Heart failure (HF), most simply defined as the inability of the heart to meet the demands of the tissue, results in symptoms of fatigue or dyspnea on exertion (progressing to dyspnea at rest), and is a costly and deadly disorder.1 HF is the only cardiovascular disease entity where the incidence is currently increasing. In 1991 there were ‘just’ 3.5 million reported cases of HF in the US; however, this number has recently risen to 5 million.2 While this represents a major burden now, the HF prevalence in the US is expected to double to 10 million by 2030.3 Much of the increase in prevalence can be attributed to the aging population, as the prevalence of HF increases from 2% in individuals between 40 and 50 years of age to more than 10% in those above 65 years of age.2 Moreover, hospital admissions for HF in patients above 65 years of age has increased by 131%, from 348,886 in 1980 to 807,082 in 2006.2 Consequently, annual direct and indirect treatment costs associated with managing this growing HF burden are a staggering $34 billion. While HF has become a major public health problem, unfortunately little has been done to establish systematic screening efforts (such as those for breast or prostate cancer) to detect this deadly disease at the earliest stage. HF is largely preventable, primarily through control of blood pressure and other known vascular risk factors.
The American College of Cardiology (ACC) and the American Heart Association (AHA) have developed an approach that emphasizes evolution and disease progression in HF to classify the disease into four stages.4 While these guidelines are comprehensive and provide recommendations for specific medical therapies, surgical interventions, and dietary modifications for each stage of HF, one potentially important therapy—exercise/physical activity—is noticeably absent. The absence of exercise therapy guidelines in this important document may lead to concern and/or confusion among clinicians regarding the safety and/or efficacy of exercise for HF patients. The purpose of this article is to summarize the already extensive and rapidly accumulating evidence demonstrating that properly conducted exercise therapy is safe and beneficial in stable HF patients.
Pathophysiology and Consequences of Heart Failure
It is now widely accepted that HF is not a disease but rather a pathophysiological ‘syndrome’ that occurs when there is significant left ventricular (LV) systolic and/or diastolic dysfunction5 that leads to the development of HF signs and symptoms. Whereas systolic dysfunction can be considered a defect in the ability of myofibrils to shorten against resistance, diastolic dysfunction results from an increased resistance to LV filling leading to an inappropriate upward shift of the diastolic pressure volume relation. Systolic dysfunction will result in elevated end-diastolic and end-systolic volumes, resulting in a reduced ejection fraction, whereas diastolic dysfunction results in reduced end-diastolic and end-systolic volumes, with a resultant normal or greater than normal ejection fraction. Despite significant differences in ejection fraction, signs/symptoms at presentation can be remarkably similar in patients with HF and a reduced ejection fraction (HF-REF) and in patients with HF and a preserved ejection fraction (HF-PEF). In addition to the reduced stroke volume associated with reduced LV contraction and/or filling, an inadequate heart rate response during exercise can also contribute to the reduced cardiac output seen in patients with systolic and diastolic HF. Studies from our laboratory have demonstrated that 20–25% of older HF patients have chronotropic incompetence during exercise.6 Furthermore, those patients with chronotropic incompetence have a significantly lower exercise capacity compared with similar HF patients with a normal heart rate response. Either form of LV dysfunction can result in a reduction in cardiac output during exercise that ultimately leads to a reduced perfusion to numerous organ systems and a variety of complex and inter-related pathophysiological responses. These compensatory adaptations, although initially activated to preserve vital body functions, ultimately result in a vicious spiral that produces numerous signs/symptoms, including exercise intolerance (see Figure 1).
Exercise-related Limitations in Heart Failure
Numerous studies7 over the past two decades have consistently demonstrated that the exercise capacity of HF patients, best quantified by oxygen consumption at peak exercise (VO2 peak), is 15–40% below that of age-matched healthy subjects. Based on the Fick equation, an appropriate increase in VO2 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 studies7 over 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 clearly contribute to the symptoms and exercise intolerance commonly experienced by HF patients. Other peripheral abnormalities that are often 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 non-oxidative (anaerobic) enzymes in skeletal muscle tissue; and
- generalized skeletal muscle atrophy and reduction in type I fibers.
Different Hearts but Same Exercise Responses
Despite significant underlying differences in LV structure and function, research from our laboratory8,9 has demonstrated remarkably similar acute responses to endurance-type exercise (i.e. cardiopulmonary exercise test responses) in older patients with HF-REF and HF-PEF. 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) has led to the conclusion that HF-PEF can result in the full HF syndrome. Epidemiological investigations10 have extended our pathophysiological observations and demonstrate that morbidity and mortality are also similar between these two disorders. The extent of the pathophysiological similarities between HF-PEF and HF-REF are presented in Table 1.
Exercise Therapy for Heart Failure with Reduced Ejection Fraction—Harmful or Helpful?
Over the past quarter of a century there have been dozens of studies and subsequent publications reporting on the effects of endurance-or aerobic-type exercise therapy (ET) in patients with HF (primarily in those with HF-REF).7 Despite several early positive studies, one study from Canada in 198811 suggested that exercise training conducted in post-myocardial infarction (MI) patients who had significant LV dysfunction could potentially worsen ventricular fuction and further reduce EF. This small study with questionable methodology raised concern in the medical community regarding the safety of ET for HF patients.
Fortunately, many more reports at this time and since then have emerged and consistently demonstrate that not only is appropriately prescribed ET safe in HF, but it is also highly beneficial to these patients in the following ways:7
- improvement in exercise tolerance (VO2 peak) of 12–31%;
- numerous and significant peripheral adaptations, including improved endothelial function, increased oxygen extraction, increased mitochondrial volume, and increased oxidative enzymes;
- decreased sympathetic tone, and improved neurohormonal and pro-inflammatory cytokine levels;
- improved ventilatory efficiency and decreased dyspnea;
- improved quality of life and reduction in symptoms; and
- no significant adverse events reported during ET.
A meta-analysis of 35 randomized controlled trials of endurance exercise training in HF-REF12 that included hundreds of patients clearly demonstrated more favorable changes in VO2 peak, six-minute walk distance, and health-related quality of life in patients who participated in ET compared with the control subjects.
Exercise Therapy and Ventricular Remodeling
While significant improvements in overall physical function (VO2 peak, six-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.7 Although the lack of improvement in cardiac function is somewhat disappointing, more recent evidence suggests that ET can prevent undesirable LV remodeling in HF-REF patients.13 In HF-REF there is generally progressive chamber dilatation and deterioration in LV function over time. This undesirable LV remodeling appears to be due to hemodynamic loading and/or neurohormonal stress. Furthermore, the LV remodeling commonly seen in HF-REF is associated with increased morbidity and mortality. A recent meta-analysis of 14 trials that included 812 HF-REF patients14 demonstrated that those in ET groups tended to maintain their LV function (EF and end-systolic and end-diastolic volume) better than patients in the control arm of these studies. Interestingly, when ET was combined with resistance training, antiremodeling effects were no longer present.14 Perhaps the pressure overload associated with resistance exercise training negatively counterbalances the favorable adaptations associated with ET.
Exercise and Mortality in Heart Failure with Reduced Ejection Fraction—Time for Action
While ET has been shown to have many positive effects in HF-REF, of particular interest is the potential effect of ET on the substantial mortality observed with this chronic condition. Several small studies and meta-analyses15 have attempted to examine this issue and have generally reported favorable effects of ET on morbidity. One meta-analysis16 included 11 randomized controlled trials (729 subjects) and determined that ET in HF-REF resulted in a 39% reduction in overall mortality in subjects who took exercise versus non-exercise control subjects. While generally positive, these studies were often limited by small sample sizes and single-center designs, were underpowered to evaluate mortality and morbidity outcomes, lacked randomized assignment or adequate control groups, were not blinded, and had limited safety data. To overcome the limitations of previous studies, in 2003 the HF—A Controlled Trial Investigation Outcomes of Exercise Training (HF-ACTION) multicenter study was designed17 and funded by the National Institutes of Health (NIH). The main outcomes from this trial were recently presented at the 2008 AHA scientific sessions18 and are being prepared for publication. HF-ACTION is the largest clinical exercise trial conducted to date and included 2,331 patients with chronic HF-REF (EF <35%). Patients were randomized to usual care, which included a recommendation for mild to moderate exercise most days per week, or enrollment into a 36-session supervised aerobic-type exercise program that was followed by a five-times-weekly home-based program (intensity set at 60–70% of heart rate reserve) for up to three years. A variety of strategies were implemented to retain compliance among patients in the exercise group, including maintaining an exercise log, providing each subject with a heart rate monitor and a treadmill or stationary bike for home use, and telephone calls from research co-ordinators that employed targeted behavioral techniques. Mean follow-up was 2.5 years. More than 92% of all patients were taking an angiotensin-converting enzyme (ACE) inhibitor/angiotension receptor blocker, 95% were on beta-adrenergic blockade, and 40% had an implantable cardioverter defibrillator (ICD) at the time of enrollment. The key findings for the trial are summarized19 below by Dr Steven Keteyian, a primary investigator of the HF-ACTION study.
Exercise training in HF-REF patients was found to be safe, with very few untoward events reported. Such a finding might seem trivial, but prior to the HF-ACTION study, adequate safety data did not exist. The exercise group showed a small reduction in risk (unadjusted 7%; p=0.13, adjusted 11%; p=0.03) for the combined end-point of all-cause death or all-cause hospitalization. The exercise group showed a ~14% reduction in risk (unadjusted 13%; p=0.06, adjusted 15%; p=0.03) for the important 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 the usual care group, and this difference was maintained throughout the follow-up period. Additionally, at 12 months 53% of subjects in the exercise group experienced a clinically meaningful improvement in health status versus only 33% of patients in the usual care group (p<0.05). Compliance during the trial among both study groups was a challenge. Although more than 30% of subjects assigned to the exercise arm of the study exercised for more than 120 minutes per week, median minutes of exercise per week for all subjects in the exercise group declined over time (~95 minutes/week at six months; ~75 minutes/week at 12 months; ~60 minutes/week at 24 months). Among patients in the usual care control group who were asked not to start a regular structured exercise program at both 12 and 24 months, ~22% of these subjects stated that they had been exercising for the past three months.
Since the effect of exercise training on all-cause mortality or hospitalization was not significant in the unadjusted analysis, one view of HF-ACTION might be that this was a neutral or possibly even a negative study. One should caution against adopting this interpretation for two very important reasons. First, the clinician must keep in mind that unlike other HF-related device or drug trials completed to date, the use of evidence-based therapy among subjects enrolled into the HF-ACTION study was excellent. Thus, the allbeit modest and additional 14% reduction in risk for cardiovascular death or HF hospitalization that occurred on top of an already excellent level of evidence-based care was quite meaningful. Second, the 14% reduction seen in the HF-ACTION study is consistent with two prior HF drug trials that evaluated and proved the effectiveness of using an angiotensin receptor blocker in patients with HF. In those two trials there was a 13 and 17% reduction in clinical events—a level remarkably similar to the reduction seen in the HF-ACTION study. Given that the HF-ACTION study found no difference between groups for cardiovascular mortality, the majority of the effect that exercise imparted on the combined end-point of cardiovascular death or HF hospitalization was likely through HF hospitalization alone— a very important cause of morbidity in these patients.
Like all clinical trials, the HF-ACTION study was not without its limitations. Toward the top of the list, despite tremendous efforts by the research team, were the lower than expected levels of compliance among patients in the exercise group. However, despite this shortcoming, trial results still included modest improvements in clinical outcomes and health status. Through additional analyses, trial investigators are currently addressing the effect of exercise training on clinical outcomes, fitness, and health status among those subjects in the exercise group that undertook exercise as prescribed. Although post hoc observational analyses such as this cannot be considered definitive, they will provide additional important insight as to any actual effect between exercise training and outcomes. Additionally, an analysis that addresses the cost-effectiveness of exercise training is now being completed.
Exercise Therapy for Heart Failure with Preserved Ejection Fraction
While numerous studies have evaluated the effects of ET in HF-REF, few to date have performed similar exercise-based interventions in HF-PEF subjects. We completed a 16-week, randomized, controlled trial of a traditional, center-based ET intervention in older (>60 years of age) HF-PEF patients. Compared with the non-exercise control group, those in the ET group demonstrated a 23% increase in VO2 peak and other measures of exercise tolerance, as well as health-related quality of life. Similar to the HF-REF patients, our preliminary analyses20 suggest that the favorable improvement associated with ET is due to ‘peripheral’ rather than ‘central’ adaptations. Similar results and conclusions have been drawn from a similar study, conducted in Australia, of ET in HF-PEF.21 Clearly, more research on the specific mechanisms and adaptation associated with ET in HF-PEF is warranted and needed to confirm these preliminary studies.
Novel/Emerging Exercise Therapies for Heart Failure Patients
Of the numerous studies discussed throughout this article, the ET interventions have all been of the endurance/aerobic type, performed three to five times per week at a moderate intensity (usually regulated by heart rate), typically for a duration of 30–60 minutes. Several provocative studies have challenged this traditional ET approach and suggested 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 study22 of 27 older HF-REF (EF 29%) patients on optimal medical therapy examined the effects of moderate continuous training ([MCT] exercise at 70% peak heart rate continuously for a total of 47 minutes) versus aerobic interval training ([AIT] exercise at 95% peak HR for four minutes followed by three-minute ‘active’ pauses performed in interval fashion for a total of 38 minutes). Both groups exercised three times each week for 12 weeks (two supervised and one at home) on a uphill treadmill and overground walking, respectively. While both groups showed similar favorable improvements in VO2 peak and flow-mediated arterial dilation, the AIT produced more favorable changes than MCT in mitochrondrial biogenesis, pro-B-type natriuretic peptide (proBNP), and oxidized low-density lipoprotein (LDL) levels, total antioxidant status, and the ability to more effectively transport calcium within the sarcoplasmic reticulum.
Historically, the use of resistance training (RT) in HF-REF patients has been contraindicated and avoided for fear that the pressure overload associated with the static component of muscular contractions would exacerbate the weakened state of the failing heart. Several studies23 have assessed the effectiveness of RT, often combined with ET for six months, and have found that for most stable HF-REF this mode of training is generally safe and effective. Specifically, this type of training:
- improves New York Heart Association (NYHA) class and health-related quality of life;
- increases VO2 peak and anaerobic threshold by 14%;
- does not cause undesirable LV remodeling (no change in EF, end-diastolic volume [EDV], or end-systolic volume [ESV]); and
- increases muscular strength and endurance by 10–20% and 20–25%, respectively.
The same research group recently24 compared three different exercise interventions in HF-REF patients. One group performed exclusively endurance training (exercise at 60–75% of V02 peak for 40 minutes), whereas a second group performed exclusively strength training (ST: 10 different lifting exercises times four sets of 10 repetitions each), and a third group performed circuit training (CT), which is a combination of the other two approaches (20 minutes of cycling plus five different lifting exercises times four sets of 10 repetitions). While there were subtle differences between the approaches, ST, endurance training, and CT all produced significant and similar improvements in VO2 peak, cardiac function, thigh skeletal muscle volume, knee extensor strength, and health-related quality of life in HF-REF patients. While 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 widespread clinical application. Moreover, these novel exercise interventions have not been evaluated in HF-PEF patients.
Exercise training (including endurance training and RT) in patients with stable HF (regardless of EF) has a number of significant health benefits and minimal risk. Furthermore, the majority of the benefits of ET and RT in stable HF patients (also regardless of EF) are mainly due to ‘peripheral’ rather than ‘central’ physiological adaptations. These physiological adaptations may 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 training and RT) in HF-REF does not cause undesirable LV remodeling (it may actually be antiremodeling), is well tolerated, and appears 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 paper25 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 LVEF.” Consequently, based on current research and published guidelines it would be appropriate and desirable for clinicians to recommend appropriately prescribed exercise therapy for stable HF patients. One mechanism to accomplish this is through the referral of stable HF patients to an established cardiac rehabilitation program.