Heart failure (HF), also known as congestive or chronic heart failure, is a costly and deadly disorder (15) and is the only cardiovascular disease condition where the number of new cases is actually increasing over time. In 1991, 3.5 million cases of HF were reported in America; however, this number has now risen to 5 million (24). Whereas this represents a major burden to our society, the HF prevalence in America is expected to double to more than 10 million by 2030 (6). Much of the increase can be attributed to the aging of the population because the prevalence of HF increases from just 2% in individuals aged 40 to 50 years to more than 10% in those older than 65 years (24). Moreover, hospital admissions for HF in patients older than 65 years has increased 131%, from 348,886 cases in 1980 to 807,082 cases in 2006 (24). Consequently, the direct and indirect treatment costs associated with managing this growing HF burden are a staggering $34 billion a year!
Although HF has become a major public health problem, little has been done to establish systematic screening efforts, such as those for breast or prostate cancer, to detect this deadly disease at earliest stages. Heart failure is largely preventable, primarily through the control of blood pressure, diabetes, dyslipidemia, and other factors that increase the risk for ischemic heart disease. Furthermore, evidence continues to mount, indicating that obesity, renal disease, and disordered sleeping place patients at increased risk for developing HF. The American College of Cardiology (ACC) and the American Heart Association (AHA) have developed an approach that emphasizes the evolution and disease progression to classify HF into four defined stages (14). Although these guidelines are very comprehensive and provide recommendations for specific medical therapies, surgical interventions, as well as dietary modifications for each stage of HF, one potentially important therapy, exercise/physical activity, is noticeably absent from these guidelines. The absence of exercise therapy (ET) guidelines in this important document may lead to concern and/or confusion among health and fitness practitioners regarding the safety and/or efficacy of ET for HF patients. Consequently, the purpose of the present report is to summarize the already extensive and rapidly accumulating evidence demonstrating that properly conducted ET is safe and beneficial in stable HF patients.
WHAT IS HEART FAILURE AND WHAT CAUSES IT?
It is now widely accepted that HF is not a disease but rather a pathophysiological "syndrome" that occurs when there are abnormalities in either contraction and/or relaxation of the left ventricle (LV). The subsequent diminished cardiac output provides inadequate blood flow to vital organs/tissue (kidney, lungs, skeletal muscle), which then evokes numerous compensatory pathophysiological responses that worsen the condition and produce a downward spiral of health and function. Ultimately, this syndrome results in fatigue, exercise intolerance, and/or shortness of breath - the most common and consistent HF signs and symptoms (see Figure) (18).
The reduced cardiac function, subsequent to reduced contractile force of the LV, is generally identified as a reduction in the ejection fraction (EF% = stroke volume/end-diastolic volume), a value most commonly obtained by echocardiography. Whereas a "normal" LV EF% is generally 55% to 60%, significant LV dysfunction is present when this value drops to less than 35%. An LV EF% as low as 10% to 15% is seen in patients with very severe LV dysfunction. Patients with HF associated with this poor LV contractility are commonly classified as having "systolic" HF or HF with a reduced ejection fraction (HF-REF). This type of HF is often further categorized as being of either an "ischemic" or "nonischemic" etiology. An ischemic cardiomyopathy (cardiomyopathy is a general term used to describe cardiac muscle weakness) is usually caused by an inadequate coronary blood supply, subsequent to coronary artery disease, that results in a myocardial infarction and/or chronic myocardial ischemia. A nonischemic cardiomyopathy is most commonly caused by heart valve disorders or from a viral infection that damaged the cardiac muscle cells (myocytes).
In contrast, those patients who develop HF signs and symptoms caused by inadequate/incomplete relaxation of the LV are presently referred to as having diastolic HF or HF with a preserved or "normal" EF (HF-NEF) because their EF% remains above the normal level of 55%. Although systolic function is normal, those with impaired relaxation of the LV have reduced LV filling capacity. As described by the Starling law (where cardiac output = [heart rate × stroke volume]/arterial-venous oxygen difference), inadequate LV filling (i.e., diminished preload) will result in a decreased stroke volume and cardiac output. Although HF-NEF also can be caused by ischemic heart disease, other common risk factors for this condition include long-standing hypertension, diabetes, obesity, female gender, and older age (14). Despite significant differences in EF% and other measures of cardiac function (shown in the Table), clinical signs/symptoms can be remarkably similar in patients with a reduced (HF-REF) versus normal ejection (HF-NEF).
In addition to the diminished stroke volume associated with impaired LV contraction and/or relaxation, an inadequate heart rate response during exercise also can contribute to the reduced cardiac output seen in patients with systolic and diastolic HF. Studies from our laboratory have demonstrated that 20% to 25% of older HF patients have an impaired heart rate response (called chronotropic incompetence) during exercise (3). Furthermore, those patients with chronotropic incompetence have a significantly lower exercise capacity compared with similar HF patients with a normal heart rate response during exercise.
WHY SO TIRED? THE PHYSIOLOGICAL LIMITATIONS OF HF PATIENTS
A myriad of studies during the past two decades have consistently demonstrated that the exercise capacity of HF patients, best quantified by oxygen consumption at peak exercise (V˙O2 peak), is 15% to 40% below that of age-matched healthy subjects (21). Based on the Fick equation (as described earlier), an appropriate increase in V˙O2 peak is dependent on both an increase in cardiac output (which depends on appropriate heart rate and stroke volume responses) and a concomitant widening of the arterial-venous oxygen content difference (i.e., increased oxygen extraction). Numerous studies during the past two decades have described the plethora of peripheral abnormalities in HF patients that limit oxygen supply and/or extraction by active skeletal muscle tissue. Abnormalities in vascular structure and function including endothelial dysfunction, elevated neurohormonal responses, and/or pulmonary dysfunction also can contribute to the symptoms and exercise intolerance commonly experienced by HF patients. Other peripheral abnormalities commonly observed in HF that contribute to exercise intolerance include:
- increased sympathetic tone and peripheral vasoconstriction
- reduced skeletal muscle blood flow
- abnormal/inefficient ventilation during exercise
- reduction in oxidative (aerobic) enzymes in skeletal muscle
- decreased skeletal muscle mitochondrial volume and density
- increased nonoxidative (anaerobic) enzymes in skeletal muscle
- generalized skeletal muscle atrophy and reduction in Type I fibers
DIFFERENT HEARTS - SAME EXERCISE RESPONSES
Despite significant underlying differences in LV structure and function, research from our laboratory (4,17) has demonstrated remarkably similar acute responses to endurance type exercise (i.e., cardiopulmonary exercise test responses) between older patients with HF-REF and HF-NEF. Similarities between these two HF groups in the four pivotal HF domains (exercise capacity, health-related quality of life, neurohormonal levels, and LV structure and function) have led to the conclusion that HF-NEF can result in the full HF syndrome. Epidemiological investigations (5) have demonstrated that morbidity and mortality also are similar between these two disorders. The extent of the pathophysiological similarities (and slight differences) between HF-REF and HF-NEF are presented in the Table.
ASSESSING EXERCISE INTOLERANCE IN HF
The acute exercise responses of HF patients are best evaluated during a graded exercise test, either on a variable-resistance lower-extremity cycle ergometer or motor-driven treadmill, to the subject's symptom-limited maximal (i.e., peak) capacity. The protocol used for testing with either modality should begin with a very low workload (unloaded cycling/1-2 mph walking) and progress slowly and gradually until the patient it unable to continue generally because of fatigue and/or dyspnea. Of course, abnormal exercise responses (1) should result in exercise test termination even if the patient is willing/able to continue. Because HF patients will typically have only a 4 to 5 maximal MET capacity (V˙O2 peak, 14.0 vs. 17.5 mL/kg per minute), the workload should only be increased by 0.5 to 1.0 MET every 2 to 3 minutes. Although there are many low-level treadmill protocols to choose from for this population, the individualized RAMP and modified Naughton are most commonly used. For bike testing, a low-level RAMP (5-10 W/minute increment) or a conventional staged protocol (12.5- to 25-W increments every 2- to 3-minute stage) are commonly used in this population. In addition to traditional measurements obtained during an exercise test (electrocardiogram, blood pressure, rating of perceived exertion, signs/symptoms), it is very important to obtain expired gas exchange measures in HF patients (if possible). Variables obtained from expired gas analysis include V˙O2 peak, ventilatory "anaerobic" threshold, and other measures of ventilatory efficiency such as VE/VCO2 slope. Individually and collectively, these variables have important prognostic values and can accurately quantify functional capacity as well as aid in formulating an exercise prescription.
The 6-minute walk testing (6MWT) has become a widely used tool for the functional assessment of HF patients because it is relatively easy to conduct and does provide a reasonable estimate of prognosis and submaximal exercise capacity. Despite the appeal and widespread use of 6MWT, the ACC (13) does not recommend using it in place of the graded exercise test with expired gas analysis when assessing HF patients. Despite these recommendations, many clinical HF programs will still use the 6MWT to evaluate the physical capacity of their patients and evaluate the effectiveness of their medical management.
EXERCISE THERAPY FOR HF-REF: A BRIEF HISTORY
During the past quarter century, dozens of studies and subsequent publications have reported on the effects of endurance/aerobic-type ET in patients with HF, primarily those with HF-REF (21). Although one small study of questionable methodology (16) in the late 1980s raised some concern about the safety of ET for HF patients, many more reports have emerged since then and consistently demonstrate that not only is appropriately prescribed ET safe in HF patients, but it is highly beneficial to these patients in the following ways (21):
- improves exercise tolerance; V˙O2 peak by 12% to 31%
- produces numerous and significant peripheral adaptations including improved endothelial function, increased oxygen extraction, increased mitochondrial volume, and increased oxidative enzymes
- decreases sympathetic tone as well as improves neurohormonal and proinflammatory cytokine levels
- improves ventilatory efficiency and decreases dyspnea
- improves quality of life and reduces symptoms
- no significant adverse events have been reported during ET!
A meta-analysis of 35 randomized controlled trials of endurance exercise training in HF-REF (26) demonstrated significant improvements in V˙O2 peak, 6-minute walk distance, and health-related quality of life in patients that participated in ET versus the control subjects.
CAN EXERCISE TRAINING IMPROVE A DAMAGED HEART?
Although significant improvements in overall physical function (V˙O2 peak, 6-minute walk distance) are generally expected with supervised ET, most are associated with the aforementioned peripheral adaptations, as very few studies have observed meaningful improvement in central hemodynamics/cardiac volume responses in HF patients (21). Although the lack of improvement in cardiac function is somewhat disappointing, the preponderance of evidence suggests that ET may prevent undesirable LV remodeling in HF-REF patients (10). Generally there is progressive chamber dilatation and deterioration in LV function over time in HF-REF. This undesirable LV remodeling seems to be caused by hemodynamic loading and/or neurohormonal stress. Furthermore, the LV remodeling commonly seen in HF-REF is associated with increases in morbidity and mortality. A recent meta-analysis of 14 trials that included 812 HF-REF patients (12) demonstrated that those in ET groups tended to maintain their LV function (i.e., EF%) better than those patients in the control arm of these studies. Interestingly, in this meta-analysis, when ET was combined with resistance training, the antiremodeling benefits were no longer present (12). The pressure overload associated with resistance exercise training may negatively counterbalance the favorable adaptations associated with ET, a concept to be further addressed at a later section on resistance training.
CAN EXERCISE TRAINING REDUCE MORTALITY IN HF-REF - WHAT ARE WE LEARNING FROM THE RECENT HF ACTION TRIAL?
Although ET has been shown to have many positive effects on HF-REF, of particular interest is the potential impact of ET on the excessive mortality associated with this chronic condition. Several small studies and a meta-analysis (2) have examined this issue and generally demonstrate favorable effects of ET on HF mortality. In particular, one meta-analysis (23) included 11 randomized controlled trials (729 subjects) and determined that ET in HF-REF resulted in a 39% reduction in overall mortality versus nonexercise control subjects. Although favorable, these studies have been limited by small sample sizes and single-center designs that were underpowered to evaluate mortality and morbidity outcomes. In addition, these studies lacked randomized assignment or adequate control groups, were unblinded, and/or provided limited safety data. To overcome the limitations of previous studies, the Heart Failure - A Controlled Trial Investigating Outcomes of exercise traiNing (HF-ACTION) multicenter study was funded by the National Institutes of Health in 2003. The main outcomes from this trial were presented at the 2008 AHA scientific sessions and are now published (9,20). The HF-ACTION included 2,331 patients with chronic HF-REF (EF%, <35%). Patients were randomized to either a usual care treatment (which included a one-time recommendation for mild to moderate exercise most days per week) or into a supervised aerobic-type exercise program of 36 sessions (12 weeks) that was followed by a five-times-per-week home-based program (intensity set at 60% to 70% heart rate reserve) for up to three years. A variety of strategies were implemented to retain compliance among patients in the exercise group including (a) maintaining an exercise log, (b) providing each subject with a heart rate monitor and a treadmill or stationary bike for in-home use, and (c) and telephone calls from research coordinators that used targeted behavioral techniques. Mean follow-up was 2.5 years, and more than 92% of all patients were taking an angiotensin converting enzyme (ACE) inhibitor/angiotension receptor blocker, 95% were on a β-blocker, and 40% had an implanted cardiodefibrillator at the time of enrollment. The key findings for the trial are summarized.
- Exercise training of HF-REF patients was found to be safe - with very few reported untoward events. Although this might seem intuitive, before HF-ACTION, adequate safety data for this population did not exist.
- The exercise group showed a small (unadjusted, 7%, P = 0.13; adjusted, 11%, P = 0.03) reduction in risk for the combined end point of all-cause death or all-cause hospitalization.
- The exercise group showed an approximate 14% (unadjusted, 13%, P = 0.06; adjusted, 15%, P = 0.03) reduction in risk for the disease-specific combined end point of cardiovascular death or HF hospitalization.
- Overall health status/quality of life, as measured by the Kansas City Cardiomyopathy Questionnaire, was improved after three months in the exercise group versus usual care, and this difference was maintained throughout the follow-up period. In addition, at 12 months, 53% of subjects in the exercise group (vs. only 33% of patients in the usual care group) experienced a clinically meaningful improvement in health status.
- Adherence/compliance during the trial among both study groups was different than expected. Although more than 30% of subjects assigned to the exercise arm of the study exercised more than 120 minutes per week, median minutes of exercise per week for all subjects in the exercise group declined over time (∼95 minutes per week at 6 months; ∼75 minutes per week at 12 months; ∼60 minutes per week at 24 months). In addition, among patients in the usual care control group who were asked not to start a regular structured exercise program, approximately 22% of these subjects stated that they were exercising at both 12 and 24 months.
Similar to all clinical trials, HF-ACTION was not without its limitations. Of particular concern in this trial was the lower-than-expected compliance in the exercise group. Yet, despite this shortcoming, trial results still included modest improvements in clinical outcomes and health status. Through additional analyses, trial investigators are currently evaluating if there is a dose-response relationship between the volume of exercise performed and clinical events. They are asking the question, "Did patients who were more compliant to the exercise program have fewer clinical events (death, hospitalization, etc.) than those who were less compliant?" Additional analyses to evaluate the cost-effectiveness of exercise training in HF-ACTION also are being completed and will provide important information regarding the benefits of exercise training in HF patients.
IS ET AS BENEFICIAL FOR PATIENTS WITH HF-NEF?
Although numerous studies have evaluated the effects of exercise training in HF-REF, few have performed similar exercise-based interventions in HF-NEF subjects. We have completed a randomized controlled trial of a traditional center-based ET intervention in older (≥60 years) HF-NEF patients lasting 16 weeks. Our unpublished data indicate that in comparison with the nonexercise control group, those in the ET group demonstrated a 23% increase in V˙O2 peak and other measures of exercise tolerance, as well as health-related quality of life. Similar to the HF-NEF patients, our preliminary analyses suggest that the favorable improvements associated with exercise training are mainly caused by peripheral rather than central cardiac adaptations. Similar results and conclusions have been reported in an Australian study of exercise training HF-NEF patients (22). Clearly, more research on specific mechanisms and adaptations associated with exercise in HF-NEF is warranted to confirm these preliminary studies.
ARE OTHER EXERCISES SAFE AND EFFECTIVE FOR HF PATIENTS?
Of the numerous studies discussed throughout this article, the exercise training protocol has been the endurance/aerobic/cardio type, performed three to five times per week, at a moderate intensity (usually regulated by heart rate at 60% to 80% of heart rate reserve), and typically for a duration of 30 to 60 minutes. Several provocative studies (11,19,25,27) have questioned this traditional exercise prescription and suggest that high-intensity interval training may provide a better exercise stimulus in HF-REF patients. In theory, the higher-intensity training can stimulate greater change in the skeletal muscle abnormalities (i.e., mitochondrial levels and oxidative enzyme activity) with less stress on the weakened heart. One particular study (27) of 27 older HF-REF (EF, 29%) on optimal medical therapy examined the effects of moderate continuous training ([MCT] exercise at 70% peak heart rate continuously for total of 47 minutes) versus aerobic interval training [AIT] exercise at 95% peak heart rate × 4 minutes followed by 3-minute active pauses performed in interval fashion for a total of 38 minutes). Both groups exercised three times per week for 12 weeks (two supervised + one at home) on an uphill treadmill and overground walking, respectively. Although both groups showed similar favorable improvements in V˙O2 peak and flow-mediated arterial dilation, a measure of endothelial function, the AIT produced more favorable changes than MCT in mitochrondrial biogenesis, proBNP (an important hormone in HF), oxidized LDL levels, total antioxidant status, as well as the ability to more effectively transport calcium within the sarcoplasmic reticulum.
Historically, the use of resistance training in HF-REF patients has been contraindicated and avoided for fear that the pressure overload associated with the static component of muscular contractions could exacerbate the weakened state of the failing heart. Several studies (7,8) have assessed the effectiveness of resistance training, often combined with endurance training, and have found that for most stable HF-REF, this mode of training is generally safe and effective. Specifically, six months of resistance training often combined with endurance training results in:
- improvement in symptoms and health-related quality of life
- increase in V˙O2 peak and anaerobic threshold by 14%
- no undesirable remodeling of LV (i.e., no worsening of EF%)
- increases in muscular strength and endurance by 10% to 20% and 20% to 25%, respectively
The same research group recently (8) randomly compared three different exercise interventions in HF-REF patients. One group exclusively performed endurance training (exercise at 60% to 75% of V˙O2 peak for 40 minutes), whereas a second group exclusively performed strength training [ST] 10 different lifting exercises × 4 sets of 10 repetitions each), and a third group performed circuit training, which is a combination of the other two approaches [CT] 20 minutes of cycling + 5 different lifting exercises × 4 sets of 10 repetitions). Although there were subtle differences in the results, the three approaches (ST, endurance training, and CT) all produced similar significant improvements in V˙O2 peak, cardiac function, thigh skeletal muscle volume, knee extensor strength, and health-related quality of life in HF-REF patients. Although high-intensity interval and/or resistance training interventions have produced significant benefits and no reported untoward events in HF-REF patients, these studies have generally been short in duration and warrant further study before clinical application. Moreover, these novel exercise interventions have not been evaluated in HF-NEF patients.
Exercise training (including endurance and resistance exercise training) in patients with stable HF (regardless of EF) has a number of significant health benefits and minimal risk. Furthermore, most of the benefits of endurance and resistance exercise training in stable HF patients (also regardless of EF) are caused mainly by peripheral rather than central (i.e., cardiac) physiological adaptations. These physiological adaptations may (although further studies are warranted) be best elicited by higher-intensity interval training and/or small muscle group training, particularly in HF-REF patients with a limited cardiac output response to exertion. Finally, exercise training (including endurance and resistance exercise training) in HF-REF does not cause undesirable LV remodeling (may actually be antiremodeling), is well tolerated, and seems to have a favorable effect on morbidity and mortality in these high-risk patients. Although published before the HF-ACTION study was completed, the ACC/AHA position paper (13) concluded that exercise training is beneficial as an adjunctive approach to improve clinical status in ambulatory patients with current or prior symptoms of HF and reduced LV EF. Consequently, based on current research and published guidelines, it would be appropriate and, in fact, desirable for clinicians to recommend appropriately prescribed ET for stable HF patients. One mechanism to accomplish this is through referral of stable HF patients to an established cardiac rehabilitation program where they can be properly supervised and monitored.
CONDENSED VERSION AND BOTTOM LINE
Numerous studies have demonstrated that moderate-intensity aerobic exercise training, when properly prescribed and monitored, results in a myriad of physiological and psychological benefits for stable heart failure patients. Furthermore, aerobic exercise training seems to lower (albeit modestly) morbidity and mortality in these patients. The long-term effects and safety of resistance training and/or high-intensity aerobic training, while appearing beneficial, have not been fully evaluated. Exercise testing, with expired gas analysis, remains the most appropriate method to evaluate exercise responses and estimate prognosis in HF patients. Exercise clinicians should be aware of the acute responses as well as the chronic adaptations of HF patients to aerobic and resistance exercise training.
1. ACSM Guidelines for Exercise Testing and Prescription
. Baltimore (MD): Lippincott Williams & Wilkins. 8th Edition. 2009.
2. Belardinelli R, Georgiou D, Cianci G, Purcaro A. Randomized, controlled trial of long-term moderate exercise training in chronic heart failure: effects on functional capacity, quality of life, and clinical outcome. Circulation
3. Brubaker PH, et al
. Chronotropic incompetence and its contribution to exercise intolerance in older heart failure patients. J Cardiopulm Rehabil
4. Brubaker PH, et al
. Exercise responses of elderly patients with diastolic versus systolic heart failure. Med Sci Sports Exerc
5. Bursi F, et al
. Systolic and diastolic heart failure in the community. JAMA
6. Croft JB, et al
. National trends in the initial hospitalization for heart failure. J Am Geriatr Soc
7. Delagardelle C, et al
. Strength/endurance training versus endurance training in congestive heart failure. Med Sci Sports Exerc
8. Feiereisen P, et al
. Is strength training the more efficient training modality in chronic heart failure? Med Sci Sports Exerc
9. Flynn KE, et al
. Effects of exercise training on health status in patients with chronic heart failure: HF-ACTION randomized controlled trial. JAMA
10. Giannuzzi P, et al
. Attenuation of unfavorable remodeling by exercise training in postinfarction patients with left ventricular dysfunction: results of the Exercise in Left Ventricular Dysfunction (ELVD) trial. Circulation
11. Gordon A, Tyni-Lenné R, Jansson E, Jensen-Urstad M, Kaijser L. Beneficial effects of exercise training in heart failure patients with low cardiac output response to exercise - a comparison of two training models. J Intern Med
12. Haykowsky MJ, et al
. A meta-analysis of the effect of exercise training on left ventricular remodeling in heart failure patients: the benefit depends on the type of training performed. J Am Coll Cardiol
13. Hunt SA, et al
. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines College of Chest Physicians and the International Society for Heart. Circulation
14. Hunt SA, et al
. 2009 Focused update incorporated into the ACC/AHA 2005 guidelines for the diagnosis and management of heart failure in adults. J Am Coll Cardiol
15. Jessup M, Brozena S. Heart failure. N Engl J Med
16. Jugdutt BI, Michorowski BL, Kappagoda CT. Exercise training after anterior Q wave myocardial infarction: importance of regional left ventricular function and topography. J Am Coll Cardiol
17. Kitzman DW, et al
. Pathophysiological characterization of isolated diastolic heart failure in comparison to systolic heart failure. JAMA
18. Marwick TH, Wong CY. Role of exercise and metabolism in heart failure with normal ejection fraction. Prog Cardiovasc Dis
19. Meyer K. Exercise training in heart failure: recommendations based on current research. Med Sci Sport Exerc
20. O'Connor CM, et al
. Efficacy and safety of exercise training in patients with chronic heart failure: HF-ACTION randomized controlled trial. JAMA
21. Pina IL, et al
. Exercise and heart failure: A statement from the American Heart Association Committee on exercise, rehabilitation, and prevention. Circulation
22. Smart N, et al
. Exercise training in systolic and diastolic dysfunction: effects on cardiac function, functional capacity, and quality of life. Am Heart J
23. Smart N, Marwick TH. Exercise training for patients with heart failure: a systematic review of factors that improve mortality and morbidity. Am J Med
24. Thom T, et al
. Heart disease and stroke statistics-2006 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation
25. Tyni-Lenné R, et al
. Aerobic training involving a minor muscle mass shows greater efficiency than training involving a major muscle mass in chronic heart failure patients. J Card Fail
26. van Tol BA, et al
. Effects of exercise training on cardiac performance, exercise capacity and quality of life in patients with heart failure: a meta-analysis. Eur J Heart Fail
27. Wisloff U, et al
. Superior cardiovascular effect of aerobic interval training versus moderate continuous training in heart failure patients: a randomized study. Circulation