- Exercise and pharmacologic interventions to prevent ischemic heart disease have advanced largely in parallel over the last 50 yr, a fact that is likely to change in an era of translational science and molecular biology applications.
- First-line pharmacotherapies to treat cardiovascular disease (CVD) often embrace or mimic significant exercise adaptations that include synergistic benefits in addition to potential contraindications.
- Exercise protects against CVD through anatomical remodeling, mitigation of disease risk factors, improved nitric oxide vasodilator function, biochemical preconditioning against ischemic damage, autonomic adaptations, or combinations thereof, all of which have important considerations for exercise-pharma interactions.
- Emerging knowledge of biochemical exercise preconditioning holds promise for integrated exercise-pharma development.
- Additional preclinical investigations using reductionist animal models, in addition to clinical trials, are needed to further elucidate novel exercise-pharma interventions to combat ischemic injury of the myocardium.
Cardiovascular disease (CVD), including ischemic heart disease, remains a major international public health problem (1). From an epidemiologic perspective, mitigation of CVD incidence and severity has been predicated largely on the remarkable scientific and medical advances of late. Independent of medical interventions, favorable cardiovascular outcomes largely are achieved by combined pharmacological therapies and healthy lifestyles that include structured exercise or regular physical activity (2). These research sub-areas have advanced in parallel over the last 50 yr, with occasional convergence to resolve associated interactions, which are mostly assumed to be additive, subadditive, antagonistic, or synergistic. Modern medical approaches increasingly use both exercise and pharmacotherapies to treat CVD. This review provides the perspective that acute exercise responses and adaptations should be central to all medical advances in CVD treatment, but are especially relevant to novel pharmacologic interventions.
Unique to the current perspective, foundational information from meta-analyses, epidemiological studies, and preclinical and clinical trials currently are woven into a common narrative. This two-pronged discussion presents the reader with an update on the independent and interrelated cardioprotective effects of exercise and commonly prescribed pharmacotherapies used to treat ischemic heart disease. Addressing exercise-pharmacologic interactions and mechanisms of cardiac preconditioning, in spectral fashion, are essential in bridging knowledge gaps between clinical and basic scientific settings. Indeed, the contemporary clinician should have a clear understanding of exercise and cardioprotective pharmacologic interventions and their potential interactions, efficacy, and effectiveness.
Balanced understanding of exercise and pharmacologic interventions should be viewed as unique to the patient and part of the growing trend in personalized medicine. Accordingly, moderate-to-vigorous exercise is among the most potent interventions for the prevention and treatment of CVD (3). The introduction of structured exercise, increased lifestyle physical activity, or both, in previously sedentary individuals can be a potent strategy to achieve clinical benchmarks while simultaneously complementing pharmacologic effects. Because exercise and common pharmacologic interventions can provide independent and additive benefits (2), lowered dosing may be warranted in some cases. Conversely, fragile conditions may present a heightened risk-benefit ratio for strenuous exercise, which may necessitate that pharmacology take precedence. Unaccustomed vigorous physical activity also may trigger acute cardiac events, particularly in habitually sedentary individuals with known or occult CVD. According to this narrative, the use of pharmacologic agents will be discussed relative to exercise prescription in patients with CVD. In addition, new horizons for exercise-pharmacologic interactions will be discussed as a prelude to understanding preclinical research into exercise-induced cardioprotection using animal models. In this regard, basic science studies of cardioprotection against ischemic heart disease have demonstrated that the exercised heart is protected by upregulation of a host of endogenous factors that counter the major manifestations of ischemic pathology in the ventricle. Clinical applications of these findings are emerging and require additional scientific investigation, but the potential for beneficial and deleterious interactions with existing pharmacologic approaches remain.
Relative to yet-to-be-discovered pharmacologic interventions, novel mechanistic understanding of the exercised heart includes recent discoveries that cardioprotection is evoked through autonomic adaptations, improved nitric oxide vasodilator function, receptor-mediated processes, hormonal axis control, cytokine release, and metabolic optimization. This review provides a theoretical bench-to-bedside delineation of exercise and pharmacologic approaches with potential implications for cardioprotection against ischemic insults and their adverse sequelae (e.g., myocardial fibrosis). Discussion will provide the reader with important theoretical research avenues for consideration of exercise-pharma interactions in the treatment of CVD.
CARDIOVASCULAR DISEASE: A MAJOR PUBLIC HEALTH PROBLEM
CVD has remained the leading cause of morbidity and mortality in industrialized nations for more than half a century. Most cases of CVD manifest as atherosclerotic, ischemic heart disease including myocardial infarction (MI) (1). The Centers for Disease Control and Prevention report a modest but meaningful decline in total CVD deaths between 2000 and 2010 (4). Late improvements in CVD morbidity and mortality cannot persist indefinitely because unhealthy lifestyle habits are the etiological cornerstone of CVD incidence. In support, recent National Health and Nutrition Examination Survey (NHANES) data summarize ongoing trends for the seven key metrics of cardiovascular health: smoking, body mass index, diet, total cholesterol, blood pressure, fasting plasma glucose, and physical activity. Other than a population-wide decline in smoking behaviors, highly modifiable CVD risk factors have remained largely unchanged or worsened (5). Pertinent to this review, NHANES data reveal that 64% of the population exhibit either inadequate or intermediate physical activity participation. Second only to a strong trend to embrace unhealthy diets (deemphasized currently due to fewer years of available data), physical inactivity is the most prevalent CVD risk factor exhibited by individuals in industrialized countries (5).
Physical inactivity as the normative practice is particularly notable when compared with findings from landmark investigations of secondary prevention. The EUROASPIRE (European Action on Secondary and Primary Prevention by Intervention to Reduce Events) study serves as a prime example. EUROASPIRE commenced in the early 1990s to investigate CVD secondary prevention and therapeutic management and remains an ongoing and insightful resource (6). EUROASPIRE III reported that pharmacologic interventions were found in virtually all of the approximately 13,000 medical records and 9000 patient interviews collated from 22 European countries. In contrast, physical activity participation reports from EUROASPIRE III were on par with the abysmal rates derived from studies conducted in the United States (2,7). More recent findings from EUROASPIRE IV indicate modest improvements in physical activity (6% increase in vigorous physical activity participation), but with overall adherence rates (37%) that are likely too low to further mitigate disease incidence (8).
The factors underpinning disparate adherence to pharmacologic and physical activity participation are beyond the scope of this review. Nonetheless, there are significant practical implications. First, pharmacologic interventions for CVD treatment and prevention provide robust protection against cardiovascular morbidity and mortality (9–15). Second, without quantum advances in the next generation of pharmacologic agents, further reductions in cardiovascular events are not likely to occur because therapeutic targets for risk factor management go largely unmet (16). Most importantly, engaging at-risk individuals in regular physical activity is among the lifestyle benefits most likely to mitigate CVD incidence and severity (17). Finally, basic science research conducted over the last decade has clarified the mechanistic underpinnings of cardioprotection (18–21). A strong rationale exists whereby pharmacologic drugs could have complementary effects on exercise-induced cardioprotection. This later point, although theoretical, is strongly supported by scientific rationale and represents a promising research venue.
CVD PHARMA: FROM REVOLUTION TO PLATEAU
Beyond coronary artery revascularization, it is commonly held that pharmacologic agents, especially in combination, have been essential in combating the manifestations of CVD (22). A few classes of drugs — including aspirin, statins, adrenergic β-blockers (β-blockers), renin-angiotensin system (RAS) blockers, and calcium antagonists — are responsible for many clinical advances over the last 40 yr. Reductions in morbidity and mortality are largely attributed to aggressive CVD risk factor management via lifestyle modification and pharmacotherapies; however, recent evidence indicates some of the cardioprotective medications exert direct mechanistic effects, and will be subsequently discussed. A brief summary is provided of selected drug classes that have profoundly impacted CVD treatment over the last 50 yr. In the wake of medical success, however, pharmacologic agents often are prescribed in inadequate doses (23) or simply not adhered to (24), leading to suboptimal outcomes (25).
As a prelude to understanding potential exercise-pharma interfaces for mechanistic cardioprotection, the current pharma discussion highlights clinical limitations in risk factor modification, ongoing prescriptive controversies (the reader is directed to the Contemporary Cardiology Series Cardiac Drug Therapy, 8th Ed, (22)), and confounding adverse effect management challenges. Regarding the latter, it is easy to recognize why pharma-derived adverse effects often are overlooked given that CVD is a complex disease that is linked to numerous comorbidities with varied symptomology.
Statins are among the most potent pharmacotherapies in managing dyslipidemias and combating CVD. In the early 1970s, it was learned that the rate-limiting step in cholesterol formation could be blunted by competitive inhibition of 3-hydroxy-3-methly-glutarly-coenzyme A (HMG-CoA) reductase (26). Within a decade of this discovery, several statins were developed and marketed for the control of dyslipidemia, ultimately leading to future generations of lipid-lowering medications (27). A recent meta-analysis of 174,000 participants across 27 randomized controlled trials found overwhelming evidence that statin therapy prevents future cardiac events and the need for coronary revascularization. Moreover, beneficial outcomes were independent of sex and not associated with a rise in comorbidities such as cancer and other non-CVD mortality (28). For all the benefits derived from statin use (14), achievement of population-wide cholesterol goals seems unrealistic (16). This notion is particularly true for some demographic subsets, including those of advancing age, where diminishing efficacy is reported (29). Interestingly, a recent study in previously sedentary middle-aged individuals with hypercholesterolemia reported that post-training improvements in V˙O2peak and muscle citrate synthase levels were attenuated in simvastatin-treated exercisers (30). In contrast, a retrospective investigation of cardiac rehabilitation patients found that statin use did not impair cardiorespiratory fitness gains (31) and suggested that additional research is needed to further clarify the influence of statin therapy on exercise trainability.
Statin use also is associated with exercise-limiting myopathies in up to 10% of patients (32), a challenge that has only recently become negotiable because of the advent of numerous statin options with fewer adverse effects (33). Once the appropriate statin drug and dosage are matched to the individual, it seems that favorable exercise-mediated outcomes can occur. In this regard, an investigation of statin-tolerant individuals reported that indices of muscle morphology were unaltered after performance of a strenuous knee extensor protocol (34). These findings seem to support recent animal studies, which suggest that in certain applications, statin use may exert synergistic effects in other exercise-derived adaptations, including muscle strength (35). Again, additional research is needed to clarify not just the likelihood of adverse exercise-drug interactions, but the potential for synergistic benefits as well.
In aggregate, studies conducted in middle-aged and older at-risk adults suggest that statin therapy and moderate-to-high fitness levels provide independent and additive mortality benefits (36). Perhaps most importantly, exercise in combination with statin therapy is shown via meta-analysis to produce additive effects in terms of CVD risk modification via dyslipidemia, insulin sensitivity, and markers of systemic inflammation (3). A recent review emphasized that statins per se were not associated with a reduced exercise level or intensity, and that when combined with statin therapy, cardiorespiratory fitness can provide a powerful survival advantage to the patients we counsel (37). To date, direct links between statin use and cellular mechanisms of cardioprotection against ischemic insults have not been clearly elucidated. The issue is further complicated by complementary nutritional practices, in addition to efficacious nutraceutical approaches to combat dyslipidemia. Consumption of varied omega-3 fatty acid formulations, for example, is linked to more cardioprotective cholesterol profiles without statin-related adverse effects or deleterious drug interactions (38).
Adrenergic blockade in the treatment of CVD primarily involves β-blockers. Three generations of pharmacologic β-blockers have been used in the treatment of CVD and related symptoms. In those with a history of MI, the most widely recognized benefit of β-blockers is the attenuation or relief of symptomatic angina and reduction of myocardial O2 demand (39). Although large cohort studies clearly link β-blocker therapy to decreased morbidity and mortality (11), opinions are mixed in terms of the salutary impact of this drug class. At the heart of the issue (pun intended) is the fact that CVD is a broad medical condition whereby β-blockers elicit a diverse set of adverse effects that must be navigated on an individual basis. For these reasons, growing consensus suggests that β-blocker efficacy may vary, with benefits derived in direct proportion to patient disease severity and symptomology (10,40). Nonetheless, as medically indicated, β-blockers seem to offer cardioprotective benefits via specific cellular mechanisms, as subsequently delineated.
Renin-Angiotensin System Blockers
The RAS is a hormonal axis essential to the control of isovolumetric and hypertensive stress responses. Effective control of hypertension through chemical inhibition of the RAS is among the most impactful interventions in combating CVD. Two overarching classes of RAS inhibitors exist: angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB). As pharmacologic subgroups, ACEi and ARB are composed of III and I drug classes, respectively (22). ACEi variations were developed in the first several generations of RAS inhibitors. Subsequently, ARB evolved in the hope of curbing the adverse effects of ACEi, including persistent cough (22). The salubrious effects of ACEi stem from the competitive inhibition of angiotensin I-to-angiotensin II conversion. ARB prevent tissue-level effects of angiotensin through competitive blockade of the angiotensin receptor 1 (41). Physiologic benefits of RAS blockade are complex and include a host of effects that seem to be synergistic. Altered physiologic outcomes include attenuation of sympathetic tone, improved fluid control, vasodilation, and prevention of vascular oxidative stress (22). In the context of ischemic CVD, ACEi have proven effectiveness in combating hypertension before acute events. Of the currently available pharmacologic interventions, ACEi (ramipril, specifically) have a notably favorable cost-effectiveness/lives saved ratio (15). Importantly, however, cost ratios make most sense for high-risk hypertensive patients who receive ACEi for years to decades (15) especially when adjunctive lifestyle interventions are not embraced or seem ineffective. ARB, whereas also important, have been somewhat less effective (13,42). Post-MI use of ACEi/ARB also favorably influences cardiac remodeling and long-term prognoses (42,43). Unfortunately, current discussion of ACEi and ARB as individual therapeutics do not consider the increasing practice of using multiple pharmacologic agents to control CVD risk factors. However, combining ARB (for example) with selected cardioprotective medications is not necessarily additive in terms of clinical benefits and has been linked to deleterious cardiac outcomes (44,45).
A forthcoming clinical trial will soon report on the outcomes of a combined exercise-pharma approach using ACEi and ARB, alone and in combination (46). However, until these and other additional studies are completed, the relation between exercise and ACEi/ARB remains unclear. Research into the exercise-pharma interaction of RAS is particularly important given that 1) hypotension is among the most common adverse effects of ACEi/ARB use (9), and 2) exercise is a potent intervention in the modulation of blood pressure (47). As such, exercise intolerance may result in some patients treated with ACEi/ARB as a first-line therapy.
Calcium antagonists, or calcium channel blockers (CCB), control CVD risk by mitigating hypertension. Mechanistic control of blood pressure occurs by CCB primarily through inhibition of voltage-dependent (L-type) calcium channels within smooth muscle. Similar to other CVD drugs detailed within, CCB is available in several forms (nondihydropyridines/dihydropyridines) based on their chemical composition (22). Ongoing debates remain in terms of whether fast-acting or long-acting CCB are most efficacious. Current opinions indicate that drug outcomes should be balanced with adverse drug reactions (12). Navigation of CCB adverse effect profiles are at first glance similar to RAS blockers, and include hypotension (22). Clearly, additional information is needed about potentially severe hypotensive responses during acute exercise under the influence of short-acting versus long-acting CCB. Additional consideration also should be given to chronic dosing of various CCB in regular exercisers.
The aforementioned cardiovascular drug classes are efficacious in the cost-effective treatment of CVD (15). As such, these pharmacotherapies are likely to remain as widely prescribed agents for decades to come. However, the perspective presented currently raises concern about pharmaceutical over-reliance in the absence of lifestyle interventions, including exercise. Although the optimal dose of exercise needed to prevent and treat CVD has been recently clarified (17), adherence remains poor (5). Magnifying the reliance gap between pharmacologic and exercise interventions, adverse reactions to selected CVD-prevention drugs may be associated with exercise intolerance. Additional clinical studies are sorely needed to guide physicians in the combined use of exercise-pharma to treat CVD. There is a growing body of evidence to suggest that adjunctive lifestyle modification, including exercise, would better achieve clinical threshold goals for CVD prevention with lower pharmacologic doses and fewer adverse effects. Moreover, recent trends to initiate CVD prevention pharma as a first line of treatment in younger, lower risk individuals may not be as cost-effective (15) as initiation of exercise in the least fit, least active population cohort (17). Although some barriers to routinely prescribing exercise to our patients may remain, physician influence is significant. In extension of this rationale, the potential impact of the Exercise as a Vital Sign initiative seems to be particularly important (48,49) when considering a balance of exercise-pharma to treat CVD.
EXERCISE AND THE FOUR FACETS OF CARDIOPROTECTION
Comprehensive understanding of the potential independent and additive benefits of combined exercise-pharma interventions is arguably limited without a fundamental grasp of clinical and basic science investigations regarding exercise ischemic preconditioning. In this regard, the multifactorial role of regular physical activity as a potent cardioprotective intervention is well described, with evidence of antiatherosclerotic, antithrombotic, anti-ischemic, antiarrhythmic, and psychologic benefits (Fig. 1) (50). To condense decades of research, exercise protects the heart against ischemic manifestations of CVD in four distinct ways: 1) Anatomical heart remodeling prevents CVD occurrence and lessens disease severity in those who exercise regularly; 2) Beneficial CVD risk factor modification occurs in those who undertake regular exercise training; 3) Exercise-based cardiac rehabilitation in the days, weeks, and months after an acute MI can partially restore cardiac function and significantly decreases mortality; and 4) Biochemical cardiac preconditioning occurs in response to each bout of exercise. Specifically, acute bouts of exercise impose a hermetic stress on the heart such that cellular biochemistry is favorably altered and an ischemic-resistant phenotype is conferred, at least temporarily. Of the four facets of exercise-induced cardioprotection, this one is the least understood and serves as the primary focus of this section. The reader is directed to several well-documented sources that describe anatomical remodeling of coronary circulation (51), tissue remodeling (52), risk factor modification (50), and exercise-based cardiac rehabilitation (37,53,54).
A Brief Overview of Biochemical Cardiac Preconditioning
The physiological basis and rationale for exercise-induced biochemical cardiac preconditioning is detailed in several excellent reviews on the topic from prominent research groups (18–21). The exercise preconditioning phenomenon derives from rodent-based research, where conventional exercise recommendations are scaled to a variety of animal models (55,56). Exercise studies typically involve an experimentally induced MI, and key dependent outcomes include clinically relevant ECG tracings (57), ventricular performance indices (58), and markers of infarction/tissue damage (59).
Exercise preconditioning against ischemic injury is among the most consistently observed findings in experimental models, with reproducible outcomes reported across multiple species (60,61). Foundational to understanding biochemical exercise preconditioning is the fact that short-term exercise (1–3 d) will precondition the myocardium against a subsequent ischemic insult (62,63). Given that cardiac remodeling for cardioprotection takes weeks to months to occur, short-term exercise preconditioning is attributed to upregulation of biochemical mediators within the heart and persists for at least 9 d after the exercise regimen is concluded (64). This cardioprotective phenomenon represents an excellent “return on investment” in terms of the number of exercise days needed to evoke more than a week of robust protection. From a cellular perspective, the observed protection is believed to be threshold-dependent because neither long-term (65) nor higher intensity exercise protocols seem to further enhance the protected phenotype (66).
Clinical takeaways from biochemical studies of exercise preconditioning include several important facts. Hearts from male and female animals seem to be equally protected by short-term exercise, although subtle sex-specific mechanistic differences may exist (67,68). The aged heart also adapts to short-term exercise preconditioning (69–71), a fact that is particularly important given that CVD incidence in humans occurs in proportion to advancing age (72). In addition, clinically directed outcome variables including ECG (73,74), ventricular contractility (61,71,75), preservation of systolic pressures (62,76,77), circulating markers of myocardial damage (66), and analyses of infarct size (59,78) are universally responsive to a short-term exercise preconditioning regimen. Clinically relevant end points to exercise preconditioning research are bolstered by recent findings that the volume of self-selected running wheel distances (79) approximate those of forced exercise (e.g., rodent treadmills with electric shockers). In extension, rodents housed with running wheels exhibited a cardioprotected phenotype comparable with animals exposed to forced exercise (80). Such animal models are experimentally advantageous in that biological processes linked to post-MI heart failure in humans can be quantified via postmortem analyses of exercised and sedentary hearts. Specifically, apoptosis (59,69) and autophagy (78) seem to be favorably influenced by exercise preconditioning.
Mechanisms of Biochemical Cardiac Preconditioning
Among the crossroad issues of clinical and basic science research is whether exercise preconditioning may reveal new drug targets for cardioprotection. In fact, the overarching goal of cardiac preconditioning research is to better understand cellular cardioprotective mechanisms so that pharmacological CVD countertherapies can be “reverse engineered” (81). In theory, knowledge generated from these efforts will yield pharmacologic interventions for ischemic resistance in high-risk individuals. Accordingly, it is not inconsequential that most cardiac preconditioning research uses nonexercise stimuli to evoke anti-ischemic outcomes in preclinical investigations. Nevertheless, concern within scientific circles has been expressed that exogenous treatments for cardioprotection remain elusive (82). Because of persistent hurdles in therapeutic discovery, ongoing research efforts have been refocused on understanding the mechanisms of exercise-induced cardioprotection against ischemic injury. The pragmatic, sustainable, and cost-effective nature of exercise may provide new cardioprotective insights that overcome the scientific hurdles of nonexercise stimuli (19–21,83). Figure 2 highlights the currently identified mechanisms of exercise-induced cardioprotection. Although some overlap exists between all forms of preconditioning, numerous mechanisms central to exercise-induced cardioprotection are unique. Moreover, many of the cardioprotective mechanisms upregulated by ischemic preconditioning seem to be nonessential in the exercised heart (59,60,70,77,84).
The first discovered mechanisms of exercise-induced cardioprotection were related to the upregulation of endogenous antioxidants and improvements in cytosolic calcium control. These defenses are important given that free radical overload and calcium dyshomeostasis are the hallmarks of cellular pathology during acute MI (85). A series of experiments by several laboratories clearly demonstrated that the endogenous antioxidant manganese superoxide dismutase (SOD2, formerly called MnSOD) prevented ventricular dysrhythmias and tissue death during MI (63,73). SOD2 likely works within a cellular antioxidant network, including components of the glutathione system (86,87). Early evidence indicated the exercised heart also exhibits improved calcium control during an acute MI (88), although limits exist (89). Later findings suggested that improved antioxidant status in exercised hearts preserved sarcoplasmic endoplasmic calcium adenosine triphosphate (ATP)ase-2A (SERCA2A) from deleterious oxidative modification and provided strong evidence that antioxidant upregulation and calcium control in exercised hearts work in concert to elicit cardioprotective benefits (90,91).
Among the most heralded potential mechanisms of cardiac preconditioning are the putative ATP-sensitive potassium channels (KATP) located in the mitochondria and sarcolemma membranes (92). Early studies in exercised hearts demonstrated that exercise upregulates subunit expression of KATP channel components, albeit in a sex-dependent fashion (67,68). Later investigations in the exercised heart revealed that mitochondrial KATP channels prevented ventricular dysrhythmias during the early phases of an acute MI (74), whereas sarcolemmal KATP channels were more protective of adverse sequelae over time (67,68,78). Sustainable activation of KATP channels with exercise is an important scientific departure from nonexercise approaches to precondition the heart. Indeed, exercise is distinct from other forms of preconditioning in that inflammatory pathway mediators, including inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 are not consistently altered by exercise (60,70) but are essential to ischemic preconditioning (93–95).
From a fundamental perspective, the unique aspects of exercise preconditioning are significant to future pharmacologic applications in that long-term activation of inflammatory mediators are biologically untenable (96). In similar fashion, a variety of heat shock proteins are unessential to cardioprotect the exercised heart (59,84,97) but are central to several nonexercise forms of preconditioning (98–100). In consideration of potential pharmacologic applications, exogenous activation of cytoprotective mediators may include upstream receptor manipulation. Given that cardiac preconditioning is multifaceted, it is not surprising that recent investigations demonstrate exercise-induced cardioprotection occurs through activation of more than one type of surface receptor (60,101,102). Receptor-derived activation of exercise preconditioning will be further discussed in the next section.
NAVIGATING EXERCISE-PHARMACOLOGIC CARDIOPROTECTIVE POTENTIAL
Underpinning the clinical and basic science arms of this perspective is the rationale that new horizons in pharmacologic cardioprotection must include components of a healthy lifestyle, not the least of which is exercise. This closing section provides a theoretical premise for future cardioprotection research avenues that bridge prior discussions of preclinical and clinical research. Exercise-pharma potentials for cardioprotection also are presented, as are possible contraindications. Strategic discussion points guide the reader through integrated considerations of human and animal studies focused on varied receptor targets, chosen primarily for their links to existing pharmacologic approaches or potential applications. As a point of clarification, cellular cardioprotective mechanisms are unique from those due to risk factor modification, which cardioprotect by countering the manifestations of CVD. In the spirit of stimulating novel research in the area of exercise and cardioprotection, all theoretical points raised herein require additional basic science and clinical research substantiation.
Adrenergic Mediated Cardioprotection
Pharmacologic β-adrenergic receptor blockers remain invaluable in the treatment of CVD. Given that vigorous exercise evokes sympathetic drive, β-adrenergic receptor blocker use has long been recognized as a modulator of cardiac work during dynamic exercise (103). Interestingly, training adaptations in heart failure patients receiving β-adrenergic blocker therapy are generally favorable (104). Accordingly, the influence of β-adrenergic blockers should be factored into clinical decisions where individual improvements in V˙O2max approach threshold values for critical treatment decisions. Central to the current review, cellular cardioprotection occurs via adrenergic activation. The astute reader may then question whether pharmacologic β-blockade and exercise work in opposition when it comes to preconditioning the heart against ischemic damage. The answer seems to be “no” because pharmacologic blockade generally involves β1-adrenergic receptors (22), whereas exercise likely cardioprotects via β3-adrenergic receptor activation (105).
Thus, there seem to be no mechanistic contradictions when pharmacologic agents protect through adrenergic blockade, whereas exercise preconditions the heart through adrenergic activation. To explain, chronic adrenergic activity has deleterious effects on the heart — a common feature of heart failure. In contrast, regular adrenergic activity due to exercise or physical activity is associated with protection. The pathological effects of experimental sympathetic hyperactivity, in fact, are attenuated by exercise training in rodents (106). Cellular mechanisms secondary to β-adrenergic receptor activation seem to be due to nitric oxide production through sustained activation and upregulation of endothelial nitric oxide synthase (eNOS) (106,107). Protection via eNOS is robust and persists for approximately 2 wk after the cessation of exercise (107). A convincing series of separate experiments confirm that eNOS-mediated cardioprotection in exercised hearts is downstream of β3-adrenergic receptors (105). A recent finding suggests that exercise also may evoke iNOS (108). However, iNOS is an inflammatory mediator central to non-exercise preconditioning (109) and, as discussed previously, is thought to be unsustainable for long-term viability (96). Accordingly, it is not surprising that contradictory findings from studies in both mice and rats suggest iNOS isn’t essential in the exercised heart (60,70).
Renin Angiotensin System–Related Cardioprotection
Independent of CVD risk factor modification, potential links between RAS pharma and cellular cardioprotective mechanisms have been identified in knockout mouse models. In concept, ARB may precondition the heart through tissue kallikrein metabolite production, a consequence of compensatory angiotensin 2 receptor upregulation. In contrast, ACEi seem to precondition by blunting kinin (including bradykinin) degradation by ACE (110). Elevated bradykinin levels are largely responsible for the dry cough sometimes associated with ACEi use in humans, an adverse drug reaction that partially spurred ARB development (22). Nonetheless, increasing tissue kallikrein and kinins collectively activate the B2 bradykinin receptor, facilitating a cardioprotected phenotype by multiple cellular mediators (110). Among the potential mediators of cardiac preconditioning linked to bradykinin activity are the powerful KATP channels mentioned previously (111). Although conceptually exciting, the sustainability of this pharma-mediated cardioprotection pathway is questionable because current findings are derived from ischemic preconditioning, one of the problematic nonexercise experimental models (82). And perhaps most important for future exercise-related research in this area, some humans express genetic polymorphisms of the B2 bradykinin receptor (112). Therefore, the cardioprotective link between exercise-pharma may be highly variable in these individuals, raising important considerations for emerging trends in genetic testing and personalized medicine.
Opioid Receptors and Cardioprotection
The role of endogenous opioids and their conjugate receptors has garnered significant attention in recent years for the potential to elicit cardioprotection against ischemic injury. Endogenous opioid-induced cardioprotection is biochemically complicated, a fact that cannot be overstated, and extends well beyond the release of endorphins during long-duration exercise. The exercise dose required to elicit a meaningful rise in circulating endorphins is, in fact, not insignificant (113). Thus, a postexercise rise in endorphins is not typical after a “traditional” exercise prescription. Similarly, endorphins are not obligatory to the experimental dose of cardioprotective exercise used in contemporary animal studies. Although exercise-derived endorphins do not seem to be central to opioid-mediated cardioprotection, a classic investigation reported that use of a CCB potentiated the β-endorphin response to exercise, a finding that was associated with improved quality of life (114) and may implicate exercise-pharma considerations outside the scope of this review.
Enkephalins, most likely released by the heart, may provide exercise-induced cardioprotection by opioid receptor activation (115). Serial experiments from different research groups clearly demonstrate that short-term exercise confers cardioprotection against ischemic injury by opioid receptor activation (101,102,116). Although the delta opioid receptor isoform seems to be most important to exercise preconditioning (101,102), more recent evidence suggests “promiscuous” protection also may occur by kappa opioid receptor activation (117). Interestingly, opioid receptors in the heart are found only on intrinsic cardiac adrenergic (ICA) cells and not ventricular myocytes. Thus, cardioprotection must be extended to the myocardium through an intermediary molecule, presumably calcitonin gene-related peptide (CGRP) released from ICA cells (118).
Finally, recent experiments confirm a downstream role for eNOS/NO after opioid receptor activation (119). Other redundant cardioprotective mechanisms downstream of opioid receptors include KATP channel activation (120). Because opioids are frequently used to control pain or satisfy addiction, this raises ethical questions of whether exogenous opioid use may transiently facilitate cardioprotection. Although short-term use of opioid agonists (including methadone) reduces ischemia/reperfusion injury (118), cellular habituation occurs within a matter of days, after which the heart is no longer preconditioned (121). Thus, the question of whether illicit or prescription opiates should be considered in those at high risk for CVD is, therefore, of little or no practical value.
Important questions have been raised about adenosine receptor manipulation and cardioprotection. Recent findings using non-exercise stimuli evoked transient cardioprotection and suggest that adenosine, like endogenous opioids, precondition through CGRP release from the heart (122). Consistent with CGRP-mediated preconditioning, adenosine receptor activation also is linked to increased KATP channel activity as a cellular cardioprotective mediator (123). Compounded production of CGRP through adenosine and opioid receptor stimulation is a particularly promising new research avenue. In theory, the heart could precondition in response to minute doses of cardioprotective agents released in paracrine fashion. In support, a classic canine investigation demonstrated that adenosine levels rise within the pericardial space, proportional to the exercise intensity (124). Collectively, these findings highlight the need for future investigations into adenosine-mediated research and exercise preconditioning.
Both testosterone and estrogen are potent physiologic compounds in the maintenance of heart health and ischemic resistance. The topic of sex hormones and cardioprotection is relevant to the current review for several reasons, including the indisputable role of vigorous exercise as a cardioprotective stimulus. Moreover, exercise-mediated changes in lean and fat mass can influence circulating sex hormone levels with advancing age. Variable outcomes on ischemic heart disease incidence and severity occur in response to both spontaneously occurring and exogenous alterations in circulating sex hormone levels. Accordingly, the reader is cautioned against making wide-ranging physiologic conclusions based on limited data. Nonetheless, some basic understanding exists, including the fact that at the ends of the physiologic spectrum, adverse heart health outcomes are linked to both low and high circulating levels of testosterone (125) and estrogen (126). It also is well established that illicit use of androgens is linked with devastating CVD outcomes. This finding was recently reported in an animal study, where anabolic steroid use was associated with lower levels of endogenous antioxidants and increased cardiac dysfunction postinfarction (127). But not all exogenous sex hormone administration is deleterious to the heart. Recent investigation of isolated hearts from female ovariectomized rats demonstrated that both exogenous testosterone and combined testosterone + estrogen treatments conferred cardioprotection against ischemic insults (126). Similarly, supraphysiologic testosterone administration in orchiectomized male rats restored or improved postinfarct cardiac function as compared with physiologically intact rats (128).
A burgeoning area of cardioprotection and sex hormone research is focused on exogenous restoration of sex hormones after reproductive decline. Emerging insights suggest that the formulation and route of hormone delivery may be most important in determining clinical efficacy. To this end, a recent meta-analysis reported that intramuscular delivery of testosterone abolishes the deleterious effects generally associated with oral testosterone replacement therapy (129). To clarify the relation between exercise and elevated sex-specific hormones, a recent clinically directed investigation in rats used intramuscular injections of nandrolone to elevate circulating testosterone before an ischemic insult. Exogenous testosterone delivery was linked to deleterious outcomes postinfarction and diminished the protective benefits derived from exercise. Interestingly, use of ARB in a separate group of animals partially restored these testosterone-related losses in exercised hearts. As with other modulators of cardioprotection, indirect evidence convincingly suggested that KATP channels may mediate the observed cardioprotection due to exercise and ARB use (130). This finding is of particular importance to the current discussion because it suggests that exercise and sex hormones may offer protection against ischemic insults via common cellular mechanisms. How closely these findings apply to both sexes is uncertain. Based on available information, however, it seems premature to assume that parallel outcomes occur in the female heart. Indeed, sex hormone-linked cardioprotection is perhaps more nuanced in the female heart, where endogenous estrogen, exogenous estrogen delivery, and even nutraceutical activation of intracellular estrogen receptors and cardioprotective signaling are not well understood (131). Nonetheless, these studies highlight the distinct relation between sex hormones and pharmacology to treat CVD and serves as a foundation for future work in the area.
Mitochondrial Targeting and Cardioprotection
It is widely accepted that exercise bolsters mitochondrial function in the ischemic heart (88,132). More recent evidence advances this understanding by demonstrating that subpopulations of subsarcolemmal mitochondria and intermyofibrillar mitochondria exhibit distinct advantages in the exercised heart (133,134). Although many of these adaptations are associated with endogenous antioxidant content (133), calcium ion regulation is vitally important to the exercise response (88). In this regard, improved calcium control seems to be finitely benefited even in exercised hearts (89). As such, recent attention has been focused on mitochondrially directed pharmaceuticals as potential cardioprotective agents (135). Many of these compounds are positively charged lipophilic antioxidant molecules that preferentially translocate to the inner mitochondrial membrane or matrix. As such, these are different from many of the aforementioned drugs that manipulate receptors or ion channels. Among the various mitochondrially directed compounds is SS-31 (Bendavia), a promising agent that provides profound cardioprotection through faceted protection of the mitochondria during ischemia and reperfusion injury (136). A recent investigation examined postinfarct outcomes in hearts that received exercise and one of two mitochondrially directed compounds, SS-31 or mitoTEMPO. The compounds were compared with the infarct-sparing effects of NADPH-oxidase inhibition in exercised hearts. Inhibition of NADPH-oxidase completely abolished exercise-induced cardioprotection, whereas neither SS-31 nor mitoTEMPOL impacted exercise preconditioning (86). These provocative preliminary findings highlight the potential for prospective exercise-pharma approaches related to mitochondrial targets.
Another aspect of mitochondrial free radical production and cardioprotection relates to monoamine oxidase (MAO), an enzyme that catalyzes numerous amine oxidation reactions and the production of reactive oxygen species (137). Pharmacologic inhibition of MAO is associated with improved outcomes during acute MI (138). MAO reactions are potentially important to the current review because cardioprotective exercise is associated with MAO downregulation (133). In terms of exercise-pharma interactions, MAO inhibitors also are used in the treatment of depression, diabetes, and Parkinson disease — conditions for which CVD is a primary comorbidity (137). As such, there is reason to suspect that MAO inhibitors may be indicated for cardioprotection in addition to other approved FDA uses, although these links need to be confirmed through future clinical investigation.
Future Directions for Cardioprotective Exercise-Pharma Interventions
Next generation exercise and pharmacotherapy research efforts need to better clarify why some hearts are more responsive to these therapies than others. This point is particularly true in the aged heart, which is largely unresponsive to cardiac preconditioning approaches (139) other than exercise (69–71). In this regard, cell signaling due to exercise and nonexercise stimuli may be the key. For example, protein kinase C epsilon seems to be central to sustainable cardioprotective signaling by exercise in young (140) and aged hearts but exhibits age-dependent insensitivity apart from exercise (141). In similar fashion, a recent investigation of exercise and cardiac preconditioning to combat ischemic injury reported that cardiac signaling characteristics differed in hearts exposed to nonexercise stimuli (60). Although these findings are thematically consistent, they are preliminary at best and require additional verification. Moreover, the cost to evaluate aged animals often is viewed as prohibitively expensive but should be further emphasized in the next generation of exercise preconditioning studies in an attempt to bring more clinical relevance to animal-based studies.
Another promising research avenue involves the role of cytokines as a cardioprotective mediator of exercise. This line of inquiry is a natural extension to the previously referenced hormone- and receptor-based studies. Indeed, the examination of tissue-to-tissue communication by cytokines released during exercise has expanded dramatically over the last decade (142). A recent investigation demonstrated an infarct-sparing role for interleukin-6 (IL-6) in the exercised heart. Moreover, secondary experiments within the same study provided convincing evidence that skeletal muscle was the primary source for the IL-6 release after treadmill exercise in mice (60). A related investigation in rats provided new evidence that circulating cytokine profiles are preferentially altered in response to exercise or exercise hypoxia. Biochemical examination of the hearts, postmortem, indicated that variable cytokine profiles were associated with subtle differences in cardioprotective mediator upregulation. This finding is particularly interesting in light of the fact that both exercise and exercise hypoxia interventions were equally cardioprotective (143). Finally, comparisons across experimental approaches suggest that differing cytokine profiles linked to cardioprotection between exercise and nonexercise stimuli (143,144) should be further delineated in future investigations.
Final consideration of novel research avenues within cardioprotective interventions relate to the incorporation of data-generating molecular biology techniques into exercise science. With the applications of “omics-type” research to exercise, the utility for understanding cardioprotection by microarray and other techniques is significant. Early investigations using microarray have already provided initial insights into gene transcript profiles in young and old hearts exposed to short-term exercise (145). More recent use of microarray in rats, with real-time polymerase chain reaction validation suggests that exercise in youth confers epigenetic advantages that persist into senescence (146). Transitioning to metabolomics, recent findings suggest that acute exercise is marked by a unique cardioprotective metabolite profile (147), although confirmational research is needed. MicroRNA represents another technique by which exercise preconditioning can be examined. A recent investigation of microRNA responses in the exercised diabetic heart provided important links to both protection and pathophysiology as related to CVD risk factors (148), highlighting the profound impact of molecular biology applications in modern medicine. Thus, among the lofty goals of omics-type research is to delineate individual bioprofiles that are indicative of benefit, or detriment, from exercise interventions. Where physiologic understanding has long since revealed exercise metabolic profiles that are highly predictive of long-term mortality (149), biometric profiles are less well understood. Ongoing research, however, has identified provocative associations between commonly measured blood biomarkers as they relate to physical performance variables like V˙O2peak and treadmill gate speed (150). As such, the groundwork has been laid for exercise-pharma discoveries and molecular biology approaches to personalized medicine.
Statistical projections for improvements in CVD incidence and prevalence are likely to remain incremental, at best, and are not expected to achieve American Heart Association 2020 Strategic Impact goals (5). First-line therapies to treat CVD will invariably include potent pharmacologic agents. If pharmacotherapy preempts equally potent complementary lifestyle interventions, cardiovascular outcomes will suffer. Given recent evidence about exercise as a sustainable, cost-effective, and pragmatic approach to treating chronic disease, it’s hard to understand why exercise as a vital sign isn’t a universal consideration in the treatment and prevention of CVD. All the more, the cost-effectiveness of pharmacologic interventions is invariably diminished in younger and lower risk individuals where cardiorespiratory fitness and habitual physical activity may be largely preserved (15).
Accordingly, the key facets of exercise-induced cardioprotection may be uniquely altered by the complexities of exercise-pharma interactions. Whether the emphasis is clinical, scientific, or both, holistic perspectives should be considered when evaluating the potential synergies and favorable outcomes that may result. A short list of mitigating factors includes individual biochemistry, genetics, age, body habitus, comorbid conditions, cardiorespiratory fitness, and disease severity. Not surprisingly, exercise-pharma interactions can be potentially negating, additive, or benign. Preclinical animal studies over the last 30 yr have proved to be as invaluable as clinical trials in navigating exercise-pharma interactions. The burgeoning field of exercise and cardioprotection seems on the cusp of a scientific revolution as advances in gene editing and omics applications mature and become commonplace in exercise science. Conceptual examples provided within this review illustrate how the next generation of personalized medicine could incorporate understanding of exercise-pharma approaches for improved CVD outcomes.
The authors acknowledge the facilities and staff of the Cardioprotection Laboratory within the Department of Health and Human Performance at University of Montana and the Department of Preventive Cardiology/Cardiac Rehabilitation, William Beaumont Hospital, Royal Oak, Mich. Special thanks to Brenda White for her assistance with the preparation of this manuscript, laboriously checking the accuracy and placement of our references.
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