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MYOCARDIAL ISCHEMIA AND EXERCISE
D.K. Bowles*, Ph.D. and J.W. Starnes, Ph.D.
Department of Kinesiology and Health Education
University of Texas, Austin, TX 78751
*Current address
Dalton Cardiovascular Research Center
University of Missouri, Columbia, MO, 65211
Though epidemiological evidence has mounted for years demonstrating a beneficial effect of physical activity on coronary heart disease, only recently was a sedentary lifestyle elevated to the level of a primary risk factor for heart disease by the American Heart Association (5). It was concluded that physical activity lowers the morbidity and mortality of coronary heart disease when all other factors (i.e. smoking, blood lipids, etc.) are equal. What process(es) of the disease is altered by physical activity is yet to be determined. However, there is evidence that part of the protection may result from an adaptation intrinsic to the heart itself, which increases the tolerance to ischemia and subsequent reperfusion often associated with atherosclerosis. Epidemiological studies show that while the incidence of both fatal and nonfatal heart attacks is decreased with physical activity, there is a greater reduction in the incidence of fatal attacks (7). In other words, the survivability of a heart attack is increased with physical activity. Thus, the benefit of regular exercise may be two-fold, to lower the risk of developing coronary heart disease and to lower the damage associated with myocardial ischemia should it occur.
Myocardial ischemia is defined as the reduction or cessation of blood flow to the myocardial tissue. In addition to being a clinical manifestation of coronary artery disease itself, the latest clinical treatments for this disease (i.e. coronary bypass surgery, balloon angioplasty) subject the heart to episodes of ischemia and subsequent restoration of blood flow (reperfusion). Following a period of ischemia and reperfusion the heart undergoes a period of contractile dysfunction which can persist for hours or days and compromise recovery. Experimental evidence thus far is equivocal on whether the exercise-trained heart is more resistant to ischemic damage and the contractile dysfunction associated with ischemia. However, recent evidence strongly suggests that exercise training does have a direct beneficial effect on the ability of heart tissue itself to resist ischemic/reperfusion damage and improve the recovery of contractile function upon reperfusion. Furthermore, the intensity of prior exercise training appears to be directly related to the increased ischemic tolerance (2).
Experimental studies in intact animals have produced evidence of a positive, negative or an unaltered response regarding the effect of exercise training and ischemic tolerance. Swim training has been reported to decrease the size of infarction following left coronary artery occlusion in rats (6). This protection was attributed to an increase in myocardial vascularity as a result of training. As little or no increase in coronary vascularity occurs in normal, healthy human hearts as a result of exercise training, it is important to note that similar experiments in treadmill-trained dogs, which do not increase collateral flow due to training, showed no reduction in infarct size as a result of training. However, contrary to humans, dogs possess an innate collateral system, thus it is difficult to extrapolate this data to humans.
These studies point out an inherent difficulty of experiments done on the intact animal, namely that there are too many variables to control which can affect the experimental outcome (infarct size, enzyme release, contractile dysfunction, etc.). The isolated, working heart model has several advantages that make it a rigorous measure of the organ's intrinsic tolerance to ischemia. In the isolated, working heart model, the heart is removed from the animal and therefore conditions affecting both cardiac performance and ischemic response (i.e. preload, afterload, heart rate, temperature, etc.) can be accurately controlled. In addition, global ischemia negates the contribution of collateral blood supply, mentioned above, to reduce infarct size in trained hearts. Most pertinent, several parameters of cardiac pump function (such as cardiac output, +dP\dt, aortic pressure) can be evaluated in the isolated, working heart at energy demands and hemodynamic conditions similar to those in vivo. Using this model, swim-training in rats has been shown to improved contractile and pump performance during ischemia (1). Improved functional recovery following ischemia and protection from hypoxic/re-oxygenation damage has also been reported as a result of swim-training (4). However, swimming elicits dramatically different cardiovascular, sympathetic and hormonal responses compared to treadmill running in the rat. Surface swimming results in a redistribution of cardiac output rather than the increase typical of exercise in larger mammals, including humans. Also, tail-weighting and high swimming density can produce a "diving-reflex" and anoxic-training, rather than true exercise training. On this basis, the appropriateness of the swim-trained rat model for mimicking typical exercise can be questioned.
Treadmill running in the rat produces hemodynamic changes more similar to those of exercise in humans. While not all studies are in agreement (8), recent experiments strongly support an intrinsic myocardial adaptation associated with treadmill training in rats that improves functional recovery of the heart following ischemia/reperfusion (2,3). Rats were treadmill trained at one of three intensities (low, moderate and high) and compared to a group who underwent no training (sedentary). Cardiac function was evaluated prior to and following ischemia in hearts from each group using the isolated, working heart model. Following 25 minutes of global ischemia, hearts from exercise-trained rats showed greater recovery of cardiac function and reperfusion coronary flow response compared to hearts from sedentary animals. Cardiac recovery following ischemia was approximately two-fold greater in hearts from trained animals compared to hearts from sedentary animals. Coronary flow was also significantly higher in trained hearts during the initial 10 minutes of reperfusion. Furthermore, this increased coronary flow was positively correlated with the greater cardiac function.
One important aspect of these studies was the evaluation of the effect of training intensity. When the hearts were required to work at a high workload following ischemia, a beneficial effect of high training intensity was revealed. Cardiac output following ischemia was greatest in the high intensity trained group. In addition, when preload was increased following ischemia, the hearts from the high intensity trained group showed a normal increase in stroke volume while the response of all other groups was depressed. Despite this apparent correlation between intensity of exercise training and ischemic protection, it is important to note that the greatest benefit of exercise training occurred between the sedentary group and the low intensity trained group. This supports human epidemiological studies showing that the greatest protection against coronary heart disease associated with exercise comes in the transition from a sedentary to an active lifestyle.
By what mechanism does exercise training increase the intrinsic tolerance of the heart to ischemia? The major pathological mechanisms deemed responsible for the decline in contractile function of the heart following ischemia and reperfusion are energy depletion, free-radical damage, metabolite accumulation (i.e. lactate), calcium overload and a depressed calcium response of the myofilaments. We have recently examined the possible contribution of each of these to the training-induced protection of cardiac function following ischemia (3).
During ischemia, both ATP and creatine phosphate (PCr) decrease in the myocardium. Upon reperfusion PCr levels typically return to pre-ischemic levels, while ATP remains depressed, however this pattern can be altered by the duration of ischemia. The finding of a depressed high energy phosphate status following ischemia at a time when contractile function was impaired led to the hypothesis that post-ischemic contractile dysfunction was caused by the depressed ATP and PCr levels. In support of this, moderate intensity treadmill training has been shown to increase both ATP and PCr levels following ischemia compared to sedentary controls (2,3). In hearts from sedentary animals, both ATP and PCr levels were depressed following ischemia, while hearts from trained animals maintained greater ATP levels and, in fact, increased PCr levels to pre-ischemic values. Thus, prior exercise training may increase ischemic tolerance by preserving myocardial energy status following ischemia. However, a causal role of energy depletion in post-ischemic contractile dysfunction is controversial and most studies have found no correlation between contractile function and energy status. It is more probable that high energy phosphate levels and total adenine nucleotide content may be an indicator of ischemic/reperfusion damage.
Ischemia/reperfusion is known to increase free-radical production and antioxidants have been shown to improve contractile function recovery following ischemia. In addition, exercise training has been shown to both increase the antioxidant metabolite glutathione and decrease hypoxic/reoxygenation damage to isolated hearts. In our model of exercise-induced ischemic protection, no changes in free-radical production were noted that would account for the greater recovery of contractile function following ischemia in the trained myocardium (3). No differences were noted in lipid peroxidation, total glutathione or thiol oxidation. Thus, at least part of the training-induced protection can occur apart from alterations in handling of free-radicals.
Calcium overload is a common toxic event in cellular pathology. Following ischemia functional recovery is also inversely correlated with the amount of calcium accumulated during the initial minutes of reperfusion (9). Furthermore, interventions which reduce calcium overload following ischemia improve functional recovery. Based on this, it is important to note that when subjected to ischemia and reperfusion, heart from trained animals accumulate significantly less calcium than hearts from sedentary animals (3). As a matter of fact, trained hearts showed no increase in calcium accumulation compared to a two-fold increase in heart from sedentary animals. This finding, combined with the significant number of studies showing calcium overload as a crucial event in ischemic/reperfusion damage, would indicate that decreased reperfusion calcium overload may be an important effect of exercise training. However, this area needs further experimental study.
Recent studies have shown that post-ischemic myocardial dysfunction is associated with a depressed sensitivity of the myofilaments to calcium. That is, contractile force is lower at a given intracellular calcium concentration following ischemia. Though the exact mechanism is unknown, it can be attenuated by preventing calcium overload. Decreased sensitivity to extracellular calcium has also been reported in the working rat heart model following myocardial infarction. Interestingly, hearts from trained animals retain a greater sensitivity to extracellular calcium following ischemia. In addition, these hearts have a greater efficiency of work and a lower diastolic stiffness compared to hearts from sedentary animals. Due to the evidence that exercise training alters myocardial calcium handling, one can speculate that this may be a major link in the training-induced increase in ischemic tolerance.
While many have regarded the lowering of the incidence and severity of coronary heart disease through regular exercise as fact, only recently has epidemiological evidence been strong enough to elevate a sedentary lifestyle to the level of a primary risk factor in heart disease. Though the gap between experimental animal models and human application is large, we believe there is convincing evidence that a number of pathological events associated with myocardial ischemia are attenuated by prior exercise training. These include greater post-ischemic cardiac function, increased coronary flow, increased energy status, increased efficiency of work, lower calcium accumulation, lower diastolic stiffness and increased sensitivity to extracellular calcium. Furthermore, these adaptations are intrinsic to the heart itself and thus are independent of other factors (i.e. neural control, blood lipids). Determining the mechanism(s) responsible for the prophylactic effect of exercise on ischemic heart disease will allow optimal prescription of exercise in preventative cardiovascular medicine.
REFERENCES
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