Early and late results of coronary artery bypass in patients with hyperlipoproteinemia

J

THORAC CARDIOVASC SURG

79:372-380, 1980

Early and late results of coronary artery bypass in patients with hyperlipoproteinemia Hyperlipoproteinemia is a known risk factor for the development of coronary artery disease. To assess the perioperative and late results of myocardial revascularization for angina pectoris in patients with hyperlipoproteinemia, we reviewed the records of 200 patients (age range 24 to 75 years). Preoperatively the average New York Heart Association (N.Y.H.A.) angina class was 3.1 ± 0.7. One hundred three patients (51.5%) had type JJ disease, 95 patients (47.5%) type lV, and two (1%) had type JJJ or V disease. The mean age of the patients with type JJ disease was 3 years less than that of patients with type IV disease (50 versus 53 years, p < 0.05). When compared with subjects with type 1V disease, those with type JJ disease were shown by angiography to have a significantly higher incidence of left main coronary artery stenosis (28% versus 6%), a greater average number of proximal coronary artery lesions per patient (2.8 ± 0.9 versus 2.4 ± 0.7), and more frequent atheromatous disease in distal coronary artery segments (74% versus 49%) (all p < 0.01). The operative mortality rate of coronary revascularization was 6% (12/200), including nine patients with type JJ disease (9.5%) and three with type IV disease (2.9%). All deaths occurred in patients with three- and four-vessel coronary artery disease. Seven (58%) of these 12 patients had left main coronary artery disease and 10 (83%) had significant distal lesions. The nonfatal perioperative infarct rate was 4%. At a mean follow-up period of 33 months (range 10 to 90 months), there have been four late deaths (2.2%), including three patients with type JJ disease (3.5%) and one with type 1V disease (1.0%). There have been nine late nonfatal myocardial infarctions (4.9%). One hundred thirty-nine patients (73%) have had complete relief of angina and 34 (19%) have had substantial improvement. The average postoperative N.Y.H.A. class was similar for the two groups (1.6 ±O.7). Myocardial revascularization can be accomplished with acceptable risk and excellent long-term results in patients with hyperlipoproteinemia. However, patients with type JJ disease have higher hospital and late mortality rates. These findings are consistent with the known increased prevalence of left main coronary stenosis and diffuse distal coronary artery disease in patients with this type of hyperlipidemia.

Eric C. Hanson, M.D., Frederick H. Levine, M.D., N. Scott Adzick, M.D., Robert S. Lees, M.D., Willard M. Daggett, M.D., W. Gerald Austen, M.D., and Mortimer J. Buckley, M.D., Boston, Mass.

Although many clinical aspects of the metabolic disorders now termed hyperlipoproteinemias had been described by physicians in the early nineteenth century , it was not until the 1930 's that Thannhauser and Magendantz' and Muller" recognized the association of hypercholesterolemia (familial type II hyperlipoproteinemia) and the premature onset of coronary artery From the Departments of Surgery and Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Mass. Supported in part by United States Public Health Service Grant H-L-17665. . Read at the Fifth Annual Meeting of The Samson Thoracic Surgical Society, Sun Valley, Idaho, June 5'10 8,1979. Address for reprints: Frederick H. Levine, M.D., Department of Surgery, Massachusetts General Hospital, Boston, Mass. 02114.

372

and peripheral vascular disease. Fredrickson and Lees" made additional progress in 1965 by introducing a classification system of hyperlipoproteinemias based upon patterns of elevation of specific lipoproteins in the plasma. Their findings have enabled clinical investigators to evaluate and treat affected patients in hopes of delaying the development of atherosclerosis. Unfortunately, however, in the majority of patients with abnormal lipoprotein profiles (principally types II and IV), the disease is discovered only after the development of severe angina or myocardial infarction or both.v 5 Since many of these patients are considered candidates for coronary artery bypass, we performed this retrospective study to assess the effects of lipoprotein phenotype on the perioperative and late results of myocardial revascularization.

0022-5223/80/030372+09$00.90/0 © 1980 The C. V. Mosby Co.

Volume 79

Hyperlipoproteinemia

Number 3 March,1980

Methods and study group To identify the patients in this study, we reviewed the hospital records of over 3,000 patients who underwent coronary artery bypass grafting at this institution from 1972 to 1978. Two hundred patients (154 men and 46 women) with an average age of 52 ± 9 years (range 24 to 75 years) were identified who had significant evidence of hyperiipoproteinemia and had undergone coronary artery revascularization. All patients were assigned lipoprotein phenotypes according to the classification system of Fredrickson and Lees. 3 Diagnoses were based on the finding of at least two sets of abnormal fasting levels of serum triglycerides or cholesterol or both (triglycerides > 160 mg/IOO ml, cholesterol> 280 mg/lOO ml) and one or more abnormal lipoprotein electrophoretic patterns. The patients with type II hyperlipoproteinemia included four presumed to be homozygous for the disease. All patients' phenotypic diagnoses were assigned to one of three categories. In Category I were patients whose plasma lipid concentrations, lipoprotein electrophoretic patterns, and family history left no doubt as to diagnosis. Category II comprised patients with lipoprotein electrophoretic patterns or lipid values which were borderline or were obtained while the patients were receiving lipid-lowering medications. Category III included those patients whose lipid values and electrophoretic analyses were intermediate between classification groups; their phenotype was assigned as type II or IV by the presence or absence of xanthomas and by the appropriate family history. Patients were evaluated for historic and electrocardiographic evidence of prior myocardial infarction. The severity of angina was assessed by use of the New York Heart Association (N.Y.H.A.) classification system. All patients with unstable angina or angina at rest were placed in Class IV. Other significant risk factors evaluated included smoking, diabetes, hypertension, coexisting vascular disease, and strong family history of premature coronary artery disease. The catheterization and angiographic data on all patients were reviewed. The technique of Bloch and associates" was used to divide the four major portions of the coronary arteries (the left main coronary artery, the left anterior descending branch, the left circumflex branch, and the right coronary artery) into proximal and distal segments, and the location and number of all significant lesions were evaluated. Those designated as proximal included the left main coronary artery, the proximal two thirds of the left anterior descending branch, the left circumflex coronary artery to the origin

37 3

of the last significant marginal branch, including the proximal third of the major marginal branch, and the dominant right coronary artery to the origin of the posterior descending branch. In patients with a dominant left coronary system, the left circumflex artery was considered proximal to the origin of the posterior descending branch, and the entire right coronary artery was considered to be distal. All other remaining arterial branches were designated distal. Coronary lesions were defined as significant if a 50% reduction in the diameter of the arterial lumen could be demonstrated. All comments on the general size of the coronary arteries were recorded. The presence or absence of calcium in the aortic valve, anulus, outflow tract, or coronary arteries was determined, as was the presence and severity of all valvular heart lesions. The indication for operation in all patients was moderate-to-severe angina pectoris. All patients received one to five coronary artery bypass grafts constructed of autologous saphenous vein. A small percentage of patients underwent associated aortic or mitral valve replacement, left ventricular aneurysmectomy, or coronary artery endarterectomy. The postoperative courses of all patients were reviewed. Development of new Q waves on electrocardiogram and serial cardiac enzyme elevation, as described elsewhere," were used as criteria for a diagnosis of perioperative myocardial infarction. Autopsies were performed on all patients who died in the hospital. At the time of study all surviving patients were evaluated as to the presence of angina, subsequent myocardial infarctions, and current levels of activity. All late deaths were evaluated as fully as possible. All numerical averages were presented as the mean with the standard deviation. Groups were compared by chi square analysis or, where expectations were too small for chi square analysis, by the Fisher exact test. Results Ninety-five patients were given a diagnosis of type II disease (47.5%) and 103, type IV disease (51.5%). No type I disease was encountered and only one case each of types III and V (total 1%) (Fig. I). Certainty of diagnosis was high, as 88% of the patients were in Category I and only 9% and 3%, respectively, were in Categories II and III. Lipoprotein electrophoretic patterns were obtained in 40% of all patients. Since so few patients with types III and V disease were encountered, statistical comparisons were formulated only between types II and i V. Among patients with type II disease the average cholesterol concentration was 363 ± 86 mg/IOO m1 and

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374 Hanson et at.

/

Types mond TIl 2 pts,

Fig. 1. Distribution of patients by phenotype and by sex.

the average triglyceride level, 176 ± 76 mg/100 ml, Thirty-four percent of these patients had oculocutaneous stigmata of hyperlipoproteinemia. Among patients with type IV disease the average triglyceride level was 328 ± 162 mg/ 100 mland the average cholesterol value, 214 ± 41 mg/100 ml. Significantly fewer of these patients (9%) had ocular or cutaneous stigmata of hyperlipoproteinemia (p < 0.001). On the average, patients with type II disease were 3 years younger than those with type I V disease (50 ± 10 years, range 24 to 75 years, versus 53 ± 7 years, range 34 to 67 years). Altogether, 46 of 200 (23%) patients were women. However, far more female patients had type II (27/95, 28%) than type IV disease (19/103, 18%). Comparison of ages among women was even more significant, as those with type II disease averaged 49 ± 12 years and those with type IV disease, 58 ± 6 years. Consequently, more patients with type II hyperlipoproteinemia presented with coronary artery disease at ages less than 30 or 40 years (3% and 17%) than did patients with type IV disease (0% and 4%). These findings were all significant (p < 0.05). Appreciable differences also existed in the risk factor patterns between types II and IV. Whereas patients with type IV disease had a higher incidence of smoking (83% versus 72%) and diabetes (22% versus 9%) (both P < 0.05), those with type II disease had a more significant family history of premature coronary disease (88% versus 73%, p < 0.01). Although more subjects

with type IV disease were hypertensive (47% versus 36%) and more with type II disease had coexisting vascular disease (20% versus 12%), neither finding was statistically significant. A similar proportion of each major lipoprotein phenotype had a prior history of myocardial infarction (type II 53% versus type IV 55%); however, no patient had more than two prior myocardial infarctions. There were no important differences in the distribution within the N.Y.H.A. angina classes. The two groups had identical average N.Y.H.A. classifications (3.1 ± 0.7) (Table I). Angiography demonstrated appreciable differences in the number and location of lesions within the coronary circulation of the patients with types II and IV disease. Twenty-eight percent (27/95) of patients with type II disease had left main coronary artery stenoses, whereas only 6% (6/103) of those with type IV disease had a left main lesion (p < 0.001). Similar distributions of patients in each major phenotype category had stenoses of the proximal segments of each of the three large coronary arteries after the left main coronary artery: type II-LAD* 84/95 (88%), LCfx 70/95 (74%), RCA 75/95 (79%); type IV-LAD 94/103 (91%), LCfx, 69/103 (67%), RCA, 82/103 (80%). The incidence of four-vessel coronary artery disease was significantly higher in patients with type II disease (21/95, 22%) than in those with type IV disease (3/ 103, 3%) (p < 0.001), and the average number of proximal lesions (including left main) was also higher in those patients with type II disease (2.8 ± 0.9) than in those with type IV disease (2.4 ± 0.7 (p < 0.01). Overall, the incidence of one-, two-, three-, and fourvessel coronary artery disease was 10%, 33%, 45%, and 12%, respectively. Angiography demonstrated that more patients with type II disease than type IV had one or more severe distal coronary artery stenoses (70/95, 74%, versus 50/103,49%); p < 0.001). Furthermore, in the distribution of each distal coronary artery, more patients with type II than type IV disease presented with significant obstructions: type II-distal LAD* 39/95 (41%), distal LCfx 33/95 (37%); distal RCA 56/95, 59%; type IV-distal LAD 22/103 (21%), distal LCfx 18/103 (17%), distal RCA 29/103 (28%) (all p < 0.01). Consequently, the average number of distal lesions in type II was greater than in type IV (1.5 ± 1.1 versus 0.7 ± 0.9). These findings were highly significant (p < 0.001). *LAD = Left anterior descending branch. LCfx branch. RCA = Right coronary artery.

= Left circumflex

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March,1980

Table I. Preoperative factors in patients with hyperlipoproteinemias

Average age (yr) Male Female Prior myocardial infarctions (%) None One Two Average N.Y.H.A. angina class Diabetes (%) Hypertension (%) Smoking (%) Family history (%) Vascular disease (%)

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I

Table II. Preoperative angiographic findings

Type II

Type IV

Total group

50 ± 10 50 ± 10 49 ± 12

53 ± 7 52 ± 7 58 ± 6

52 ± 9 51 ± 8 53 ± II

47 42 II

45 45 10

47 43 10

3.1 ± 0.7

3.1 ± 0.7

3.1 ± 0.7

9 36 72 88 20

22 47 83 73 12

17 42 78 80 16

Subjective differences in the size of coronary arteries were noted on angiography. Forty-three percent (41/ 95) of patients with type II disease were thought to have small coronary arteries, whereas this comment was reported in only 16% (15/103) of those with type IV disease. Extensive calcification was present in the ascending aorta or coronary arteries in 34 of 95 (36%) patients with type II disease but in only nine of 103 (9%) with type IV disease (p < 0.001). Significant aortic stenosis was found in eight of 95 (8%) patients with type II disease but only two of 103 (2%) with type IV disease (p < 0.05). Equal numbers of patients in each group presented with mitral stenosis or regurgitation (three each) or left ventricular aneurysm (four each) (Table II). Both groups received approximately the same average number of grafts per patient (type II 2.4 ± 0.8; type IV 2.3 ± 0.9). The operation was the second revascularization procedure for six patients with type II disease (6%) but only one with type IV disease (l %) (p < 0.05). Three patients with type II disease underwent associated aortic valve replacement, and two with type IV disease underwent valve replacement (one mitral and one aortic valve replacement). One patient with type IV disease underwent left ventricular aneurysm resection. Eight patients (4%) had nonfatal perioperative myocardial infarctions. The distribution of infarctions within each phenotype was similar (type II 3/95, 3%; type IV 5/103,5%). Twelve patients died in the perioperative period, for a total hospital mortality rate of 6%. Significantly more

I Main left coronary artery stenosis (%) Proximal disease (%) Four vessel Three vessel Two vessel One vessel Distal disease (%) Three vessel Two vessel One vessel None Average stenoses (No.) Proximal Distal Small vessels (%) Aortic root or coronary artery calcium (%) Aortic stenosis (%) Mitral stenosis or regurgitation

Type II

28

I Type IV I Total group 6

18

22 40 28 10

3 49 37 II

12 45 33 10

18 36 20 26

5 16 28 51

II 25 24 40

2.8 ± 0.9 1.5 ± 1.1 43 36

2.4 ± 0.7 0.7 ± 0.9 16 9

2.6 ± 0.8 1.1 ± 1.0 29 22

8 3

2 3

5 3

Table III. In-hospital mortality and perioperative infarct rates

Hospital mortality Mortality With left main disease Without left main disease Three- or four-vessel disease One- or two-vessel disease Distal disease Perioperative infarct rate

Type II

Type IV

Total group

No·1 %

No·1 %

No·1 %

9

9.5

3

2.9

12

6

6 3 9 0 7 3

22 4 15 0 10 3

0 3 3 0 3 5

0 3 6 0 6 5

6 6 12 0 10 8

18 3 11 0 8 4

deaths occurred among patients with type II disease (9/95, 9.5%) than among those with type IV disease (3/103, 2.9%) (p < 0.05). The overall mortality rate for left main coronary artery stenosis was 18%. Six of the 12 patients who died during hospitalization had left main lesions and all had type II disease. All deaths occurred in patients with three and four-vessel coronary artery disease (average of 3.4 significant coronary artery lesions per patient versus 2.6 for the group as a whole). In addition, 10 of 12 (83%) had significant distal-vessel coronary artery disease, and seven of 12 (58%) were in N.Y.H.A. Class IV. Of the 12 patients who died, eight could not be weaned from cardiopulmonary bypass and died in the operating room of cardiogenic shock despite use of

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Thoracic and Cardiovascular Surgery

-Unchanged

or Worse, 2 %

Fig. 2. Extent of angina after revascularization.

intra-aortic balloon pump support. Six of these eight patients had type II hyperlipoproteinemia and seven (88%) had previous myocardial infarctions. Five (63%) had left main coronary stenosis. All had small vessel disease, six having two- or three-vessel involvement. In this group the average number of small vessel stenoses per patient was 2.3 compared to 1.1 for the entire series. Six patients (75%) had preoperative ejection fractions of less than 35%-an indication of significant compromise of left ventricular function. Postmortem examinations revealed extensive myocardial infarctions in all of these cases of intraoperative death. Among other patients who died was a 24-year-old woman with type II hyperlipoproteinemia, aortic stenosis, and diffuse three-vessel disease. She was treated with antiplatelet agents. After aortic valve operation and revascularization, a graft occluded when the bleeding parameters returned to normal. Two additional patients with type II disease died suddenly from massive pulmonary emboli during their second postoperative week. Altogether, three patients with type II disease died of thrombotic complications. One patient with type IV disease died of a respiratory arrest secondary to endotracheal tube failure (Table III). All surviving patients were followed for an average period of 33 months (range 10 to 90 months). Seventythree percent (134/182) reported no angina and 19% (34/182) had minimal angina and were greatly im-

proved. Five percent (10/182) were improved but still possessed significant anginal symptoms. Four patients (4/182, 2%) did not improve or were worse (Fig. 2). Equivalent results were seen in each major lipoprotein phenotype. The average N.Y.H.A. Class was 1.6 ± 0.7, with similar averages and distributions in each group (type II 1.6 ± 0.5; Type IV 1.5 ± 0.4). Altogether, 94/182 (52%) were in Class I, 73/182 (41%) were in Class II, 13/182 (7%) were in Class III, and 2/182 (1%) were in Class IV. Nine patients had nonfatal myocardial infarctions in the follow-up period (9/182, 4.9%). There were no significant differences in the incidence of infarction between groups (type IV 6/99, 6%, versus type II 3/83. 4%). There were four late deaths (2.1 %), three deaths in type II (3/86, 3.5%) and only one in type IV (1/100, 1%), occurring 13,24,25, and 33 months after operation. Prior to their deaths, there were two patients each in N.Y.H.A. Classes III and IV. All had significant angina and two of these four had undergone multiple coronary artery revascularizations. Although autopsies were not obtained in these cases, all deaths were sudden and presumed to be related to cardiac disease. Discussion

Hyperlipoproteinemia is a significant risk factor for the development of coronary artery disease." 5 Although recent reviews of patients undergoing coronary revascularizations have shown a 33% to 42% incidence

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of hyperlipidemia, 8. 9 this diagnosis could be accurately confirmed in only 7% of our cases, since the records of many patients suspected of hyperlipidemia frequently lacked adequate verification by our criteria. The majority of cases were either phenotype II or IV. Premature atherosclerosis is not a recognized complication of type I disease, and although it is associated with types III and V, both of these conditions are much less common." Hence, we found only one case of each type, representing 1% of our experience. The fact that patients with type II hyperlipoproteinemia were significantly younger (3 years), included significantly more women (27%), and presented with a somewhat different risk factor background than those with type I V disease has been previously reported.": 10-14 Seventeen percent of patients with type II disease were less than 40 years of age (mean age 50 years). Beaumont.!? Stone;" and their colleagues have shown that clinical coronary artery disease develops in 20% of heterozygous subjects with type II disease before age 40 and in half before age 50. Similarly, Laks and associates 16 have identified hypercholesterolemia as a risk factor in 77% of patients undergoing coronary artery operation before the age of 40 years. The significant penetrance of coronary artery disease in women with the type II phenotype, as shown by several authors;'?: 16. 17 is confirmed by our finding of a relatively high percentage of women within this group. Patients with type II disease have a higher incidence of positive family histories of premature atherosclerosis and associated peripheral vascular disease. This observation is consistent with the well-known dominant pattern and high penetrance of type II hyperlipoproteinemia and confirms similar reports of Beaumont, 10 Stone;" and their colleagues. The significantly increased incidence of diabetes in patients with type IV disease emphasizes an association previously reported by Hamby, 13 Dortimer /4 and their associates. Evidence linking both conditions to interrelated metabolic pathways has been previously presented." A most impressive finding in this study has been the difference in the pattern of coronary artery disease between subjects with types II and IV hyperlipoproteinemia. Those with type II disease presented with a greater incidence of left main coronary artery disease (28%) and severe distal coronary artery involvement (74%), a greater average number of major coronary artery stenoses per patient (2.8), and a higher incidence of calcium within the coronary arteries or the aortic outflow tract. Those with type IV disease had fewer and more proximal coronary artery stenoses (av-

erage 2.4 major lesions per patient), only a 49% incidence of distal coronary artery disease, and a much lower incidence of left main coronary artery stenosis and coronary artery and aortic root calcification. Subjective assessment of coronary artery size revealed a significantly higher incidence of small vessels among patients with type II disease. This confirms findings of Bloch, Dinsmore, and Lees," who first appreciated the combined severity of the proximal and distal coronary lesions in subjects with type II disease and noted the high incidence of left main coronary stenosis as well as small coronary arteries. Left main coronary artery stenosis is a welldocumented high-risk condition. 19. 20 Its prevalence in subjects with type II disease may in part explain the high early death rate reported among studies of type II phenotypes. 5. 15 The persistent finding of associated severe distal vessel disease in these patients would also predispose to higher early and late mortality rates of coronary artery revascularization in this group. The hospital mortality rate of patients with type IV disease was 3%. This figure is similar to those reported in many general studies of coronary artery revascularization.": 22 The 9% mortality rate of subjects with type II disease appears to be due largely to the high proportion of patients with left main coronary artery disease and diffuse disease of small distal vessels, the latter making revascularization technically difficult. In addition to intraoperative deaths, two patients died of massive pulmonary emboli and another died of sudden graft thrombosis. All three patients had type II hyperlipoproteinemia. The incidence of fatal pulmonary emboli among cardiac surgical patients is exceeding low (approximately 0.1 % in this institution). Hence, this finding of excessive thrombotic complications in patients with type II disease may support recent studies-'- 24 demonstrating a hypercoagulable state in such patients. Currently, many patients with type II disease are given anticoagulants or antiplatelet medications in the hope of preventing thromboembolic complications. Such therapy may be of value in such patients after revascularization. Even though the patients in this study had extensive coronary artery disease, follow-up evaluation demonstrated excellent symptomatic relief of anginacomparable to most unselected studies of patients undergoing revascularization. 21. 22 At a mean follow-up of 33 months, 73% of patients had no angina and 92% were greatly improved. Exercise tolerance was appreciably improved, with 52% of patients in N.Y.H.A. Class I and 41 % in Class II. These findings were

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applicable to patients both with type II and type IV hyperlipoproteinemia and demonstrate that revascularization can provide good clinical results even in patients with a high incidence of left main coronary lesions and severe proximal and distal disease. Recent studies by Lie,25 Barboriak.f" and their coworkers have shown the swift and inexorable progress of atherosclerotic disease in the native vessels and saphenous vein grafts of patients with type II disease; Norwood and associates" demonstrated that 73% of patients undergoing reoperation for angina had hyperlipidemia. Therefore, the late mortality rate in this study (type II 3%, type IV 1%) is lower than one might expect, perhaps because the majority of patients are currently under aggressive medical treatment. Although type IV and especially type II hyperlipoproteinemia represent a significant risk factor for the development of coronary artery disease, coronary artery revascularization in the symptomatic patient can be accomplished with acceptable risk and excellent longterm results. However, patients with type II disease appear to have higher hospital and late mortality rates. These findings are consistent with the known increased prevalence of left main coronary stenosis and diffuse distal coronary artery disease in patients with this type of hyperlipidemia. We are grateful to Ms. Marcia Leavitt for statistical analysis and to Ms. Ruthellen Cerrone for preparation of the manuscript.

8

9

10

II

12

13

14

15

16

17

2 3 4

5

6

7

REFERENCES Thannhauser SJ, Magendantz H: The different clinical groups of the xanthamatous diseases. A clinical physiological study of22 cases. Ann Intern Med 11:1662-1666, 1938 Muller C: Xanthomata, hypercholesterolemia, and angina pectoris. Acta Med Scand (Suppl) 89:75-79, 1938 Fredrickson DS, Lees RS: A system for phenotyping hyperlipoproteinemia. Circulation 31:321-327, 1965 Goldstein JL, Hazzard WR, Schrott HG, Bierman EL, Motulsky AG: Hyperlipidemia in coronary heart disease. I. Lipid levels in 500 survivors of myocardial infarction. J Clin Invest 52: 1533-1539, 1973 Fredrickson DS, Goldstein JL, Brown MS: The familial hyperlipoproteinemias, The Metabolic Basis of Inherited Disease, chap 30, 18 Stanbury, ed., New York, 1978, McGraw-Hill Book Company, Inc., pp 604-655 Bloch A, Dinsmore RE, Lees RS: Coronary arteriographic findings in Type II arid Type I V hyperlipoproteinemia. Lancet 1:928-930, 1976 Langou RA, Wiles JC, Peduzzi PN, Hammond GL, Cohen LS: Incidence and mortality of perioperative myo-

18

19

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21

22

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cardial infarction in patients undergoing coronary artery bypass grafting. Circulation 56:Suppl 2:54-58, 1977 Wiles JC, Peduzzi PN, Hammond GL, Cohen LS, Langou RA: Preoperative predictors of operative mortality for coronary bypass grafting in patients with unstable angina pectoris. Am J Cardiol 39:939-943, 1977 Kaiser GC, Bamer HB, Tyras DH, Codd JE, Mudd JG, Willman VL: Myocardial revascularization. Ann Surg 188:331-340, 1978 Beaumont V, Jacotol B, Beaumont JL: Ischemic disease in men and women with familial hypercholesterolemia and xanthomatosis. Atherosclerosis 24:441-450, 1976 Brunzell JD, Schrott HG, Motulsky AG, Bierman EL: Myocardial infarction in the familial forms of hypertriglyceridemia. Metabolism 25:313-320, 1976 Sale! AF, Riggs K, Mason D, Amsterdam EA, Zelis R: The importance of Type I V hyperlipoproteinemia as a predisposing factor in coronary artery disease. Am J Med 57:897-903, 1974 Hamby RI, Sherman L, Mehta J, Aintablian A: Reappraisal of the role of the diabetic state in coronary artery disease. Chest 70:251-257, 1976 Dortimer AC, Shenoy PN, Shiroff RA, Leaman DM, Babb JD, Liedtke AJ, Zelis R: Diffuse coronary artery disease in diabetic patients. Fact or fiction?: Circulation 57:133-136, 1978 Stone NJ, Levy RI, Fredrickson DS, Verter J: Coronary artery disease in 116 kindred with familial Type II hyperlipoproteinemia. Circulation 49:476-488, 1974 Laks H, Kaiser GC, Bamer HB, Codd JE, Willman VL: Coronary revascularization under age 40 years. Am J Cardiol 41:84-89, 1978 Dick TBS, Stone MC: Prevalence of three major risk factors in random sample of men and women and in patients with ischemic heart disease. Br Heart J 40:617-626, 1978 Olefsky MM, Farquhar JW, Reaven GM: Reappraisal of the role of insulin in hypertriglyceridemia. Am J Med 57:551-559, 1974 Iskandrian AS, Segal BL, Mundth ED: Appraisal of treatment for left main coronary artery disease. Am J Cardiol 40:291-293, 1977 Alford WC, Page HL, Burrus GR, Frist RA, Stoney WS, Thomas CS, Walker WE: Further evaluation of the surgical treatment of obstructive disease of the left main coronary artery. Ann Surg 187:658-664, 1978 Hurst JW, King SB, Logue BR, Hatcher CR, Jones EL, Craver JM, Douglas JS, Franch RH, Dorney ER, Cobbs BW, Robinson PH, Clements SD, Kaplan JA, Bradford JM: Value of coronary bypass surgery. Am J Cardiol 42:308-329, 1978 Mundth ED, Austen WG: Surgical measures for coronary heart disease. N Engl J Med 293:13-19,75-79,124-129, 1975 Carvalho AC, Colman RW, Lees RS: Platelet function in hyperlipoproteinemia. N Engl J Med 290:434-438, 1974

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24 Carvalho AC, Lees RS, Vaillanlove RR, Cabral RB, Weinberg RM, Colman RW: Intravascular coagulation in hyperlipidemia. Thromb Res 8:843-857, 1976 25 Lie JT, Lawrie GM, Morris GC Jr: Aortocoronary bypass saphenous vein graft atherosclerosis. Am J Cardiol 40:906-914,1977 26 Barboriak 11, Barboriak DP, Anderson AJ, Rimm AA, Tristani FE, Flemma RJ: Risk factors in patients undergoing a second aorta-coronary bypass procedure. J THORAC CARDIOVASC SURG 76:111-114, 1978 27 Norwood WI, Cohn LH, Collins 11; Results of reoperation for recurrent angina pectoris. Ann Thorac Surg 23:9-13, 1977

Discussion DR. RICHARD P. ANDERSON Seattle, Wash.

Dr. Hanson has done a prodigious amount of work in reviewing more than 3,000 patients operated upon at the Massachusetts General Hospital over the years 1972 to 1978. The patients represented here were selected because they fulfill fairly rigorous criteria for inclusion in the Fredrickson and Lee system of classifications of hyperlipoproteinemias. We do not know the true proportion of these patients in this group of 3,000 patients, because only those who had the tests done and recorded in a manner which could be recovered were identified. Probably, a larger number of patients could have been identified had the data been available, and this selection factor influences the results in an unpredictable fashion. The Fredrickson and Lee classification of hyperlipoproteinemias has been enormously popular, particularly during the past decade, but it has also been found to be without very much genetic reality, poorly reproducible, and no more helpful in management than a determination of serum cholesterol. Furthermore, it is my impression that a decade of publicity by the American Heart Association and the salad oil and spread industry has failed to yield any convincing evidence that either drugs or diet very much alter the morbidity or mortality for patients with coronary artery disease. What is fairly well proven, however, is that the level of serum cholesterol, which is generally greater in patients with type II than type I V disease, is a definite risk factor in coronary artery disease. Dr. Hanson has shown in this study that very high serum cholesterol is a definite risk factor in coronary artery operations, as well. This study has two important lessons for us. First, left main coronary artery stenosis is relatively common in patients with a very high cholesterol value. Second, left main stenosis in patients with a very high cholesterol value, the type II group, may be more dangerous surgically than would be the case in individuals with left main stenosis but lower cholesterol values, the type IV group. The operative mortality rates in the two groups were 22% and 0%, respectively. Dr. Han-

Hyperlipoproteinemia

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son's careful review of the coronary angiograms seems to provide a clue. The patients with a very high cholesterol value also have a high prevalence of both distal obstruction and of abnormally small vessels. This combination seems particularly lethal from a surgical standpoint and may account for this high mortality rate in patients with type II disease. Unfortunately, we have not learned very much about the late follow-up results in these patients. I think that an actuarial analysis of experience following operation in these two groups of patients will yield important information, and I look forward to seeing that analysis undertaken. DR. HAN SON (Closing) I would like to thank Dr. Anderson for his generous comments. At this time I do not feel that actuarial analysis of our data would be revealing. Although the patients in this study were selected from those presenting for operation over a 7 year period, nearly 95% of them were operated upon during a shorter 36 month period between 1975 and 1977. Since the follow-up data, that is, late deaths and N.Y.H.A. angina classes, were so similar between patients with type II and those with type IV disease, no statistical significance could be demonstrated, regardless of the analytic method used. On the other hand, we do believe that by following these patients for an average of 5 years we will be able to show important differences between groups and make some important conclusions concerning the long-term prognosis of operation in patients with hyperlipoproteinemias. What we expect to see among patients with type II disease are a higher late mortality rate, more frequent return of anginal symptoms, and a higher incidence of reoperation. Our data at this point imply but do not substantiate these theories. We believe that a longer follow-up period and an actuarial analysis at that time may help clarify these issues. Dr. Anderson states that a fasting cholesterol value may be of equal value to a more complex lipoprotein profile in determining a patient's risk for the development of coronary artery disease. I disagree. Besides totally failing to diagnose rare types of hyperlipoproteinemias, which have specific prognoses, a single fasting cholesterol can be exceedingly misleading or insufficient in diagnosing the more common forms of the disease and, therefore, assessing risk. Although the risk factor associated with progressive atherosclerosis has been thought of as the total cholesterol, it is actually the low-density lipoprotein (LDL) cholesterol. Patients with type IV disease who have elevated triglyceride levels can have elevated total cholesterol values, since nearly 20% of the very low-density lipoproteins (VLDL) are VLDL cholesterol. The actual LDL cholesterol level in these patients may be normal. We have found that many patients with grossly elevated triglycerides have elevated levels of cholesterol in addition, and it is important to separate those with true mixed hyperlipoproteinemias (type lIB) from these with type IV disease. We have shown that the prognoses between these groups are very different and that detailed analysis of these

380 Hanson et at.

patients' lipoprotein profiles is more than of passing scientific interest. During the period of 1975 through 1977, the hospital mortality rate for patients undergoing revascularization at our institution has been about 1.5%. This group includes many patients with severely depressed ejection fractions. The incidence of left main coronary artery stenosis has been 7.5%, with this subgroup experiencing a 3% mortality rate. In this study, the hospital mortality rate of patients with left main coronary artery stenosis was very high. The difficulty

The Journal of Thoracic and Cardiovascular Surgery

with this group was not just the presence of left main coronary artery stenosis but, rather, this lesion combined with severe distal coronary artery disease. In most institutions, patients with left main coronary artery stenosis can safely undergo revascularization. However, the revascularization of patients with diffuse distal coronary artery disease presents significant technical problems that make complete revascularization difficult and explains to a great extent the high operative mortality rate in this group of patients.

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