were now diagnosed as having resting hypertension. In multivariate analysis, exercise hypertension was not a significant predictor for death or any individual cardiovascular event, but was for total cardiovascular events and new resting hypertension. The multivariate risk ratio for exercise hypertension was 3.62 (p = 0.03) in predicting a major cardiovascular event. Other significant predictors included body mass index and age. For predicting new resting hypertension, the multivariate odds ratio for exercise hypertension was 2.41 (p = 0.02). These data suggest that exercise hypertension carries a small but significant risk for major cardiovascular events in healthy, asymptomatic persons with normal resting blood pressures.

Effect of intervention for psychological distress on rehospitalization rates in cardiac rehabilitation patients.

Psychosocial factors affect the development of coronary heart disease and morbidity and mortality of patients with known coronary heart disease. A prior study has shown that psychological distress in patients with known coronary heart disease increased medical and economic costs. This study examined the effects of commonly available psychological interventions offered to patients entering cardiac rehabilitation after hospitalization for angina, myocardial infarction, angioplasty, or coronary artery bypass grafting. A total of 380 patients were screened with the Symptom Checklist-90-Revised (SCL-90-R). Those with T-scores > or = 63 (> or = 91 percentile) on the General Severity Index (GSI) subscale were randomly assigned to usual care or special intervention. Special intervention included a psychiatric evaluation, plus one to seven sessions of behavioral therapy. The percentage of patients rehospitalized for cardiac symptoms within 12 months of psychological evaluation was 43% for special intervention and 40% for usual care (NS). A correction for crossover between the treatment groups resulted in a favorable trend toward intervention, with 35% of the psychologically treated patients rehospitalized vs. 48% of the untreated patients (NS). Although there was a nonsignificant reduction of the SCL-90-R's GSI T-score, the depression score was significantly reduced in the special intervention group.

Predictors of smoking cessation after percutaneous coronary revascularization.

OBJECTIVE: To identify factors predictive of smoking cessation after successful percutaneous coronary revascularization. MATERIAL AND METHODS: We undertook a case-control study of the smoking status of all patients at Mayo Clinic Rochester from September 1979 through December 1995 who were smokers at the time of an index percutaneous coronary revascularization procedure in the non-peri-infarction setting (no myocardial infarction within 24 hours). Maximal duration of prospective follow-up was 16 years. Patients were classified into those who permanently quit smoking immediately after the procedure (N = 435; mean follow-up, 5.1 +/- 3.7 years) or those who continued to smoke at some time during follow-up (N = 734; mean follow-up, 5.3 +/- 3.7 years). Logistics regression models were formulated to determine independent predictors of smoking cessation. RESULTS: Predictors of continued smoking were greater prior cigarette consumption (odds ratio [OR] = 1.009 for each pack-year; 95% confidence interval [CI] = 1.004 to 1.014) and having one or more risk factors for coronary artery disease other than cigarette smoking (OR = 1.49; 95% CI = 1.15 to 1.93). Older age (OR = 0.98 for each additional year; 95% CI = 0.97 to 0.99) and unstable angina at time of initial assessment (OR = 0.69; 95% CI = 0.52 to 0.91) were associated with less likelihood of continued smoking. CONCLUSION: Younger patients with a worse risk profile and greater prior cigarette consumption were more likely than other patients to continue smoking after percutaneous coronary revascularization in the non-peri-infarction setting. Patients who had unstable angina were more likely to quit smoking than those who had stable angina. Despite the proven benefits of smoking cessation after percutaneous coronary revascularization, a substantial proportion of smokers (63%) continue to smoke; thus, smoking-cessation counseling should be addressed in this population.

Comparison of peak exercise oxygen uptake in men versus women in chronic heart failure secondary to ischemic or idiopathic dilated cardiomyopathy.

Results of exercise testing in 150 patients with chronic heart failure show that women were characterized by shorter exercise time, peak oxygen consumption, and lower peak oxygen pulse than men. There was a 4.1-ml/kg/min difference in peak oxygen uptake between genders after the adjustment of age, peak heart rate, respiratory exchange ratio, ejection fraction, and etiology of heart failure.

Peak exercise blood pressure stratified by age and gender in apparently healthy subjects.

OBJECTIVE: To determine the peak blood pressure responses during symptom-limited exercise in a large sample of apparently healthy subjects, including both men and women over a wide range of ages. DESIGN: We retrospectively studied the blood pressure response during maximal treadmill exercise testing with use of the Bruce protocol in apparently healthy subjects. MATERIAL AND METHODS: Peak exercise blood pressures in 7,863 male and 2,406 female apparently healthy subjects who underwent a screening treadmill exercise test with the Bruce protocol between 1988 and 1992 were analyzed by age and gender. RESULTS: In this large referral population of apparently healthy subjects, peak exercise systolic and diastolic blood pressures and delta systolic blood pressure (rest to peak exercise) were higher in men than in women and were positively associated with age. In men, the 90th percentile of systolic blood pressure increased from 210 mm Hg for the age decade 20 to 29 years to 234 mm Hg for ages 70 to 79 years; the corresponding increase among women was from 180 mm Hg to 220 mm Hg. Delta diastolic blood pressure also increased with advancing age. The difference in peak and delta systolic blood pressures between men and women seemed to decrease after age 40 to 49 years. Exercise hypotension, defined as peak exercise systolic pressure less than rest systolic pressure, occurred in 0.23% of men and 1.45% of women and was not significantly related to age. CONCLUSION: Overall, peak exercise systolic and diastolic, as well as delta systolic, blood pressures were higher in men than in women and increased with advancing age. The reported data will enable clinicians to interpret more accurately the significance of peak exercise blood pressure response in a subject of a specific age and gender and will allow investigators to define exercise hypertension in statistical terms stratified by age and gender.

Sequential assessment of exercise tolerance in heart transplantation compared with coronary artery bypass surgery after phase II cardiac rehabilitation.

To investigate the improvement in exercise capacity of transplant patients after an early postoperative (phase II) cardiac rehabilitation program during the first year after surgery, we analyzed retrospectively exercise capacity within 3 months (at the completion of phase II rehabilitation) and 1 year after surgery in 17 orthotopic heart transplantation patients (15 men and 2 women) and 17 age- and gender-matched coronary artery bypass graft (CABG) patients. All patients participated in a phase II cardiac rehabilitation exercise program followed by a home-based exercise program. At the completion of phase II cardiac rehabilitation, mean peak oxygen (VO2) adjusted for body weight in heart transplant patients was not significantly different from that in CABG patients (19.7 +/- 3.7 vs 21.9 +/- 4.1 ml/kg/min), and oxygen pulse at peak exercise did not differ between the 2 groups (11.5 +/- 2.5 vs 12.6 +/- 2.4 ml/beat). Between 3 months and 1 year after surgery, CABG patients had a marked increase in exercise time, increase in heart rate from rest to peak exercise (heart rate reserve), peak VO2, and oxygen pulse. In contrast, heart transplant patients had a significant but only modest increase in peak VO2, and were much more limited in exercise capacity at 1 year than were CABG patients (21.3 +/- 3.9 vs 27.4 +/- 4.7 ml/kg/min, p <0.0001). In our limited patient population, usual phase I rehabilitation with subsequent home-based exercise training was inadequate to improve the exercise capacity of heart transplant patients, and different rehabilitation protocols, such as long-term supervised exercise training, specific to this patient group may be indicated.

Further increase in oxygen uptake during early active recovery following maximal exercise in chronic heart failure.

STUDY OBJECTIVE: Some patients with chronic heart failure manifest a further increase in oxygen uptake (VO2) after maximal exercise whereas others do not. The purpose of this study was to determine the characteristics of chronic heart failure patients with further increase in VO2 in early active recovery following maximal exercise. DESIGN: Retrospective analysis of clinical and exercise testing characteristics in patients with or without a further increase in VO2 during early active recovery. PATIENTS: One hundred forty-two patients with a history of congestive heart failure and left ventricular ejection fraction of 45%, or less who performed a symptom-limited graded treadmill exercise test. MEASUREMENTS AND RESULTS: Expired gases were monitored breath by breath from rest throughout exercise and during 1 min of active recovery. Patients were defined as having a further increase in VO2 if the average VO2 during the initial 30 s of active recovery was greater than or equal to VO2 during the final 30 s of graded exercise and the instantaneous VO2 (from the breath-by-breath plot) at 30 s of active recovery was greater than or equal to the instantaneous VO2 at peak exercise. Thirty patients (21%) showed a further increase in VO2 following peak exercise (group 1), and 112 had decreased VO2 at 30 s after peak exercise (group 2). In group 1, treadmill time was significantly shorter, peak VO2 was significantly lower (16.6 +/- 3.6 vs 21.6 +/- 6.4 mL/kg/min), and peak ventilatory equivalent for carbon dioxide (VE/VCO2) was significantly higher than those in group 2. There was no difference in etiology of heart failure or functional class and medication status. CONCLUSION: A further increase in VO2 during early active recovery was associated with poorer exercise tolerance, lower peak VO2, and higher peak VE/VCO2 in chronic heart failure patients. This sign may be a new functional variable for assessment of chronic heart failure. Further investigations are warranted to clarify the mechanisms and clinical implications of this phenomenon.

Medical and economic costs of psychologic distress in patients with coronary artery disease.

OBJECTIVE: To determine the effect of psychologic distress, measured with a commonly used screening questionnaire, on 6-month morbidity and rehospitalization costs in coronary patients. DESIGN: Psychologic distress was determined by screening with the Symptom Checklist-90--Revised (SCL-90-R) self-report inventory during the second week of cardiac rehabilitation. Costs associated with cardiovascular rehospitalization during a 6-month follow-up period were recorded, and differences between "distressed" and "nondistressed" patients were analyzed statistically. MATERIAL AND METHODS: The study cohort consisted of 381 patients (311 men and 70 women) referred for cardiac rehabilitation after an index hospitalization for unstable angina, myocardial infarction, coronary angioplasty, or coronary bypass procedure. Patients with SCL-90-R scores above the 90th percentile for outpatient adults were considered distressed (N = 41); patients with scores below this level were considered nondistressed (N = 340). RESULTS: The 6-month follow-up was complete in all but 1 of the 381 patients. Distressed patients had significantly higher rates of cardiovascular rehospitalization, any recurrent events, and recurrent "hard events" (cardiac death, myocardial infarction, or cardiac arrest and resuscitation) within 6 months after dismissal from their index hospitalization in comparison with nondistressed patients. Adjustment for other factors associated with a risk of early rehospitalization and recurrent events did not reduce the strength or significance of the association between psychologic distress and early cardiovascular rehospitalization or recurrent events. The mean rehospitalization costs were significantly higher in the distressed than in the nondistressed patients ($9,504 versus $2,146). CONCLUSION: These data add support to the hypothesis that psychologic distress adversely affects the prognosis in coronary patients, confirm the added morbidity and rehospitalization costs attributable to psychologic distress, and suggest the potential for improving the prognosis in selected coronary patients by identification and appropriate treatment of psychologic distress.

Cardiovascular responses to immersion in a hot tub in comparison with exercise in male subjects with coronary artery disease.

In order to test the safety of hot tub use for persons with heart disease, 15 men with clinically stable coronary artery disease underwent 15 minutes of immersion in a hot tube at 40 degrees C. On another day, they exercised on a cycle ergometer for 15 minutes; target heart rate was determined by standard methods. Tympanic temperature, skin temperature, electrocardiographic findings, blood pressure, plasma catecholamines, subjective comfort, and cardiovascular symptoms were monitored. The peak heart rate was significantly lower during the hot tub session versus the exercise session (85 +/- 14 versus 112 +/- 19 beats/min), as were the systolic (106 +/- 15 versus 170 +/- 21 mm Hg) and diastolic (61 +/- 6 versus 83 +/- 8 mm Hg) blood pressure measurements (P < 0.01). Tympanic temperature increased by a mean of 0.6 +/- 0.3 degrees C during immersion and 0.1 +/- 0.1 degrees C during exercise. No ischemic electrocardiographic changes or clinical complications occurred. Simple ventricular ectopic activity and "just noticeable" chest pain were more frequent during exercise than during immersion. Plasma norepinephrine increased during exercise but not during immersion. These data suggest that hot tub use within these time and temperature constraints should be safe for men with stable heart disease who can follow an exercise regimen at home.

Low-dose, time-release nicotinic acid: effects in selected patients with low concentrations of high-density lipoprotein cholesterol.

In a retrospective analysis, 63 participants in a cardiac rehabilitation-preventive cardiology program were identified as having low blood concentrations (mean, 34 mg/dl) of high-density lipoprotein cholesterol (HDL-C) and a mean total cholesterol level of 223 mg/dl after 3 months of hygienic measures (aerobic exercise, avoidance of tobacco, diet, and weight loss) designed to increase the HDL-C level. These patients (treatment group) were treated with low-dose, time-release nicotinic acid (mean, 1,297 mg/day) for a mean duration of 7.4 months. All subjects were able to take the drug without intolerable side effects. Fifty-four patients similar to those in the treatment group participated in the same program but were not treated with nicotinic acid (control group). Exercise, diet, body weight, and smoking remained stable throughout the period of observation. For the treatment group, HDL-C levels increased a mean of 18% (+6 mg/dl), total cholesterol concentrations decreased 9% (-20 mg/dl), the ratio of total cholesterol to HDL-C decreased 25% (from 6.8 to 5.1), low-density lipoprotein cholesterol levels decreased 13% (-20 mg/dl), and triglyceride levels decreased 20% (from 165 mg/dl to 132 mg/dl). Aspartate aminotransferase and uric acid concentrations were minimally increased after treatment, and the blood glucose level was unchanged. In the control group, HDL-C levels increased a mean of 8% (+3 mg/dl) and the other blood lipid variables were not improved after a mean of 8.3 additional months of diet and exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

Niacin-induced hepatitis: a potential side effect with low-dose time-release niacin.

Hepatitis developed in five patients who were taking low dosages (3 g/day or less) of time-release niacin. In four of the five patients, clinical symptoms of hepatitis developed after the medication had been taken for a relatively short time (2 days to 7 weeks). This manifestation of hepatotoxicity seems to differ from that previously reported in association with use of crystalline niacin, which occurred with high dosage and prolonged usage of the medication. In view of the recent increased frequency of prescribing niacin for the treatment of hyperlipidemia, physicians should be aware of the potential for hepatotoxicity with even low-dose and short-term use of time-release niacin.

High-density lipoprotein cholesterol. Recommendations for routine testing and treatment.

Evidence from epidemiologic, lipid intervention, and coronary angiographic studies demonstrates the importance of high-density lipoprotein cholesterol (HDL-C) in coronary artery disease (CAD) risk. Data from these studies strongly support the measurement of HDL-C in all patients screened for CAD. Patients with low levels should be treated using nonpharmacologic measures. High-risk patients deserve consideration for specific drug treatment.

Cardiovascular rehabilitation: status, 1990.

Cardiovascular rehabilitation is defined as the process of development and maintenance of a desirable level of physical, social, and psychologic functioning after the onset of a cardiovascular illness. Patient education, counseling, nutritional guidance, and exercise training play prominent roles in the process of rehabilitation. Benefits from cardiac rehabilitation include improved exercise capacity and decreased symptoms of angina pectoris, dyspnea, claudication, and fatigue. Recent pooled data regarding exercise training after myocardial infarction demonstrated a 20 to 25% reduction in mortality and major cardiac events. Exercise training may result in an improvement in systemic oxygen transport, a reduction in the myocardial oxygen requirement for a given amount of external work, and a decrease in the extent of myocardial ischemia during physical activity. The efficacy of modification of risk factors in reducing the progression of coronary artery disease and future morbidity and mortality has been established. Herein we review the history, current practice and results, and future challenges of cardiovascular rehabilitation.