Can Exercise Teach Us How to Treat Heart Disease?

Exercise is one of the mainstay clinical interventions for the prevention and treatment of cardiovascular disease. Not only does exercise reduce cardiovascular risk factors, such as diabetes and hypertension, thereby helping prevent heart disease, it also appears to improve the functional status and outcomes in patients with existing heart disease.1-6 The cardiovascular benefits of exercise are multifactorial, and include important systemic effects (Figure 1) on skeletal muscle, the peripheral vasculature, and metabolism, as well as beneficial alterations within the myocardium itself.7, 8 Figure 1 Overview of the systemic and cardiac-specific effects of exercise Many current pharmacological treatments for cardiovascular disease are targeted towards inhibiting the adverse remodeling process associated with pathological stress. Specifically, they focus on abrogating the pathological hypertrophy, fibrosis, electrical remodeling, and cavity dilatation that accompany disease states such as longstanding hypertension and myocardial infarction.9-11 Interestingly, exercise, like many of these pathological stimuli, can also induce cardiac and cardiomyocyte hypertrophy. However, growing evidence suggests that such physiological remodeling, rather than leading to adverse sequelae, may actually be cardioprotective and that activating pathways associated with exercise can help to prevent and treat cardiovascular disease.8, 12, 13 In this review, we discuss recent advances in our understanding of the cellular and molecular mechanisms (Figure 2) that mediate the cardiac response to exercise, including cardiomyocyte hypertrophy and renewal, vascular remodeling, and alterations in calcium handling and metabolism. In addition to classical signaling mechanisms and transcriptional networks, we describe the role of secreted molecules and miRNAs. Finally, an emerging theme is that pathways that are either regulated by exercise or that mediate the heart's response to exercise often also have the potential to mitigate or even reverse cardiac disease. Thus, we suggest that understanding the effects of exercise more fully may provide useful biological insights and open the door to new therapeutic approaches aimed at restoring cardiovascular health. Figure 2 Key signaling pathways involved in mediating exercise-induced cardiac remodeling Physiological Cardiac Remodeling Exercise is perhaps one of the cheapest — and most effective — interventions for reducing the morbidity and mortality of cardiovascular disease.14 In fact, as little as 45-75 minutes of brisk walking each week appears to reduce the relative risk for adverse cardiac events.15, 16 Additionally, exercise-based cardiac rehabilitation is recommended by the American Heart Association (AHA) as one of the mainstay interventions following acute myocardial infarction (MI), with maximal benefit derived from early initiation of exercise (as early as one week post MI-hospital discharge) and from increased duration of exercise rehabilitation.1-3 Multiple studies have also demonstrated a dose-response relationship between exercise and cardiovascular benefit, but the shape of that curve, and the optimal dosage, intensity, frequency, and duration of exercise remain incompletely defined.15, 17, 18 The health benefits of exercise are multifactorial. Studies have demonstrated that physical activity is effective in reducing adipocyte mass and body mass index as well as positively affecting insulin sensitivity, glucose uptake by skeletal muscle, and cholesterol profiles.19 Physical activity — aerobic exercise, in particular — has also been associated with beneficial changes in both the systemic and coronary vasculature, including enhanced endothelial-mediated vasodilation, improved arterial compliance, and reductions in both systolic and diastolic blood pressure.20-22 Although these global effects of exercise are all implicated in improving cardiovascular health, here, we will focus primarily on the cardiac-specific effects of exercise. Cardiac Growth The heart has considerable plasticity9 and its capacity to hypertrophy in response to pathological stimuli, such as hypertension, aortic stenosis, or genetic mutations, is familiar to clinical cardiologists. However, a robust hypertrophic response is also seen with physiological stimuli, including exercise, pregnancy, and postnatal growth. Endurance exercise and pregnancy, for example, can induce up to a 20% increase in left ventricular (LV) mass, while, even more impressively, the hearts of Burmese pythons can grow by up to 40% following meals.23, 24 The cellular response to growth signals is often categorized as either hypertrophic — an increase in cell size — or hyperplastic — an increase in cell number. The adult heart has traditionally been viewed as capable only of hypertrophic growth; however, recent data from animal models and human studies suggest that the heart also has a limited capacity to generate new cardiomyocytes from progenitor cells and existing cardiomyocytes.25-27 In clinical practice, it is impossible, with current imaging modalities, to distinguish between these two distinct mechanisms of growth when characterizing cardiac hypertrophy. However, animal studies suggest that an increase in both cardiomyocyte size and number may contribute to heart growth in response to pathological and physiological stimuli.12, 28 Exercise-induced cardiac remodeling is the prototypical example of physiological cardiac growth, and the hypertrophic response to exercise can broadly be described as either concentric or eccentric hypertrophy, or a combination of the two. Isometric exercises — strength training activities like weight lifting — lead to transient increases in systemic vascular resistance, thereby increasing afterload and predominantly produce concentric hypertrophy, in which sarcomere fibers are added in parallel with subsequent thickening of the ventricular wall. Endurance — or isotonic — exercise, such as swimming and running, present a volume challenge to the heart and tend to result in eccentric hypertrophy, with increased preload and end-diastolic volume.29, 30 Cardiac MRI studies have suggested that isometric exercises induce minimal changes in right ventricular (RV) structure and function, while isotonic exercises lead to a balanced biventricular hypertrophy with symmetric enlargement of both the right and left ventricles.31 Cardiomyocyte hypertrophy is likely the dominant contributor to exercise-induced heart growth, and studies have reported an increase in cardiomyocyte size by up to 17-32% following exercise training.32 As noted above, however, recent work suggests that exercise also induces markers of cardiomyocyte proliferation, although the fate and contribution of these newly formed cells remains to be established.12 A recently described model for studying physiological remodeling is the Burmese python, which demonstrates an impressive increase in cardiac size — up to 40% — following meals, which regresses over the subsequent 28 days.24 Emerging data suggest that this increase in heart size is primarily a hypertrophic, rather than hyperplastic, process, that it is not associated with the characteristic changes seen in pathological cardiac growth such as fibrosis and upregulation of the fetal gene program.33 This lends support to the idea that physiological hypertrophy is primarily an adaptive and beneficial process. Interestingly, new evidence suggests that some of these postprandial cardiac growth effects are mediated by secreted lipids,33 which will be discussed in more detail below. It should be acknowledged that the clinical relevance of post-prandial changes in the Burmese python remain unclear. Interestingly, the combination of fatty acids identified in python serum also induced cardiomyocyte hypertrophy in mice.33