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Angina pectoris and intermittent claudication
Angina pectoris and intermittent c!audication Robert I. Hamby, M.D. Agop Aintablian, M.D. Stanley Shanies, M.D. B. George Wisoff, M.D. Daniel Weisz, M.D. Chaudary Voleti, M.D. New Hyde Park, Jamaica, and Stony Brook, N. Y.
Angina pectoris and intermittent claudication are both manifestations of transient ischemia to cardiac and skeletal muscle, respectively, brought on by exertion and relieved by rest. In the majority of cases, atherosclerosis appears to be the pathologic basis for both angina pectoris and intermittent claudication. ~ Patients with intermittent claudication have both a propensity for developing ischemic heart disease and an increased risk of dying from cardiovascular disease. -~Thus, in any patient population referred with angina pectoris it would not be unusual to find a subgroup of patients also having evidence of atherosclerosis of the femoral-popliteal artery system. The purpose of the following report is to present a group of patients referred for evaluation of angina pectoris who also had clinical evidence of peripheral vascular disease of the lower extremities. These patients will be compared with two other groups of patients, one with only symptomatic coronary disease and a second without evidence of either coronary or peripheral vascular disease. Methods
A review of 1,200 consecutive patients referred for evaluation of angina pectoris revealed 60 patients (5 per cent) with a prior history of intermittent claudication and diminished or From the Department of Medicine and Surgery, Cardiology and Cardiothoracic Divisions, Long Island Jewish-Hillside Medical Center, New Hyde Park, N. Y., Queens Hospital Center Affiliation, Jamaica, N. Y., and School of Medicine, Health Sciences Center, State University of New York at Stony Brook, Stony Brook, N. Y. Received for publication June 24, 1976. Accepted for publication Aug. 9, 1976. Reprint request: Robert I. Hamby, M.D., Long Island Jewish-Hillside Medical Center, New Hyde Park, N. Y. 11040.
November, 1977, Vol. 94, No. 5, pp. 573-578
absent pulses in the lower extremities. These 60 patients form the basis of this report and were compared with two other groups of patients. Group I consisted of patients without clinical evidence of peripheral vascular disease and normal coronary arteriograms. These patients were evaluated because of one of the following problems; recurrent atypical chest pain, abnormal electrocardiogram, intractable arrhythmia, or an unexplained heart murmur. Group II consisted of patients referred because of angina pectoris, b u t without clinical evidence of peripheral vascular disease; all had arteriographic evidence of coronary artery disease. Patients in Group I and II were matched for both age and sex with the 60 patients having both coronary artery and peripheral vascular disease (Group III). All patients were interviewed, examined, and evaluated by one of the authors (R.I.H., A.A.). The history included the duration of symptoms for both angina pectoris and intermittent claudication. A history of a myocardial infarction was accepted if documented by the referring doctor or if the patient had a prior hospitalization for at least three weeks for prolonged chest pain. A diagnosis of hypertension required either a history of antihypertensive therapy or a persistent diastolic pressure of 90 ram. Hg or over when admitted for evaluation. A positive history of cigarette smoking required consumption of 20 cigarettes or more per day for at least ten years prior to the onset of symptoms. A diagnosis of diabetes mellitus required either a history of diabetes mellitus accompanied by an elevated fasting blood sugar on admission, or if no known prior diagnosis was ever made, an elevated fasting blood sugar on admission accompanied by glycos-
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Table I. Clinical profile of p a t i e n t s
60
60
60
--
3.1 _+ 3.5 -
3.6 +_ 3.9 4.3 -+r3.6
-
26 (43)t
26 (43)
14 (23) 19 (32) 2 (3):~
18 (30) 27 (45) 13 (22)
23 (38! 30 (50) 27 (45)
26 (43)w
35 (58)
41 (68)
13 (22i 10 (16)w -
19 (32) 11 (18) 19 (32)
25 (45) 22 (37) 23 (38)
of t h e three m a j o r c o r o n a r y arteries were graded on the basis of score f r o m 0 to 6 as previously described 6 a n d defined b y Bruschke. 7 T h e t o t a l c o r o n a r y Score, used as a n i n d i c a t o r of the severity of the c o r o n a r y a r t e r y disease, was the s u m of t h e score of t h e t h r e e m a j o r c o r o n a r y arteries. I n v o l v e m e n t of the m a i n left ~c o r o n a r y arterY was considered s e p a r a t e l y , Significant c o r o n a r y a r t e r y disease was defined a s n a r r o w i n g of a c o r o n a r y a r t e r y b y m o r e t h a n 50 p e r c e n t of the l u m e n . Single vessel disease was defined as significant c o r o n a r y a r t e r y disease of only one vessel, while double a n d triple vessel disease indicated significant disease of t w o or t h r e e coron a r y arteries, respectively. F o l l o w - u p a f t e r coron a r y surgery was o b t a i n e d b y office visit or by telephone. S t a t i s t i c a l e v a l u a t i o n of all the d a t a was o b t a i n e d by t h e t w o - t a i l e d S t u d e n t ' s t t e s t for u n p a i r e d d a t a a n d X2 test 8 w i t h t h e assistance of a statistician.
8 (13)
12 (20)
Results
I
Group II Group I (ASHD)* Total number Duration of symptoms (yrs. _+ 1 S.D.) Angina pectoris Intermittent claudication Medical history: Myocardial infarction (by history) Hypertension Cigarette smoking Diabetes mellitus Family history: Arteriosclerotic heart disease Hypertension Diabetes mellitus Myocardial infarction (by ECG) Cardiomegaly (by x-ray)
-
Group1II (ASHD § PVD)
*ASHD = arteriosclerotic heart disease; PVD = peripheral vascular disease. tNumbers in parenthesis represent the per cent for each group. :~When Group I compared to Group II p < 0.005; when Group I compared with Group III p < 0.001; when Group II compared to Group III p < 0.01. w Group I compared to Group III p < 0.01.
uria. On admission, each p a t i e n t was closely questioned as to a family history in first generation relatives of arteriosclerotic h e a r t disease, hypertension, or diabetes mellitus. A twelve-lead s t a n d a r d electrocardiogram was t a k e n on all p a t i e n t s a n d was i n t e r p r e t e d on t h e basis of accepted criteria. 3 C h e s t radiologic e v a l u a t i o n a n d i n t e r p r e t a t i o n w a s p e r f o r m e d b y a radiologist to define the presence Or absence of c a r d i o m e g a l y . After a 12- to 16-hour fast and d i s c o n t i n u a t i o n of all medication, blood was d r a w n in t h e m o r n i n g for a glucose tolerance test and lipid studies. S e r u m cholesterol was d e t e r m i n e d using an a u t o a n a l y z e r and s e r u m triglyceride was determined by a modification of the m e t h o d described by Soloni. 4 F o r b o t h cholesterol a n d triglyceride an a b n o r m a l value was defined as t h a t value above a recommended age-adjusted normal range as r e c o m m e n d e d b y Fredrickson. 5 All p a t i e n t s u n d e r w e n t c o m p l e t e cardiac catheterization a n d selective c o r o n a r y a r t e r i o g r a p h i c studies by m e t h o d s previously described. 6 Selective c o r o n a r y a n g i o g r a m s were reviewed a n d e a c h
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E a c h of the t h r e e groups, m a t c h e d for b o t h age a n d sex, consisted of 49 m a l e a n d 11 f e m a l e patients. T h e a v e r a g e age of the m a l e a n d f e m a l e p a t i e n t s was 56 __ 8.4 a n d 60 _+ 8.5 years, respectively. T h e ages of t h e p a t i e n t s r a n g e d f r o m 37 to 75 y e a r s with 80 per cent of the p a t i e n t s 50 y e a r s or over. Seven p a t i e n t s were 70 y e a r s or older. A c o m p a r i s o n of the clinical profile of t h e t h r e e groups of p a t i e n t s is s h o w n in T a b l e I. T h e frequency of h y p e r t e n s i o n or cigarette s m o k i n g revealed no significant differences w h e n all t h r e e groups were c o m p a r e d with e a c h other. T h e f r e q u e n c y of diabetes m e l l i t u s was significantly higher in b o t h G r o u p I I (p < 0.005) a n d I I I (p < 0.001) w h e n c o m p a r e d to G r o u p I. F u r t h e r more, in G r o u p I I I , 45 per cent of t h e p a t i e n t s h a d diabetes mellitus, significantly higher t h a n t h e frequency in G r o u p II. T h e f r e q u e n c y of a f a m i l y history of arteriosclerotic heart disease (p < 0.01), diabetes mellitus (p < 0.01) a n d h y p e r t e n s i o n (p < 0.025) was higher in G r o u p I I I t h a n G r o u p I (Table i). I n t e r m i t t e n t claudication, which w a s p r e s e n t only in G r o u p I I I , preceded a n g i n a pectoris in 41 p a t i e n t s (68 per cent). One of these p a t i e n t s h a d a h i s t o r y of a l u m b a r s y m p a t h e c t o m y a n d t w o p a t i e n t s h a d previous f e m o r a l - p o p l i t e a l b y p a s s surgery. A l m o s t u n i f o r m l y , with t h e onset of exertional a n g i n a pectoris, the i n t e r m i t t e n t claudication caused either no f u n c t i o n a l disability or
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Angina pectoris and intermittent claudication showed no progression. In the 19 p a t i e n t s with the i n t e r m i t t e n t claudication developing after the onset of angina pectoris, the functional disability was due p r e d o m i n a n t l y to the angina pectoris. T h e serum cholesterol for Groups II and III were 246 + and 46 and 2 5 9 _ 47 mg. per cent, respectively, which are significantly higher (p < 0.01) t h a n 203 • 36 mg. per cent, observed in Group I. T h i r t e e n per cent of the patients in both Group II and III had an a b n o r m a l cholesterol, as compared to 4 per cent n o t e d in G r o u p I. T h e serum triglyceride for Group II and III were 177 ___ 87 and 176 • 93 mg. per cent, which was significantly higher (p < 0.01), t h a n 134 • 64 mg. per cent found in Group I. T h e f r e q u e n c y of an abnormal triglyceride in Group II and I I I were 38 and 47 per cent, respectively, as c o m p a r e d to 11 per cent in Group I. Comparing Group II and III in respect to the n u m b e r of vessels involved with significant coron a r y a r t e r y disease and the t o t a l c o r o n a r y score, revealed no significant differences (Table II). On the basis of the functional s t a t u s of the patient, together with the c o r o n a r y a n a t o m y and left ventricular function, a o r t o c o r o n a r y bypass surgery was performed on 48 and 47 patients in Group II and III, respectively. T h e n u m b e r of grafts placed at the time of surgery and the postoperative course were c o m p a r a b l e in b o t h groups. Only one p a t i e n t died at surgery in G r o u p III. In the remaining patients in b o t h of these groups, surgery was not performed for several reasons (Table III), including poor left v e n t r i c u l a r function, diffuse c o r o n a r y a r t e r y disease, infarction or expiration while waiting for surgery, or insufficient disease judged not to w a r r a n t bypass. Postoperative follow-up revealed f u n c t i o n a l cardiac improvement in the majority of patients in b o t h groups (Table III). Of the 43 patients in Group III, functional d e t e r i o r a t i o n on follow-up due to i n t e r m i t t e n t claudication was observed in 12 patients (28 per cent). In six of these patients surgery was performed six to 24 m o n t h s after coronary surgery and included l u m b a r s y m p a t h e c t o m y in one, femoral-popliteal bypass in four, and a m p u t a t i o n in one patient. Discussion T h e pathophysiologic basis of b o t h angina pectoris and i n t e r m i t t e n t claudication are rem a r k a b l y similar. B o t h clinical conditions are usually manifested on exertion as a result of
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Table II. C o r o n a r y a r t e r y a n a t o m y
l GroupII I. Group III Number of vessels involved Single lYo~ble Triple Main left coronary disease Total coronary arterv score (mean ___1 S.D.)
11 22 27 4 10.0 • 2.8
10 24 26 5 9.9 • 2.8
Table III. Surgery and follow-up
Ioroo, llOro "I Aortocoronary bypass surgery Surgical mortality Coronary surgery not performed Poor left ventricular function and/or diffuse coronary artery disease Infarction or expired waiting for surgery Surgery not recommended for single vessel disease of right coronary or circumflex artery Postoperative follow-up (mean; range) Number followed Cardiac status Improved Unchanged Worse Intermittent claudication Improved Unchanged Worse
48
47 0
12
1 13
8
9
1
2
3
2
2.6; 1/2-5.4
2.2 yrs; 1~-5.1
42
43 38 3 1
40 1 2 3 28 12
a t h e r o m a t o u s changes in t h e arterial system. B o t h are related to t r a n s i e n t ischemia which m a y be relieved by rest. T h e F r a m i n g h a m S t u d y ~ indicated t h a t the risk of one of these ischemic clinical states is increased by the presence of the other. In the F r a m i n g h a m S t u d y , m e n with preexisting angina pectoris h a d almost t h r e e times and w o m e n had five times the risk of developing i n t e r m i t t e n t claudication when c o m p a r e d t o a population not having evidence of ischemic h e a r t disease. In a similar m a n n e r , p a t i e n t s with preexisting i n t e r m i t t e n t claudication were f o u n d to have a p r o n o u n c e d increased risk of developing angina pectoris. Such a relationship suggests a
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common etiologic basis for both peripheral vascular and coronary artery disease. In studies devoted to patients with peripheral vascular disease, the frequency of coexisting coronary disease varied from 16 to 29 per cent2 -11 In the present study of a patient population referred for ischemic heart disease, the frequency of intermittent claudication was observed to be five per cent. This frequency cannot be used as representative of the true frequency of intermittent claudication with angina pectoris since the patients in the present study represent a select group referred primarily because of disabling symptoms of angina pectoris. Furthermore, it is quite conceivable that pre-existing intermittent claudication will limit and protect against the functional restriction that angina pectoris would otherwise have brought on. In the present study, in almost two-thirds of the patients, the clinical manifestations of peripheral vascular disease preceded those of coronary artery disease. In three of these patients, surgical intervention (lumbar sympathectomy in one and femoral-popliteal bypass in two) was required because of major restrictions as a result of the peripheral vascular disease. In the majority of patients, once the symptoms of coronary artery disease developed, the intermittent claudication caused only minor disability. It is apparent that the physical restriction brought on by angina pectoris resulted in a limited protection from the compromised circulation in the lower extremities. It was not uncommon for a patient to note significant improvement in the anginal status as a result of medication only to find himself limited by exertional cramps in his legs. This is further exemplified by the events that occurred after aortocoronary bypass surgery. In almost 30 per cent of the patients the intermittent claudication was reported on follow-up to have worsened, necessitating some form of surgery in six patients. Thus, the alleviation of the myocardial ischemic symptoms from the coronary artery disease permitting an increased functional tolerance unmasked the compromised circulation to the lower extremities. The patients with both coronary artery and peripheral vascular disease (Group III) were compared to patients also referred for angina pectoris, but not having peripheral vascular disease (Group II), in order to determine wliether there were any distinct characteristics other than intermittent claudication which could distinguish
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one group from the other. Furthermorr both of the groups with angina pectoris were compared with an age- and sex-matched control group (Group I) that had neither evidence of peripheral or coronary artery disease in order to determine whether the factors evaluated were simply characteristic of any patient population of similar age and sex having arteriosclerotic heart disease. Epidemiologic studies 12. 13 have indicated that both hypertension and cigarette smoking are distinct risk factors for the occurrence of coronary artery disease. Similar types of epidemiologic studies on peripheral vascular disease are not available. In the present study both of these factors were more frequent in the patients with coronary artery disease (Group II and III), as compared to the control group (Group I); however, the differences were not statistically significant (Table I). Diabetes mellitus appeared to be the one factor which distinguished patients with peripheral vascular disease from both groups of patients with no evidence of peripheral vascular disease (Table I). Furthermore, the frequency of diabetes mellitus in both groups with coronary artery disease (Groups II and III) was significantly higher than the group of patients without coronary artery disease. The association of coronary artery disease 14-16 and peripheral vascular disease 14. 1~. 18 with diabetes mellitus has been well documented. The present study confirms these observations and indicates that the diabetic patient has an increased risk of clinically developing simultaneously both coronary artery and peripheral vascular disease. A comparative review of all three groups of patients for a family history of coronary artery disease, hypertension, and diabetes mellitus revealed no significant differences between the two groups with angina pectoris. However, comparing the angina pectoris patients who also had peripheral vascular disease, with the control group, revealed an increased frequency of a family history of arteriosclerotic heart disease ( p < 0 . 0 1 ) and hypertension (p < 0.025). Serum cholesterol and triglyceride were significantly higher in both of the groups with coronary artery disease, as compared to the control group. Neither cholesterol nor triglyceride levels distinguished the patients having only angina pectoris from those having intermittent claudication as well. The lipid studies reported by Greenhalgh and coworkers 11 on patients with peripheral vascular
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Angina pectoris and intermittent claudication
disease are c o m p a r a b l e to those found in b o t h groups of the present s t u d y w i t h c o r o n a r y a r t e r y disease. In t h a t study, an a b n o r m a l cholesterol level was observed in 14.5 per cent of the patients, as compared to 13 per cent in G r o u p II and I I I of the present study. An elevated triglyceride level was present in 39.5 per cent of the p a t i e n t s in Greenhalgh's series, as compared to 38 and 47 per cent in Group II and III, respectively. In the s t u d y of Vyden and associates 9 of patients with peripheral vascular disease, 50 per cent had an elevated serum triglyceride level, whereas the serum cholesterol levels were similar to a control group. These studies, as w e l l as those on patients with coronary a r t e r y disease, 19-21 suggest an i m p o r t a n t role of a b n o r m a l serum triglyceride level in the pathogenesis of atherosclerosis. This s t u d y d e m o n s t r a t e s t h a t the severity of the coronary a r t e r y disease, as reflected by either the n u m b e r of vessels involved with significant disease or the c o r o n a r y a r t e r y score (Table II), was in no way different in patients with intermitt e n t claudication and angina pectoris when compared to a group of patients m a t c h e d for age and sex having only c o r o n a r y a r t e r y disease. T h e n u m b e r of patients undergoing a o r t o c o r o n a r y bypass surgery, n u m b e r of grafts placed at the tim~ of surgery, postoperative course and followu p of their cardiac status, were c o m p a r a b l e in b o t h groups. Thus, it is a p p a r e n t t h a t peripheral vascular disease of the lower extremities in a patient with c o r o n a r y a r t e r y disease should not interdict coronary revascularization, if clinically warranted. However, as indicated by our followup experience, the patient should u n d e r s t a n d t h a t clinical i m p r o v e m e n t in the cardiac s t a t u s m a y be accompanied by recurrence or a p p a r e n t deterioration of the vascular insufficiency in the lower extremities. If such a course of events does occur, consideration m a y be required for surgical revascularization in the lower extremities.
Summary Sixty patients referred for angina pectoris and having coexisting i n t e r m i t t e n t claudication (Group III) were compared with two groups of patients m a t c h e d for b o t h age and sex. One group (Group I), had no evidence of either c o r o n a r y or peripheral vascular disease, while G r o u p II had only s y m p t o m a t i c c o r o n a r y a r t e r y disease. T h e ages of the patients ranged from 37 to 75 years with 80 per cent of the patients 50 years or over.
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In Group III, i n t e r m i t t e n t claudication preceded the d e v e l o p m e n t of angina pectoris in 41 p a t i e n t s (68 p e r cent) and with the onset of exertional angina pectoris, the i n t e r m i t t e n t claudication usually caused no m a j o r disability. T h e f r e q u e n c y of h y p e r t e n s i o n and cigarette smoking was n o t different when all three groups were compared. Diabetes mellitus was significantly higher in b o t h Group II (p < 0.005) and G r o u p III (p < 0.001) t h a n in G r o u p I. In G r o u p III, 45 per cent of the patients had diabetes mellitus as c o m p a r e d to 22 per cent in G r o u p II (p < 0.01). T h e f r e q u e n c y of a family history of arteriosclerotic h e a r t disease (p < 0.01), diabetes mellitus (p < 0.01) a n d hypertension (p < 0.025) was higher in G r o u p III, as compared to G r o u p I. S e r u m cholesterol and triglyceride comparison revealed no differences between Groups II a n d I I I , b u t b o t h groups were significantly higher (p < 0.01), as c o m p a r e d to Group I. T h e severity of c o r o n a r y a r t e r y disease as reflected by the n u m b e r of vessels involved and c o r o n a r y a r t e r y score were similar in b o t h G r o u p II and III. T h e n u m b e r of p a t i e n t s o p e r a t e d on for c o r o n a r y surgery, n u m b e r of grafts required, postoperative course and follow up of their cardiac s t a t u s was similar for b o t h G r o u p II and III. In 12 of 43 patients followed in G r o u p III, a recurrence or a p p a r e n t deterioration of the vascular insufficiency in the lower extremities required surgery in six patients. T h u s , peripheral vascular disease of the lower extremities s h o u l d not be a d e t e r r e n t against r e c o m m e n d i n g a patient for c o r o n a r y surgery if otherwise clinically warranted. The authors would like to acknowledge the critical review given by Dr. Irwin Hoffman, as well as the assistance given by Mrs. Brenda Hamby.
REFERENCES 1. Gould, S. E.: Pathology of the heart and blood vessels, 3rd ed., Springfield, Ill., 1968, Charles C Thomas, Publisher, p. 562. 2. Kannel, W. B., Skinner, J. J., Jr, Schwartz, M. J., and Shurtleff, D.: Intermittent claudication. Incidence in the Framingham Study, Circulation 41:875, 1970. 3. Massie, E., and Walsh, T. J.: Clinical vectorcardiography and electrocardiography, Chicago, 1960, Year Book Publishers, Inc. 4. Soloni,F. G.: Simplified manuel micromethod for determination of serum triglycerides, Clin. Chem. 17:529, 1971. 5. Fredrickson, D. S.: A physician's guide to hyperlipidemia, Mod. Concepts Cardiovasc. Dis. 41-31, 1972. 6. Hamby, R. I., Gupta, M. P., and Young, M. W.: Clinical and hemodynamic aspects of single vessel coronary artery disease, AM. HEARTJ. 85:458, 1973. 7. Bruschke, A. V. G.: The diagnostic significance of the
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8. 9.
10.
11.
12. 13.
578
coronary arteriogram. A study of its value in relation to other diagnostic methods, Utrecht, 1970, Kemink en Zoon, N.V. Baston, H. C.: An introduction to statistics in the medical science, 6th ed., Minneapolis, 1963, Burgess Publishing Co. Vyden, J. K., Thorner, J., Nagasawa, K., Takano, T., Groseth-Dittrich, M. F., Perlow, R., and Swan, H. J. C.: Metabolic and cardiovascular abnormalities in patients with peripheral arterial disease, AM. HEART J. 90:703, 1975. Juergens, J. L., Barker, NI W., and Hines, E. A.: Atherosclerosis obliterans: Review of 520 cases with special reference to pathogenic and prognostic factors, Circulation 21:188, 1960. Greenhalgh, R. H., Rosengarten, D. S., Mervart , I., Lewis, B., Calnon, J. S., and Martin, P.: Serum lipide and lipoproteins in peripheral vascular disease, Lancet 2:947, 1971. Kannel, W. B., Kagan, A., Dawber, T. R., and Revotskie, N.: Epidemiology of coronary heart disease. Implications for the practicing physician, Geriatrics 1 7:675, 1962. Rosenman, R. H., Brand, R. J., Jenkins, D., Friedman, M., Straus, R., and Wurm, M.: Coronary heart disease in the western collaborative group study. Final follow-up experience of 81A years, J.A.M.A. 233:872, 1975.
14. LeCompte, P. M.: Vascular lesions in diabetes mellitus, J. Chronic Dis. 2:178, 1958. 15. Clawson, B. J., and Bell, E. T.: Incidence o f fatal coronary disease in non-diabetic and in diabetic persons, Arch. Pathol. 48:105, 1949. 16. Bell, E. T.: A post mortem study of vascular disease in diabetes, Arch. Pathol 53:444, 1952. 17. Lisa, J. R., Magiday, M., and Hart, J. F.: Peripheral arteriosclerosis in the diabetic and the nondiabetic, J.A.M.A. 1 18:1353, 1942. 18. Wessler, S, and Silberg, N. R.: Studies in peripheral arterial occlusive disease II. Clinical findings in patients with advanced arterial obstruction and gangrene, Circu" lation 7:810, 1953. 19. Barboriak, J. J~, Renim, A. A., Anderson, A. J., Tristani, F. E., Walker, J. A., and Flemma, R. J.: Coronary artery occlusion and blood lipids, AM. HEART J. 87:718, 1974. 20. Gustafson, A., Elmfeldt, D., Wilhelmsen, L., and Tibblin, G.: Serum lipidE and lipoproteins in men after myocardial infarction compared with representative population sample, Circulation 46:709, 1972. 21. Leren, P., and Hasbrekke, O.: Blood lipidE in patients with coronary heart disease, Acta Med. Scand. 189:505, 1971.
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Angina pectoris and intermittent claudication are both manifestations of transient ischemia to cardiac and skeletal muscle, respectively, brought on by exertion and relieved by rest. In the majority of cases, atherosclerosis appears to be the pathologic basis for both angina pectoris and intermittent claudication. ~ Patients with intermittent claudication have both a propensity for developing ischemic heart disease and an increased risk of dying from cardiovascular disease. -~Thus, in any patient population referred with angina pectoris it would not be unusual to find a subgroup of patients also having evidence of atherosclerosis of the femoral-popliteal artery system. The purpose of the following report is to present a group of patients referred for evaluation of angina pectoris who also had clinical evidence of peripheral vascular disease of the lower extremities. These patients will be compared with two other groups of patients, one with only symptomatic coronary disease and a second without evidence of either coronary or peripheral vascular disease. Methods
A review of 1,200 consecutive patients referred for evaluation of angina pectoris revealed 60 patients (5 per cent) with a prior history of intermittent claudication and diminished or From the Department of Medicine and Surgery, Cardiology and Cardiothoracic Divisions, Long Island Jewish-Hillside Medical Center, New Hyde Park, N. Y., Queens Hospital Center Affiliation, Jamaica, N. Y., and School of Medicine, Health Sciences Center, State University of New York at Stony Brook, Stony Brook, N. Y. Received for publication June 24, 1976. Accepted for publication Aug. 9, 1976. Reprint request: Robert I. Hamby, M.D., Long Island Jewish-Hillside Medical Center, New Hyde Park, N. Y. 11040.
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absent pulses in the lower extremities. These 60 patients form the basis of this report and were compared with two other groups of patients. Group I consisted of patients without clinical evidence of peripheral vascular disease and normal coronary arteriograms. These patients were evaluated because of one of the following problems; recurrent atypical chest pain, abnormal electrocardiogram, intractable arrhythmia, or an unexplained heart murmur. Group II consisted of patients referred because of angina pectoris, b u t without clinical evidence of peripheral vascular disease; all had arteriographic evidence of coronary artery disease. Patients in Group I and II were matched for both age and sex with the 60 patients having both coronary artery and peripheral vascular disease (Group III). All patients were interviewed, examined, and evaluated by one of the authors (R.I.H., A.A.). The history included the duration of symptoms for both angina pectoris and intermittent claudication. A history of a myocardial infarction was accepted if documented by the referring doctor or if the patient had a prior hospitalization for at least three weeks for prolonged chest pain. A diagnosis of hypertension required either a history of antihypertensive therapy or a persistent diastolic pressure of 90 ram. Hg or over when admitted for evaluation. A positive history of cigarette smoking required consumption of 20 cigarettes or more per day for at least ten years prior to the onset of symptoms. A diagnosis of diabetes mellitus required either a history of diabetes mellitus accompanied by an elevated fasting blood sugar on admission, or if no known prior diagnosis was ever made, an elevated fasting blood sugar on admission accompanied by glycos-
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Table I. Clinical profile of p a t i e n t s
60
60
60
--
3.1 _+ 3.5 -
3.6 +_ 3.9 4.3 -+r3.6
-
26 (43)t
26 (43)
14 (23) 19 (32) 2 (3):~
18 (30) 27 (45) 13 (22)
23 (38! 30 (50) 27 (45)
26 (43)w
35 (58)
41 (68)
13 (22i 10 (16)w -
19 (32) 11 (18) 19 (32)
25 (45) 22 (37) 23 (38)
of t h e three m a j o r c o r o n a r y arteries were graded on the basis of score f r o m 0 to 6 as previously described 6 a n d defined b y Bruschke. 7 T h e t o t a l c o r o n a r y Score, used as a n i n d i c a t o r of the severity of the c o r o n a r y a r t e r y disease, was the s u m of t h e score of t h e t h r e e m a j o r c o r o n a r y arteries. I n v o l v e m e n t of the m a i n left ~c o r o n a r y arterY was considered s e p a r a t e l y , Significant c o r o n a r y a r t e r y disease was defined a s n a r r o w i n g of a c o r o n a r y a r t e r y b y m o r e t h a n 50 p e r c e n t of the l u m e n . Single vessel disease was defined as significant c o r o n a r y a r t e r y disease of only one vessel, while double a n d triple vessel disease indicated significant disease of t w o or t h r e e coron a r y arteries, respectively. F o l l o w - u p a f t e r coron a r y surgery was o b t a i n e d b y office visit or by telephone. S t a t i s t i c a l e v a l u a t i o n of all the d a t a was o b t a i n e d by t h e t w o - t a i l e d S t u d e n t ' s t t e s t for u n p a i r e d d a t a a n d X2 test 8 w i t h t h e assistance of a statistician.
8 (13)
12 (20)
Results
I
Group II Group I (ASHD)* Total number Duration of symptoms (yrs. _+ 1 S.D.) Angina pectoris Intermittent claudication Medical history: Myocardial infarction (by history) Hypertension Cigarette smoking Diabetes mellitus Family history: Arteriosclerotic heart disease Hypertension Diabetes mellitus Myocardial infarction (by ECG) Cardiomegaly (by x-ray)
-
Group1II (ASHD § PVD)
*ASHD = arteriosclerotic heart disease; PVD = peripheral vascular disease. tNumbers in parenthesis represent the per cent for each group. :~When Group I compared to Group II p < 0.005; when Group I compared with Group III p < 0.001; when Group II compared to Group III p < 0.01. w Group I compared to Group III p < 0.01.
uria. On admission, each p a t i e n t was closely questioned as to a family history in first generation relatives of arteriosclerotic h e a r t disease, hypertension, or diabetes mellitus. A twelve-lead s t a n d a r d electrocardiogram was t a k e n on all p a t i e n t s a n d was i n t e r p r e t e d on t h e basis of accepted criteria. 3 C h e s t radiologic e v a l u a t i o n a n d i n t e r p r e t a t i o n w a s p e r f o r m e d b y a radiologist to define the presence Or absence of c a r d i o m e g a l y . After a 12- to 16-hour fast and d i s c o n t i n u a t i o n of all medication, blood was d r a w n in t h e m o r n i n g for a glucose tolerance test and lipid studies. S e r u m cholesterol was d e t e r m i n e d using an a u t o a n a l y z e r and s e r u m triglyceride was determined by a modification of the m e t h o d described by Soloni. 4 F o r b o t h cholesterol a n d triglyceride an a b n o r m a l value was defined as t h a t value above a recommended age-adjusted normal range as r e c o m m e n d e d b y Fredrickson. 5 All p a t i e n t s u n d e r w e n t c o m p l e t e cardiac catheterization a n d selective c o r o n a r y a r t e r i o g r a p h i c studies by m e t h o d s previously described. 6 Selective c o r o n a r y a n g i o g r a m s were reviewed a n d e a c h
574
E a c h of the t h r e e groups, m a t c h e d for b o t h age a n d sex, consisted of 49 m a l e a n d 11 f e m a l e patients. T h e a v e r a g e age of the m a l e a n d f e m a l e p a t i e n t s was 56 __ 8.4 a n d 60 _+ 8.5 years, respectively. T h e ages of t h e p a t i e n t s r a n g e d f r o m 37 to 75 y e a r s with 80 per cent of the p a t i e n t s 50 y e a r s or over. Seven p a t i e n t s were 70 y e a r s or older. A c o m p a r i s o n of the clinical profile of t h e t h r e e groups of p a t i e n t s is s h o w n in T a b l e I. T h e frequency of h y p e r t e n s i o n or cigarette s m o k i n g revealed no significant differences w h e n all t h r e e groups were c o m p a r e d with e a c h other. T h e f r e q u e n c y of diabetes m e l l i t u s was significantly higher in b o t h G r o u p I I (p < 0.005) a n d I I I (p < 0.001) w h e n c o m p a r e d to G r o u p I. F u r t h e r more, in G r o u p I I I , 45 per cent of t h e p a t i e n t s h a d diabetes mellitus, significantly higher t h a n t h e frequency in G r o u p II. T h e f r e q u e n c y of a f a m i l y history of arteriosclerotic heart disease (p < 0.01), diabetes mellitus (p < 0.01) a n d h y p e r t e n s i o n (p < 0.025) was higher in G r o u p I I I t h a n G r o u p I (Table i). I n t e r m i t t e n t claudication, which w a s p r e s e n t only in G r o u p I I I , preceded a n g i n a pectoris in 41 p a t i e n t s (68 per cent). One of these p a t i e n t s h a d a h i s t o r y of a l u m b a r s y m p a t h e c t o m y a n d t w o p a t i e n t s h a d previous f e m o r a l - p o p l i t e a l b y p a s s surgery. A l m o s t u n i f o r m l y , with t h e onset of exertional a n g i n a pectoris, the i n t e r m i t t e n t claudication caused either no f u n c t i o n a l disability or
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Angina pectoris and intermittent claudication showed no progression. In the 19 p a t i e n t s with the i n t e r m i t t e n t claudication developing after the onset of angina pectoris, the functional disability was due p r e d o m i n a n t l y to the angina pectoris. T h e serum cholesterol for Groups II and III were 246 + and 46 and 2 5 9 _ 47 mg. per cent, respectively, which are significantly higher (p < 0.01) t h a n 203 • 36 mg. per cent, observed in Group I. T h i r t e e n per cent of the patients in both Group II and III had an a b n o r m a l cholesterol, as compared to 4 per cent n o t e d in G r o u p I. T h e serum triglyceride for Group II and III were 177 ___ 87 and 176 • 93 mg. per cent, which was significantly higher (p < 0.01), t h a n 134 • 64 mg. per cent found in Group I. T h e f r e q u e n c y of an abnormal triglyceride in Group II and I I I were 38 and 47 per cent, respectively, as c o m p a r e d to 11 per cent in Group I. Comparing Group II and III in respect to the n u m b e r of vessels involved with significant coron a r y a r t e r y disease and the t o t a l c o r o n a r y score, revealed no significant differences (Table II). On the basis of the functional s t a t u s of the patient, together with the c o r o n a r y a n a t o m y and left ventricular function, a o r t o c o r o n a r y bypass surgery was performed on 48 and 47 patients in Group II and III, respectively. T h e n u m b e r of grafts placed at the time of surgery and the postoperative course were c o m p a r a b l e in b o t h groups. Only one p a t i e n t died at surgery in G r o u p III. In the remaining patients in b o t h of these groups, surgery was not performed for several reasons (Table III), including poor left v e n t r i c u l a r function, diffuse c o r o n a r y a r t e r y disease, infarction or expiration while waiting for surgery, or insufficient disease judged not to w a r r a n t bypass. Postoperative follow-up revealed f u n c t i o n a l cardiac improvement in the majority of patients in b o t h groups (Table III). Of the 43 patients in Group III, functional d e t e r i o r a t i o n on follow-up due to i n t e r m i t t e n t claudication was observed in 12 patients (28 per cent). In six of these patients surgery was performed six to 24 m o n t h s after coronary surgery and included l u m b a r s y m p a t h e c t o m y in one, femoral-popliteal bypass in four, and a m p u t a t i o n in one patient. Discussion T h e pathophysiologic basis of b o t h angina pectoris and i n t e r m i t t e n t claudication are rem a r k a b l y similar. B o t h clinical conditions are usually manifested on exertion as a result of
American Heart Journal
Table II. C o r o n a r y a r t e r y a n a t o m y
l GroupII I. Group III Number of vessels involved Single lYo~ble Triple Main left coronary disease Total coronary arterv score (mean ___1 S.D.)
11 22 27 4 10.0 • 2.8
10 24 26 5 9.9 • 2.8
Table III. Surgery and follow-up
Ioroo, llOro "I Aortocoronary bypass surgery Surgical mortality Coronary surgery not performed Poor left ventricular function and/or diffuse coronary artery disease Infarction or expired waiting for surgery Surgery not recommended for single vessel disease of right coronary or circumflex artery Postoperative follow-up (mean; range) Number followed Cardiac status Improved Unchanged Worse Intermittent claudication Improved Unchanged Worse
48
47 0
12
1 13
8
9
1
2
3
2
2.6; 1/2-5.4
2.2 yrs; 1~-5.1
42
43 38 3 1
40 1 2 3 28 12
a t h e r o m a t o u s changes in t h e arterial system. B o t h are related to t r a n s i e n t ischemia which m a y be relieved by rest. T h e F r a m i n g h a m S t u d y ~ indicated t h a t the risk of one of these ischemic clinical states is increased by the presence of the other. In the F r a m i n g h a m S t u d y , m e n with preexisting angina pectoris h a d almost t h r e e times and w o m e n had five times the risk of developing i n t e r m i t t e n t claudication when c o m p a r e d t o a population not having evidence of ischemic h e a r t disease. In a similar m a n n e r , p a t i e n t s with preexisting i n t e r m i t t e n t claudication were f o u n d to have a p r o n o u n c e d increased risk of developing angina pectoris. Such a relationship suggests a
575
H a m b y et al.
common etiologic basis for both peripheral vascular and coronary artery disease. In studies devoted to patients with peripheral vascular disease, the frequency of coexisting coronary disease varied from 16 to 29 per cent2 -11 In the present study of a patient population referred for ischemic heart disease, the frequency of intermittent claudication was observed to be five per cent. This frequency cannot be used as representative of the true frequency of intermittent claudication with angina pectoris since the patients in the present study represent a select group referred primarily because of disabling symptoms of angina pectoris. Furthermore, it is quite conceivable that pre-existing intermittent claudication will limit and protect against the functional restriction that angina pectoris would otherwise have brought on. In the present study, in almost two-thirds of the patients, the clinical manifestations of peripheral vascular disease preceded those of coronary artery disease. In three of these patients, surgical intervention (lumbar sympathectomy in one and femoral-popliteal bypass in two) was required because of major restrictions as a result of the peripheral vascular disease. In the majority of patients, once the symptoms of coronary artery disease developed, the intermittent claudication caused only minor disability. It is apparent that the physical restriction brought on by angina pectoris resulted in a limited protection from the compromised circulation in the lower extremities. It was not uncommon for a patient to note significant improvement in the anginal status as a result of medication only to find himself limited by exertional cramps in his legs. This is further exemplified by the events that occurred after aortocoronary bypass surgery. In almost 30 per cent of the patients the intermittent claudication was reported on follow-up to have worsened, necessitating some form of surgery in six patients. Thus, the alleviation of the myocardial ischemic symptoms from the coronary artery disease permitting an increased functional tolerance unmasked the compromised circulation to the lower extremities. The patients with both coronary artery and peripheral vascular disease (Group III) were compared to patients also referred for angina pectoris, but not having peripheral vascular disease (Group II), in order to determine wliether there were any distinct characteristics other than intermittent claudication which could distinguish
576
one group from the other. Furthermorr both of the groups with angina pectoris were compared with an age- and sex-matched control group (Group I) that had neither evidence of peripheral or coronary artery disease in order to determine whether the factors evaluated were simply characteristic of any patient population of similar age and sex having arteriosclerotic heart disease. Epidemiologic studies 12. 13 have indicated that both hypertension and cigarette smoking are distinct risk factors for the occurrence of coronary artery disease. Similar types of epidemiologic studies on peripheral vascular disease are not available. In the present study both of these factors were more frequent in the patients with coronary artery disease (Group II and III), as compared to the control group (Group I); however, the differences were not statistically significant (Table I). Diabetes mellitus appeared to be the one factor which distinguished patients with peripheral vascular disease from both groups of patients with no evidence of peripheral vascular disease (Table I). Furthermore, the frequency of diabetes mellitus in both groups with coronary artery disease (Groups II and III) was significantly higher than the group of patients without coronary artery disease. The association of coronary artery disease 14-16 and peripheral vascular disease 14. 1~. 18 with diabetes mellitus has been well documented. The present study confirms these observations and indicates that the diabetic patient has an increased risk of clinically developing simultaneously both coronary artery and peripheral vascular disease. A comparative review of all three groups of patients for a family history of coronary artery disease, hypertension, and diabetes mellitus revealed no significant differences between the two groups with angina pectoris. However, comparing the angina pectoris patients who also had peripheral vascular disease, with the control group, revealed an increased frequency of a family history of arteriosclerotic heart disease ( p < 0 . 0 1 ) and hypertension (p < 0.025). Serum cholesterol and triglyceride were significantly higher in both of the groups with coronary artery disease, as compared to the control group. Neither cholesterol nor triglyceride levels distinguished the patients having only angina pectoris from those having intermittent claudication as well. The lipid studies reported by Greenhalgh and coworkers 11 on patients with peripheral vascular
November, 1977, Vol. 94, No. 5
Angina pectoris and intermittent claudication
disease are c o m p a r a b l e to those found in b o t h groups of the present s t u d y w i t h c o r o n a r y a r t e r y disease. In t h a t study, an a b n o r m a l cholesterol level was observed in 14.5 per cent of the patients, as compared to 13 per cent in G r o u p II and I I I of the present study. An elevated triglyceride level was present in 39.5 per cent of the p a t i e n t s in Greenhalgh's series, as compared to 38 and 47 per cent in Group II and III, respectively. In the s t u d y of Vyden and associates 9 of patients with peripheral vascular disease, 50 per cent had an elevated serum triglyceride level, whereas the serum cholesterol levels were similar to a control group. These studies, as w e l l as those on patients with coronary a r t e r y disease, 19-21 suggest an i m p o r t a n t role of a b n o r m a l serum triglyceride level in the pathogenesis of atherosclerosis. This s t u d y d e m o n s t r a t e s t h a t the severity of the coronary a r t e r y disease, as reflected by either the n u m b e r of vessels involved with significant disease or the c o r o n a r y a r t e r y score (Table II), was in no way different in patients with intermitt e n t claudication and angina pectoris when compared to a group of patients m a t c h e d for age and sex having only c o r o n a r y a r t e r y disease. T h e n u m b e r of patients undergoing a o r t o c o r o n a r y bypass surgery, n u m b e r of grafts placed at the tim~ of surgery, postoperative course and followu p of their cardiac status, were c o m p a r a b l e in b o t h groups. Thus, it is a p p a r e n t t h a t peripheral vascular disease of the lower extremities in a patient with c o r o n a r y a r t e r y disease should not interdict coronary revascularization, if clinically warranted. However, as indicated by our followup experience, the patient should u n d e r s t a n d t h a t clinical i m p r o v e m e n t in the cardiac s t a t u s m a y be accompanied by recurrence or a p p a r e n t deterioration of the vascular insufficiency in the lower extremities. If such a course of events does occur, consideration m a y be required for surgical revascularization in the lower extremities.
Summary Sixty patients referred for angina pectoris and having coexisting i n t e r m i t t e n t claudication (Group III) were compared with two groups of patients m a t c h e d for b o t h age and sex. One group (Group I), had no evidence of either c o r o n a r y or peripheral vascular disease, while G r o u p II had only s y m p t o m a t i c c o r o n a r y a r t e r y disease. T h e ages of the patients ranged from 37 to 75 years with 80 per cent of the patients 50 years or over.
American Heart Journal
In Group III, i n t e r m i t t e n t claudication preceded the d e v e l o p m e n t of angina pectoris in 41 p a t i e n t s (68 p e r cent) and with the onset of exertional angina pectoris, the i n t e r m i t t e n t claudication usually caused no m a j o r disability. T h e f r e q u e n c y of h y p e r t e n s i o n and cigarette smoking was n o t different when all three groups were compared. Diabetes mellitus was significantly higher in b o t h Group II (p < 0.005) and G r o u p III (p < 0.001) t h a n in G r o u p I. In G r o u p III, 45 per cent of the patients had diabetes mellitus as c o m p a r e d to 22 per cent in G r o u p II (p < 0.01). T h e f r e q u e n c y of a family history of arteriosclerotic h e a r t disease (p < 0.01), diabetes mellitus (p < 0.01) a n d hypertension (p < 0.025) was higher in G r o u p III, as compared to G r o u p I. S e r u m cholesterol and triglyceride comparison revealed no differences between Groups II a n d I I I , b u t b o t h groups were significantly higher (p < 0.01), as c o m p a r e d to Group I. T h e severity of c o r o n a r y a r t e r y disease as reflected by the n u m b e r of vessels involved and c o r o n a r y a r t e r y score were similar in b o t h G r o u p II and III. T h e n u m b e r of p a t i e n t s o p e r a t e d on for c o r o n a r y surgery, n u m b e r of grafts required, postoperative course and follow up of their cardiac s t a t u s was similar for b o t h G r o u p II and III. In 12 of 43 patients followed in G r o u p III, a recurrence or a p p a r e n t deterioration of the vascular insufficiency in the lower extremities required surgery in six patients. T h u s , peripheral vascular disease of the lower extremities s h o u l d not be a d e t e r r e n t against r e c o m m e n d i n g a patient for c o r o n a r y surgery if otherwise clinically warranted. The authors would like to acknowledge the critical review given by Dr. Irwin Hoffman, as well as the assistance given by Mrs. Brenda Hamby.
REFERENCES 1. Gould, S. E.: Pathology of the heart and blood vessels, 3rd ed., Springfield, Ill., 1968, Charles C Thomas, Publisher, p. 562. 2. Kannel, W. B., Skinner, J. J., Jr, Schwartz, M. J., and Shurtleff, D.: Intermittent claudication. Incidence in the Framingham Study, Circulation 41:875, 1970. 3. Massie, E., and Walsh, T. J.: Clinical vectorcardiography and electrocardiography, Chicago, 1960, Year Book Publishers, Inc. 4. Soloni,F. G.: Simplified manuel micromethod for determination of serum triglycerides, Clin. Chem. 17:529, 1971. 5. Fredrickson, D. S.: A physician's guide to hyperlipidemia, Mod. Concepts Cardiovasc. Dis. 41-31, 1972. 6. Hamby, R. I., Gupta, M. P., and Young, M. W.: Clinical and hemodynamic aspects of single vessel coronary artery disease, AM. HEARTJ. 85:458, 1973. 7. Bruschke, A. V. G.: The diagnostic significance of the
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8. 9.
10.
11.
12. 13.
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coronary arteriogram. A study of its value in relation to other diagnostic methods, Utrecht, 1970, Kemink en Zoon, N.V. Baston, H. C.: An introduction to statistics in the medical science, 6th ed., Minneapolis, 1963, Burgess Publishing Co. Vyden, J. K., Thorner, J., Nagasawa, K., Takano, T., Groseth-Dittrich, M. F., Perlow, R., and Swan, H. J. C.: Metabolic and cardiovascular abnormalities in patients with peripheral arterial disease, AM. HEART J. 90:703, 1975. Juergens, J. L., Barker, NI W., and Hines, E. A.: Atherosclerosis obliterans: Review of 520 cases with special reference to pathogenic and prognostic factors, Circulation 21:188, 1960. Greenhalgh, R. H., Rosengarten, D. S., Mervart , I., Lewis, B., Calnon, J. S., and Martin, P.: Serum lipide and lipoproteins in peripheral vascular disease, Lancet 2:947, 1971. Kannel, W. B., Kagan, A., Dawber, T. R., and Revotskie, N.: Epidemiology of coronary heart disease. Implications for the practicing physician, Geriatrics 1 7:675, 1962. Rosenman, R. H., Brand, R. J., Jenkins, D., Friedman, M., Straus, R., and Wurm, M.: Coronary heart disease in the western collaborative group study. Final follow-up experience of 81A years, J.A.M.A. 233:872, 1975.
14. LeCompte, P. M.: Vascular lesions in diabetes mellitus, J. Chronic Dis. 2:178, 1958. 15. Clawson, B. J., and Bell, E. T.: Incidence o f fatal coronary disease in non-diabetic and in diabetic persons, Arch. Pathol. 48:105, 1949. 16. Bell, E. T.: A post mortem study of vascular disease in diabetes, Arch. Pathol 53:444, 1952. 17. Lisa, J. R., Magiday, M., and Hart, J. F.: Peripheral arteriosclerosis in the diabetic and the nondiabetic, J.A.M.A. 1 18:1353, 1942. 18. Wessler, S, and Silberg, N. R.: Studies in peripheral arterial occlusive disease II. Clinical findings in patients with advanced arterial obstruction and gangrene, Circu" lation 7:810, 1953. 19. Barboriak, J. J~, Renim, A. A., Anderson, A. J., Tristani, F. E., Walker, J. A., and Flemma, R. J.: Coronary artery occlusion and blood lipids, AM. HEART J. 87:718, 1974. 20. Gustafson, A., Elmfeldt, D., Wilhelmsen, L., and Tibblin, G.: Serum lipidE and lipoproteins in men after myocardial infarction compared with representative population sample, Circulation 46:709, 1972. 21. Leren, P., and Hasbrekke, O.: Blood lipidE in patients with coronary heart disease, Acta Med. Scand. 189:505, 1971.
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