Cardiovascular disease (CVD) is potentiated by risk factors including physical inactivity and remains a leading cause of morbidity and mortality. Although regular physical activity does not reverse atherosclerotic coronary disease, precursory exercise improves clinical outcomes in those experiencing life-threatening CVD events. Exercise preconditioning describes the cardioprotective phenotype whereby even a few exercise bouts confer short-term multifaceted protection against acute myocardial infarction. First described decades ago in animal investigations, cardioprotective mechanisms responsible for exercise preconditioning have been identified through reductionist preclinical studies, including the upregulation of endogenous antioxidant enzymes, improved calcium handling, and enhanced bioenergetic regulation during a supply-demand mismatch. Until recently, translation of this research was only inferred from clinically-directed animal models of exercise involving ischemia-reperfusion injury, and reinforced by the gene products of exercise preconditioning that are common to mammalian species. However, recent clinical investigations confirm that exercise preconditions the human heart. This discovery means that simply the initiation of a remedial exercise regimen in those with abnormal CVD risk factor profiles will provide immediate cardioprotective benefits and improved clinical outcomes following acute cardiac events. In conclusion, the prophylactic biochemical adaptations to aerobic exercise are complemented by the long-term adaptive benefits of vascular and architectural remodeling in those who adopt a physically active lifestyle.
Sedentary behavior is one of the most preventable causative factors for cardiovascular disease (CVD), while habitual, structured physical activity (PA) is one of the most potent countermeasures in treating and preventing CVD. PA confers a cardioprotected phenotype which includes anti-atherosclerotic, anti-thrombotic, anti-ischemic, and anti-arrhythmic effects ( Figure 1 ). Recent discoveries reveal that the immediate cardioprotective impact of short-term exercise includes transient biochemical upregulation of protective cellular mediators, a phenomenon termed exercise preconditioning , as a prophylactic therapy for acute coronary events. Because this subfield is based on a wealth of preclinical investigations, the clinical relevance of exercise and ischemic models from animal-based studies are reviewed. Next, emergent translational applications are detailed as confirmation that exercise cardiac preconditioning enhances clinical outcomes. Finally, we discuss the practical introduction of lifestyle PA, in addition to structured exercise, in the medical management of previously sedentary individuals at high risk for CVD.
Practical Relevance of Preclinical Investigations on Exercise Preconditioning
Exercise preconditioning is a line of scientific inquiry into the short-term biochemical mediators of cardioprotection in exercised hearts. Relative to scientific lineage, exercise preconditioning evolved from the 1986 discovery of ischemic preconditioning, the observation that conditioned animal hearts could be rendered resilient to acute myocardial infarction (AMI) within hours following sub-lethal bouts of coronary artery ligation. The time needed to acquire a preconditioned phenotype following the adaptive stimulus (due to exercise or ischemia) is on the order of hours. This finding highlights the fundamental conclusion that cardiac preconditioning necessitates upregulation, or allosteric control, of endogenous biochemical mediators of protection. , Once evoked, the endogenous protective mediators work in concert to strategically counter the associated mechanisms of myocardial injury during AMI.
An ischemia reperfusion insult is characterized by cellular oxidative stress, cytosolic (and mitochondrial) calcium overload, and bioenergetic dysregulation. From a cellular perspective, these 3 facets of ischemic pathology are biologically intertwined, with oxidative stress and calcium dysregulation being subsequent to the bioenergetic crisis caused by cardiac ischemia. Accordingly, the mechanisms responsible for ischemic resilience in the preconditioned heart include: antioxidant enzyme fortification; prevention of calcium dyshomeostasis through bolstered calcium regulation; and, improvements in bioenergetic supply-demand ratios. , The mechanisms of exercise preconditioning have been previously described. Related studies demonstrate that intracellular processes of cardioprotection appear to be activated through receptor-mediated, autocrine/paracrine pathways, due to multiple circulating factors including endogenous opioids and interleukin-6. , Importantly, the mechanisms responsible for the exercise preconditioning effects described herein are gene products common to mammalian species. Moreover, exercise preconditioning induces a phenotype which is largely unique and in contrast to the protective mediators conferred by ischemic preconditioning. Mechanistic differences between the exercise and ischemia stimuli are founded on the fact that the former is a sustainable hermetic stress, , whereas the latter is transient.
The unique features, and clinical relevance, of the exercise stimulus was advanced by the observation that rats exposed to 3 days of moderate intensity treadmill running were equally protected against a surgically induced MI as compared with rats that performed several months of exercise training. , A subsequent investigation by different investigators, also using treadmill run rats, found that preconditioning against ischemia-reperfusion (IR) injury could be evoked by as little as a single bout of exercise, further highlighting the temporal nature of biochemical cardioprotection. Subsequently, it was discovered that MI resistant phenotype lasted for at least 9 days following the final bout of a 3-day moderate intensity exercise regimen.
With respect to clinical applicability, it was important to clarify, “ how much exercise is needed to precondition a heart? ” The encouraging answer, derived from a series of animal studies, suggests that even a minimal amount of exercise provides robust cardioprotection against an ischemic insult. To understand this finding, several aspects of the animal “exercise prescription” should be considered. First, across different animal species (albeit mostly rodents), performed by independent research groups, the exercise modalities used to precondition hearts have been experimentally designed to parallel human exercise recommendations. Thus, within these research studies, exercise frequency generally varied from 3 days/week to daily sessions. The employed cardiovascular exercise intensities ranged from ∼50% to 75% of aerobic capacity (VO 2max ) for that particular animal species. In addition, the duration of an individual exercise session ranged from 30 to 60 minutes. These research applications of animal exercise as compared with humans are illustrated in Figure 2 . Finally, the exercise modalities common to cardiac preconditioning research studies include forced running on treadmills or other rodent ergometers, swimming, or ladder climbing. Although most of the previously reported investigations used aerobic exercise, researchers found that a rodent model of strength training also provided significant cardioprotection against an experimental infarction challenge. ,
A second important aspect of clinical relevance derived from preclinical exercise preconditioning studies is that there appears to be an intensity threshold, above which the heart becomes preconditioned. Evidence for this conclusion was primarily derived from 2 different studies by independent laboratory groups working in parallel on exercise preconditioning in the early 2000s. The first observation was that regimented exercise below a moderate intensity (∼50% VO 2max ) does not protect against experimental MI in isolated perfused rodent hearts. , The second observation revealed that while moderate intensity exercise cardioprotects against AMI, higher intensity exercise does not bolster the magnitude of protection in a dose-dependent fashion. Accordingly, the biochemical mechanisms of protection are activated in a threshold-dependent fashion within exercise hearts. Moreover, it cannot be inferred that higher exercise volumes (or cumulative doses of PA), performed at a low intensity relative to VO 2max , aren’t cardioprotective. Although this requires additional research, cardioprotection afforded by long duration PA (<50% VO 2max ) would also likely manifest in a threshold dependent fashion.
Another tested hypothesis in animal exercise models is that forced, regimented exercise is not required to precondition the heart. A series of studies examined whether rodents provided free access to running wheels would self-select PA the extent that their hearts would be preconditioned against IR injury. Findings indicated ventricular ectopy was attenuated during experimental MI, and myocardial bioenergetic status was preserved in the animals with running wheel access. , However, these findings cannot necessarily be generalized to clinical applications in that rodent behavior on running wheels does not replicate spontaneous PA in most humans. That is, rodents typically sprint on the running wheels for dozens of 30-60 second bouts spread throughout a 24-hour period. Other evidence, however, suggests that PA performed by rodents on running wheels may equate to humans in that the 24-hour cumulative distance run by rodents with access to a running wheel is comparable to the assigned distance run during forced exercise (i.e., equal to the distance covered for 30 to 60 minutes at 50% of VO 2 max). , Although lacking confirmation, it is tempting to speculate that biological signals prompt animals to self-select a volume of PA that elicits a cardioprotected phenotype. Nonetheless, scientific verification indicates that accumulating discontinuous bouts of daily PA will precondition the heart if the intensity of movement is sufficient. In this regard, we recently employed ethnographic models (counts of typical species behaviors) of quantifying daily PA in rodents, ranging from activities of daily living to high intensity running and jumping. , As applied to humans, these approaches to prescribing and implementing cardioprotective levels of PA in preclinical animal studies have relevance for mobilizing sedentary populations at risk for CVD.
Lastly, animal studies of preclinical exercise preconditioning are reinforced by investigations which employ quantification metrics of CVD that parallel clinical applications. IR injury is an evolutionary pathology, characterized by the appearance of electrocardiographic (ECG) abnormalities within moments of significant coronary artery occlusion. Prolonged ischemia then causes deficits in ventricular pump function, while ECG profiles worsen. Finally, unremitting ischemia results in cardiomyocyte death due to either necrotic or apoptotic processes. , , ,
Induction of an experimental MI is most commonly performed via ligation of the left anterior descending coronary. The heart is accessed through a left thoracotomy in anesthetized and mechanically ventilated animals. Another common approach is to perform either regional or global ischemia using isolated perfused hearts from animals assigned to sedentary or exercise groups. Advantages to the former in vivo technique is that the animal is fully “intact,” and subject to the pathological influences of the circulating factors and immune system responses. Advantages to the latter, that is, isolated perfused heart technique, is that preload and afterload can be precisely controlled, providing essential insights into ventricular function during MI. , , Regardless of the methodology, exercise preconditioning remains one of the most scientifically reproducible observations in animal models, independent of age, sex, strain, or species. , ,
Preclinical approaches to quantify myocardial injury and tissue death due to IR are similar to those used in humans. ECG tracings are obtained from limb electrodes provide identical lead options to humans, typically defaulting to a lead II configuration. Assessments typically involve arrhythmia scoring rubrics, including ventricular ectopy. Ventricular performance can be quantified using clinical imaging techniques (e.g., transthoracic echocardiography, magnetic resonance imaging) or implanted arterial catheters. Figure 3 illustrates several common experimental approaches in our preconditioned animal studies which parallel clinical outcomes.
Finally, use of animal models has proven essential for uncovering the mechanisms of tissue death due to AMI. While the clinical standards for circulating biomarkers of cardiac injury (e.g., cardiac specific troponin, cTnT) are also common to animal-based exercise preconditioning studies, it is the post mortem analyses from the harvesting of heart tissues that can be most revealing. Indeed, the cellular processes of necrosis, apoptosis, and even the contribution of autophagy, have been partially resolved from post mortem histological, biochemical, and molecular examination of hearts generated from exercise preconditioning studies. , ,
In summary, exercise preconditioning is founded on clinically relevant metrics of ECG abnormalities, ventricular pump function, and biological quantification of cardiac tissue death. Interestingly, the mechanisms of exercise preconditioning are not common to all forms of IR injury. For example, the upregulation of endogenous antioxidant enzymes prevent ventricular arrhythmias and tissue death during MI, but do not protect against ventricular pump dysfunction. , The cellular mechanisms essential for exercise preconditioning against cardiac dysrhythmias, ventricular contractility losses, and tissue death caused by IR injury have been previously described. , Conclusions from preclinical animal studies that underpin current scientific consensus on exercise preconditioning of the heart are summarized in Figure 4 . These findings reinforce numerous lines of evidence which confirm that the mechanisms responsible for exercise-induced cardioprotection observed in animal studies are generalizable to humans.
