Exercise and Pharmacology as Medicine for Cardiovascular Diseases: From Bench to Bedside and Back

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Despite concerted scientific and clinical efforts, cardiovascular diseases (CVD) remain the leading cause of death within the United States and industrialized world. As part of the effort to counteract this public health concern, the American Heart Association assembled a comprehensive cardiovascular health index of Life’s Simple 7 key metrics of cardiovascular health: smoking, body mass index, total cholesterol, blood pressure, fasting plasma glucose, and physical activity. Although success has been achieved in improving some of these metrics over the last decade, physical activity remains largely unchanged or worsened (1). In nearly all populations examined thus far, cardiorespiratory fitness is the strongest predictor of CVD mortality (2) and, in many cases, is a stronger predictor of mortality than traditional risk factors. As such, it’s not surprising that exercise is becoming increasingly recognized as medicine, and thus, its interaction with common CVD medications must be considered.
Historically, exercise and pharmacology have been studied as independent means to treat or prevent CVD-related outcomes. As such, little is known about the convergence of these CVD therapies, leaving researchers and clinicians to assume whether pharma-exercise interactions are additive, antagonistic, or synergistic. Although exercise-pharma interactions are important for primary prevention as well as in clinical rehabilitation, they are particularly important in the setting of secondary prevention, where better knowledge of an exercise-pharma interaction could contribute to more effective prevention of diagnosed CVD. In this issue of Exercise and Sport Sciences Reviews, Quindry et al. (3) propose that exercise adaptations be central to all pharmaceutical advancements in CVD therapy, especially with novel pharmacologic interventions. The authors provide a bench-to-bedside discussion of exercise and pharmacological approaches, specifically aimed to address whether exercise and CVD drug therapies can work synergistically to provide cardioprotection against ischemic injury and disease.
Regular physical activity is potently cardioprotective through direct impact on cardiac remodeling, modification of risk factors, and activation of biochemical mechanisms to protect the heart against stress. In fact, exercise preconditioning is one of the most robust means to protect the heart against ischemic injury. Because identification of exogenous treatments for cardioprotection has remained elusive, growing efforts have focused on mechanisms of exercise-induced cardioprotection against ischemic injury for exploitation for new CVD pharmacology. Quindry et al. discuss what little is known about exercise-pharma interactions of adrenergic and renin angiotensin signaling, opiod receptors, adenosine, sex hormones, and mitochondrial targeting and the promise of using these pathways for combined lifestyle and drug therapy.
Much work still needs to be done at both the bench and the bedside to advance pharmacology and exercise as synergistic CVD therapy. Successful promotion of exercise adherence is lacking as is the inclusion of cardiorespiratory fitness as a vital sign in regular clinical practice. Much of what we know about traditional CVD pharma-exercise interactions is at physiological levels — best exemplified by the clinically important observation that statins cause muscle myopathy and exercise intolerance (4). Only recently have investigations been undertaken to elucidate underlying mechanisms that contribute to this intolerance and to understand how this intolerance can be overcome at cellular or physiological levels. Further adding to the complexity of exercise-pharma interactions is the notion that exercise influences pharmacology through both chronic and acute adaptations in nearly every organ system (5). Quindry et al. make a plea for understanding personalized therapy in the context of exercise and drug interactions. They posit that some hearts may be more responsive to therapies and that certain biomarkers may predict which patients would benefit most from exercise.
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