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The role of physical training in patients with coronary artery disease
Appraisal Edited
The
and reappraisal
by Arthur
role
C. DeGraff
and Julian
of physical
coronary
artery
training
of cardiac
therapy
Frieden
in patients
with
disease
Mark A. Greenberg, M.D. Sidney Arbeit, M.D.t Ira L. Rubin, M.D. Bronx, N. Y.
Interest in the role of physical fitness and training in the prevention and treatment of coronary artery disease has increased over recent years. Multiple symposia,‘. 2review papers,3-sand monograpl-&” have appeared on this subject. The scene of joggers in the streets and parks has become common, and the enrollment in medically supervised exercise programs has increased. The favorable effect of physical training on improvement of cardiovascular function is well documented. However, many of those engaged in a regular exercise program hope not only to improve cardiovascular fitness, but also to prevent or attenuate the risks of atherosclerotic coronary disease, specifically myocardial infarction and death. Unfortunately, the studies on the effect of sustained exercise on longevity and reinfarction are equivocal. Thus, because of the uncertain role of physical training in either the prevention or treatment of coronary artery disease, as well as the potential risks and costs, exercise therapy has become a highly controversial issue. This review will discuss the physiologic effects of exercise in patients with coronary artery disease and its role in treatment. Prophylactic prevention
value of exercise of coronary artery
in the disease
Anecdotal experiences are often cited as examples of the beneficial effects of physical training. From the Division of Cardiology, fiore Hospital and Medical Center, Medicine, Bronx, N. Y. Received
for publication
Nov.
Department of Medicine and the Albert Einstein
27, 1978.
Reprint requests: Mark A. Greenberg, gy, Mont&ore Hospital and Medical Bronx, N. Y. 10467. tDr. Arbeit died on July 21, 1978.
0002-8703/79/040527
at MonteCollege of
+ 08$00.80/O
M.D., Department Center, 111 East
0 1979
The
of Cardiolo210th Street,
C. V. Mosby
Co.
The autopsy findings of the famous runner Clarence DeMar, who continued long distance running until his death at the age of 70, typifies these reports.12 On postmortem examination, the coronary arteries were two to three times normal size with only non-obstructive atherosclerotic involvement. One might conclude that the many years of long distance running had resulted in enlarged coronary arteries. However, an equally plausible conclusion would be that DeMar had become a great runner because of a genetic predisposition to large coronary arteries. Bass1er,13based on his extensive observations of autopsy results, has claimed that marathon runners are completely immune to fatal atherosclerosis. Others have refuted this as an exaggerated claim by documenting casesof fatal myocardial infarction in marathon runners and by emphasizing that self-selection and other variables such as diet and smoking habits must be considered in evaluating the “protective effect” of long distance running.14 Population studies have been done to decide whether exercise might be effective prophylaxis against coronary artery disease. The classic work by Morris and associate@ demonstrated a decreased incidence in both the frequency and severity of myocardial infarction in civil servants with more physically active jobs (bus conductors) as compared to more sedentary workers (bus drivers). These findings seemingly support a role for physical activity in the prevention of coronary artery disease. However, Morris and co-workers16 published additional data 3 years later, and noted that the sedentary drivers had both a greater girth and weight prior to employment than the more active conductors, thus raising the question
American
Heart
Journal
527
Greenberg,
Arbeit,
and
Rubin
of self-selection and personal preference of more obese workers-already at greater risk for the development of coronary artery disease-for the sedentary jobs. Other population studies have investigated the risks of cardiac events in physically active population groups compared to sedentary controls in an attempt to establish the possible protective effect of physical activity against cardiac events. Probably the best known of these studies is the work by Paffenbarger” who studied the incidence of fatal myocardial infarctions among San Francisco longshoremen. These longshoremen represent a stable population observed over many years with well described workloads as defined by their union contract. The workers were classified into groups according to their workday energy expenditure. The more sedentary longshoremen had an 80 per cent increased risk of fatal myocardial infarction when compared to workers with higher energy output jobs. The work energy output level was either of equal or greater influence in predicting death from coronary disease as other risk factors such as cigarette smoking, hypertension, previous known heart disease, obesity, and cholesterol. The results of this study are strongly supportive of a protective effect of a lifetime of extremely vigorous physical activity against fatal myocardial infarction and especially against sudden death. Whether a protective effect can also be seen with lesser degrees or different types of physical activity is yet to be shown. A recent review by Froelicher’ summarized the multiple epidemiologic studies. He emphasized both the difficulty in differentiating between self-selection and protection, and the problems in these population studies in controlling for other risk factors and assessing physical activity from job descriptions and questionnaires. He concluded that although .the studies to date are suggestive of a protective effect of physical activity against myocardial ischemic events, the data are not definitive. Physiologic
concepts-definition
of terms
The physiologic effects of physical training have been studied in both normal subjects and in patients with symptomatic coronary artery disease. The terms physical training, exercise training, and physical conditioning will be used interchangeably in this paper to refer to repetitive isotonic muscular exercise carried out on a regu528
lar basis for the purpose of improving an individual’s ability to perform a specific task. The amount of aerobic work which the body performs can be measured in terms of oxygen consumption (VO,). The more work an individual performs, the higher will be his energy demand, and therefore the greater the amount of oxygen consumed. Different tasks which require the same oxygen consumption can be compared. For example, a 70 kilogram man, walking on a treadmill at 1.7 miles/hour at a 10 per cent grade would expend approximately 14 C.C. O,/Kg./minute, which is the same oxygen expenditure for swimming at 20 yards/minute. The energy demand for a variety of submaximal tasks can thus be quantified in terms of oxygen consumption. With increasing energy expenditures, there is a normal increase in heart rate, blood pressure, and cardiac output. As the body reaches its maximum ability to consume oxygen (VO, max), there is a leveling off of the blood pressure and pulse rate with increased load. The maximum oxygen consumption is a reproducible measure of one’s work capacity or state of physical fitness. Values for VO? max may range from 24 c.c./Kg./minute in sedentary middle-aged individuals to values as high as 80 c.c./Kg./minute in highly trained individuals. Thus the state of physical fitness and improvement in physical fitness are quantifiable. In addition to the state of physical training, other factors such as age, sex, and underlying disease processes are determinants of VO, max. Patients with coronary artery disease have an additional limitation to their exercise capacity in that the diseased coronary circulation cannot keep up with the increased myocardial oxygen demand during exercise. Such patients will develop myocardial ischemia before their theoretical VO? max. and stop exercise because of angina. This endpoint is referred to as the symptom limited oxygen consumption (VO, sl). Exercise in patients with coronary artery disease can also induce left ventricular dysfunction, as demonstrated by elevation in left ventricular enddiastolic pressure (LVEDP) or reduction of stroke volume without chest pain. Thus the response of patients with coronary disease to exercise can be limited not only by symptoms of angina but also by extreme dyspnea or fatigue. An additional endpoint is the development of ventricular arrhythmias, possibly secondary to myocardial &hernia or left ventricular failure. An important objective of a physical training April,
1979,
Vol.
97, No.
4
Physical
Table
okygen demand
Physiologic determinants
Left ventricular wall tension Myocardial contractility Heart rate
Clinical correlates
Rate pressure product arterial pressure
= heart
Myocardial
with
CAD
program in patients limited by coronary artery disease is to train the body to perform a given amount of work with lessdemand for the limited myocardial oxygen supply. The major determinants of myocardial oxygen demand are heart rate, wall tension, and contractility (Table I). In the clinical assessment of patients with angina pectoris, the product of heart rate and mean blood pressure (rate-pressure product or RPP) is used as an index of myocardial oxygen demand. Other indices such as the double product, triple product, and tension time index have also been used (Table I). Robinson’” has demonstrated that in patients with stable angina chest pain occurs at a reproducible RPP. It has further been shown that the RPP at angina1 threshold is the same regardless of the type of stress provoking the angina. Hence an improvement in exercise capacity can be brought about by reducing the rate pressure product and therefore the myocardial oxygen demand for a given task. If an individual can exercise to a higher rate pressure product before experiencing angina, it is implied that he has increased his myocardial oxygen supply. of exercise
training
Maximum exercise. Although normal physical activities do not call for maximal exertion, physical fitness is quantified in terms of the maximum work capacity. A consistent effect of physical training is to increase the work capacity as measured by VO? max. The amount of increase in VO, max depends both on the pretraining level of fitness and the intensity and duration of exercise. Heart
Journal
oxygen supply
Coronary blood flow Myocardial oxygen extraction Transmural diastolic pressure gradient (aortic diastolic pressure-left ventricular diastolic pressure) Duration of diastole Regional distribution of myocardial blood flow rate
x
mean
Double product = heart rate x systolic blood pressure Triple product = heart rate x systolic blood pressure X systolic ejection time Tension-time index = heart rate x integralof left ventricular pressure during systole
American
in patients
I. Physiologic determinants and clinical correlates of myocardial oxygen demand and supply Myocardial
Effects
training
Maximal rate pressure product, double product, triple product or tension-time index achieved at time of angina Aortic diastolic pressure x time-ventricular diastolic pressure x time
Studies by Detry and colleagues,1gRedwood and associates 2o and others??” have shown that patients w:th coronary artery diseasecan increase their maximum oxygen consumption. The mechanism by which VO, max is increased is different in coronary patients from that in healthy individuals. Oxygen consumption is dependent on the product of cardiac output and arterial venous oxygen difference. While normal subjects increase VO, max by increasing both the maximal cardiac output and the maximum arterial-venous oxygen extraction (A-VOJ, coronary patients increase only the maximal A-VO,.?’ The predominant mechanism for this increase in A-VO, is an increase in oxygen extraction by the peripheral muscle thought to be due to mitochondrial and enzyme changes in the trained skeletal muscle. Hence, the increase in maximal work capacity in cardiac patients is primarily due to the effect of exercise on the trained peripheral muscles. Physical training does not usually alter the maximum attainable heart rate; however, some patients previously limited by angina are capable of exercising to higher heart rates following exercise training.‘“, “O Submaximal exercise. Daily activities require only submaximal levels of exertion and therefore the benefit of conditioning to patients should also be evaluated during submaximal exercise. The absolute oxygen consumption required to perform a specific submaximal work load is not altered by physical training except insofar as repetition of a particular task facilitates more efficient performance of that task. As the maxi529
Greenberg, Arbeit, and Rubin ma1 work capacity (VO, max) is increased with training, however, a specific submaximal work load represents a lower relative percentage of VO, max. Changes in heart rate as well as the degree of vasoconstriction in visceral vascular beds is proportional to this relative oxygen demand.‘“, z Following a period of physical training, individuals have a slower resting pulse and a lower heart rate and blood pressure response to exercise. The rate pressure product and therefore the myocardial oxygen demand are reduced during submaximal exercise. This lower heart rate at submaximal exercise has been shown by Varnauskasz6 to be accompanied by a rise in the systemic arterial venous oxygen difference. As demonstrated with maximal exercise, during submaximal exercise trained muscles are better able to extract oxygen and maintain oxygen consumption at a reduced muscle blood flow. Clausen and Trap-Jensen“ have shown that after training, both cardiac output and muscle blood flow are reduced during submaximal exercise as compared to pre-training values, and that there is a redistribution of blood flow to the visceral organs. Moreover, the usual rise in peripheral lactate levels during submaximal exercise is attenuated after training, implying more rapid and efficient oxidation in the peripheral muscle cells.z7 Letac and co-workersz8 have demonstrated by comparative hemodynamic and angiographic studies in patients with coronary artery disease that physical training does not directly affect resting myocardial contractility as measured by ejection fraction, segmental contractility, or velocity of circumferential fiber shortening. Although these studies do not preclude changes in myocardial contractility that may occur during stress, the lack of a direct influence of physical conditioning on the myocardium further supports the importance of changes in the peripheral skeletal muscles. In summary, therefore, following a period of physical training, patients with coronary artery disease can exercise to the same submaximal work load with a slower heart rate, a decreased rate pressure product, and therefore a decrease in myocardial oxygen demand. Local changes in the trained skeletal muscles are primarily responsible for this decrease in myocardial work. Myocardial
oxygen
supply-demand
ratio
A major beneficial effect of physical training in patients with coronary artery disease would be alteration of the myocardial oxygen supply-de530
mand relationship. The indirect indices of myocardial oxygen demand (rate pressure product, double product and others) are often used to examine this relationship. The effect of physical training in reducing the indirect indices of myocardial oxygen consumption has been discussed in detail above. Several studies have shown that not only is the RPP decreased at any specified submaximal workload, but that a group of patients can exercise to a higher rate pressure product (or triple product) before angina or exercise to exhaustion without angina.15’,?‘~l This implies either an increased myocardial oxygen supply or a decrease in a determinant of oxygen demand not measured by RPP. A recent study of the effect of physical training on coronary sinus blood flow in patients with angina pectoris demonstrated that the decrease in heart rate and rate-pressure product which occurs during submaximal exercise after training is accompanied by a decrease in coronary blood flo~.~’ The coronary blood flow during maximal exercise was not significantly changed after training. A group of patients, however, was able to increase both the maximum rate pressure product and coronary sinus blood flow at the onset of angina, implying that at least a subgroup of patients may have increased myocardial oxygen supply after training. Although a study by Sim and Neill’” demonstrated an increased triple product to angina when tested by exercise on a bicycle ergometer, there was no change in angina1 threshold when tested by atria1 pacing. This suggests that conditioning might possibly alter the relationship between actual MVO, and the indices by which it is often measured (RPP, triple product). A study by Detry and Bruce,“” which demonstrated an increased RPP threshold to angina after training, found that training did not alter the relationship between ST segment depression and rate pressure product. Thus although the RPP at the time of angina was higher, so was the extent of ST segment depression, raising the possibility that training altered the relationship between angina and myocardial &hernia as measured by ST segment depression. Because of the high myocardial oxygen extraction in the basal state (approximately 70 per cent compared to 20 per cent in the systemic circulation), increased myocardial oxygen needs must usually be met by increased coronary blood flow. The transmural myocardial blood flow is dependent on the difference between the aortic and left April,
1979,
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97, No.
4
Physical
in patients
with
CAD
II. Physiologic effects of physical training in patients with coronary disease
Table
Parameter Z
Effect of training
Measured during maximal exercise Work capacity Maximum oxygen uptake (VO, max) or symptom limited oxygen uptake (V02 sl) Maximum heart rate Maximum A-VO, difference Maximum cardiac output Maximum double product, triple product or tension time index at time of angina
zz
submaximal
Measured
zzz
Heart Blood
bypass
triple
product,
tension-time
rate pressure
index
No change No change
or no change or no change
surgery
Journal
or decreased or decreased
in the treatment of angina
Decreased Decreased No change Decreased
ventricular diastolic pressures and the duration of diastole. Relative bradycardia induced by exercise training prolongs diastole and allows for increased coronary filling. In patients with fixed obstructive coronary artery disease, the ability to increase coronary blood flow with increased demand is severely limited. Collateral coronary vessels may potentially serve to increase blood flow to ischemic areas of myocardium. Although some studies have shown increased vascularity in rats after training and increased collateral flow in dogs,” none of the studies in man with coronary artery disease has shown increased collateral circulation resulting from a physical training program. 23.lR.w 32 This may be due to the fact that (1) coronary angiograms are done at rest, (2) the collateral vessels may be too small to visualize on coronary angiograms, (3) the duration of training necessary to produce an increased collateral circulation might have to be longer than that Heart
or no change
No change Decreased Variable effects No change or decreased Increased No change or decreased Decreased
Rate pressure product (RPP) at specified submaximal work load (myocardial oxygen demand)
Intervention
American
Increased Increased Decreased Increased
at rest
Ill. Comparison of various interventions
Nitroglycerin Propranolol Coronary artery Physical training
Increased Increased
Measured during exercise at specified work loads Oxygen uptake Heart rate Stroke volume Cardiac output A-VO, difference Blood pressure Double product,
Table
training
Maximum rate pressure product at time of angina (myocardial oxygen supply) No change No change Increased No change
or increased or decreased or increased
performed in these studies, or (4) there is no increase in collateral vessels in man. Thus the evidence that exercise training improves myocardial oxygen supply is indirect and inconclusive. The physiologic effects of physical training in patients with coronary artery diseaseare summarized in Table II. In addition to these hemodynamic effects, other beneficial effects on coronary risk factors such as decreased weight, decreased serum triglycerides and free fatty acidsZ7 and improved glucose tolerance have been observed? Moreover, psychological changes such as increased self-confidence, and reduced depression and hypochondriasis have been reportedSSJ Comparison of physical and propranolol
training,
nitroglycerin,
As shown in Table III, different modalities for the treatment of angina have varying effects on myocardial oxygen supply and demand. Both 531
Greenberg,
Arbeit,
and Rubin
nitroglycerin and physical training have similar effects in terms of decreasing the double product at specific submaximal workloads. While physical training primarily decreasesthe heart rate during submaximal exercise, nitroglycerin decreases the blood pressure and may often actually increase the heart rate though the RPP remains lower. Both physical training and nitroglycerin may increase the double product at the angina1 threshold in certain patients.?O, XL3i Beta-adrenergic blockade, like physical training, reduces myocardial oxygen consumption during submaximal exercise by reducing heart rate and blood pressure, and thus increases the exercise capacity. Propranolol however, may cause a decrease in maximal heart rate and maximal rate pressure product at the time of onset of angina? The decreased angina1 threshold values for heart rate and RPP following j3 blockade may be related to an elevated left ventricular diastolic volume with its increased wall tension and myocardial oxygen demand (Table I). As emphasized by Clausen,” although both propranolol and physical training blunt the heart rate and blood pressure responsesto specific submaximal workloads, the mechanism of action is different. Physical training causes a decrease in sympathetic stimulation to the heart and a redistribution of blood flow to non-exercising tissue and more efficient oxygen utilization by exercising muscle. Beta blockade, on the other hand, prevents the heart from responding to increased sympathetic stimuli, and results in a-induced peripheral vasoconstriction and decreased blood supply to the visceral organs. Coronary artery bypass surgery results in increased blood supply to the myocardium and an increased maximal heart rate and maximal double product. Bypass surgery does not affect the double or triple product at specific submaximal work loads. Of interest is the recent report by Bloch and associates38demonstrating an increase in exercise duration, maximum rate pressure product, and maximum heart rate in a group of patients after unsuccessful (all grafts occluded) myocardial revascularization, suggesting that increased myocardial blood supply is not the only mechanism by which bypass surgery improves exercise tolerance. Long-term
results
of cardiac
exercise
programs
An improvement in cardiovascular fitness, an increased exercise capacity, and an increased 532
angina1 threshold would be sufficient motivation for many physicians to recommend exercise therapy for their patients. Other physicians and their patients, however, want to know whether exercise therapy will decrease the incidence of myocardial infarction and prolong life. These remain unsettled questions at present. The multiple studies on rehabilitation of cardiac patients have recently been reviewed.” Although several studies show a tendency to lower death rate and lower incidence of myocardial infarction, these studies suffer from methodological problems in terms of sample size and control groups. Kellerman”” studied patients who participated in both short-term (4 months) and long-term (12 to 42 months) exercise programs. Only those patients participating in the long-term exercise program had a mortality rate different from control. These results imply that one must continue exercising for prolonged periods to have a beneficial effect in terms of a reduced cardiovascular mortality rate. In two randomized control trials carried out in Scandinavia, no statistical improvement in the incidence of recurrent myocardial infarction or cardiovascular mortality could be documented.l”. $’ Both studies, however, suffered from a high drop-out rate in the exercise group. No study has shown an increased incidence of myocardial infarction or cardiovascular mortality in patients who have been physically trained. A multicenter collaborative study might help to answer some of these unresolved questions.JZ Exercise
program
The prescription of an exercise program for patients with coronary artery disease must be individualized. The patient should undergo a medical screening procedure to assess the presence, severity, and stability of angina1 symptoms as well as to rule out signs of congestive heart failure, impaired cardiac output, valvular heart disease, severe hypertension, and other systemic disease. Certain drugs such as propranolo1 may impair the effectiveness of an exercise program by preventing the patient from achieving an appropriate heart rate. Prior to prescription of an exercise program, a symptom-limited exercise stress test is recommended to determine the individual’s work capacity, the possible occurrence of exercise-induced arrhythmias, and abnormal heart rate and blood pressure responses to exercise. The work load and heart rate at which the patient develops signifiApril,
1979,
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Physical
cant ischemic ST depression should also be noted so as to keep his heart rate below this level during training. The principles of an exercise program are the same in both normal patients and in those with coronary artery disease. The usual prescription calls for repetitive ‘endurance type exercise with large muscle groups. Most work physiologists further specify the frequency, duration, and intensity of exercise. A typical program would call for 20 to 40 minutes of exercise three to four times a week with an intensity of exercise of between 50 per cent and 80 per cent of the endurance capacity. Certain questions are left unresolved by present studies. The question of supervised vs. community-based or home exercise has implications in terms of accessibility of a program to patients and allocation of health resources and cost. Some authorities recommend an indefinitely prolonged supervised exercise program for cardiac patients while others recommend an initial supervised program with graduation to unsupervised exercise after a specific period (3 months to 1 year) and periodic evaluation with exercise stress tests. Even in well-organized and supervised cardiac programs, the major cardiovascular complication rate (fatal and nonfatal) is approximately one in 26,700 man-hours of participation.43 Another question which is unresolved at present is whether previously physically active postmyocardial infarction patients can resume previous athletic activity on a symptom-limited basis without undergoing formal exercise testing and training. In spite of this common clinical practice, the safety of such activity has not been evaluated. Conclusion
American
Heart
Journal
in p&ents
with
CAD
dium in man. Exercise training increases a patient’s sense of well-being and may have a favorable influence on certain coronary risk factors. The evidence that physical training programs have any effect on life expectancy or the incidence of coronary events is inconclusive. No study has demonstrated an increase in morbidity or mortality in cardiac patients participating in supervised exercise programs. Studies presently underway may help to answer this important question. Many post-myocardial infarction patients do not have the motivation, time, or money to enroll in a supervised exercise program. Facilities for such a program may not be available. For these patients the physician usually encourages a gradual return to full daily activities. In addition, many physicians encourage such activities as walking or other individualized, symptom-limited but unsupervised exercise programs. Whether this type of program can substitute for a supervised exercise program and achieve similar physiological and psychological benefits is a question which has not been studied. Exercise training programs, although based on sound physiological principles, should be subjected to the same cost-benefit analysis as other alternative forms of treatment. We are grateful to Drs. James Scheuer and Michael Cohen for their advice and help, and to Ms. Janet Holwell Ms. Betty Merson for typing the manuscript.
V. and
REFERENCES
1.
2. 3.
Exercise training is widely recommended as a tool to improve the cardiovascular function of selected patients with coronary artery disease. Following a period of physical training, the patient may perform specific activities (or tasks) at a slower heart rate and with a lower myocardial oxygen demand. The mechanism of this improved cardiovascular function ia an increased efficiency of oxygen extraction and metabolism in the trained peripheral muscles. There is no evidence at the present time that exercise training alone increases collateral coronary circulation, nor does exercise training have either a direct beneficial or detrimental effect on the myocar-
training
4.
5.
6. 7.
a.
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1979, Vol. 97, No. 4
The
and reappraisal
by Arthur
role
C. DeGraff
and Julian
of physical
coronary
artery
training
of cardiac
therapy
Frieden
in patients
with
disease
Mark A. Greenberg, M.D. Sidney Arbeit, M.D.t Ira L. Rubin, M.D. Bronx, N. Y.
Interest in the role of physical fitness and training in the prevention and treatment of coronary artery disease has increased over recent years. Multiple symposia,‘. 2review papers,3-sand monograpl-&” have appeared on this subject. The scene of joggers in the streets and parks has become common, and the enrollment in medically supervised exercise programs has increased. The favorable effect of physical training on improvement of cardiovascular function is well documented. However, many of those engaged in a regular exercise program hope not only to improve cardiovascular fitness, but also to prevent or attenuate the risks of atherosclerotic coronary disease, specifically myocardial infarction and death. Unfortunately, the studies on the effect of sustained exercise on longevity and reinfarction are equivocal. Thus, because of the uncertain role of physical training in either the prevention or treatment of coronary artery disease, as well as the potential risks and costs, exercise therapy has become a highly controversial issue. This review will discuss the physiologic effects of exercise in patients with coronary artery disease and its role in treatment. Prophylactic prevention
value of exercise of coronary artery
in the disease
Anecdotal experiences are often cited as examples of the beneficial effects of physical training. From the Division of Cardiology, fiore Hospital and Medical Center, Medicine, Bronx, N. Y. Received
for publication
Nov.
Department of Medicine and the Albert Einstein
27, 1978.
Reprint requests: Mark A. Greenberg, gy, Mont&ore Hospital and Medical Bronx, N. Y. 10467. tDr. Arbeit died on July 21, 1978.
0002-8703/79/040527
at MonteCollege of
+ 08$00.80/O
M.D., Department Center, 111 East
0 1979
The
of Cardiolo210th Street,
C. V. Mosby
Co.
The autopsy findings of the famous runner Clarence DeMar, who continued long distance running until his death at the age of 70, typifies these reports.12 On postmortem examination, the coronary arteries were two to three times normal size with only non-obstructive atherosclerotic involvement. One might conclude that the many years of long distance running had resulted in enlarged coronary arteries. However, an equally plausible conclusion would be that DeMar had become a great runner because of a genetic predisposition to large coronary arteries. Bass1er,13based on his extensive observations of autopsy results, has claimed that marathon runners are completely immune to fatal atherosclerosis. Others have refuted this as an exaggerated claim by documenting casesof fatal myocardial infarction in marathon runners and by emphasizing that self-selection and other variables such as diet and smoking habits must be considered in evaluating the “protective effect” of long distance running.14 Population studies have been done to decide whether exercise might be effective prophylaxis against coronary artery disease. The classic work by Morris and associate@ demonstrated a decreased incidence in both the frequency and severity of myocardial infarction in civil servants with more physically active jobs (bus conductors) as compared to more sedentary workers (bus drivers). These findings seemingly support a role for physical activity in the prevention of coronary artery disease. However, Morris and co-workers16 published additional data 3 years later, and noted that the sedentary drivers had both a greater girth and weight prior to employment than the more active conductors, thus raising the question
American
Heart
Journal
527
Greenberg,
Arbeit,
and
Rubin
of self-selection and personal preference of more obese workers-already at greater risk for the development of coronary artery disease-for the sedentary jobs. Other population studies have investigated the risks of cardiac events in physically active population groups compared to sedentary controls in an attempt to establish the possible protective effect of physical activity against cardiac events. Probably the best known of these studies is the work by Paffenbarger” who studied the incidence of fatal myocardial infarctions among San Francisco longshoremen. These longshoremen represent a stable population observed over many years with well described workloads as defined by their union contract. The workers were classified into groups according to their workday energy expenditure. The more sedentary longshoremen had an 80 per cent increased risk of fatal myocardial infarction when compared to workers with higher energy output jobs. The work energy output level was either of equal or greater influence in predicting death from coronary disease as other risk factors such as cigarette smoking, hypertension, previous known heart disease, obesity, and cholesterol. The results of this study are strongly supportive of a protective effect of a lifetime of extremely vigorous physical activity against fatal myocardial infarction and especially against sudden death. Whether a protective effect can also be seen with lesser degrees or different types of physical activity is yet to be shown. A recent review by Froelicher’ summarized the multiple epidemiologic studies. He emphasized both the difficulty in differentiating between self-selection and protection, and the problems in these population studies in controlling for other risk factors and assessing physical activity from job descriptions and questionnaires. He concluded that although .the studies to date are suggestive of a protective effect of physical activity against myocardial ischemic events, the data are not definitive. Physiologic
concepts-definition
of terms
The physiologic effects of physical training have been studied in both normal subjects and in patients with symptomatic coronary artery disease. The terms physical training, exercise training, and physical conditioning will be used interchangeably in this paper to refer to repetitive isotonic muscular exercise carried out on a regu528
lar basis for the purpose of improving an individual’s ability to perform a specific task. The amount of aerobic work which the body performs can be measured in terms of oxygen consumption (VO,). The more work an individual performs, the higher will be his energy demand, and therefore the greater the amount of oxygen consumed. Different tasks which require the same oxygen consumption can be compared. For example, a 70 kilogram man, walking on a treadmill at 1.7 miles/hour at a 10 per cent grade would expend approximately 14 C.C. O,/Kg./minute, which is the same oxygen expenditure for swimming at 20 yards/minute. The energy demand for a variety of submaximal tasks can thus be quantified in terms of oxygen consumption. With increasing energy expenditures, there is a normal increase in heart rate, blood pressure, and cardiac output. As the body reaches its maximum ability to consume oxygen (VO, max), there is a leveling off of the blood pressure and pulse rate with increased load. The maximum oxygen consumption is a reproducible measure of one’s work capacity or state of physical fitness. Values for VO? max may range from 24 c.c./Kg./minute in sedentary middle-aged individuals to values as high as 80 c.c./Kg./minute in highly trained individuals. Thus the state of physical fitness and improvement in physical fitness are quantifiable. In addition to the state of physical training, other factors such as age, sex, and underlying disease processes are determinants of VO, max. Patients with coronary artery disease have an additional limitation to their exercise capacity in that the diseased coronary circulation cannot keep up with the increased myocardial oxygen demand during exercise. Such patients will develop myocardial ischemia before their theoretical VO? max. and stop exercise because of angina. This endpoint is referred to as the symptom limited oxygen consumption (VO, sl). Exercise in patients with coronary artery disease can also induce left ventricular dysfunction, as demonstrated by elevation in left ventricular enddiastolic pressure (LVEDP) or reduction of stroke volume without chest pain. Thus the response of patients with coronary disease to exercise can be limited not only by symptoms of angina but also by extreme dyspnea or fatigue. An additional endpoint is the development of ventricular arrhythmias, possibly secondary to myocardial &hernia or left ventricular failure. An important objective of a physical training April,
1979,
Vol.
97, No.
4
Physical
Table
okygen demand
Physiologic determinants
Left ventricular wall tension Myocardial contractility Heart rate
Clinical correlates
Rate pressure product arterial pressure
= heart
Myocardial
with
CAD
program in patients limited by coronary artery disease is to train the body to perform a given amount of work with lessdemand for the limited myocardial oxygen supply. The major determinants of myocardial oxygen demand are heart rate, wall tension, and contractility (Table I). In the clinical assessment of patients with angina pectoris, the product of heart rate and mean blood pressure (rate-pressure product or RPP) is used as an index of myocardial oxygen demand. Other indices such as the double product, triple product, and tension time index have also been used (Table I). Robinson’” has demonstrated that in patients with stable angina chest pain occurs at a reproducible RPP. It has further been shown that the RPP at angina1 threshold is the same regardless of the type of stress provoking the angina. Hence an improvement in exercise capacity can be brought about by reducing the rate pressure product and therefore the myocardial oxygen demand for a given task. If an individual can exercise to a higher rate pressure product before experiencing angina, it is implied that he has increased his myocardial oxygen supply. of exercise
training
Maximum exercise. Although normal physical activities do not call for maximal exertion, physical fitness is quantified in terms of the maximum work capacity. A consistent effect of physical training is to increase the work capacity as measured by VO? max. The amount of increase in VO, max depends both on the pretraining level of fitness and the intensity and duration of exercise. Heart
Journal
oxygen supply
Coronary blood flow Myocardial oxygen extraction Transmural diastolic pressure gradient (aortic diastolic pressure-left ventricular diastolic pressure) Duration of diastole Regional distribution of myocardial blood flow rate
x
mean
Double product = heart rate x systolic blood pressure Triple product = heart rate x systolic blood pressure X systolic ejection time Tension-time index = heart rate x integralof left ventricular pressure during systole
American
in patients
I. Physiologic determinants and clinical correlates of myocardial oxygen demand and supply Myocardial
Effects
training
Maximal rate pressure product, double product, triple product or tension-time index achieved at time of angina Aortic diastolic pressure x time-ventricular diastolic pressure x time
Studies by Detry and colleagues,1gRedwood and associates 2o and others??” have shown that patients w:th coronary artery diseasecan increase their maximum oxygen consumption. The mechanism by which VO, max is increased is different in coronary patients from that in healthy individuals. Oxygen consumption is dependent on the product of cardiac output and arterial venous oxygen difference. While normal subjects increase VO, max by increasing both the maximal cardiac output and the maximum arterial-venous oxygen extraction (A-VOJ, coronary patients increase only the maximal A-VO,.?’ The predominant mechanism for this increase in A-VO, is an increase in oxygen extraction by the peripheral muscle thought to be due to mitochondrial and enzyme changes in the trained skeletal muscle. Hence, the increase in maximal work capacity in cardiac patients is primarily due to the effect of exercise on the trained peripheral muscles. Physical training does not usually alter the maximum attainable heart rate; however, some patients previously limited by angina are capable of exercising to higher heart rates following exercise training.‘“, “O Submaximal exercise. Daily activities require only submaximal levels of exertion and therefore the benefit of conditioning to patients should also be evaluated during submaximal exercise. The absolute oxygen consumption required to perform a specific submaximal work load is not altered by physical training except insofar as repetition of a particular task facilitates more efficient performance of that task. As the maxi529
Greenberg, Arbeit, and Rubin ma1 work capacity (VO, max) is increased with training, however, a specific submaximal work load represents a lower relative percentage of VO, max. Changes in heart rate as well as the degree of vasoconstriction in visceral vascular beds is proportional to this relative oxygen demand.‘“, z Following a period of physical training, individuals have a slower resting pulse and a lower heart rate and blood pressure response to exercise. The rate pressure product and therefore the myocardial oxygen demand are reduced during submaximal exercise. This lower heart rate at submaximal exercise has been shown by Varnauskasz6 to be accompanied by a rise in the systemic arterial venous oxygen difference. As demonstrated with maximal exercise, during submaximal exercise trained muscles are better able to extract oxygen and maintain oxygen consumption at a reduced muscle blood flow. Clausen and Trap-Jensen“ have shown that after training, both cardiac output and muscle blood flow are reduced during submaximal exercise as compared to pre-training values, and that there is a redistribution of blood flow to the visceral organs. Moreover, the usual rise in peripheral lactate levels during submaximal exercise is attenuated after training, implying more rapid and efficient oxidation in the peripheral muscle cells.z7 Letac and co-workersz8 have demonstrated by comparative hemodynamic and angiographic studies in patients with coronary artery disease that physical training does not directly affect resting myocardial contractility as measured by ejection fraction, segmental contractility, or velocity of circumferential fiber shortening. Although these studies do not preclude changes in myocardial contractility that may occur during stress, the lack of a direct influence of physical conditioning on the myocardium further supports the importance of changes in the peripheral skeletal muscles. In summary, therefore, following a period of physical training, patients with coronary artery disease can exercise to the same submaximal work load with a slower heart rate, a decreased rate pressure product, and therefore a decrease in myocardial oxygen demand. Local changes in the trained skeletal muscles are primarily responsible for this decrease in myocardial work. Myocardial
oxygen
supply-demand
ratio
A major beneficial effect of physical training in patients with coronary artery disease would be alteration of the myocardial oxygen supply-de530
mand relationship. The indirect indices of myocardial oxygen demand (rate pressure product, double product and others) are often used to examine this relationship. The effect of physical training in reducing the indirect indices of myocardial oxygen consumption has been discussed in detail above. Several studies have shown that not only is the RPP decreased at any specified submaximal workload, but that a group of patients can exercise to a higher rate pressure product (or triple product) before angina or exercise to exhaustion without angina.15’,?‘~l This implies either an increased myocardial oxygen supply or a decrease in a determinant of oxygen demand not measured by RPP. A recent study of the effect of physical training on coronary sinus blood flow in patients with angina pectoris demonstrated that the decrease in heart rate and rate-pressure product which occurs during submaximal exercise after training is accompanied by a decrease in coronary blood flo~.~’ The coronary blood flow during maximal exercise was not significantly changed after training. A group of patients, however, was able to increase both the maximum rate pressure product and coronary sinus blood flow at the onset of angina, implying that at least a subgroup of patients may have increased myocardial oxygen supply after training. Although a study by Sim and Neill’” demonstrated an increased triple product to angina when tested by exercise on a bicycle ergometer, there was no change in angina1 threshold when tested by atria1 pacing. This suggests that conditioning might possibly alter the relationship between actual MVO, and the indices by which it is often measured (RPP, triple product). A study by Detry and Bruce,“” which demonstrated an increased RPP threshold to angina after training, found that training did not alter the relationship between ST segment depression and rate pressure product. Thus although the RPP at the time of angina was higher, so was the extent of ST segment depression, raising the possibility that training altered the relationship between angina and myocardial &hernia as measured by ST segment depression. Because of the high myocardial oxygen extraction in the basal state (approximately 70 per cent compared to 20 per cent in the systemic circulation), increased myocardial oxygen needs must usually be met by increased coronary blood flow. The transmural myocardial blood flow is dependent on the difference between the aortic and left April,
1979,
Vol.
97, No.
4
Physical
in patients
with
CAD
II. Physiologic effects of physical training in patients with coronary disease
Table
Parameter Z
Effect of training
Measured during maximal exercise Work capacity Maximum oxygen uptake (VO, max) or symptom limited oxygen uptake (V02 sl) Maximum heart rate Maximum A-VO, difference Maximum cardiac output Maximum double product, triple product or tension time index at time of angina
zz
submaximal
Measured
zzz
Heart Blood
bypass
triple
product,
tension-time
rate pressure
index
No change No change
or no change or no change
surgery
Journal
or decreased or decreased
in the treatment of angina
Decreased Decreased No change Decreased
ventricular diastolic pressures and the duration of diastole. Relative bradycardia induced by exercise training prolongs diastole and allows for increased coronary filling. In patients with fixed obstructive coronary artery disease, the ability to increase coronary blood flow with increased demand is severely limited. Collateral coronary vessels may potentially serve to increase blood flow to ischemic areas of myocardium. Although some studies have shown increased vascularity in rats after training and increased collateral flow in dogs,” none of the studies in man with coronary artery disease has shown increased collateral circulation resulting from a physical training program. 23.lR.w 32 This may be due to the fact that (1) coronary angiograms are done at rest, (2) the collateral vessels may be too small to visualize on coronary angiograms, (3) the duration of training necessary to produce an increased collateral circulation might have to be longer than that Heart
or no change
No change Decreased Variable effects No change or decreased Increased No change or decreased Decreased
Rate pressure product (RPP) at specified submaximal work load (myocardial oxygen demand)
Intervention
American
Increased Increased Decreased Increased
at rest
Ill. Comparison of various interventions
Nitroglycerin Propranolol Coronary artery Physical training
Increased Increased
Measured during exercise at specified work loads Oxygen uptake Heart rate Stroke volume Cardiac output A-VO, difference Blood pressure Double product,
Table
training
Maximum rate pressure product at time of angina (myocardial oxygen supply) No change No change Increased No change
or increased or decreased or increased
performed in these studies, or (4) there is no increase in collateral vessels in man. Thus the evidence that exercise training improves myocardial oxygen supply is indirect and inconclusive. The physiologic effects of physical training in patients with coronary artery diseaseare summarized in Table II. In addition to these hemodynamic effects, other beneficial effects on coronary risk factors such as decreased weight, decreased serum triglycerides and free fatty acidsZ7 and improved glucose tolerance have been observed? Moreover, psychological changes such as increased self-confidence, and reduced depression and hypochondriasis have been reportedSSJ Comparison of physical and propranolol
training,
nitroglycerin,
As shown in Table III, different modalities for the treatment of angina have varying effects on myocardial oxygen supply and demand. Both 531
Greenberg,
Arbeit,
and Rubin
nitroglycerin and physical training have similar effects in terms of decreasing the double product at specific submaximal workloads. While physical training primarily decreasesthe heart rate during submaximal exercise, nitroglycerin decreases the blood pressure and may often actually increase the heart rate though the RPP remains lower. Both physical training and nitroglycerin may increase the double product at the angina1 threshold in certain patients.?O, XL3i Beta-adrenergic blockade, like physical training, reduces myocardial oxygen consumption during submaximal exercise by reducing heart rate and blood pressure, and thus increases the exercise capacity. Propranolol however, may cause a decrease in maximal heart rate and maximal rate pressure product at the time of onset of angina? The decreased angina1 threshold values for heart rate and RPP following j3 blockade may be related to an elevated left ventricular diastolic volume with its increased wall tension and myocardial oxygen demand (Table I). As emphasized by Clausen,” although both propranolol and physical training blunt the heart rate and blood pressure responsesto specific submaximal workloads, the mechanism of action is different. Physical training causes a decrease in sympathetic stimulation to the heart and a redistribution of blood flow to non-exercising tissue and more efficient oxygen utilization by exercising muscle. Beta blockade, on the other hand, prevents the heart from responding to increased sympathetic stimuli, and results in a-induced peripheral vasoconstriction and decreased blood supply to the visceral organs. Coronary artery bypass surgery results in increased blood supply to the myocardium and an increased maximal heart rate and maximal double product. Bypass surgery does not affect the double or triple product at specific submaximal work loads. Of interest is the recent report by Bloch and associates38demonstrating an increase in exercise duration, maximum rate pressure product, and maximum heart rate in a group of patients after unsuccessful (all grafts occluded) myocardial revascularization, suggesting that increased myocardial blood supply is not the only mechanism by which bypass surgery improves exercise tolerance. Long-term
results
of cardiac
exercise
programs
An improvement in cardiovascular fitness, an increased exercise capacity, and an increased 532
angina1 threshold would be sufficient motivation for many physicians to recommend exercise therapy for their patients. Other physicians and their patients, however, want to know whether exercise therapy will decrease the incidence of myocardial infarction and prolong life. These remain unsettled questions at present. The multiple studies on rehabilitation of cardiac patients have recently been reviewed.” Although several studies show a tendency to lower death rate and lower incidence of myocardial infarction, these studies suffer from methodological problems in terms of sample size and control groups. Kellerman”” studied patients who participated in both short-term (4 months) and long-term (12 to 42 months) exercise programs. Only those patients participating in the long-term exercise program had a mortality rate different from control. These results imply that one must continue exercising for prolonged periods to have a beneficial effect in terms of a reduced cardiovascular mortality rate. In two randomized control trials carried out in Scandinavia, no statistical improvement in the incidence of recurrent myocardial infarction or cardiovascular mortality could be documented.l”. $’ Both studies, however, suffered from a high drop-out rate in the exercise group. No study has shown an increased incidence of myocardial infarction or cardiovascular mortality in patients who have been physically trained. A multicenter collaborative study might help to answer some of these unresolved questions.JZ Exercise
program
The prescription of an exercise program for patients with coronary artery disease must be individualized. The patient should undergo a medical screening procedure to assess the presence, severity, and stability of angina1 symptoms as well as to rule out signs of congestive heart failure, impaired cardiac output, valvular heart disease, severe hypertension, and other systemic disease. Certain drugs such as propranolo1 may impair the effectiveness of an exercise program by preventing the patient from achieving an appropriate heart rate. Prior to prescription of an exercise program, a symptom-limited exercise stress test is recommended to determine the individual’s work capacity, the possible occurrence of exercise-induced arrhythmias, and abnormal heart rate and blood pressure responses to exercise. The work load and heart rate at which the patient develops signifiApril,
1979,
Vol.
97, No.
4
Physical
cant ischemic ST depression should also be noted so as to keep his heart rate below this level during training. The principles of an exercise program are the same in both normal patients and in those with coronary artery disease. The usual prescription calls for repetitive ‘endurance type exercise with large muscle groups. Most work physiologists further specify the frequency, duration, and intensity of exercise. A typical program would call for 20 to 40 minutes of exercise three to four times a week with an intensity of exercise of between 50 per cent and 80 per cent of the endurance capacity. Certain questions are left unresolved by present studies. The question of supervised vs. community-based or home exercise has implications in terms of accessibility of a program to patients and allocation of health resources and cost. Some authorities recommend an indefinitely prolonged supervised exercise program for cardiac patients while others recommend an initial supervised program with graduation to unsupervised exercise after a specific period (3 months to 1 year) and periodic evaluation with exercise stress tests. Even in well-organized and supervised cardiac programs, the major cardiovascular complication rate (fatal and nonfatal) is approximately one in 26,700 man-hours of participation.43 Another question which is unresolved at present is whether previously physically active postmyocardial infarction patients can resume previous athletic activity on a symptom-limited basis without undergoing formal exercise testing and training. In spite of this common clinical practice, the safety of such activity has not been evaluated. Conclusion
American
Heart
Journal
in p&ents
with
CAD
dium in man. Exercise training increases a patient’s sense of well-being and may have a favorable influence on certain coronary risk factors. The evidence that physical training programs have any effect on life expectancy or the incidence of coronary events is inconclusive. No study has demonstrated an increase in morbidity or mortality in cardiac patients participating in supervised exercise programs. Studies presently underway may help to answer this important question. Many post-myocardial infarction patients do not have the motivation, time, or money to enroll in a supervised exercise program. Facilities for such a program may not be available. For these patients the physician usually encourages a gradual return to full daily activities. In addition, many physicians encourage such activities as walking or other individualized, symptom-limited but unsupervised exercise programs. Whether this type of program can substitute for a supervised exercise program and achieve similar physiological and psychological benefits is a question which has not been studied. Exercise training programs, although based on sound physiological principles, should be subjected to the same cost-benefit analysis as other alternative forms of treatment. We are grateful to Drs. James Scheuer and Michael Cohen for their advice and help, and to Ms. Janet Holwell Ms. Betty Merson for typing the manuscript.
V. and
REFERENCES
1.
2. 3.
Exercise training is widely recommended as a tool to improve the cardiovascular function of selected patients with coronary artery disease. Following a period of physical training, the patient may perform specific activities (or tasks) at a slower heart rate and with a lower myocardial oxygen demand. The mechanism of this improved cardiovascular function ia an increased efficiency of oxygen extraction and metabolism in the trained peripheral muscles. There is no evidence at the present time that exercise training alone increases collateral coronary circulation, nor does exercise training have either a direct beneficial or detrimental effect on the myocar-
training
4.
5.
6. 7.
a.
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1979, Vol. 97, No. 4