Exercise-induced cardioprotection: From endogenous to exogenous mechanisms

Abstract

Background: Acute myocardial infarction (AMI) remains the leading form of cardiovascular morbidity and mortality, while exercise is a preventative and therapeutic countermeasure. The collective benefits of exercise on the heart are called cardioprotection. Exercise-induced cardioprotection encompasses four broad areas: 1) cardiovascular disease (CVD) risk factor improvement, 2) anatomical remodeling of the heart, 3) improved cardiac physiologic function, and 4) mechanisms of exercise preconditioning.

Discussion: With respect to the latter area of cardioprotection, research indicates that a few days of moderate intensity aerobic exercise preconditions the heart against cardiac dysrhythmias, ventricular pump dysfunction, and tissue death. The short duration protective timeframe, hours to days after exercise, indicates that the mechanisms are biochemical in nature. Protective mechanisms within exercised hearts include endogenous antioxidant enzymes, better regulation of cytosolic Ca²⁺, and more efficient bioenergetics. However, a formative body of work conducted over the last decade indicates that additional exogenous mechanisms may be receptor mediated, presumably providing cardioprotection via circulating factors. Preliminary findings indicate that tissue-to-tissue cross talk involves cardioprotective paracrine factors derived from muscle or autocrine factors originating from the heart itself. This protection is termed exogenous (or remote) cardiac preconditioning, and appears to include δ-opioid receptors, IL-6 receptors, and perhaps other surface receptors on exercised cardiac tissue.

Conclusion: The current review outlines existing knowledge on exercise and factors of cardiac preconditioning, and highlights the avenues for next-step scientific advances to understanding treatments against AMI.

Keywords: Cardioprotection; Exercise; Ischemia-reperfusion injury; Preconditioning.

Graphical abstract

Fig. 1

The four facets of exercise induced cardioprotection. The exercised heart is resistant to acute myocardial infarction (AMI) because of four types of cardioprotection. A) The four facets include (1) cardiovascular disease (CVD) risk factor improvement, (2) physiologic adaptations, (3) anatomical adaptations, and (4) exercise preconditioning. B) The mechanisms of exercise preconditioning include endogenous and exogenous factors. Notably, the cardioprotective areas 1–3 are evoked by prolonged exercise training, while exercise preconditioning occurs after 1–3 bouts of exercise.

Fig. 2

The time course of exercise induced cardioprotection. Exercise induced cardioprotection includes 1) cardiovascular disease (CVD) risk factor improvement (e.g., sustained effect on resting blood pressure, waist/hip ratios, etc), 2) Anatomic remodeling of the heart and coronary blood supply, 3) physiologic adaptations (e.g., improved stroke volume, etc.), and 4) biochemical factors of exercise preconditioning. Exercise preconditioning occurs within 1–3 days after the first bout of regimented physical activity. Exercise preconditioning, which includes endogenous and exogenous biochemical mechanisms, is the first level of cardioprotection to benefit heart health, with the other factors accumulating over weeks to years of continued exercise training.

Fig. 3

Suspected mediators of exercise and exogenous cardiac preconditioning. Strong evidence indicates that exercise preconditioning includes tissue-to-tissue cross talk via exogenous (remote) factors. Specifically, these circulating factors include the myokine interleukin-6 (IL-6) released from exercise skeletal muscle appears to interact with IL-6 receptors, and an endogenous δ opioid (e.g., pro-enkephalin/enkephalin) is produced by the heart and interacts with 8-opioid receptors in paracrine fashion. As proposed, IL-6 is acting as a myokine. How these ligand-receptor interactions interface with cellular mediators of exercise preconditioning is currently unknown.

Fig. 4

A summary of the endogenous and exogenous mechanisms of exercise preconditioning. Exercise preconditioning includes several endogenous mechanisms of cellular protection. Endogenous factors include the up-regulation of the antioxidant enzymes superoxide dismutase-2 (SOD-2), glutathione reductase (GR), in addition to ATP-sensitive potassium channels (KATP) located on the outer membrane of the mitochondria and sarcolemma. Exogenous (remote) factors of exercise preconditioning include interleukin-6 (IL-6) and enkephalin. To date, it is unknown how exogenous factors of exercise preconditioning may activate and/or support endogenous mechanisms of exercise preconditioning.