Exercise Training for Refractory Angina: Why Does It Work?

Cardiac rehabilitation with exercise training and ancillary support services remains one of the most effective treatments for heart disease [1,2]. It can reduce mortality by 25–30% after myocardial infarction and improve survival after percutaneous coronary interventions [3,4,5]. Exercise training can optimize physical capacity in chronic heart disease and after cardiac events, and perhaps more important, it can reduce cardiac work at the submaximal levels of activity that are reached during the general activities of daily living [6,7,8,9]. These outcomes favorably modulate symptoms of heart disease and restore confidence in physical capabilities for many patients. It is clear from data obtained prior to the routine use of percutaneous coronary interventions that patients with stable angina can benefit from exercise training [10,11,12,13]. In this issue of Cardiology, Asbury et al. [14] present results from a pilot study of cardiac rehabilitation in patients with stable but refractory angina who have been maximally treated in the current therapeutic era and are not candidates for further revascularization. They show that cardiac rehabilitation in these patients can improve physical capacity as measured by walking time and distance without adverse effects on the frequency or severity of angina, and with concomitant improvement in psychological well-being and quality of life. Why does it work? These important findings are consistent with the physiology of exercise training and with the pathophysiology of ischemic heart disease. Total oxygen utilization during exercise is determined by cardiac output, equal to stroke volume times heart rate, multiplied by the amount of oxygen extracted from the blood [15]. In normal trained subjects, resting oxygen consumption can increase 13- to 14-fold during maximum exercise, but only one third of this increase is due to changing cardiac output, which can increase about 4.5-fold (1.5-fold for stroke volume and 3-fold for heart rate). The difference between changing oxygen utilization due to increased cardiac output alone and maximum oxygen availability during peak exercise is provided by an approximately 3-fold increase in arteriovenous oxygen (a-vO2) difference across the working muscle beds of active people. Accordingly, much of the ability to exercise to a maximum level in normal subjects is a function of oxygen extraction, totally separate from any change in cardiac output [16].What are the implications of these relationships for maximum exercise capacity in patients with stable refractory angina on maximal medication who are not suitable for further revascularization? In these patients, an increase in cardiac output during exercise may be constrained when stroke volume is limited by infarction or ischemia. Cardiac output may also be constrained when the heart rate is limited by the angina threshold or, intentionally, by first-line medication such as a beta-blockade [17]. Peripheral adaptation of the muscular extraction of oxygen then becomes one of the most important consequences of exercise training for the angina patient [16]. Adaptations include changes in blood flow to muscle, capillary density, myoglobin content, numbers of mitochondria and oxidative capacity. It is well known that exercise training can increase maximum exercise capacity in patients with heart disease in the absence of changes in stroke volume and heart rate [16]. But no one operates at maximum effort tolerance throughout the day, so the ability of exercise training to improve effort tolerance and cardiovascular efficiency at the submaximal workloads that occur during the activities of daily living is central to the benefits of cardiac rehabilitation in maximally managed patients with refractory angina [6,7,8,9]. What is most relevant is how the body works at effort levels that are necessary for usual activities, like carrying packages or walking up stairs.Some years ago, Detry et al. [13] examined the effects of 3 months of exercise training on the determinants of total body oxygen utilization at matched submaximal rather than maximal exercise workloads in patients with myocardial infarction or stable angina pectoris. They found that at a constant level of submaximal work, cardiac output was actually lower after training, largely due to a decrease in heart rate. This occurred because the decrease in cardiac output after training was offset by a corresponding increase in a-vO2 extraction, which allowed the oxygen utilization at a constant workload to be preserved. In effect, the same amount of submaximal work can be done by cardiac patients at a significantly lower myocardial oxygen demand after exercise training. This allows patients of all ages to achieve substantial increases in submaximal effort tolerance throughout the course of a standard program of cardiac rehabilitation, with only minimal, if any, increase in perceived exertion, heart rate or systolic blood pressure [6].Comparable physical work with less heart work is an obvious advantage for the patient with refractory angina, where the myocardial oxygen demand exceeds the available supply with effort. Todd and Ballantyne [10 ]found exercise training in patients with stable angina to be associated with reduced maximal ST segment depression, fewer episodes of ST depression and a reduced total duration of ST depression as measured by ambulatory electrocardiography. This can translate to less depression, improved functional status and a better overall quality of life for patients with symptomatic coronary disease, as assessed by Milani et al. [18] and documented in this study.The approximately 25% increment in walking distance (and increase in walking speed) documented by Asbury et al. [14] is consistent with the adaptive responses to exercise known to occur during cardiac rehabilitation, beyond the effects of maximal medication and revascularization. It is possible that even further benefit might be achieved with longer periods of training [19,20]. The absence of an observed reduction in the frequency of anginal episodes in the rehabilitation group is consistent with the persistence of limiting myocardial oxygen demand, notwithstanding greater effort tolerance. Whether hospitalizations and mortality will be reduced as a direct result of cardiac rehabilitation in patients with medically managed refractory angina remain to be seen in a larger group of patients with longer-term evaluation. As the study moves out of its pilot phase, we look forward to further insights into the short- and long-term consequences of cardiac rehabilitation in this population.