Effects of Exercise Training and Physical Activity in Patients with Coronary Artery Disease

Abstract

Cardiovascular disease is a leading cause of mortality across the globe. More than one-third of these deaths are due to coronary artery disease (CAD). Importantly, 80% of CAD and atherosclerosis-related morbidity and mortality can be prevented by modifying behaviors like physical inactivity. However, exercise is often “under-prescribed” to CAD patients; among those referred, only 40% actually participate. Improved understanding of benefits and recent advances in cardiac rehabilitation by patients and physicians may help improve referral and compliance to exercise training in these patients. In the current review, we discuss how increasing physical activity over the long-term leads to improvement in coronary blood flow and consequently reduces morbidity and mortality in patients with CAD.

Introduction

Cardiovascular disease (CVD) is a leading cause of mortality across the globe. More than one-third of these deaths are due to coronary artery disease (CAD). Importantly, 80% of CAD and atherosclerosis-related morbidity and mortality can be prevented by modifying behaviors such as physical inactivity, dyslipidemia, stress, tobacco, and alcohol abuse. The current review focusses on increasing physical activity (PA), a risk modification behavior that is easily accessible and also inexpensive. In patients with stable CAD, the current recommendation for PA is up to 60 minutes of moderate intensity PA (at nearly 75% of target heart rate), done at least 5 days of the week. ¹ Few examples of aerobic PA that involve large muscle groups like quadriceps are brisk walking/jogging, cycling, and swimming. Reportedly, regular PA is associated with increases in peak aerobic capacity and reduction in all-cause mortality in patients with CAD. ² Importantly, recent studies suggest that despite achieving prescribed PA levels, continuous sitting for up to 7 hours per day will negate the benefits of prescribed moderate-intensity PA/exercise training (ET) levels. ³ In the current review, we discuss how increasing PA over the long-term leads to improvement in coronary blood flow (CBF) and consequently reduces morbidity and mortality in patients with CAD. The reported findings of the current review should be interpreted carefully as the evidence of literature is not weighed independently. The existing literature on the subject that adheres with independent blinded peer-review is summarized in this review.

Barriers to Physical Activity and Exercise Therapy

Existing literature from studies not only involving patients with CAD but also other cardiac and non-cardiac pathologies reveal that compliance is a major barrier to healthy lifestyle. These same studies have also reported that exercise is often “under-prescribed” to CAD patients, where only an estimated that 20%–30% of eligible patients are referred to cardiac rehabilitation (CR) programs.^4-7 Among those referred, only 40% actually participate. Improved understanding of benefits may improve compliance by patients. Similarly, an understanding of recent advances in CR by physicians may help improve referral. Moreover, a comprehensive referral program by the cardiologists to qualified and certified professionals will make the CR safe, as lack of knowledge of whom to approach for CR may also be an important barrier for utilization of CR in India.

Systemic Effects of Exercise Training and Intensity of Exercise

In addition to benefits of regular aerobic exercise on mortality and morbidity in patients with CAD, other forms of PA with established systemic benefits include endurance training—which aims at improving muscle strength and quality of life (QoL). ⁸ The spillover benefits of PA include other positive lifestyle modifications like maintaining a healthy body-weight and improved mood and self-esteem. ⁸ These spill-over changes in turn help to reduce risk factors of CAD such as high blood pressure, hyperlipidemia, diabetes. Therefore, exercise could be a “polypill,” in patients with CAD. ⁹

Cerqueira E et al, ¹⁰ reviewed published literature on the systemic effects of various exercise intensities on inflammatory markers. The authors conclude that pro-inflammatory cytokines (IL-6 and IL- 1β) increase with intense than moderate intensity exercise. These increases in pro-inflammatory markers after high intensity exercise could be as high as 26.79 times to 32.99 times, corresponding to an aerobic fitness (VO₂ max) of 75.33%. The authors conclude that although regular exercise results an anti-inflammatory effect, high-intensity exercise, may lead to “persistent dysregulation” of the immune system with increased susceptibility to illness. Although desirable, detailed description of effect of exercise and PA on inflammatory markers is beyond the scope of this review.

Benefits of Exercise Training Specific to Coronary Artery Disease

An important benefit of PA that is exclusive to CAD is enhanced blood flow and oxygen delivery to myocardium. This enhanced CBF results in reduction of angina and its precipitation, thus increasing patients’ QoL. The stated increase in CBF is due to ET-induced graded increase in myocardial oxygen demand, ¹¹ leading to a compensatory increase in myocardial oxygen supply. However, these adaptations should be graded, progressive and hence require adherence to ET programs. Additionally, it has been shown that ET over a long-term induces both arteriogenesis and ischemia-induced angiogenesis. ¹²

This graded increase in demand-supply of CBF also requires increased cardiac output achieved through systemic hemodynamic adjustments. The progression and magnitude of both CBF and systemic adjustments depend on the dosage of ET. The dosage of ET includes adjustments of intensity, type, duration, and frequency of exercise. In a nutshell, more or larger the muscle groups recruited, greater is the hemodynamic adjustment required. Similarly, intensity of exercise, often determines activation of the autonomic nervous system. Although desirable, discussion of exercise prescription is not the scope of the current review. ¹¹

Although the accurate dosage of ET (aerobic and endurance) that’s most beneficial in CAD patients is not well established, but consensus exists that dosage varies with individuals and relies upon baseline cardiorespiratory fitness (CRF) level and severity of CAD. What is well-established though is that functional adaptations to ET generally take usually more than a year of consistent ET and frequent optimization of the dosage of ET. ¹³ Furthermore, compelling evidence is documented that patients with CAD who engage in CR programs experience nearly one-third reduction in all-cause mortality.^{14, 15} On the contrary, a low CRF increases the prevalence of CAD by 8 times.

Exercise Training and Coronary Plaque Burden

Large multi-centered trials like The Lifestyle Heart Trial reported that with five-years of CR (which included ET with diet and lifestyle modification) results in 2.5 fold regression of relative coronary stenosis. ¹⁶ Additionally, 7 year CR programs have shown to reduce electrocardiographic ST segment depression. ¹⁷ An interesting study done by Hambrecht et al ¹⁸ examined the role of leisure time activity on plaque progression. The authors report that luminal lesion size is inversely proportional to leisure time activity, suggesting that not only structured CR programs but also PA play a major role in CAD. Another important study done by Madssen et al ¹⁹ reported that a 12 week aerobic ET in patients with CAD on optimal medical therapy post intracoronary stent placement ¹⁹ reduces the necrotic core volume of the plaques and results in reduction in the overall plaque burden measured by Grayscale and radiofrequency intra-vascular ultrasound.

Malik et al, ²⁰ evaluated the association between exercise capacities, exercise intensity, fatty plaque, and coronary artery calcification (CAC) score in CAD patients. The authors report moderate intensity exercise like brisk walking to lower CAC scores and reduce CAD events. Furthermore, the authors add that moderate intensity exercise may yield more benefits than vigorous intensities of exercise. ²⁰

Effect of Exercise Training on Endothelial Function

Another important ET-induced adaptation in patients with CAD is improvement in endothelial function and stabilization of phenotype of vascular smooth muscles. Endothelial dysfunction, one of the major pathophysiological changes that occur in CAD, results in production of vasoconstrictors. In CAD patients with endothelial dysfunction, short-term ET (4 weeks) on a cycle ergometer 6 times a day for at least 10 minutes attenuated Ach-induced vasoconstriction. The landmark study of Hambrecht et al. ¹⁸ demonstrated that 4 weeks of ET resulted in attenuation of coronary vasoconstriction to Ach; however, restoration to normal levels was not observed in patients with CAD. Similarly, improved production of Nitrous Oxide (NO) after ET reduces the atherosclerosis changes by its vasodilatory and vasoprotective properties. ²¹

Conclusion

PA and ET are helpful in both prevention and/or reversal of the pathology in patients with CAD. Enhanced CBF due to multiple reasons like structural and functional changes in coronary circulation is the primary reason of these reported benefits of ET. Additionally, improvements in endothelial function due to increase in NO-dependent factors overhaul the vasoconstrictor factors. Moreover, long-term results of ET suggest increased formation of collateral circulation for myocardium with resultant improvement in perfusion of the ischemic myocardium. Importantly, most of the observed benefits are with moderate intensity ET, which also has an anti-inflammatory effect, unlike intense exercise that are pro-inflammatory. The observations of this review suggest the need for increased promotion of PA/ET in patients with CAD.