13 Exercise and Fitness

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Introduction

Since the late 1950s, numerous scientific reports have examined the relationships between physical activity, physical fitness, and cardiovascular health. Expert panels convened by organizations such as the Centers for Disease Control and Pre- vention (CDC), American College of Sports Med- icine (ACSM), the European Working Group on Exercise Physiology and Rehabilitation, and the American Heart Association (AHA),^1–5along with the US Surgeon General’s Report on Physi- cal Activity and Health,⁶ have reinforced scientific evidence linking regular physical activity to various measures of cardiovascular health.

The prevailing view in these reports is that more active or ﬁt individuals tend to experience less coronary heart disease (CHD) than their sedentary counterparts, and when they do acquire CHD, it occurs at a later age and tends to be less severe.

Cardiac rehabilitation, as both a science and an industry, has evolved in large part owing to the abundance of evidence indicating that regular exercise improves physical function, and reduces the risk of reinfarction and sudden death in patients with known CHD.^7–11 Despite this evidence, however, most adults in Western societies remain effectively sedentary,^3,6 and more than 80% of patients who sustain a myocardial infarction (MI) are not referred to a cardiac rehabilitation program. This is in part due to the fact that physical activity is not currently integrated into the Western healthcare paradigm, and the major- ity of physicians fail to prescribe exercise to their patients.¹²

Given the well-documented association between physical inactivity and adverse health outcomes worldwide, the prevalence of physical inactivity, and the growth in the prevalence of obesity in the US and Europe, the healthcare provider’s role is more critical than ever in terms of encouraging societies to become more physically active, and to develop strategies that promote the adoption of physically active lifestyles in all their patients. This chapter provides an overview of the scientiﬁc evidence linking physical activity and health, and summarizes the physiologic changes that occur with a program of regular exercise.

Role of Exercise in Cardiovascular Health

Physiologic Fitness and Health

In the last two decades, a striking amount of data have been published demonstrating the importance of ﬁtness level in predicting risk for adverse health outcomes.^2,3,13,14A consistent observation in these studies is that after adjustment for age and other risk factors, exercise capacity has been shown to be a stronger marker of risk for cardiovascular morbidity or all-cause mortality than established risk factors such as hypertension, smoking, obesity, hyperlipidemia, diabetes, and obesity. In addition, exercise capacity has been shown to be a more powerful predictor of risk than other exercise test variables, including ST depression, symptoms, and hemodynamic

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Exercise and Fitness

Jonathan Myers

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responses.^13,15–19 Moreover, the lower levels of ﬁtness in these studies did not appear to be associated with subclinical disease.A number of recent studies have expressed exercise capacity in the context of survival beneﬁt per MET (metabolic equivalent); these studies are presented in Table 13-1. These studies are noteworthy in that each increase in 1-MET (a small increment achievable by most individuals) is associated with large (10–25%) improvements in survival. The importance of exercise capacity in the risk paradigm has historically received inadequate attention because of the tendency for clinicians to focus on the ST

segment.²⁰Some of the major recent studies are reviewed in the following.

Blair and associates¹⁴assessed fitness by treadmill performance in >13,000 asymptomatic subjects and followed them for 110,482 person-years (averaging >8 years) for all-cause mortality. These results are presented in Table 13-2. Age-adjusted mortality rates were lowest (18.6 per 10,000 man- years) among the most fit and highest (64.0 per 10,000 man-years) among the least fit men, with the corresponding rates among women 8.5 and 39.5 per 10,000 woman-years, respectively. These findings closely parallel an earlier report among TABLE13-1. Survival benefit per MET in recent epidemiologic studies using maximal

exercise testing as a measure of fitness Blair et al. JAMA 1995:

Nearly 16% survival benefit per minute increase (roughly 1-MET) on the treadmill with serial testing

Dorn et al. Circulation 1999:

NEHDP: 8–14% survival benefit per MET increase during cardiac rehabilitation over 19 years Goraya et al. Ann Intern Med 2000:

14% and 18% survival benefit per MET for younger and elderly subjects, respectively Myers et al. N Engl J Med 2002:

12% survival benefit per MET among patients referred for treadmill testing Gulati et al. Circulation 2003:

17% survival benefit per MET among healthy women Mora et al. JAMA 2003:

20% survival benefit per MET among women in the Lipid Research Clinics Trial Balady et al. Circulation 2004:

13% reduction in risk of events per MET among high risk men in Framingham Offspring Study Myers et al. Am J Med 2004:

20% survival benefit per MET, roughly equivalent to 1000 kcal/week adulthood activity

TABLE13-2. Rates and relative risks of death* among 10,244 men and 3120 women, by gradients of physical fitness

Men Women

Quintiles Deaths per Relative Deaths per Relative

of No. of 10,000 risk of No. of 10,000 risk of

fitness† deaths man-years death‡ deaths woman-years death‡

1 (low) 75 64.0 1.00 18 39.5 1.00

2 40 25.5 0.40 11 20.5 0.52

3 47 27.1 0.42 6 12.2 0.31

4 43 21.7 0.34 4 6.5 0.15

5 (high) 35 18.6 0.29 4 8.5 0.22

*Age-adjusted.

†Quintiles of fitness determined by maximal exercise testing.

‡P value for trend 0.05.

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asymptomatic men from the Lipid Research Clinics (LRC) Mortality Follow-up,¹⁸ in which each 2 SD decrement in exercise capacity was associated with a 2- to 5-fold higher CHD or all- cause death rate. More recent studies, including one from the LRC, have reinforced the fact that these ﬁndings also apply to women who are healthy at the time of evaluation.^18,19Gulati et al.¹⁹ suggested that the strength of exercise capacity in predicting risk of mortality was even greater among women than men, reporting a 17% reduction in risk for every 1-MET increase in ﬁtness.

In the LRC, nearly 3000 asymptomatic women underwent exercise testing and were followed for up to 20 years.¹⁸A 20% decrease in survival was observed for every 1-MET decrement in exercise capacity. This study also pointed out the relative weakness of ischemic ECG responses in predicting cardiovascular and all-cause mortality among women.

More recently, this issue has been addressed in clinical populations, e.g. patients referred for exer-

cise testing for clinical reasons.^13,15–17 In a recent study performed among US Veterans, 6213 men underwent maximal exercise testing for clinical reasons and were followed for a mean of 6.2 years.¹³The subjects were classified into five categories by gradients of fitness. After adjustment for age, the researchers observed that the largest gains in terms of mortality were achieved between the lowest fitness group and the next lowest fitness group. Figure 13-1 illustrates the age-adjusted relative risks associated with the different categories of fitness. Among both normal subjects and those with cardiovascular disease, the least fit individuals had more than four times the risk of all-cause mortality compared to the most fit. Importantly, an individual’s fitness level was a stronger predictor of mortality than established risk factors such as smoking, high blood pressure, high cholesterol, and diabetes. Over the last several years, other cohorts, such as those from the Cleveland Clinic¹⁷ and the Mayo Clinic,^15,16 have documented the importance of exercise capacity as a predictor of

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(2.95-6.83) (3.29-5.16)

(2.40-3.73)

(1.54-3.75)

1 2 3

Quintiles of Exercise Capacity

4 5

(1.12-2.75) (1.73-2.76)

Normal group Disease group

(1.35-2.19) (0.68-2.22) 4.5

3.5

2.5

1.5

0.5 4

3

Relative Risk 1.0-5.9 METs 1.0-4.9 METs 6.0-7.9 METs 8.0-9.9 METs 10.0-12.9 METs 8.3-10.6 METs ≥13.0 METs ≥10.7 METs

6.5-8.2 METs

5.0-6.4 METs

2

1

0

FIGURE13-1. Age-adjusted relative risks of mortality by quintiles of exercise capacity among normal subjects and patients with cardiovascular disease. The subgroup with the highest exercise capacity (group 5) is the reference category. For each quintile, the range of values for exercise capacity represented appears within each bar; 95% confidence intervals for the relative risks appear above each bar. (From Myers et al.¹³) © 2002 Massachusetts Medical Society. All rights reserved. Reprinted with permission.

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mortality among clinically referred populations.

These clinically based studies confirm the obser- vations of Blair et al.,¹⁴ Framingham,²¹ and the LRC trial^18,22 among asymptomatic populations, underscoring the fact that fitness level has a strong influence on the incidence of cardiovascular and all-cause morbidity and mortality.

Epidemiologic Evidence Supporting Physical Activity

In the United States alone, it has been estimated that roughly 250,000 deaths per year are attributed to lack of regular physical activity³ (roughly one-quarter of all preventable deaths annually).

However, others have suggested that these figures may be significantly underestimated.²³ Ongoing longitudinal studies have provided consistent evidence of varying strength documenting the pro- tective effects of activity for a number of chronic diseases, including CHD, chronic heart failure (CHF), type 2 diabetes, hypertension, osteoporo- sis, and site-specific cancers.^2,3,6 In contrast, low levels of physical fitness or activity are consistently associated with higher cardiovascular and all-cause mortality rates.^2,3,13,14Midlife increases in physical activity, fitness level, or both, through change in occupation or recreational activities, are associated with a decrease in mortality rates.^24,25 Considering the last few years alone (2000–2004), an impressive volume of data has been published throughout the European Union and the US confirming the association between physical activity and cardiovascular health; some notable examples of these cohorts are presented in Table 13-3.

The landmark epidemiologic work of Paffen- barger and associates among Harvard alumni^24,26 has been particularly persuasive in support of physical activity, and thus the development of the CDC, AHA, ACSM, and European Working Group guidelines. Table 13-4 illustrates the rates and relative risks of death over a 9-year period among 11,864 Harvard alumni by patterns of physical activity. Several findings in Table 13-4 are particularly noteworthy. The largest benefits in terms of mortality appear to accrue through engaging in moderate activity levels; moderate is generally defined as activity performed at an intensity of 3 to 6 METs, roughly equivalent to

brisk walking for most adults. Note also that regular, moderate walking or sports participation is associated with 30% to 40% reductions in mortality (relative risk of death 0.60 to 0.70). Likewise, the physical activity index, expressed as kilocalo- ries per week (the sum of walking, stair climbing, and sports participation), suggests that a 40%

reduction in mortality occurs by engaging in modest levels of activity (1000 to 2000 kcal/week, equivalent to three to ﬁve 1-hour sessions of activity), whereas only minimal additional beneﬁts are achieved by engaging in greater-intensity activity.

These ﬁndings agree closely with earlier results among 16,936 Harvard alumni assessed in the early 1960s and followed for all-cause mortality for nearly 20 years.²⁶ Similar results have been reported from large studies that have followed cohorts for CHD morbidity and mortality in the range of 10 to 20 years among British civil ser- vants, US railroad workers, San Francisco long- shoremen, nurses, physicians, other healthcare workers, and other cohorts (for review, see Kohl²⁷ or Lee and Paffenbarger²⁸). Clearly, the evidence linking a physically active lifestyle and cardiovascular health is substantial.

TABLE13-3. Recent cohorts (2000–2004) supporting the role of physical activity in predicting health outcomes

Framingham Heart Study (Boston) Belgian Physical Fitness Study

Physicians Health Follow-up Study (Boston) Nurses Health Study (Boston)

VA Health Care System (Palo Alto) The Whitehall Study (London)

Seven Countries Study (US, Europe, multicenter)

National Center for Chronic Disease Prevention and Health Promotion (CDC, Atlanta)

The SENECA Study (Europe, multicenter) Baltimore Longitudinal Study on Aging Finnish Twin Study

Aerobics Center for Longitudinal Research (Dallas) Honolulu Heart Study

Canada Health Survey

Harvard Alumni Health Study (Boston) Copenhagen Male Study

Zutphen Elderly Study (Greece)

Osteoporotic Fractures Research Group (US, multicenter) Caerphilly Wales Study

Puerto Rico Heart Health Program Nordic Research Project on Aging (NORA) Lipid Research Clinics Follow-up (Baltimore)

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Specific Recommendations for Activity from Major Health Organizations

A variety of consensus reports from major health organizations worldwide have been published with speciﬁc recommendations for physical activity.^1–6 Consistent in these reports is the recommendation that all individuals participate in a minimum of 30 minutes of moderate activity on most, and preferably all, days of the week.

Repeated intermittent or shorter bouts of activity (e.g. 10 minutes), including occupational, non- occupational, or tasks of daily living, have similar cardiovascular and health beneﬁts if performed at a level of moderate intensity (e.g. brisk walking, cycling, swimming, home repair, and yard work) with an accumulated duration of at least 30 minutes per day. Individuals who already meet these standards receive additional beneﬁts from increasing this amount to more vigorous activity.

The 30 minutes/day recommendation is generally consistent with an energy expenditure in the order of 1000 kcal/week. Energy expenditure of this magnitude has been associated with 20–30%

reductions in all-cause and cardiovascular mortality.^2–6 The 30 minutes per day/1000 kcal/week recommendation is at the heart of a noteworthy theme that is consistent in each of the aforemen- tioned consensus statements on physical activity and health. It is now appreciated that considerable health benefits are derived from moderate levels of activity. Many researchers have argued that it is generally not necessary to engage in vigorous, sus- tained activity to derive many of the health benefits of exercise. Prior to the release of these reports in the mid-1990s, guidelines generally promoted the concept that exercise was thought to be effec- tive only if an improvement in some measure of cardiopulmonary fitness was observed, imply- ing that only physically “trained” individuals TABLE13-4. Rates and relative risks of death* among Harvard alumni, by patterns of physical activity

Deaths per Relative

Physical activity No. of 10,000 risk of P value

(weekly) Man-years (%) deaths man-years death of trend

Walking (km) <5 26 228 86.2 1.00

5–14 42 275 67.4 0.78 <0.001

15+ 32 194 57.7 0.67

Stair-climbing (floors) <20 37 341 80.0 1.00 0.001

20–54 48 293 62.9 0.79

55+ 15 80 59.6 0.75

All sportsplay None 12 156 88.9 1.00

Light only 10 152 97.4 1.10

<0.001

Light and moderate 36 208 59.7 0.67

Moderate only‡ 42 178 56.4 0.63

Moderate sportsplay (h) <1 30 308 92.9 1.00

1–2 41 126 58.2 0.63 <0.001

3+ 29 64 43.6 0.47

Index (kcal)§ <500 12 197 110.3 1.00

500–999 18

58 135 69.1

78.9 0.63

1000–1499 15 111 68.9 0.62 1.00

1500–1999 13 73 61.4 0.56

2000–2499 10 51 52.4 0.48 <0.001

2500–2999 8

42 44 64.6

55.4 0.59

3000–3400 6 36 74.7 0.68 0.70

3500+ 18 82 48.1 0.44

METs, metabolic equivalents.

*Age-adjusted.

†<4.5 METs intensity.

‡4.5+ METs intensity.

§Sum of walking, stair climbing, and all sportsplay.

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benefited from physical activity. In recent years, the philosophy on exercise as a means to this end (“fitness” measured by exercise capacity) has changed significantly. Current guidelines reflect the concept that substantial health benefits can be achieved through modest amounts of regular exercise, regardless of whether exercise results in a measurable improvement in exercise capacity.

Physical Activity Pattern Versus Fitness Level in Defining Health Risk

Although physical activity status and physiologic fitness are clearly linked, the latter carries an important genetic component; that is, some people remain comparatively fit without engaging in a great deal of physical activity. The above- mentioned studies by Blair and colleagues,^14,25 those at the VA,¹³and elsewhere,^15–19provide com- pelling evidence that one’s fitness level has a profound influence on mortality. There has been some recent debate as to whether daily physical activity patterns largely determine one’s fitness level and therefore health risk, or whether fitness level predicts mortality independently from activity pattern.^29,30 In a recent meta-analysis, Williams²⁹compared the dose–response relationships between leisure-time physical activity and

ﬁtness from published reports and their association with cardiovascular disease endpoints. The analysis included a remarkable 1,325,000 person- years of follow-up.

The results of the Williams meta-analysis²⁹are summarized in Figure 13-2. Relative risks are plotted as a function of the cumulative percent- ages of the samples when ranked from least fit or active to most fit or active. In combining study results, a weighted average of the relative risks from the physical activity and fitness cohorts was computed at every 5th percentile between 5 and 100%. As illustrated in Figure 13-2, the risks of CHD decrease linearly with increasing percentiles of physical activity. This is contrasted by the fitness cohorts, in which a sharp drop in risk occurs before the 25th percentile of the fitness dis- tribution. This suggests that the largest benefits in terms of CHD morbidity occur by the most unfit becoming moderately fit, confirming the observa- tions of previous studies in both asymptomatic and clinically referred populations.^3,6,13,14Perhaps more importantly, the precipitous drop in risk before the 25th percentile of the fitness distribu- tion results in fitness being a more powerful predictor of CHD risk than physical activity. Stated differently, at all percentiles greater than the 25th, the relative risk reduction is greater for fitness

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

0 20 40 60 80 100

Physical activity

Physical fitness

Percentile activity/fitness level

Risk Reduction

Williams P. Med Sci Sports Exerc 2001:33;754 8 fitness cohorts (>300,000 person-yrs) 30 activity cohorts (>2 million person-yrs) Baseline risk

Highest Lowest

FIGURE13-2. Degree of risk reduction in coronary heart disease or other cardiovascular diseases from 8 physical fitness and 30 physical activity cohorts, from the meta-analysis of Williams.²⁹

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than physical activity. Williams²⁹interpreted these findings to mean that formulating activity recommendations on the basis of fitness studies may inappropriately demote the status of cardiorespiratory fitness as a risk factor while exaggerating the public health benefits of moderate amounts of physical activity.

It is important to note that dozens of studies over the last three decades have reported that both higher physical fitness levels and greater amounts of physical activity have an inverse association with the incidence of cardiovascular disease and all-cause mortality. Answering the question regarding whether fitness or activity more strongly predicts outcomes is a difficult under- taking, complicated by the fact that the two measures are related (with correlation coefficients ranging in the order of 0.30 to 0.60), and because fitness also has a strong genetic component, in addition to the fact that fitness may be influenced by subclinical disease and other factors. Even with large, prospective analyses addressing both fitness and activity measures in the same population, a complete answer to this issue will remain elu- sive. Physical activity develops physical fitness, although the magnitude of the response to an exercise stimulus is likely genetically determined.

Nevertheless, activity is likely required to develop and maintain a ﬁtness level that is consistent with good health. This scientiﬁc question should not be a distraction from the important public health message that sedentary individuals should become more physically active.

Resistance Training

Traditionally, exercise programs have empha- sized aerobic lower extremity exercise. This was particularly true for individuals with cardiovascular disease, among whom training beneﬁts were generally thought to occur only through dynamic exercise. Resistance exercise was generally limited to athletes attempting to improve performance. In addition, for many years resistance exercise was considered potentially dangerous for individuals who had existing cardiovascular disease. However, an increasing amount of recent research has demonstrated that resistance training not only improves both muscular strength and cardiovascular endurance,

but it also has positive influences on existing conditions such as hypertension, hyperlipidemia, obesity, and diabetes.³¹One of the most important effects of resistance training is its influence on bone health. Numerous cross-sectional and longitudinal studies have observed higher bone mineral density at multiple sites after resistance training. For these reasons, many governing bodies, including the AHA, ACSM, American Association of Cardiovascular and Pulmonary Rehabilitation, and the Surgeon General’s Report on Physical Activity and Health, now consider resistance training an integral component of a fitness or rehabilitation program.^1–4,6

Resistance exercise should complement, rather than replace, an aerobic conditioning program.

Gains in muscular strength and endurance as well as beneﬁts related to bone health and metabolism can occur by either static (isometric) or dynamic (isotonic or isokinetic) exercises. Dynamic exercises are generally recommended for healthy adults and patients in rehabilitation programs, both because they mimic activities of daily living and because they are associated with lower degrees of hemodynamic stress. Resistance training should be performed at a moderate-to-slow speed, should be rhythmical, and with a normal breathing pattern throughout the movement.

Patients with cardiovascular disease should in particular avoid heavy resistance or isometric exercises, which can cause a dramatic increase in both systolic and diastolic pressures, particularly during the Valsalva maneuver.

Guidelines suggest that one set of 8 to 12 repetitions of 8 to 10 exercises that condition the major muscle groups, performed at least 2 days/week, is the recommended minimum to develop and maintain the beneﬁts of resistance exercise.

Patients with cardiovascular disease should begin a program using relatively lighter weights with higher repetitions (e.g. ≈15) and progress the resistance gradually as strength increases. Studies have shown that there is little additional beneﬁt in terms of muscular strength and endurance from performing multiple sets. Thus, multiple sets should be limited in patients with cardiovascular disease. Resistance training can be reasonably included as a supplement to an aerobic session, or performed on a day separate from an aerobic session.

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Physiologic Benefits of Exercise Training

Regular exercise increases work capacity; hun- dreds of studies have been performed cross- sectionally that document higher maximal oxygen uptake (VO2max) values among active versus sedentary individuals, or between groups after a period of training. The magnitude of improvement in VO2max with training varies widely, usually ranging from 10% to 25%, but increases as large as 50% have been reported. The degree of change in exercise capacity depends primarily on initial state of ﬁtness and intensity of training.

Training increases exercise capacity by increasing both maximal cardiac output and the ability to extract oxygen from the blood. The physiologic benefits of a training program can be classified as morphologic, hemodynamic, and metabolic (Table 13-5). Many animal studies have demonstrated significant morphologic changes with training, including myocardial hypertrophy with improved myocardial function, increases in coronary artery size, and increases in the myocardial capillary-to- fiber ratio. However, such changes have been difficult to demonstrate in humans.³²The major morphologic outcome of a training program in humans is probably an increase in cardiac size;

however, this adaptation appears to occur mainly in younger, healthy subjects, and is an unlikely outcome among individuals beyond the age of 40 or in patients with heart disease. However, signiﬁcant hemodynamic changes have been well

documented among patients with heart disease after training. These include reductions in heart rate at rest and any matched submaximal workload, which is beneﬁcial in that it results in a reduction in myocardial oxygen demand during activities of daily living. Other hemodynamic changes that have been demonstrated after training include reductions in blood pressure, increases in blood volume, and increases in maximal oxygen uptake. The most important physiologic beneﬁts of training among patients with heart disease occur in the skeletal muscle.

The metabolic capacity of the skeletal muscle is enhanced through increases in mitochondrial volume and number, capillary density, and oxida- tive enzyme content. These adaptations enhance perfusion and the efﬁciency of oxygen extraction.

An additional important influence of training is a favorable influence on the cardiovascular risk profile (Table 13-6). While this may include such things as reductions in blood pressure, reductions in body weight, reductions in total cholesterol and LDL, and an increase in HDL, recent studies suggest that a particularly potent influence of regular exercise is an improvement in insulin sensitivity. Recent studies also suggest that programs of regular exercise have favorable effects on plasma concentrations of inflammatory risk markers (C-reactive protein, homocysteine). As mentioned above, the condition of being sedentary has a profound effect on cardiovascular morbidity and mortality, so becoming more physically active lowers cardiac risk. It is also important to note that while the effect of exercise on any single risk factor may generally be small, the overall effect of continued, regular exercise on overall cardiovascular risk, when combined with other TABLE13-5. Physiologic adaptations to physical training in

humans

Hemodynamic adaptations Increased cardiac output Increased blood volume Increased end-diastolic volume Increased stroke volume

Reduced heart rate for any submaximal workload Metabolic adaptations

Increased mitochondrial volume and number Greater muscle glycogen stores

Enhanced fat utilization Enhanced lactate removal

Increased enzymes for aerobic metabolism Increased maximal oxygen uptake Morphologic adaptations

Myocardial hypertrophy (likely only in younger individuals)

TABLE13-6. Changes in risk factors influenced by exercise training

Decrease in blood pressure

Increase in high-density lipoprotein cholesterol level

Reduction in plasma inflammatory risk markers (C-reactive protein, homocysteine)

Augmented weight reduction efforts Psychological effects:

Less depression Reduced anxiety Improved glucose tolerance Improved fitness level

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lifestyle modiﬁcations such as proper nutrition, smoking cessation, and medication use, can be dramatic.

Newer Concepts Regarding Physiologic Benefits of Exercise Training

A longstanding and attractive hypothesis is the concept that exercise training can reverse or retard the progression of atherosclerosis. The observation that regression of atherosclerosis occurred in animal studies dating back to the 1950s continues to stimulate interest in the effects of exercise on the coronary vasculature in humans. While this idea was largely rejected during the 1970s and 1980s, several notable studies were performed during the 1990s indicating that exercise training, when combined with multidisciplinary risk management, can improve myocardial perfusion.^33–35This has been demonstrated indirectly using nuclear imaging³³ and directly by angiography.^34,35Because most of these studies involved multidisciplinary risk reduction (e.g. diet, smoking cessation, stress management, and pharmacologic management of risk factors, including statin therapy) in addition to exercise training, it is not possible to determine the inde- pendent effects of exercise training.

There is also debate regarding the mechanism by which the apparent improvement in myocardial perfusion might occur following training. It is generally considered unlikely that changes in coronary blood flow during exercise in animals would apply to humans. Three mechanisms could potentially explain an improvement in perfusion after training: (1) direct regression of atherosclerotic lesions; (2) formation of collateral vessels; or (3) a change in the dynamics of epicardial flow via flow-mediated or endogenous stimuli of the vessel. While there has been evidence of small but significant improvements in lumen diameter after intensive exercise and risk reduction programs in patients with CAD, no evidence exists that collateral vessel formation occurs after training in humans. Interestingly, although changes in lumen diameter following these intervention programs are quite small, they are associated with considerable reductions in hospital admissions for cardiac reasons.³⁵This suggests that patients in the intervention groups may achieve greater plaque stabil-

ity, without large changes in the coronary artery lumen.

In terms of the third mechanism, that is, changes in epicardial flow dynamics after training, a significant amount of recent research has demonstrated that training improves endothelial dysfunction, thus permitting enhanced peripheral and coronary blood flow in response to exercise.

This represents a paradigm shift in the patho- physiology of CAD. The last decade has brought an awareness that the luminal diameter of epicardial vessels changes rapidly in response to mechanical (flow-related) and endogenous or pharmacological stimuli. Hambrecht et al.³⁶ studied the effects of exercise training in patients with reduced ventricular function and reported that leg blood flow during acetylcholine infusion was enhanced compared to controls. The improvement after training was attributed to an increase in endothelium-dependent vasodilation with an increase in basal nitric oxide formation. In a sub- sequent study, these investigators demonstrated an improvement in endothelium-dependent vasodilation in epicardial vessels as well as resistance vessels in patients with CAD. After 4 weeks of exercise training, there was a 29% increase in coronary artery flow reserve in comparison to the non-exercise control group.³⁷

These findings have been confirmed by other groups,^38–40 and suggest an important role of endothelial dysfunction contributing to inadequate blood flow in patients with cardiovascular disease. Exercise training appears to have a profound effect on the vasodilatory properties of the vasculature. Further exploration into the effects of exercise training on the dynamic behavior of the endothelium is an important target area for future research in both patients with and without existing cardiovascular disease.

Summary

An impressive body of scientific evidence has accumulated over several decades documenting the importance of physical fitness and physical activity in reducing the risk for cardiovascular and all-cause morbidity and mortality. This evidence has met the scientific test of replication.

Even modest amounts of activity, such as the

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minimal recommendations put forth by major health organizations (30 minutes/day of moderate activity, or ≈1000kcal/week) are associated with 30–40% reductions in morbidity and mortality.

Likewise, relatively small improvements in fitness level (e.g. 1-MET) can have dramatic effects on health outcomes (10–25% reductions in cardiovascular and all-cause mortality). The greatest potential for benefit has been consistently shown to occur among the least fit or least active individuals in a given population. Stated differently, sedentary or unfit individuals appear to benefit the most from initiating an exercise program.

While an individual’s fitness level is in part genetically determined, all sedentary individuals can benefit from increasing their physical activity pattern, and activity is likely required to develop and maintain an activity level that is consistent with good health. Exercise capacity typically increases after a training program by 10–25%, depending on the initial state of fitness and the type of training program. A combination of central (cardiac) and peripheral (skeletal muscle) adaptations account for this increase. Health outcome benefits resulting from greater activity levels result in part from favorable changes in cardiovascular risk factors, including its effect on the condition of being sedentary or unfit itself. It is now appreciated that many similar benefits occur through a program of resistance exercise.

A sedentary lifestyle and lack of physical ﬁtness are major precursors for cardiovascular disease.

Western societies have become more sedentary in the last two decades, a circumstance that has contributed to marked increases in obesity, diabetes, and other conditions. The multitude of studies on the health beneﬁts of physical activity performed over the last three decades should encourage healthcare providers to recog- nize physical activity as part of the standard treatment paradigm for patients with and without cardiovascular disease.

References

1. American College of Sports Medicine Position Stand. The recommended quantity and quality of exercise for developing and maintaining cardiorespiratory and muscular ﬁtness, and ﬂexibility in healthy adults. Med Sci Sports Exerc 1998;30:975–

991.

2. Fletcher GF, Balady G, Amsterdam EA, et al. Exer- cise standards for testing and training: A statement for healthcare professionals from the American Heart Association. Circulation 2001;104:1694–1740.

3. Pate RR, Pratt MP, Blair SN, et al. Physical activity and public health: A recommendation from the Centers for Disease Control and Prevention and the American College of Sports Medicine. JAMA 1995;

273:402–407.

4. American College of Sports Medicine. Guidelines for Exercise Testing and Prescription, 6th edn.

Philadelphia: Lippincott; 2000.

5. Giannuzzi P, Mezzani A, Saner H, et al. Physical activity for primary and secondary prevention.

Position paper of the working group on cardiac rehabilitation and exercise physiology of the Euro- pean society of cardiology. Eur J Cardiovasc Prev Rehabil 2003;10:319–327.

6. US Public Health Service, Ofﬁce of the Surgeon General: Physical Activity and Health: A Report of the Surgeon General. Atlanta, US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion;

1996.

7. O’Conner GT, Buring JE, Yusaf S, et al. An overview of randomized trials of rehabilitation with exercise after myocardial infarction. Circulation 1989;80:

234–244.

8. Oldridge NB, Guyatt GH, Fischer ME, et al. Cardiac rehabilitation with exercise after myocardial infarction. JAMA 1988;260:945–950.

9. Taylor RS, Brown A, Ebrahim S, et al. Exercise-based rehabilitation for patients with coronary heart disease: Systematic review and meta-analysis of randomized controlled trials. Am J Med 2004;

116:682–692.

10. Smart N, Marwick TH. Exercise training for patients with heart failure: A systematic review of factors that improve mortality and morbidity. Am J Med 2004;116:693–706.

11. Exercise training meta-analysis of trials in patients with chronic heart failure (ExTraMATCH). BMJ 2004;328:189–195.

12. Damush TM, Stewart AL, Mills KM, et al. Prevalence and correlates of physician recommendations to exercise among older adults. J Gerontol A Biol Sci Med Sci 1999;54:M423–M427.

13. Myers JN, Prakash M, Froelicher VF, et al. Exercise capacity and mortality among men referred for exercise testing. N Engl J Med 2002;346:793–801.

14. Blair SN, Kohl HW III, Paffenbarger RS, et al. Phys- ical ﬁtness and all-cause mortality: A prospective study of healthy men and women. JAMA 1989;

262:2395–2401.

(11)

15. Roger VL, Jacobsen SJ, Pellikka PA, et al. Prognostic value of treadmill exercise testing: A population- based study in Olmsted County, Minnesota. Circu- lation 1998;98:2836–2841.

16. Goraya TY, Jacobsen SJ, Pellikka PA, et al. Prognos- tic value of treadmill exercise testing in elderly persons. Ann Intern Med 2000;132:862–870.

17. Snader CE, Marwick TH, Pashkow FJ, et al.

Importance of estimated functional capacity as a predictor of all-cause mortality among patients referred for exercise thallium single-photon emis- sion computed tomography: report of 3,400 patients from a single center. J Am Coll Cardiol 1997;30:

641–648.

18. Mora S, Redberg RF, Cui Y, et al. Ability of exercise testing to predict cardiovascular and all-cause death in asymptomatic women. A 20-year follow-up of the Lipid Research Clinics Prevalence Study.

JAMA 2003;290:1600–1607.

19. Gulati M, Pandey DK, Arnsdorf MF, et al. Exercise capacity and the risk of death in women. The St James Women Take Heart Project Circulation 2003;

108:1554–1559.

20. Myers J. Beyond ST-segment displacement: newer diagnostic and prognostic markers from the exercise test. Am J Med Sports 2003;5:332–336.

21. Kannel WB, Wilson P, Blair SN. Epidemiological assessment of the role of physical activity and ﬁtness in development of cardiovascular disease.

Am Heart J 1985;109:876–885.

22. Ekelund LG, Haskell WL, Johnson JL, et al. Physical ﬁtness as a predictor of cardiovascular mortality in asymptomatic North American men: The Lipid Research Clinics Mortality Followup Study. N Engl J Med 1988;319:1379–1384.

23. Booth FW, Gordon SE, Carlson CJ, et al. Waging war on modern chronic disease: Primary prevention through exercise biology. J Appl Physiol 2000;88:

774–787.

24. Paffenbarger RS, Hyde RT, Wing AL, et al. The association of changes in physical-activity level and other lifestyle characteristics with mortality among men. N Engl J Med 1993;328:538–545.

25. Blair SN, Kohl HW, Barlow CE, et al. Changes in physical ﬁtness and all-cause mortality. A prospective study of health and unhealthy men. JAMA 1995;273:1093–1098.

26. Paffenbarger RS, Hyde RT, Wing AL, et al. Some interrelations of physical activity, physiological ﬁtness, health, and longevity. In: Bouchard C, Shep- hard RJ, Stephens T, eds. Physical Activity, Fitness, and Health. Champaign, IL: Human Kinetics;

1994:119–133.

27. Kohl HW. Physical activity and cardiovascular disease: Evidence for a dose response. Med Sci Sports Exerc 2001;33(Suppl):S472–S483.

28. Lee IM, Paffenbarger RS. Do physical activity and physical ﬁtness avert premature mortality? Exerc Sport Sci Rev 1996;24:135–172.

29. Williams PT. Physical ﬁtness and activity as separate heart disease risk factors: a meta-analysis. Med Sci Sports Exerc 2001;33:754–761.

30. Blair SN, Jackson AS. Physical ﬁtness and activity as separate heart disease risk factors: A meta-analysis.

Med Sci Sports Exerc 2001;33:754–761.

31. Graves JE, Franklin BA. Resistance Training for Health and Rehabilitation. Champaign, IL: Human Kinetics; 2001.

32. Froelicher VF, Myers J. Exercise and the Heart, 4th edn. Philadelphia: WB Saunders; 2000.

33. Schuler G, Hambrecht R, Schlierf G, et al. Myocar- dial perfusion and regression of coronary artery disease in patients on a regimen of intensive physical exercise and low fat diet. J Am Coll Cardiol 1992;19:34–42.

34. Hambrecht R, Niebauer J, Marburger C, et al.

Various intensities of leisure time physical activity in patients with coronary artery disease: Effects on cardiorespiratory ﬁtness and progression of coronary atherosclerotic lesions. J Am Coll Cardiol 1993;

22:468–477.

35. Haskell WL, Alderman EL, Fair JM, et al. Effects of intensive multiple risk factor reduction on coronary atherosclerosis and clinical cardiac events in men and women with coronary artery disease: The Stan- ford Coronary Risk Intervention project (SCRIP).

Circulation 1994;89:975–990.

36. Hambrecht R, Wolf A, Gielen S, et al. Effect of exercise on coronary endothelial function in patients with coronary artery disease. New Engl J Med 2000;

342:454–460.

37. Hambrecht R, Fiehen E, Weigl C, et al. Regular physical exercise corrects endothelial dysfunction and improves exercise capacity in patients with chronic heart failure. Circulation 1998;98:2709–2715.

38. Edwards DG, Schoﬁeld RS, Lennon SL, et al. Effect of exercise training on endothelial function in men with coronary artery disease. Am J Cardiol 2004;93:

617–620.

39. Gokce N, Vita JA, Bader DS, et al. Effect of exercise on upper and lower extremity endothelial function in patients with coronary artery disease. Am J Cardiol 2002;90:124–127.

40. Moyna NM, Thompson PD. The effect of physical activity on endothelial function in man. Acta Physiol Scand 2004;180:113–123.