Basic Science for Clinicians 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 mellitus and hypertension, thereby helping to 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 Many current pharmacological treatments for cardiovascular disease are targeted toward inhibiting the adverse remodeling process associated with pathological stress. Specifically, they focus on abrogating the pathological hypertrophy, fibrosis, electric remodeling, and cavity dilatation that accompany disease states such as longstanding hypertension and myocardial infarction (MI).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 response of the heart 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.