CHAPTER 106: EXERCISE IN HEALTH AND CARDIOVASCULAR DISEASE

Exercise and/or physical activity is beneficial for healthy individuals and for those at high risk for cardiovascular disease (CVD), as well as those with manifest CVD. This chapter addresses the hemodynamics and health benefits of physical activity and exercise conditioning programs, both in healthy individuals and those with or at risk for CVD.

During physical activity, energy expenditure increases, and the compensatory cardiovascular response represents an integration of neural, biochemical, and physiologic factors. The cardiovascular control center is believed to reside in the ventrolateral medulla of the brain and to respond to both central and peripheral inputs. Central impulses arise from somatomotor centers of the brain. Peripheral impulses are generated by mechanoreceptors, found in muscles, joints, and the vascular system; chemoreceptors, found in the muscles and the vascular system; and baroreceptors, found in the vascular system. These impulses are transmitted by autonomic afferent fibers. The central control center regulates cardiac output (CO) and its distribution to organs and tissues according to metabolic demand.

The feed-forward command system located in the motor cortex provides a coordinated and rapid cardiovascular response to optimize tissue perfusion and maintain central blood pressure. This central command provides the greatest control over heart rate (HR) during exercise¹ and is also involved in the preexercise anticipatory response. Stimulation of the central control center by the higher command centers leads to alteration of autonomic tone. This may explain the influence of “emotions” on the cardiovascular response.

The cardiovascular control center also receives input from peripheral receptors. Stretch and tension of muscular and articular mechanoreceptors trigger afferent impulses that are important in the regulation of the circulatory response to dynamic exercise. Muscle chemoreceptors stimulated by products of metabolism influence the control center as well. This reflex neural input (termed the exercise pressor reflex) provides rapid feedback modifying the autonomic outflow in response to physical activity and exercise.²

Vascular baroreceptors are located in the aortic arch and carotid sinuses. They respond to changes in arterial blood pressure and regulate HR by eliciting reciprocal changes in both sympathetic and parasympathetic activity.³ The arterial baroreceptors protect the cardiovascular system from relatively short-term changes in blood pressure, as seen during physical exercise. Cardiopulmonary mechanoreceptors in the atria, ventricles, and pulmonary vessels aid in regulation of the circulatory response. An increase in blood pressure elicits reflex slowing of the heart, and the converse applies with hypotension. During physical activity, this feedback mechanism is altered so that blood pressure can rise. The aortic and carotid bodies contain chemoreceptors sensitive to arterial oxygen, carbon dioxide, and hydrogen ion concentrations. Whereas decreased arterial oxygen levels trigger an increase in arterial pressure, changes in carbon dioxide and hydrogen ion concentration have a relatively small effect.

The circulatory response to exercise involves a complex series of adjustments resulting in an increase in CO proportional to metabolic demands. These changes ensure that the metabolic needs of exercising muscles are met, that hyperthermia does not occur, and that blood flow to essential organs is protected. Adequate blood flow is delivered to exercising muscles through increased CO and redistribution of blood flow away from the viscera. CO is defined as the product of stroke volume (SV) and HR. The average CO at rest is approximately 5 L/min for both trained and untrained men. In women, the value is approximately 25% lower.

Resting CO increases immediately before the onset of physical exercise as a result of anticipatory changes in the autonomic nervous system resulting in tachycardia and increased venous return. After the onset of exercise, CO increases rapidly until steady-rate exercise is reached. CO then increases gradually until a plateau is achieved. The magnitude of the hemodynamic response during physical activity depends on the intensity and the muscle mass involved. In sedentary individuals, CO during maximal exercise increases approximately four times, to an average of 20 to 22 L/min. In elite-class athletes, the CO can increase eight-fold, to values of 35 to 40 L/min.

From rest to strenuous exercise, HR rapidly increases to levels of 160 to 180 bpm or higher. The initial rapid increase is likely the result of central command influences or a rapid reflex from muscle mechanoreceptors. The instant acceleration in HR is largely caused by vagal withdrawal. Later increases result from reflex activation of the pulmonary stretch receptors, which trigger increased sympathetic tone and more parasympathetic withdrawal. Increased circulating catecholamines play a role as well. During exercise, changes in HR account for a greater percentage of the increase in CO than does SV. SV plateaus when the CO has increased to only half of its maximum. Further increases in CO occur by increases in the HR, although HR response in older subjects can be blunted.

Two physiologic mechanisms influence SV. Increased venous return elicits enhanced diastolic filling and more forceful systolic contraction. Neurohormonal influences also enhance contractility through direct effects.

Diastolic ventricular filling (preload) is enhanced by slower HR or increased venous return. Increased end-diastolic volume stretches myocardial fibers, enhancing overlap of sarcomere myofilaments and improving ventricular compliance. This, in turn, results in enhanced contractility and greater SV. It is believed that this mechanism is responsible for increased SV during the transition from rest to exercise or from the upright to the supine position. Resting CO and SV are highest in the supine position. Supine SV is nearly maximal at rest and increases only slightly during exercise. In normal supine individuals, increased CO with exercise results predominantly from an increase in HR, with little contribution from SV. Venous return to the heart is lower in the upright position, resulting in a lower resting SV and CO. During upright exercise, however, SV can approach maximum SV observed in the recumbent position, usually without an increase in ventricular diastolic dimensions.

Increases in SV during upright exercise most likely occur through the combined effect of enhanced diastolic filling and more complete emptying during systole. Exercise-induced increases in circulating catecholamines enhance myocardial contractility. In the early phase of upright exercise, CO increases because of a simultaneous increase in SV and HR. In the later phases of exercise, increases in HR are primarily responsible for further increases in CO.

Blood flow to tissues is generally proportional to metabolic activity. At rest, approximately 20% of CO is distributed to the skeletal muscle. However, during physical activity, the majority (≤ 85%) of the increased CO is diverted to the working muscles. This represents an increase from 4 to 7 to 50 to 75 mL/min of blood per 100 g of muscle. Even within active muscle, the increased blood flow is highly regulated, with the greatest amount of blood being delivered to the oxidative portions of the muscle at the expense of the tissue with high glycolytic capacity. Local metabolic conditions, as well as neural and hormonal regulation of vasomotor tone, control the shunting of blood to active muscles. The local response is primarily caused by the buildup of vasodilatory metabolites in exercising muscle.

During exertion, parasympathetic activity is withdrawn, and sympathetic discharge is maximal, which results in increased release of norepinephrine from sympathetic postganglionic nerve endings. Plasma epinephrine levels are also increased. As a result, most vascular beds constrict, except those in exercising muscles, which are influenced by vasodilating metabolites. Blood flow to the skin increases during light and moderate exercise, favoring body cooling. Further increases in workload cause a progressive decrease in skin flow as the increasing cutaneous sympathetic vascular tone overcomes the thermoregulatory vasodilatory response. The kidneys and splanchnic tissues extract only 10% to 25% of the oxygen available in their blood supply. Consequently, considerable reductions in blood flow to these tissues can be tolerated through increased oxygen extraction. At rest, the heart extracts approximately 75% of the oxygen in the coronary blood flow. Because of limited margin of reserve and increased myocardial demands, coronary blood flow increases four-fold during exercise. Cerebral blood flow also increases during exercise by approximately 25% to 30%.⁴ During maximal exercise, however, cerebral flow may decrease because of hyperventilation and respiratory alkalosis.

On cessation of exercise, there is a decrease in HR and CO secondary to withdrawal of sympathetic tone and reactivation of vagal activity. In contrast, systemic vascular resistance remains lower for some time because of persistent vasodilatation in the muscles. As a result, arterial pressure decreases, often below preexercise levels, for periods up to 12 hours into recovery.⁵ Blood pressure is then stabilized at normal levels by baroreceptor reflexes.

Different types of exercise impose different loads on the cardiovascular system. Isotonic (dynamic) exercise is defined as muscular contraction of large muscle groups resulting in movement, which induces a volume load to the heart. Isometric (static) exercise is defined as a constant muscular contraction of a smaller muscle group without movement. It provokes more pressure than volume load to the heart. Significant increases in both CO and oxygen consumption (VO₂) and a decrease in systemic vascular resistance characterize the load posed by isotonic exercise. By contrast, isometric exercise increases systemic vascular resistance while producing only minimal changes in CO and VO₂.⁶ A third type of exercise is resistance exercise. This is a combination of isometric and isotonic exercise evoked by using muscular contraction with movement, as in free-weight lifting. Most activities, such as sports or those that are job related, combine all three types of exercise (Table 106–1).

Isotonic (Dynamic) Exercise

The response to isotonic exercise is mediated through central and peripheral adaptations that increase oxygen delivery to exercising muscles. In normal sedentary individuals, VO₂ typically increases 10-fold from rest to maximal exertion,⁷ but in world-class athletes, the increase is significantly greater. Maximal VO₂ is therefore considered an indicator of the level or degree of conditioning.⁸

During isotonic exercise, such as running, peripheral vascular resistance decreases, and marked vasodilatation of vessels in exercising muscles occurs in conjunction with vasoconstriction of the splanchnic and renal vessels. In active muscles, local autoregulation in response to hypoxia, decreasing pH, and increased local temperature results in vasodilatation.

During prolonged dynamic exercise, skeletal muscle metabolism is primarily aerobic and requires a significant increase in oxygen supply to meet the increased demand for adenosine triphosphate (ATP). The increased oxygen requirements are met by an augmentation of the local blood flow and improved oxygen extraction.

Isometric (Static) Exercise

The cardiovascular response to isometric exercise is different. Less oxygen is required to sustain the contraction of smaller muscle groups. With isometric exercise, the necessary VO₂ is maintained with a smaller increase in CO. Increases in regional blood flow are limited by mechanical compression of blood vessels during sustained muscular contraction, and regional blood flow can actually decrease. To maintain regional perfusion, a pressor response is evoked, which is mediated, at least in part, by reflexes originating in the contracting muscles. The increase in blood pressure is proportional both to the relative muscle tension and the mass of the muscle groups involved.

SV usually declines as a result of increased left ventricular afterload and the absence of augmented venous return. In its pure state, static exercise represents a pressure, or systolic, load. To maintain the higher CO, the HR must increase, often out of proportion to the metabolic needs of the active muscle groups.

Resistance (Resistive) Exercise

Resistance exercises are activities that use repetitive movements against a resistance, generating a low-to-moderate increase in muscle tension. The response to resistance exercise is determined by the extent of both the isotonic and isometric components. Physiologic responses are described relative to the percentage of maximal voluntary contraction (MVC). Static contractions (< 15%-25% MVC) do not fully occlude intramuscular blood flow, and oxygen can still be delivered to active muscles. If one can perform more than 30% MVC with no occlusion of blood flow, there is increased VO₂, thus the aerobic or isotonic component of resistance exercise.⁹

Weight lifting is considered the prototype resistance exercise and is thought to have a high isometric component. Blood pressure and HR responses during weight lifting are proportional to the relative intensity of muscle contraction, the mass of the muscle groups involved, and the duration of the contraction. Weight training exercises have been shown to cause a significant increase in blood pressure. This is thought to be the result of restricted muscle perfusion and a centrally mediated pressor response caused by enhanced muscle tension. The HR response during maximal upper body resistance exercise is lower than that seen during maximal isotonic exercise.¹⁰ This contributes to a lower HR-blood pressure product during maximal resistance exercise compared with maximal dynamic exercise.

Previous concerns regarding the safety of resistance training have been rebutted by several reports that reveal that moderate resistance training programs are safe even in subjects with cardiac disease.^11,12 At this time, it is believed that resistance training (done on a regular schedule) is useful for promoting muscle strength, flexibility, and functionality, but probably contributes less significantly than isotonic exercise to overall cardiovascular health and longevity. Resistance exercise should be done with care and in moderation in subjects with aortic or aortic valve disease.

Physical conditioning affects the cardiovascular and musculoskeletal systems in a variety of ways that improve work performance and exercise capacity.¹³ Maximal VO₂ can increase two- to three-fold through conditioning induced by repetitive periods of dynamic exercise. Increased CO and peripheral adaptations that improve oxygen extraction contribute equally. Conditioning alters cardiac structure and function, enhancing exercise-induced increases in SV.

At rest, CO is similar for both trained and untrained individuals. Endurance training induces an increase in resting parasympathetic tone and reduces resting sympathetic activity. Heart rates below 30 bpm have been recorded for some healthy athletes. CO is maintained in such individuals by increased SV. Training-induced increase in blood volume and intrinsic myocardial factors have been cited as the source of this enhanced resting and exercise SV (Table 106–2). During exercise, trained individuals achieve a larger maximal CO than do sedentary persons. In untrained persons, there is only a small increase in SV during the transition from rest to exercise, and the major augmentation in CO is induced by tachycardia. The improved cardiac performance after conditioning is secondary to both the Frank-Starling mechanism and augmented myocardial contraction and relaxation.

In previously sedentary individuals, 8 weeks of aerobic training increased SV. This change is associated with increased left ventricular end-diastolic dimension with preservation or even reduction of the end-systolic size.¹⁴ The enhanced end-diastolic dimensions are, however, much lower than those of well-trained athletes.¹⁵ It is not known whether this discrepancy results from prolonged training, genetic factors, or a combination of both. After cessation of training, changes largely regress within only 3 weeks, which is of great concern in adherence to exercise programs. Unfortunately, cardiovascular conditioning is more easily lost than gained, which accounts for the effort dyspnea often experienced by subjects with resumption of activity after a long absence.

Several factors contribute to the cardiac adaptations of exercise training. Parasympathetically mediated bradycardia prolongs diastolic filling time, and expanded plasma volume also increases preload.¹⁶ These changes enhance contractility through Frank-Starling mechanisms. Some studies have shown that endurance training results in increased compliance of the left ventricle, which is probably secondary to enhanced early diastolic filling and increased peak myocardial lengthening during exercise (see Table 106–2). These physiologic changes are accompanied by biochemical and ultrastructural alterations of the myocardial fibers, which have been demonstrated in the hearts of physically conditioned animals. There is an increase in lactic dehydrogenase and pyruvate kinase activity, which enhances the respiratory capacity of the cardiac myocytes. Myocytes enlarge and manifest more mitochondria and myofibrils. Observed ultrastructural changes in the sarcolemma and sarcoplasmic reticulum probably influence intracellular calcium

The cross-sectional area of the epicardial coronary arteries increases in response to exercise. Alterations in the coronary microcirculation have also been identified. Animal studies reveal increased capillary density and capillary-to-fiber ratio with training. Decreased diffusion distance between the capillaries and myocytes has also been observed. Some data suggest that training can promote coronary collateral formation in ischemic vascular beds.¹⁷ These adaptations may enable the heart to better tolerate transient ischemia and to function at a lower percentage of its total oxidative capacity during exercise.¹⁸ Thus, training-induced myocardial adaptations appear to protect against myocardial ischemia.

Skeletal muscle also adapts to long-term training with changes that enhance oxygen extraction. Capillary density and capillary-to-fiber ratio increase. The number of mitochondria increases, as do mitochondrial concentrations of oxidative enzymes. Other cellular adaptations include increases in myoglobin levels, increased concentrations of enzymes involved in lipid metabolism, and enhanced adenosine triphosphatase (ATPase) activity.¹⁹

Available data suggest qualitatively similar responses to dynamic and static exercise in both women and men. Some quantitative differences have been demonstrated in adolescent females who manifest a 5% to 10% greater CO than adolescent males at any level of submaximal oxygen uptake. This is likely related to a 10% lower hemoglobin concentration in females. To be able to deliver the same amount of oxygen, there is a proportionate increase in CO. The gross maximal aerobic capacity in women is approximately 50% lower than it is in men,²⁰ but when adjusted to lean body mass, the difference is only 10% to 15%, a more accurate reflection of sex-related differences. The absolute number of skeletal muscle fibers and the fiber-type distribution are similar in women and men; however, for reasons that are unclear, muscle fibers in men are hypertrophied relative to those in women, resulting in greater cross-sectional muscle mass. Although strength adjusted to cross-sectional muscle area is similar in men and women, men’s increased muscle mass usually yields greater isometric strength.^21,22

Exercise-induced increases in SV also differ between the sexes. Men manifest a progressive increase in ejection fraction with little or no increase in end-diastolic volume; by contrast, women tend to increase end-diastolic volume without a significant increase in ejection fraction.²³ This results in a plateau of the ejection fraction during exercise in women compared with a progressive increase in men. Regardless of these differences in men and women, a recently reported meta-analysis of cardiorespiratory fitness in both healthy mean and women revealed no sex differences in all-cause mortality and cardiovascular events in healthy men and women. Those subjects with maximal exercise capacity of 7.9 metabolic equivalents (METs) or more had substantially lower rates of all-cause death and cardiovascular events compared with those with a capacity of less than 7.9 METs.²⁴

Special considerations must be addressed when prescribing exercise for elderly individuals. In these subjects, maximal end-diastolic volume increases, but maximal HR, left ventricular ejection fraction, and CO are all lower than in young individuals. Coronary disease is common in elderly individuals and can affect the cardiac response to exercise. In addition, the increased potential for exercise-related myocardial ischemia and arrhythmias can increase the risk of adverse events. A critical factor in an elderly (> 65 years of age) person’s ability to function independently is mobility. The overall focus for exercise training should be to enhance health-related fitness, reduce the risk of various chronic diseases, and improve overall quality of life. Considerable evidence demonstrates that physical activity, both endurance and resistance-type exercise, can significantly improve these indices and facilitate functional independence and overall well-being.^{25,26,27,28,29,30,31}

Studies in community-dwelling older adults have revealed benefits in those who are physically active. One observational study involved 3075 adults (52% women, 42% black), age 70 to 79 years, who performed a long-distance corridor walking test. Those who could complete the test with no difficulty walking had less overall mortality and less CVD as well as less limitation of mobility and disability. Another smaller study evaluated free-living activity expenditure including walking, climbing stairs, caregiving, and working for pay. Total energy expenditure was assessed using doubly labeled water and indirect calorimetry in 302 community dwellings of older adults (70-82 years of age) followed over a mean of 6 to 15 years. Results revealed that objectively measured free-living activity is strongly associated with lower mortality in healthy older adults. Therefore, credible data exist to support the benefits of a physically active lifestyle in the aging population.

Elderly persons should ideally undergo a medical evaluation before initiating an exercise program. This assessment should not only include a focused history and physical examination, but should also identify psychosocial limitations to participation that are prevalent in this age group.^25,31,32 For older, apparently healthy persons desiring to participate in a low- to moderate-intensity activity such as walking, an exercise test is usually not required. However, for more vigorous activities and for all cardiac patients, an exercise test is appropriate.³³ A review of the individual’s medication regimen for possible interactions with activity programs should also be performed.

As with young persons, the combination of endurance and resistance exercise is best for achieving the health and fitness goals in elderly individuals.^34,35 However, some specific comments regarding the intensity, frequency, duration, progression, and mode of exercise for elderly persons are required. The exercise capacity of elderly individuals, both before and after exercise training, is usually lower.^25,36,37 Furthermore, because some in this age group may have been sedentary for years, specific muscle groups are often markedly deconditioned. In addition, musculoskeletal limitations, particularly arthritis, can be severely limiting. Thus, it is important to prescribe an exercise program with low-level energy expenditure, particularly during the first few weeks, with gradual increases thereafter. In these instances, however, participants can be encouraged to increase the frequency of exercise (with shorter duration), even to perhaps several times per day. Higher intensity training must be recommended with caution in this age group because of the potential for musculoskeletal injury.

Those whose exercise duration is limited (< 15 minutes per session) because of physical or psychosocial limitations should attempt to exercise more frequently or intermittently. Certain subjects can benefit more because of this intermittent activity. One study supporting this was done in overweight women assigned to the same caloric restriction, but randomized in an exercise program to either 40 minutes of continuous exercise or to four 10-minute “bouts” or periods. At the end of the activity program, those in the intermittent (bouts) group lost 8.9 kg of weight versus 6.4 kg in the continuous group. In the intermittent group, there was also improved adherence and a higher VO₂ compared with the continuous exercise group.³⁷ Conversely, for those who are not limited, increasing the duration of activity to as much as 45 to 60 minutes per session is valuable for increasing caloric expenditure and improvement of risk factors, including obesity, lipid abnormalities, hypertension, and elevated blood glucose level. Published science advisories and scientific statements from the American Heart Association have summarized current knowledge of the health outcomes of those who are overweight and the impact on cardiovascular risk of patients with type 2 diabetes mellitus.³⁸

Many elderly persons have symptomatic concomitant medical and physical limitations (orthopedic, neurologic, and vascular) that can be exacerbated by weight-bearing exercise, especially higher impact activities such as jogging. Walking can be difficult for some older and/or functionally limited persons. Thus, even seemingly innocent activities should be carefully considered for potential adverse effects for some in this age group, especially when the activity requires individuals to bear their entire weight. Select older patients may better tolerate cycle and water exercises, and these should be offered as options.

The type of activity, frequency, duration, intensity, and progression determine the effect of an exercise training program. Epidemiologic studies suggest that moderate-intensity activities, such as brisk walking, performed on a regular basis confer cardioprotection to both men and women.^39,40,41,42 More vigorous activity can confer greater cardioprotection, but the majority of the benefit is accrued with moderate levels of exertion.^39,42 Moreover, fitness appears to be a powerful, independent predictor of cardiovascular risk. High-intensity exercise programs are often associated with poor adherence rates and more musculoskeletal injuries. Thus, a highly structured program of vigorous exercise, especially in elderly individuals, is not generally recommended.

Current guidelines recommend that persons of all ages perform exercise of moderate intensity for 30 to 60 minutes, four to six times weekly or at least 30 minutes of moderate-intensity physical activity on a daily basis.^43,44,45,46 At present, only 10% to 20% of the population meets this recommendation.^46,47 Because only a small percentage of the population is employed in physically demanding occupations, most need to perform this activity in their leisure time. Examples of recommended activities include brisk walking, cycling, swimming, and active yard work. The duration of any period of activity should be at least 10 minutes, and the accumulated daily duration should be at least 30 minutes. Those who choose shorter exercise periods can benefit (as discussed previously) from the effects of intermittent exercise on improved adherence and greater increases in VO₂. In addition, during the recovery period (or periods) in an intermittent (discontinuous) exercise program, additional calories are expended in the postexercise state while the body returns to the resting metabolic state. These calories are not usually counted with those expended with the activity and amount to 20 to 30 kcal per exercise session, which could be doubled if one exercised twice daily.⁴⁸

Those who are sedentary should be encouraged to initially perform a duration of activity that is “comfortable” and to gradually increase to 30 to 60 minutes of daily activity. People who meet these daily standards and who wish to increase their activity further should be encouraged to do so. Resistance exercises should be added to the activity program to increase muscle strength. Resistance training using 8 to 10 different exercise sets with 10 to 15 repetitions each (arms, shoulders, chest, trunk, back, hips, and legs) performed at a moderate-to-high intensity (eg, 10-15 lb [4.5-6.8 kg] of free weight) for a minimum of 2 days per week is recommended.

Physicians and other health professionals should encourage the general public and their patients to follow these guidelines. Incorporating preventive services into medical practice is challenging because of time and financial constraints. To address these issues, the Centers for Disease Control and Prevention developed the Physician-Based Assessment and Counseling for Exercise (PACE) project.⁴⁹ This system includes a simple discussion of physical activity counseling and illustrates how a clinician can efficiently incorporate physical activity counseling into a busy clinical practice through the use of paramedical personnel.

As the problem with overweight and obesity continues to increase worldwide, new physical activity guidelines have been developed to hopefully combat this problem more effectively. A consensus conference was held in Bangkok with experts in exercise, energy expenditure, and body weight reduction in attendance. It was concluded that 60 to 90 min/d of moderate-intensity exercise is needed for prevention of weight regain (lesser amounts of vigorous activity). To prevent transition of overweight to obesity, 45 to 60 min/d of moderate-intensity exercise is needed. The 2005 US government recommendation is for 60 minutes of exercise on most days to prevent weight gain and 60 to 90 minutes on most days for previously overweight people who have lost weight.

Historical Perspective

Exercise training has assumed a prominent role in contemporary prevention and management of CVD.^{33,43,45,46,50,51,52,53} In the 1950s, traditional management of patients with acute myocardial infarction (MI) did not include physical exertion of any kind. Hospitalization and strict bedrest were recommended for at least 6 weeks after acute MI. In 1951, Levine and Lown described reductions in post-MI morbidity and mortality associated with limited early mobilization. This “chair treatment” involved progressive periods of sitting in an armchair starting 1 day after MI. By the end of that same decade, early inpatient mobilization was included in programs of physical activity. By the 1970s, a series of small randomized controlled trials of exercise training (typically starting 3-6 months after MI) suggested significant benefits after MI. Although these studies were individually underpowered to demonstrate survival advantage, meta-analysis suggested a 24% reduction in CVD mortality with exercise-based cardiac rehabilitation.⁴¹

Early rehabilitation programs focused almost exclusively on exercise training. As the discipline matured, patient education; risk factor management; psychological screening and intervention; and dietary, vocational, and smoking cessation counseling were integrated to forge the comprehensive cardiac rehabilitation risk reduction programs of today. In the past three decades, the benefits of comprehensive cardiac rehabilitation programs have become widely recognized.^43,50,54,55 Furthermore, the population deemed appropriate for this intervention continues to expand, incorporating higher-risk individuals, including those with left ventricular systolic dysfunction or valvular heart disease and recipients of surgical or percutaneous revascularization (Table 106–3).

More recently, secondary prevention of cardiovascular events through optimizing proven pharmacologic therapies has been woven into the fabric of contemporary cardiac rehabilitation programs.^50,54

Exercise and Secondary Prevention

Acute and chronic therapy of coronary artery disease (CAD) has evolved significantly since early meta-analyses⁴¹ suggested survival benefit from exercise-based cardiac rehabilitation. Major advances in the therapy of patients with CAD over the past quarter century call into question the validity of those potentially dated conclusions. However, more contemporary meta-analyses of randomized controlled trials of exercise-based cardiac rehabilitation have largely confirmed the findings of the 1980s.⁵⁶ One study added more than 4000 additional patients enrolled in studies of comprehensive and exercise-only rehabilitation programs for CAD published through March 2003.⁵⁶ A more recent update included 48 trials enrolling nearly 9000 individuals. Although the older studies enrolled primarily low-risk, middle-aged, white men, this review included a larger number of women (20%), elderly people (≥ 65 years), and recipients of coronary revascularization. In this analysis, cardiac rehabilitation was associated with a 20% reduction in all-cause mortality (odds ratio [OR], 0.80; 95% confidence interval [CI], 0.68-0.93) and a 26% reduction in CVD mortality (OR, 0.74; 95% CI, 0.61-0.96) compared with usual care (Table 106–4). Based on data from a limited number of trials, significant improvements in total cholesterol, triglycerides, systolic blood pressure, and self-reported smoking rates were also noted. As also shown in Table 106–4, there was a favorable trend in the rates of MI and revascularization that failed to meet statistical significance. Cardiac rehabilitation did not yield significant reductions in high-density lipoprotein (HDL) or low-density lipoprotein (LDL) cholesterol or diastolic blood pressure. Contrary to their previous review, subgroup analysis did not reveal a discrepancy in death rates between exercise-only programs and comprehensive cardiac rehabilitation programs. Similarly, there was no distinction between studies published before and after 1995.

Analysis of the US Medicare database showed a 21% to 34% lower mortality in older patients who had cardiac rehabilitation as part of their treatment for CAD versus patients who did not undergo rehabilitation, extending the benefit to older patients.⁵⁷

Exercise and Functional Capacity

Exertional intolerance is one of the principal clinical features of symptomatic CVD even in the absence of heart failure (HF). Exercise-based cardiac rehabilitation is consistently associated with improvements in functional capacity that significantly impact quality of life.⁵⁵ Exercise training reduces HR and blood pressure at submaximal workloads, improves the metabolic efficiency of both skeletal and cardiac muscle, enhances the mechanical performance of the myocardium, favorably influences autonomic tone, and prolongs the time to angina and ischemic electrocardiographic (ECG) changes during treadmill exercise.⁴³ These physiologic adaptations translate into improved ability to perform activities of daily living with fewer symptoms and fewer limitations. Furthermore, enhanced exercise capacity is associated with significantly lower CVD mortality and fewer nonfatal CVD events.

The landmark Agency for Health Care Policy and Research practice guidelines of 1995 summarized the results of 114 scientific reports on the effect of exercise-based cardiac rehabilitation on measures of exercise tolerance. These included 46 randomized controlled trials, of which 35 compared exercise-based rehabilitation with a no-exercise control group. Of these 35 trials, 30 demonstrated statistically significant improvement in exercise capacity in those assigned to exercise intervention.⁵⁵ Supervised exercise programs lasting 3 to 6 months have been associated with an 11% to 36% improvement in peak VO₂. The most deconditioned derive the greatest benefit.⁵⁰

Exercise and Risk Factor Modification

CAD is a chronic, progressive condition associated with numerous metabolic, toxic, and hemodynamic precipitants, most of which respond favorably to exercise training. Consensus guidelines emphasize the role of exercise in managing hypertension, diabetes, hyperlipidemia, the metabolic syndrome, and obesity.

Blood Pressure

Meta-analyses of randomized controlled trials of exercise in both hypertensive and normotensive individuals suggest a 3- to 4-mm Hg decline in systolic blood pressure and a 2- to 3-mm Hg decline in diastolic blood pressure with both aerobic and resistive exercise training.^57,58 From a public health perspective, even such modest effects on blood pressure significantly impact CVD mortality.⁵⁹

Blood Glucose (Diabetes)

When combined with dietary intervention, exercise lowers the incident rate of new diabetes in high-risk individuals by 42%.⁶⁰ Furthermore, it is superior to metformin in the prevention of type 2 diabetes, and at least a portion of its beneficial effects appears to be independent of weight loss.⁶⁰

Lipids

The effect of exercise on blood lipids varies among available studies. Despite these mixed results, it appears that exercise can lower plasma triglycerides, very low-density lipoprotein (VLDL) cholesterol, and, in some individuals, LDL cholesterol. It also raises HDL cholesterol. A meta-analysis of 51 studies of “moderate to hard” intensity aerobic exercise on blood lipids involved approximately 4700 participants.⁶¹ Nearly all studies involved exercise three to five times per week, lasting at least 12 weeks. The estimated weekly exercise expenditure during structured programs ranged from 500 to more than 5000 kcal/wk, with a mean of 1408.8 ± 824.7 kcal/wk. On average, LDL cholesterol decreased 5.0% (P < .05), and triglycerides decreased 3.7% (P < .05). HDL cholesterol increased by 4.6% (P < .05).

The Health, Risk Factors, Exercise Training, and Genetics (HERITAGE) Family Study prospectively evaluated serial blood lipids in a diverse population of 675 healthy, sedentary, normolipidemic individuals undergoing 20 weeks of supervised cycle ergometer exercise.⁶² They demonstrated a 3.6% increase in HDL cholesterol (1.1 mg/dL in men and 1.4 mg/dL in women). The improvement in HDL cholesterol levels was primarily caused by an increase in the HDL₂ subfraction with an associated increase in apolipoprotein (apo) A-1 (P < .001). They noted only a transient reduction in plasma total and VLDL triglycerides, reflecting the acute effects of the last training session. There were no significant changes in total, LDL, and VLDL cholesterol or apo B.

As is the case for managing hypertension, diabetes, and weight, combining diet and exercise appears to be more effective in lowering LDL cholesterol. One significant study randomized 377 men and postmenopausal women with low HDL cholesterol and moderately elevated LDL cholesterol to aerobic exercise, the National Cholesterol Education Program Step 2 diet, combined diet and exercise, or no intervention.⁶³ Serial lipids revealed significant reductions in LDL cholesterol in both men and women only in the group assigned to combined diet and exercise. Along with other studies, this study suggests that exercise mitigates the reduction in HDL cholesterol typically seen with low-fat diets.

Weight

Weight loss is also associated with improvements in blood pressure, lipid profile, and glycemic control in those with type 2 diabetes. As little as a 10-lb (4.5-kg) weight loss reduces blood pressure. Weight loss by dietary means improves plasma triglyceride levels by 2% to 44%, total cholesterol by 0% to 18%, and LDL cholesterol by 3% to 22%. Although exercise is an important component of weight-management strategies, exercise alone is a rather inefficient method of achieving weight loss. A meta-analysis of 28 studies of exercise compared with diet or control groups calculated an average weight loss of 3 kg in men and 1.4 kg in women assigned to exercise intervention compared with control subjects.⁶⁴ On average, diet alone yields a 3-kg greater weight loss than exercise alone. The combination of diet and exercise is most effective and, on average, yields 8.5 kg of weight loss.⁶⁵

Contrary to its role in initial weight loss, exercise plays a significant role in weight loss maintenance. Six randomized controlled trials examining the effects of exercise on weight loss maintenance concluded that higher levels of exercise were significantly more successful in maintaining weight loss over an average follow-up interval of 2.7 years. Those performing higher levels of physical activity maintained 54% of their initial weight loss, twice that of those assigned to lower levels of physical activity. Thus, exercise is an important component of strategies for weight management and offers synergistic benefits to weight loss itself in risk factor control. This is particularly important in the management of metabolic syndrome, a constellation of metabolic risk factors associated with increased risk for diabetes and CVD. The components of the metabolic syndrome all respond favorably to aerobic exercise, making exercise a mainstay in its management.

Resistance training has also gained favor in the treatment of obesity. Substantial evidence supports that resistance training increases total fat-free mass, muscular strength, and resting metabolic rate, as well as mobilizing visceral adipose tissue in the abdominal region.⁶⁶

More recently, high-calorie expenditure exercise has been shown to promote greater weight loss and more favorable metabolic rate profiles than usual and customary practice in overweight patients in cardiac rehabilitation. Significant weight loss was maintained for 1 year after a 5-month program.⁶⁷

Progression of Coronary Artery Disease

A number of studies have investigated the effect of exercise on progression of atherosclerotic disease. The majority of these studies incorporated exercise into a multifaceted intervention, including diet. A significant study reported long-term follow-up of one of these carefully controlled trials of diet and exercise in 113 men with stable CAD.⁶⁸ The men were randomized to an intensive diet and exercise intervention or limited diet and exercise advice. The exercise group was encouraged to perform 30 minutes of daily cycle ergometer exercise at home and attend at least two supervised 60-minute group exercise sessions weekly. The intervention group improved their physical work capacity by 28%, but the control group remained unchanged. There was no distinction between the two groups in temporal changes in total cholesterol, triglycerides, or body mass index. After 6 years, 66 patients underwent follow-up angiography. Analyzing serial quantitative coronary angiograms on a per-patient basis, these investigators found significantly less progression (59% vs 74%) and significantly more regression (19% vs 0%) in the intervention group compared with the control group.

Finally, the numbers of bone marrow–derived endothelial progenitor cells increase in the peripheral blood of mice and patients with stable CAD subjected to exercise training. Because these cells are thought to exert beneficial effects on vascular repair, angiogenesis, and CAD, much remains to be learned about the fundamental mechanisms underlying the protective and therapeutic benefits of exercise in normal humans and those with CVD.⁶⁹

Systemic Inflammation

Systemic inflammation is emerging as a significant predictor of cardiovascular risk.⁶⁸ Elevated serum levels of interleukin-6; tumor necrosis factor-α; high-sensitivity C-reactive protein (CRP); and a number of other cytokines, acute-phase reactants, and soluble cytokine receptors have been associated with increased risk of CVD events and diabetes.^70,71,72,73 Modest elevation of CRP, in particular, has been associated with CVD risk in observational studies.⁷² Furthermore, some data support that lowering high sensitivity CRP with hydroxymethylglutaryl–coenzyme A (HMG-CoA) reductase inhibitor therapy reduces risk beyond the benefits accrued from LDL cholesterol lowering alone. Obesity and visceral adiposity are associated with increased levels of CRP, and diet-induced weight loss reduces CRP levels.⁷⁰ Physical inactivity also correlates with elevated CRP levels in observational studies. Randomized controlled trials examining the effect of exercise on CRP levels are limited.⁷⁴ Three small, prospective trials of the impact of exercise training on inflammatory markers have enrolled only 104 participants. Two of the three included a control group and showed significantly greater reductions in CRP with exercise training. One small, noncontrolled prospective trial demonstrated a trend toward lower CRP after 6 months of supervised exercise.

Endothelial Function

Exercise training enhances endothelium-dependent coronary and peripheral arterial vasodilatation in individuals with CAD, peripheral arterial disease, HF, diabetes, and hypertension.^{71,72,73,75,76} The effect of exercise on vascular function in individuals free of atherosclerotic risk factors has been mixed.⁷⁷ Exercise’s influence on vascular function appears to be mediated through increased arterial wall shear stress, which promotes enhanced expression and activation of endothelial nitric oxide synthase by means of Akt-dependent phosphorylation.⁷² In addition to influencing vascular tone, nitric oxide also conveys significant antiatherogenic and antithrombotic effects.⁷⁸ Exercise also has beneficial effects of thrombotic tendencies and autonomic function in secondary prevention.

The type of exercise has been studied in 209 patients after recent acute infarction. The four groups compared included aerobic training, resistance training, resistance plus aerobic, and no training over a 4-week period. Improved endothelial function was associated with all training modalities, but this effect was no longer seen after 1 month of detraining.⁷⁹ Additional effects of exercise in secondary prevention are on coagulation, autonomic function, anti-ischemic and antiarrhythmic effects and a decrease in age-related disability.

Exercise in Patients With Heart Failure

There is a daily increase in the millions of people diagnosed with HF, creating a significant impact on the healthcare system. Exercise endurance is limited in these subjects despite advanced drug therapy.^80,81 Cardiopulmonary exercise testing is often done to risk stratify HF patients and is readily available in transplant centers. However, the treadmill exercise time with the Naughton protocol, a far simpler test available in a much larger number of hospitals and clinics, provides an inexpensive prognostic screening tool. Based on substantial data, exercise training can improve both cardiac and noncardiac indices.⁸⁰ Recommendations based on randomized controlled trials encourage exercise training for individuals with HF to impact both functional and symptomatic improvement.^82,83 Home-based exercise has been used in 173 subjects with systolic HF. The investigators recorded no differences between the experimental and control groups in the combined clinical end point at 12 months and in functional status, quality of life, or psychological states at 6 months. However, the exercise group had a reduced hospitalization rate (12.8% vs 26.6%; P = .018). Exercise training can improve physiologic indices, including exercise tolerance, ventricular function, skeletal muscle function, peripheral blood flow, endothelial function, diastolic function, and quality of life.^83,84 Experience has revealed that exercise in HF is safe and well tolerated if it is appropriately prescribed and augments the benefits of cardiac resynchronization therapy.^85,86

The largest and most important trial, Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION), randomized 2331 stable patients (mean age, 59 years; 28% women) with HF and reduced left ventricular ejection fraction (LVEF) to aerobic exercise training (36 supervised sessions followed by home-based training) plus standard pharmacologic treatment versus standard pharmacologic treatment plus usual recommendations regarding physical activity. After a mean follow-up of 2.5 years, there were no statistically significant differences in the primary end point of all-cause mortality and hospitalization (65% exercise training group vs 68% usual care) and secondary end points of mortality (16% vs 17%), CVD mortality, or CVD hospitalization (55% vs 58%) or CVD mortality or HF hospitalization (30% vs 34%). In a prespecified supplemental analysis, adjusting for known major prognostic risk factors in HF (HF cause, exercise duration, LVEF, history of atrial fibrillation or flutter, and the Beck Depression Inventory), the primary end point of all-cause mortality or hospitalization was reduced by 11% in the training group (hazard ratio, 0.89; 95% CI, 0.81-0.99; P = .03).⁸⁶ CVD mortality or CVD hospitalization was reduced 9% (hazard ratio, 0.91; 95% CI, 0.82-1.01; P = .09), and CVD mortality or HF hospitalization was reduced 15% (hazard ratio, 0.85; 95% CI, 0.74-0.99; P = .03). Because exercise was safe in this patient population in which rates of CVD events, implantable cardioverter-defibrillator firing, and fractures of the hip and pelvis were similar, exercise training of HF patients appears most appropriate.

In the same trial, the health status of the participants was assessed by the Kansas City Cardiomyopathy Questionnaire. There were improvements in the overall summary scale for the exercise group, but also in key subscales, including physical limitations, symptoms, quality of life, and social limitations. Their improvements were considered modest, but significant (P < .001), and add to the overall benefit of the exercise training.⁸⁴

Components of Contemporary Cardiac Rehabilitation

Historically, cardiac rehabilitation has been arbitrarily divided into successive phases, typically starting during hospitalization for an acute event (Table 106–5). As clinical care and medical economics have evolved, these traditional phases have lost much of their relevance. Contemporary cardiac rehabilitation emphasizes a continuum of care. The American Association of Cardiovascular and Pulmonary Rehabilitation recommends a more descriptive paradigm incorporating three levels of intervention—inpatient, early outpatient, and lifetime cardiac rehabilitation.^87,88,89

Inpatient Rehabilitation

The contemporary management of acute coronary syndromes focuses on timely reperfusion, risk stratification, and introduction of proven pharmacotherapy in appropriately selected individuals. The timeline of this intervention has become quite truncated with many patients discharged within 3 days of an acute ST-segment elevation MI. Accordingly, inpatient cardiac rehabilitation has assumed an introductory role. It is focused on early mobilization, starting as soon as patients are hemodynamically stable and free of symptoms of ischemia, arrhythmia, or HF. As the patient progresses to an ECG telemetry environment, progressive ambulation is appropriate, initially with assistance and hemodynamic assessment before, during, and after exercise.

Patients are often unable to assimilate the large amount of information that needs to be introduced. Therefore, the current emphasis is on providing written information for the patient and family, ensuring stable clinical status with activities of daily living, and referring the patient to an appropriate comprehensive cardiac rehabilitation program. In addition, ensuring that patients are discharged from the hospital on appropriate medical therapy is an important part of the initial intervention. A number of practice tools are available to help address the gap between recommended therapy and that which is delivered in practice. Patients are usually more adherent to drug therapy when it is initiated in the inpatient environment.

Early Outpatient Rehabilitation

When formal cardiac rehabilitation programs first evolved in the 1960s and 1970s, the primary concern was the safety of early exercise. As such, ECG telemetry monitoring was incorporated as a means of surveillance for significant arrhythmias. Currently, this monitoring goes beyond telemetry and includes surveillance of symptoms; hemodynamics; glycemic response to exercise (in diabetics); weight; tobacco use; emotional status; and adherence to medications, diet, and home exercise. It also includes review of each individual’s pharmacologic and device therapy to ensure adherence with consensus guidelines. This monitored phase is an intensive, multidisciplinary intervention focused on educating the individual about the disease, its manifestations, and all aspects of its treatment. The goal is to provide each participant with the tools needed to slow disease progression, maintain optimal functional status, and become an informed and active participant in managing his or her condition.

Maintenance

The distinction between traditional phase III (medically supervised) and IV (nonmedically supervised) cardiac rehabilitation has been unclear for some time. Most participants progress to independent exercise without a transitional “phase III.” Nonetheless, some patients are concerned by the prospect of continuing exercise in unfamiliar surroundings and elect to continue exercising at a cardiac rehabilitation facility where they feel safe and are familiar with the personnel, protocol, facilities, and clientele. Clinical features occasionally mandate closer supervision than an unmonitored independent exercise program because of adherence, cognitive limitations, serious comorbidities, hemodynamics, or arrhythmias that require medical supervision during exercise. Unfortunately, continuing cardiac rehabilitation services under such circumstances is generally not reimbursed by third-party payers. Regardless of the venue and the degree of medical surveillance, the goal of this maintenance phase is exercise independence and adherence to exercise prescription, healthy diet, weight management, tobacco abstinence, and medications. For further information, please refer to Chapter 45, Rehabilitation of the Patient with Coronary Heart Disease.

For subjects with CVD, exercise and/or proper physical activity is a significant component of overall long-term management. Such activity must be individually “prescribed” considering age, body habits, type and degree of CVD, medications, history of physical activity, and general attitude regarding a long-term commitment to an “active lifestyle.” With these considerations being met, a physical activity/exercise program can be a significant benefit to patients with stable CVD.