Clinical Application of Current Techniques and Treatment in Cardiology Adv. Cardiol., vol. 17, pp. 74-84 (Karger, Basel 1976)
Risk Factors and Natural History of Coronary Artery Disease JAMES S. FORRESTER, YZHAR CHARUZI and PROTASIO L. DA Luz Department of Cardiology, Cedars-Sinai Medical Center, and University of California; In-Patient Cardiology Service, Department of Cardiology, Cedars-Sinai Medical Center, and Department of Cardiology, Cedars-Sinai Medical Center, Los Angeles, Calif.
The Magnitude of the Problem
Coronary atherosclerosis is the nation's number one health problem. Figure I illustrates the magnitude of the problem - more than one million deaths occur due to heart disease in the United States each year. This cause of death far outstrips the second major cause of death, which is cancer, by a ratio of three to one. There is a common belief, however, that this high mortality rate simply represents the fact that everyone must die sometime.
I
Diseases of heart and blood vessels
1,010,000
Cancer
Accidents Pneumonia and influenza Diabetes
000
I 1
63,6 0
65 .65and eve
600
I
200
400
600
I
800 1,000 1,200
Fig. 1. Causes of death in the United States, taken from US Census figures. Diseases of the heart and blood vessels far outstripped the second leading cause of death, which was cancer, by a ratio of approximately 3: 1.
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Deaths (thousands)
FORRESTER/CHARUZI/DA Cumulative deaths 0'0 number 100 250,000 90
225,000
80
200,000
70
175,000
60
150,000
50
125,000
40
100,000
30
75,000
20
50,000
10
25,000
0
0
Time from onset to death 12 h 8h 6h 4h 2h
Luz
75
Estimated US median time intervals
Hospital waiting interval Delivery interval Delay interval
1h 30 min
15 min
Acute onset
Decision fnterval
Preparatory interval
and coronary heart disease is the disease of old age. This opinion, although reasonable, is belied by the fact that among those dying before age 65, heart disease causes twice the number of deaths as the next leading cause, which is again cancer. Otherwise stated, heart disease is the leading cause of premature death in the middle-aged group in the United States. Coronary atherosclerosis, specifically acute myocardial infarction and its complications, accounts for approximately 60% of these deaths due to heart disease: 600,000 people each year die from acute myocardial infarction in this country. Analysis of the mode of death from acute myocardial infarction leads to some striking conclusions. Of those individuals who are to die as a direct result of acute infarction within I month of the episode,
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Fig. 2. Deaths from acute myocardial infarction in the first 24 h, plotted against the time delay in delivery of patients to the coronary care unit. In the left-hand column is shown the percent of all deaths that had occurred, increasing to 100% at 24 h. In the second column are the number of deaths that occur during this time peliod. In the third column is the number of hours from the onset of symptoms, and in the fourth column is shown the causes of delay in reaching the CCU. From the onset of the signs and symptoms of acute myocardial infarction until the patient realizes he has a serious illness is approximately 15 min (the 'decision interval'). There is then approximately a 4-hour delay until the patient notifies the physician (the 'delay interval'). An additional hour is lost while the patient is delivered to the hospital (the 'delivery interval'). Finally, an additional hour is consumed as the patient is delivered to an adequate monitoring facility (the 'hospital waiting interval').
FORRESTER/CliARUZI/DA
Luz
76
about one half have died within 6-8 h of the onset of symptoms. Of those who will die, more than half will do so outside of the hospital, before receiving adequate medical care. Most of these out-of-hospital deaths are due to arrhythmias and probably are preventable. This leads not to a conclusion, but to a further question: Why does the patient not get to an adequate treatment facility in time? Figure 2 illustrates the number of deaths due to acute infarction within the first 12 h and the four main reasons for the average time of 8 h between onset of symptoms and being adequately monitored in a coronary care facility. On the average, it takes about 15 min for a patient to conclude that he is seriously ill. By this time, about 100,000 people have died. The next delay is the one which is staggering to those dealing with such statistics: there is a 4-hour delay from the onset of symptoms until the patient notifies his physician of the fact that he is seriously ill. In this period of time there have been approximately 180,000 deaths. A further delay of about 1 h ensues in delivery of the patient to the hospital, and finally another I-hour delay from the time of arrival to the hospital until the patient is in an adequately monitored coronary care unit. By the time the patient reaches the coronary care unit, approximately 250,000 deaths have already occurred. It is immediately apparent, therefore, that a major mechanism by which we could reduce the mortality rate due to acute myocardial infarction must involve public education. This education cannot be delivered solely by government or heart associations, and would probably be most effectively delivered by practicing physicians and nurses, describing to both friends and patients the critical need for early notification of a doctor after recognition of symptoms of acute myocardial infarction.
Table I summarizes a study that fell like a bombshell on the American cardiologic public in 1953, one that involved autopsies on American soldiers' killed in action in Korea. 300 autopsies were performed on American men, whose average age was 22 years. In 75% of these individuals there was evidence of atherosclerosis or preatherosclerotic lesions. In about half of these men, fatty streaks and fibrous plaques, which are preatherosclerotic lesions, were seen. The other half of these individuals had clear-cut evidence of developing atherosclerotic disease with encroachment into the coronary artery lumen. 16% had a magnitude of coronary atherosclerosis that would be
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The Natural History of Coronary Artery Disease
77
Risk Factors in Coronary Artery Disease Table I. Coronary disease in American soldiers killed in action in Korea Number of autopsies Average age Incidence of coronary artery disease Fibrous thickening/streaking Narrowing 1~0% 50-70% 80% to complete occlusion
300 22 77% 35% 26% 6% 10%
300 autopsies were performed on men with an average age of 22 years. The incidence of preatheroscIerotic lesions was approximately 35 %, and actual narrowing of vessels was seen in an additional 42%.
considered to be significant by current coronary angiographic techniques. Although the methods of analysis used 22 years ago were less precise than those used today, and the specific numbers have been disputed by other authors, the inescapable conclusion from all such studies is that although coronary artery disease is clinically a disorder of middle and older age, it is in fact a disease of younger age that is only recognized very late in its development. The popular wisdom that coronary artery disease is a disease of our older population is almost certainly a delusion. The natural history of coronary artery disease, once it is recognized, is quite different from its slow and silent initial progression. Figure 3 illustrates Cleveland Clinic. Approximately three fourths of individuals with onevessel coronary artery disease survived 7 years. Only half of those individuals with two-vessel disease were alive at 7 years, and only one third of individuals with three-vessel disease survived 7 years. Perhaps most striking of all these data was the fact that individuals with disease in the main left coronary artery also had a two-thirds mortality over the 7-year follow-up period. The capability of prognosticating survival in the patient groups based on coronary anatomy can be further refined by evaluation of left ventricular contraction pattern during cardiac catheterization, as illustrated in figure 4. An individual with three-vessel coronary artery disease and diffuse hypokinesis has a minimal chance of surviving the 5 years, whereas individuals with onevessel disease and a normal left ventricular contraction pattern had only a 6-percent 5-year mortality.
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survival rates after the angiographic diagnosis in patients studied at the
FORRESTER/CHARUZI/DA
Luz
78 90
100
x
80
90 70
80 70
60
60
50
50
.,. 40
40
~ :::; 30 ~
30 20
~
10
"
0
., ...u ,..al
E
~
In
~
.~ 20
1
J,
2
345
6
Years after coronary arteriography
7
10
O....L....--r--r--,--.--- 4 Normal Local Diffuse scar scar Aneurysm
Fig. 3. The survival time following definitive diagnosis of coronary artery disease by coronary angiography. Approximately three fourths of the patients with one-vessel disease (e; n = 202, all cases) and half of the patients with two-vessel involvement (+; n = 233) survived at 7 years. Only one third of the patients with either three-vessel disease (x ; n = 118) or obstruction of the left main coronary artery (*; n = 37) were alive 7 years following angiography [from BRUSCHKE, A.V.G. et al.: Progress study of 590 consecutive non-surgical cases of coronary disease followed 5-9 years. I. Arteriographic correlation. Circulation 47: 1147, 1973]. Fig. 4. The 5-year cardiac mortality in relationship to combined assessment of coronary vascular disease and the left ventricular contraction pattern. At the two ends of the spectrum, a patient with a normal ventriculographic contraction pattern and onevessel disease (e) had approximately a 6-percent 5-year mortality, in comparison to 90percent mortality in patients with three-vessel coronary artery disease ( x) and a diffusely hypokinetic ventricle. + = Two-vessel disease.
Fig. 5. a Relationship of serum chQlesterol to the development of new coronary artery disease in asymptomatic patients as determined by the Framingham, Massachusetts study. An increasing level of development of coronary artery disease is seen in each category of serum cholesterol levels, with approximately a fourfold increase in the development of coronary artery disease when the two ends of the spectrum are compared. b The relationship of diastolic blood pressure to the development of coronary artery disease in
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3
.,.
32.7
Risk Factors in Coronary Artery Disease Rate per 1,000
79 Rate per 1,000
200
188
200
r162
r--
150
~~
100
50
~
Events 33 pOPulation 658
a
0
.,g .£ 65
i~
92 ,591
150
100
~ 50 120 PJ3
L~ ,108
80 670
rrl 635
Under 175- 200- 225- 250- 275- 300and 175 199 224 249 274 299 over Serum cholesterol level, mg/l00 cm3
~ ~ ~
Events 70 pOPUlation 1,271 0
~
170 2,752
186 2,125
89 940
90 493
b 85 95 105 and Under 75 75 84 94 104 over Diastolic blood pressure level, mmHg
Rate per 1,000 150 131
r-100
~ ~ ~
Events 53 Population 1,188
c
0
~ ~ ..ID. 904
1 Never Past smoked only
~~
72 981
205
12,330
Pipe %pack lpack or or less per cigar per day only day
154 1,146 Over 1pack per day
asymptomatic individuals. As with the cholesterol data, approximately a fourfold increase in the development of coronary artery disease when patients with a diastolic blood pressure of 105 are compared to those with a diastolic pressure less than 75 mm Hg. c The relationship of cigarette smoking to the development of coronary artery disease. An increasing incidence of development of coronary artery disease is seen with increasing cigarette use [from Arteriosclerosis-Report by National Heart and Lung Institute Task Force on Arteriosclerosis, vol. II (US Government Printing Office, Washington, DC)].
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50
FORRESTER/CHARUZI/OA
Luz
80
Although a number of factors may contribute to the development of coronary atherosclerosis, there is reasonable agreement that there are three major risk factors for the development of coronary artery disease, excluding genetic predisposition and diabetes mellitus. These three factors are elevated serum lipids, elevated arterial blood pressure, and the use of cigarettes. Figure 5 illustrates data collected prospectively over many years in asymptomatic patients in the Framingham, Massachusetts study. The graphs show the rate of development of coronary artery disease in asymptomatic individuals plotted against the level of serum cholesterol (fig. 5a), arterial blood pressure (fig. 5b), and tobacco use (fig. 5c). When serum cholesterol levels were elevated, for instance, greater than 300 mg %, the incidence of subsequent development of coronary artery disease in the asymptomatic population was four times as great as that in a similar group of patients who had low levels of serum cholesterol. There did not appear to be a 'normal' level of serum cholesterol; rather there was a gradual increase in the incidence of development of new coronary artery disease with each increment of increase in the serum cholesterol level. This is not surprising since a level of serum cholesterol greater than 200 mg is seldom seen in animals, and is in fact predominantly a phenomenon observed only in affluent Western society. Of the people of the world, only the Finns have higher levels of serum cholesterol than citizens of the United States; and only Finland has a higher mortality rate due to coronary heart disease. The second major risk factor, elevated arterial pressure, is comparable to serum lipids in nature and magnitude. Individuals who had levels of arterial diastolic pressure exceeding 105 had a fourfold increase in the incidence of development of coronary artery disease when compared to those with an arterial diastolic pressure less than 75 mm Hg. As with the serum cholesterol level, there did not appear to be a clear-cut 'normal' level of arterial diastolic pressure. Cigarette smoking greatly increases the risk of developing coronary heart disease. Individuals who smoked more than a pack a day had a three times greater incidence of development of coronary artery disease than those who never smoked (fig. 5c). The presence of more than one risk factor is additive: a 'borderline' individual with a serum cholesterol of 250 mg %, an arterial diastolic pressure greater than 90 mm Hg, and any use of cigarettes, has an eightfold greater risk of developing coronary artery disease than the individual with
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Risk Factors in the Development of Coronary Heart Disease
Risk Factors in Coronary Artery Disease
132
Women (63) Sex and age
81
Men < 45 years (149)
128
Men 45-54 years (240)
\35
Men> 54 years (138)
141
129
0(205) Cigarette smoking
325 (83)
35
rl7 One-vessel disease; no additional narrowing (111)
Left ventricular angiogram Duration of chest pains, months
[0-12 (170) 113-72 (256) 1>72 (117)
Diabetes mellitus
1No diabetes (570) [Clinical diabetes (20)
ECG
b
i23 One-vessel disease + additi onal narrowing (91) Two-vessel disease (233) 138 Three-vessel disease (116) 154 Obstruction of the left main corona!); ,\-157 artery (37) Normal (253) J25 Local scar (145) 131 Aneurysm (SO) i 46 Diffuse scar tissue (79) J 69 J23 129
J50
133
Normal (231) 119 Rep. d ist or dig. effect (IS4~ 34 Infarction (119) i 45 Conduction disturbance or LVH (85)
J60
J64
Fig. 6. a The relationship of risk factors to mortality rates following the development of coronary artery disease as diagnosed by coronary angiography. There is little influence of cigarette smoking, obesity, serum cholesterol or isolated systolic or diastolic hypertension upon mortality rate. b In contrast to the data seen in figure 6a, the coronary arteriogram and left ventricular angiogram showed substantial relationship to mortality rates following the development of coronary artery disease, as did the duration of chest pain, diabetes mellitus, and specific electrocardiographic patterns.
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Coronary arteriogram
FORRESTER/CHARUZI/DA
82
Luz
no risk factors. When multiple risk factors are present with substantial degree of abnormality, the increased risk of developing coronary heart disease increases much further. But, frightening as such numbers are, they are of relatively little value for the individual physician trying to assess risk in an individual patient. The Framingham experience is now sufficiently large to permit prediction for any asymptomatic patient of developing coronary heart disease within the next 6 years given his serum cholesterol level, smoking history, glucose tolerance, arterial pressure and electrocardiogram. These data are available in booklet form through the American Heart Association. For instance, a 35-year-old who smokes occasionally, with no evidence of left ventricular hypertrophy by BeG, a serum cholesterol level of 235, and an arterial systolic pressure of 150 mm Hg, has a 1.8-percent risk of developing coronary artery disease within the next 6 years. A man of similar age who has more flagrant risk factors, e.g., arterial pressure of 180, serum cholesterol of 310, left ventricular hypertrophy, and a positive glucose tolerance test, has a IS-percent risk of developing coronary artery disease by the time he is 41 years of age. The same individual 20 years later, at age 55, has almost a 50-percent chance of having clinical coronary artery disease within the next 6 years. This capability of assessing the risk for an individual patient Table II. The practicing physician and his patient: how aggressive should we be?
The gray zone Surgery A
Yes~
Angiography: high risk? A
y es~ Stress ECG: positive? A No~ Yes~ v Screen all patients: high risk? Rx Risk Factors
No~
M~dical
N°Iv
A format for approach to the risk factor problem. See text for discussion.
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AdVIce
Risk Factors in Coronary Artery Disease
83
provides a rational basis for decisions regarding further evaluation and therapy, as discussed later. Critical as these risk factors are to the development of coronary heart disease, they fade in importance when the disease becomes clinically manifest. Thus, an apparent paradox exists: whereas hypertension, cholesterol and smoking contribute heavily to the risk of development of coronary artery disease, once the disease has become clinically apparent, these same factors do not significantly alter the course of the disease. Figure 6a illustrates the 5-year mortality rate in patients who smoked and did not, with normal and elevated serum cholesterol levels, and with and without hypertension. Only in those patients with both systolic and diastolic hypertension was there any significant difference in mortality rates. Instead, the 5-year mortality rate for individuals with established coronary artery disease related primarily and predominantly to the nature of coronary artery disease as it is discovered: specifically, the number and magnitude of involved vessels and the ventricular contraction pattern. In addition, the presence of continuing angina, diabetes mellitus, and specific electrocardiographic abnormalities, particularly ventricular conduction abnormalities, carried a poor prognosis. These data suggest that once coronary artery disease is clinically manifest, manipulation of the so-called risk factors is unlikely to produce substantial change in the 5-year mortality from the disease.
We must begin by recognizing that the only reasonable solution to this national health problem and to that of risk-prone individuals is prevention. To do this requires screening a large population, identifying a 'high-risk' group, and measures to prevent or impede the progression of the disease. Table II illustrates a controversial but national approach for the practicing physician. Every male patient between 35 and 65 should be 'screened' for high risk based upon the tables available through the American Heart Association. This involves only a history, blood pressure recording, electrocardiogram, and serum cholesterol. The majority will not be at high risk, and these individuals should be briefly educated about mortality in acute infarction, as discussed earlier. Individuals who are at high risk (perhaps 10% in young men, 30% in older men) should be further evaluated by stress testing. The majority of these individuals will have a normal exercise electrocardiogram. These asymptomatic patients are treated to reduce the magnitude
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An Approach to the Risk Factor Problem for the Practicing Physician
FORRESTER/CliARUZI/DA Luz
84
J. S. FORRESTER, MD, Department of Cardiology, Cedars-Sinai Medical Center, 4833 Fountain Avenue, Los Angeles, CA 90029 (USA)
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of the risk factors and educated by the physician. Individuals with a distinctly abnormal exercise test, e. g., more than 2-mm ST segment depression, move into the 'gray zone', a highly controversial area. Such patients should be sent to coronary arteriography, attempting to identify lesions that are high risk for sudden death: main left coronary artery lesions and high-grade obstruction of the left anterior descending coronary artery. These individuals are sent to surgery. To justify this approach, we believe that the surgical group must have a mortality rate of 1% for elective bypass surgery in the past year. Individuals with coronary artery disease who are not at high risk are placed on medical therapy, with particular stress placed upon education regarding preinfarction angina and myocardial infarction. In summary, coronary atherosclerosis is without question a health problem of truly staggering proportions for this country. Approximately 600,000 people die each year from myocardial infarction, placing the United States 24th among the nations of the world in terms of survival of its male population. The deaths from acute myocardial infarction involve not only the older age group, but people under 65 in great number. Half of these individuals die outside of the hospital, probably from arrhythmias which might have effectively been treated in coronary care units. Nevertheless, there is, on the average, an 8-hour delay in arriving at the hospital after the onset of symptoms, predominantly due to the reluctance of the patient to notify a physician. Contrary to public wisdom, coronary artery disease is most certainly a disease which begins in the young, and there are clearly identified factors which greatly increase the risk of developing the disease. Once coronary heart disease is clinically detectable, the vascular and cardiac changes it has already produced determine prognosis. The individual physician can utilize this information in the care of each of his patients, although at this moment the great majority do not. A reasonable way to begin is to educate all patients, identify high-risk individuals, and objectively evaluate high-risk patients. The ultimate choice of therapy - educational, medical or surgical is based on knowledge of the data discussed above, the type of medical care available, and the individual characteristics of the patient. By such an approach repeated in many communities throughout the country, we believe we might begin to solve the nation's number one health problem.
Risk Factors and Natural History of Coronary Artery Disease JAMES S. FORRESTER, YZHAR CHARUZI and PROTASIO L. DA Luz Department of Cardiology, Cedars-Sinai Medical Center, and University of California; In-Patient Cardiology Service, Department of Cardiology, Cedars-Sinai Medical Center, and Department of Cardiology, Cedars-Sinai Medical Center, Los Angeles, Calif.
The Magnitude of the Problem
Coronary atherosclerosis is the nation's number one health problem. Figure I illustrates the magnitude of the problem - more than one million deaths occur due to heart disease in the United States each year. This cause of death far outstrips the second major cause of death, which is cancer, by a ratio of three to one. There is a common belief, however, that this high mortality rate simply represents the fact that everyone must die sometime.
I
Diseases of heart and blood vessels
1,010,000
Cancer
Accidents Pneumonia and influenza Diabetes
000
I 1
63,6 0
65 .65and eve
600
I
200
400
600
I
800 1,000 1,200
Fig. 1. Causes of death in the United States, taken from US Census figures. Diseases of the heart and blood vessels far outstripped the second leading cause of death, which was cancer, by a ratio of approximately 3: 1.
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Deaths (thousands)
FORRESTER/CHARUZI/DA Cumulative deaths 0'0 number 100 250,000 90
225,000
80
200,000
70
175,000
60
150,000
50
125,000
40
100,000
30
75,000
20
50,000
10
25,000
0
0
Time from onset to death 12 h 8h 6h 4h 2h
Luz
75
Estimated US median time intervals
Hospital waiting interval Delivery interval Delay interval
1h 30 min
15 min
Acute onset
Decision fnterval
Preparatory interval
and coronary heart disease is the disease of old age. This opinion, although reasonable, is belied by the fact that among those dying before age 65, heart disease causes twice the number of deaths as the next leading cause, which is again cancer. Otherwise stated, heart disease is the leading cause of premature death in the middle-aged group in the United States. Coronary atherosclerosis, specifically acute myocardial infarction and its complications, accounts for approximately 60% of these deaths due to heart disease: 600,000 people each year die from acute myocardial infarction in this country. Analysis of the mode of death from acute myocardial infarction leads to some striking conclusions. Of those individuals who are to die as a direct result of acute infarction within I month of the episode,
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Fig. 2. Deaths from acute myocardial infarction in the first 24 h, plotted against the time delay in delivery of patients to the coronary care unit. In the left-hand column is shown the percent of all deaths that had occurred, increasing to 100% at 24 h. In the second column are the number of deaths that occur during this time peliod. In the third column is the number of hours from the onset of symptoms, and in the fourth column is shown the causes of delay in reaching the CCU. From the onset of the signs and symptoms of acute myocardial infarction until the patient realizes he has a serious illness is approximately 15 min (the 'decision interval'). There is then approximately a 4-hour delay until the patient notifies the physician (the 'delay interval'). An additional hour is lost while the patient is delivered to the hospital (the 'delivery interval'). Finally, an additional hour is consumed as the patient is delivered to an adequate monitoring facility (the 'hospital waiting interval').
FORRESTER/CliARUZI/DA
Luz
76
about one half have died within 6-8 h of the onset of symptoms. Of those who will die, more than half will do so outside of the hospital, before receiving adequate medical care. Most of these out-of-hospital deaths are due to arrhythmias and probably are preventable. This leads not to a conclusion, but to a further question: Why does the patient not get to an adequate treatment facility in time? Figure 2 illustrates the number of deaths due to acute infarction within the first 12 h and the four main reasons for the average time of 8 h between onset of symptoms and being adequately monitored in a coronary care facility. On the average, it takes about 15 min for a patient to conclude that he is seriously ill. By this time, about 100,000 people have died. The next delay is the one which is staggering to those dealing with such statistics: there is a 4-hour delay from the onset of symptoms until the patient notifies his physician of the fact that he is seriously ill. In this period of time there have been approximately 180,000 deaths. A further delay of about 1 h ensues in delivery of the patient to the hospital, and finally another I-hour delay from the time of arrival to the hospital until the patient is in an adequately monitored coronary care unit. By the time the patient reaches the coronary care unit, approximately 250,000 deaths have already occurred. It is immediately apparent, therefore, that a major mechanism by which we could reduce the mortality rate due to acute myocardial infarction must involve public education. This education cannot be delivered solely by government or heart associations, and would probably be most effectively delivered by practicing physicians and nurses, describing to both friends and patients the critical need for early notification of a doctor after recognition of symptoms of acute myocardial infarction.
Table I summarizes a study that fell like a bombshell on the American cardiologic public in 1953, one that involved autopsies on American soldiers' killed in action in Korea. 300 autopsies were performed on American men, whose average age was 22 years. In 75% of these individuals there was evidence of atherosclerosis or preatherosclerotic lesions. In about half of these men, fatty streaks and fibrous plaques, which are preatherosclerotic lesions, were seen. The other half of these individuals had clear-cut evidence of developing atherosclerotic disease with encroachment into the coronary artery lumen. 16% had a magnitude of coronary atherosclerosis that would be
Downloaded by: Weizmann Inst. of Science 132.77.150.148 - 2/13/2018 1:32:12 AM
The Natural History of Coronary Artery Disease
77
Risk Factors in Coronary Artery Disease Table I. Coronary disease in American soldiers killed in action in Korea Number of autopsies Average age Incidence of coronary artery disease Fibrous thickening/streaking Narrowing 1~0% 50-70% 80% to complete occlusion
300 22 77% 35% 26% 6% 10%
300 autopsies were performed on men with an average age of 22 years. The incidence of preatheroscIerotic lesions was approximately 35 %, and actual narrowing of vessels was seen in an additional 42%.
considered to be significant by current coronary angiographic techniques. Although the methods of analysis used 22 years ago were less precise than those used today, and the specific numbers have been disputed by other authors, the inescapable conclusion from all such studies is that although coronary artery disease is clinically a disorder of middle and older age, it is in fact a disease of younger age that is only recognized very late in its development. The popular wisdom that coronary artery disease is a disease of our older population is almost certainly a delusion. The natural history of coronary artery disease, once it is recognized, is quite different from its slow and silent initial progression. Figure 3 illustrates Cleveland Clinic. Approximately three fourths of individuals with onevessel coronary artery disease survived 7 years. Only half of those individuals with two-vessel disease were alive at 7 years, and only one third of individuals with three-vessel disease survived 7 years. Perhaps most striking of all these data was the fact that individuals with disease in the main left coronary artery also had a two-thirds mortality over the 7-year follow-up period. The capability of prognosticating survival in the patient groups based on coronary anatomy can be further refined by evaluation of left ventricular contraction pattern during cardiac catheterization, as illustrated in figure 4. An individual with three-vessel coronary artery disease and diffuse hypokinesis has a minimal chance of surviving the 5 years, whereas individuals with onevessel disease and a normal left ventricular contraction pattern had only a 6-percent 5-year mortality.
Downloaded by: Weizmann Inst. of Science 132.77.150.148 - 2/13/2018 1:32:12 AM
survival rates after the angiographic diagnosis in patients studied at the
FORRESTER/CHARUZI/DA
Luz
78 90
100
x
80
90 70
80 70
60
60
50
50
.,. 40
40
~ :::; 30 ~
30 20
~
10
"
0
., ...u ,..al
E
~
In
~
.~ 20
1
J,
2
345
6
Years after coronary arteriography
7
10
O....L....--r--r--,--.--- 4 Normal Local Diffuse scar scar Aneurysm
Fig. 3. The survival time following definitive diagnosis of coronary artery disease by coronary angiography. Approximately three fourths of the patients with one-vessel disease (e; n = 202, all cases) and half of the patients with two-vessel involvement (+; n = 233) survived at 7 years. Only one third of the patients with either three-vessel disease (x ; n = 118) or obstruction of the left main coronary artery (*; n = 37) were alive 7 years following angiography [from BRUSCHKE, A.V.G. et al.: Progress study of 590 consecutive non-surgical cases of coronary disease followed 5-9 years. I. Arteriographic correlation. Circulation 47: 1147, 1973]. Fig. 4. The 5-year cardiac mortality in relationship to combined assessment of coronary vascular disease and the left ventricular contraction pattern. At the two ends of the spectrum, a patient with a normal ventriculographic contraction pattern and onevessel disease (e) had approximately a 6-percent 5-year mortality, in comparison to 90percent mortality in patients with three-vessel coronary artery disease ( x) and a diffusely hypokinetic ventricle. + = Two-vessel disease.
Fig. 5. a Relationship of serum chQlesterol to the development of new coronary artery disease in asymptomatic patients as determined by the Framingham, Massachusetts study. An increasing level of development of coronary artery disease is seen in each category of serum cholesterol levels, with approximately a fourfold increase in the development of coronary artery disease when the two ends of the spectrum are compared. b The relationship of diastolic blood pressure to the development of coronary artery disease in
Downloaded by: Weizmann Inst. of Science 132.77.150.148 - 2/13/2018 1:32:12 AM
3
.,.
32.7
Risk Factors in Coronary Artery Disease Rate per 1,000
79 Rate per 1,000
200
188
200
r162
r--
150
~~
100
50
~
Events 33 pOPulation 658
a
0
.,g .£ 65
i~
92 ,591
150
100
~ 50 120 PJ3
L~ ,108
80 670
rrl 635
Under 175- 200- 225- 250- 275- 300and 175 199 224 249 274 299 over Serum cholesterol level, mg/l00 cm3
~ ~ ~
Events 70 pOPUlation 1,271 0
~
170 2,752
186 2,125
89 940
90 493
b 85 95 105 and Under 75 75 84 94 104 over Diastolic blood pressure level, mmHg
Rate per 1,000 150 131
r-100
~ ~ ~
Events 53 Population 1,188
c
0
~ ~ ..ID. 904
1 Never Past smoked only
~~
72 981
205
12,330
Pipe %pack lpack or or less per cigar per day only day
154 1,146 Over 1pack per day
asymptomatic individuals. As with the cholesterol data, approximately a fourfold increase in the development of coronary artery disease when patients with a diastolic blood pressure of 105 are compared to those with a diastolic pressure less than 75 mm Hg. c The relationship of cigarette smoking to the development of coronary artery disease. An increasing incidence of development of coronary artery disease is seen with increasing cigarette use [from Arteriosclerosis-Report by National Heart and Lung Institute Task Force on Arteriosclerosis, vol. II (US Government Printing Office, Washington, DC)].
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50
FORRESTER/CHARUZI/OA
Luz
80
Although a number of factors may contribute to the development of coronary atherosclerosis, there is reasonable agreement that there are three major risk factors for the development of coronary artery disease, excluding genetic predisposition and diabetes mellitus. These three factors are elevated serum lipids, elevated arterial blood pressure, and the use of cigarettes. Figure 5 illustrates data collected prospectively over many years in asymptomatic patients in the Framingham, Massachusetts study. The graphs show the rate of development of coronary artery disease in asymptomatic individuals plotted against the level of serum cholesterol (fig. 5a), arterial blood pressure (fig. 5b), and tobacco use (fig. 5c). When serum cholesterol levels were elevated, for instance, greater than 300 mg %, the incidence of subsequent development of coronary artery disease in the asymptomatic population was four times as great as that in a similar group of patients who had low levels of serum cholesterol. There did not appear to be a 'normal' level of serum cholesterol; rather there was a gradual increase in the incidence of development of new coronary artery disease with each increment of increase in the serum cholesterol level. This is not surprising since a level of serum cholesterol greater than 200 mg is seldom seen in animals, and is in fact predominantly a phenomenon observed only in affluent Western society. Of the people of the world, only the Finns have higher levels of serum cholesterol than citizens of the United States; and only Finland has a higher mortality rate due to coronary heart disease. The second major risk factor, elevated arterial pressure, is comparable to serum lipids in nature and magnitude. Individuals who had levels of arterial diastolic pressure exceeding 105 had a fourfold increase in the incidence of development of coronary artery disease when compared to those with an arterial diastolic pressure less than 75 mm Hg. As with the serum cholesterol level, there did not appear to be a clear-cut 'normal' level of arterial diastolic pressure. Cigarette smoking greatly increases the risk of developing coronary heart disease. Individuals who smoked more than a pack a day had a three times greater incidence of development of coronary artery disease than those who never smoked (fig. 5c). The presence of more than one risk factor is additive: a 'borderline' individual with a serum cholesterol of 250 mg %, an arterial diastolic pressure greater than 90 mm Hg, and any use of cigarettes, has an eightfold greater risk of developing coronary artery disease than the individual with
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Risk Factors in the Development of Coronary Heart Disease
Risk Factors in Coronary Artery Disease
132
Women (63) Sex and age
81
Men < 45 years (149)
128
Men 45-54 years (240)
\35
Men> 54 years (138)
141
129
0(205) Cigarette smoking
325 (83)
35
rl7 One-vessel disease; no additional narrowing (111)
Left ventricular angiogram Duration of chest pains, months
[0-12 (170) 113-72 (256) 1>72 (117)
Diabetes mellitus
1No diabetes (570) [Clinical diabetes (20)
ECG
b
i23 One-vessel disease + additi onal narrowing (91) Two-vessel disease (233) 138 Three-vessel disease (116) 154 Obstruction of the left main corona!); ,\-157 artery (37) Normal (253) J25 Local scar (145) 131 Aneurysm (SO) i 46 Diffuse scar tissue (79) J 69 J23 129
J50
133
Normal (231) 119 Rep. d ist or dig. effect (IS4~ 34 Infarction (119) i 45 Conduction disturbance or LVH (85)
J60
J64
Fig. 6. a The relationship of risk factors to mortality rates following the development of coronary artery disease as diagnosed by coronary angiography. There is little influence of cigarette smoking, obesity, serum cholesterol or isolated systolic or diastolic hypertension upon mortality rate. b In contrast to the data seen in figure 6a, the coronary arteriogram and left ventricular angiogram showed substantial relationship to mortality rates following the development of coronary artery disease, as did the duration of chest pain, diabetes mellitus, and specific electrocardiographic patterns.
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Coronary arteriogram
FORRESTER/CHARUZI/DA
82
Luz
no risk factors. When multiple risk factors are present with substantial degree of abnormality, the increased risk of developing coronary heart disease increases much further. But, frightening as such numbers are, they are of relatively little value for the individual physician trying to assess risk in an individual patient. The Framingham experience is now sufficiently large to permit prediction for any asymptomatic patient of developing coronary heart disease within the next 6 years given his serum cholesterol level, smoking history, glucose tolerance, arterial pressure and electrocardiogram. These data are available in booklet form through the American Heart Association. For instance, a 35-year-old who smokes occasionally, with no evidence of left ventricular hypertrophy by BeG, a serum cholesterol level of 235, and an arterial systolic pressure of 150 mm Hg, has a 1.8-percent risk of developing coronary artery disease within the next 6 years. A man of similar age who has more flagrant risk factors, e.g., arterial pressure of 180, serum cholesterol of 310, left ventricular hypertrophy, and a positive glucose tolerance test, has a IS-percent risk of developing coronary artery disease by the time he is 41 years of age. The same individual 20 years later, at age 55, has almost a 50-percent chance of having clinical coronary artery disease within the next 6 years. This capability of assessing the risk for an individual patient Table II. The practicing physician and his patient: how aggressive should we be?
The gray zone Surgery A
Yes~
Angiography: high risk? A
y es~ Stress ECG: positive? A No~ Yes~ v Screen all patients: high risk? Rx Risk Factors
No~
M~dical
N°Iv
A format for approach to the risk factor problem. See text for discussion.
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AdVIce
Risk Factors in Coronary Artery Disease
83
provides a rational basis for decisions regarding further evaluation and therapy, as discussed later. Critical as these risk factors are to the development of coronary heart disease, they fade in importance when the disease becomes clinically manifest. Thus, an apparent paradox exists: whereas hypertension, cholesterol and smoking contribute heavily to the risk of development of coronary artery disease, once the disease has become clinically apparent, these same factors do not significantly alter the course of the disease. Figure 6a illustrates the 5-year mortality rate in patients who smoked and did not, with normal and elevated serum cholesterol levels, and with and without hypertension. Only in those patients with both systolic and diastolic hypertension was there any significant difference in mortality rates. Instead, the 5-year mortality rate for individuals with established coronary artery disease related primarily and predominantly to the nature of coronary artery disease as it is discovered: specifically, the number and magnitude of involved vessels and the ventricular contraction pattern. In addition, the presence of continuing angina, diabetes mellitus, and specific electrocardiographic abnormalities, particularly ventricular conduction abnormalities, carried a poor prognosis. These data suggest that once coronary artery disease is clinically manifest, manipulation of the so-called risk factors is unlikely to produce substantial change in the 5-year mortality from the disease.
We must begin by recognizing that the only reasonable solution to this national health problem and to that of risk-prone individuals is prevention. To do this requires screening a large population, identifying a 'high-risk' group, and measures to prevent or impede the progression of the disease. Table II illustrates a controversial but national approach for the practicing physician. Every male patient between 35 and 65 should be 'screened' for high risk based upon the tables available through the American Heart Association. This involves only a history, blood pressure recording, electrocardiogram, and serum cholesterol. The majority will not be at high risk, and these individuals should be briefly educated about mortality in acute infarction, as discussed earlier. Individuals who are at high risk (perhaps 10% in young men, 30% in older men) should be further evaluated by stress testing. The majority of these individuals will have a normal exercise electrocardiogram. These asymptomatic patients are treated to reduce the magnitude
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An Approach to the Risk Factor Problem for the Practicing Physician
FORRESTER/CliARUZI/DA Luz
84
J. S. FORRESTER, MD, Department of Cardiology, Cedars-Sinai Medical Center, 4833 Fountain Avenue, Los Angeles, CA 90029 (USA)
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of the risk factors and educated by the physician. Individuals with a distinctly abnormal exercise test, e. g., more than 2-mm ST segment depression, move into the 'gray zone', a highly controversial area. Such patients should be sent to coronary arteriography, attempting to identify lesions that are high risk for sudden death: main left coronary artery lesions and high-grade obstruction of the left anterior descending coronary artery. These individuals are sent to surgery. To justify this approach, we believe that the surgical group must have a mortality rate of 1% for elective bypass surgery in the past year. Individuals with coronary artery disease who are not at high risk are placed on medical therapy, with particular stress placed upon education regarding preinfarction angina and myocardial infarction. In summary, coronary atherosclerosis is without question a health problem of truly staggering proportions for this country. Approximately 600,000 people die each year from myocardial infarction, placing the United States 24th among the nations of the world in terms of survival of its male population. The deaths from acute myocardial infarction involve not only the older age group, but people under 65 in great number. Half of these individuals die outside of the hospital, probably from arrhythmias which might have effectively been treated in coronary care units. Nevertheless, there is, on the average, an 8-hour delay in arriving at the hospital after the onset of symptoms, predominantly due to the reluctance of the patient to notify a physician. Contrary to public wisdom, coronary artery disease is most certainly a disease which begins in the young, and there are clearly identified factors which greatly increase the risk of developing the disease. Once coronary heart disease is clinically detectable, the vascular and cardiac changes it has already produced determine prognosis. The individual physician can utilize this information in the care of each of his patients, although at this moment the great majority do not. A reasonable way to begin is to educate all patients, identify high-risk individuals, and objectively evaluate high-risk patients. The ultimate choice of therapy - educational, medical or surgical is based on knowledge of the data discussed above, the type of medical care available, and the individual characteristics of the patient. By such an approach repeated in many communities throughout the country, we believe we might begin to solve the nation's number one health problem.
