Serum triglycerides and HDL cholesterol major predictors of long-term survival after coronary surgery

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1 European Heart Journal (994) 5, Serum triglycerides and HDL cholesterol major predictors of long-term survival after coronary surgery T. LINDEN, G. BONDJERS, T. KARLSSON AND O. WIKLUND The Wallenberg Laboratory for Cardiovascular Research, Division of Cardiology, Sahlgren's Hospital, University of Goteborg, Goteborg, Sweden KEY WORDS: Coronary bypass surgery, serum lipoproteins, apolipoproteins AI and B, HDL cholesterol, serum triglycerides, cardiovascular events, long-term survival. The influence of pre-operative serum lipid levels on late clinical outcome after coronary artery bypass surgery was analysed in 83 patients undergoing coronary bypass surgery for stable angina pectoris. The mean follow-up period for surviving patients was 05 ±33 months (range 65-33). Twenty-two patients (27%) had died during follow-up, of whom 4 had sustained a fatal myocardial infarction andfour had succumbed to other cardiovascular causes. Thirty-one patients sustained 35 cardiac events, defined as either fatal or non-fatal myocardial infarction, or reoperation, or PTC A during the follow-up period. With univariate analysis, pre-operative serum levels of total cholesterol and triglycerides were significantly related to cardiac events, P<005 and P<005, respectively. In a Cox proportional analysis, cardiac mortality and total mortality were related to serum triglycerides and HDL cholesterol (P<005 and P<0OJ respectively). Eighty-five percent of the patients with triglycerides <20 /MM. l~' survived for 0 years, while only 48% of patients with triglycerides >20 mu. l~' remained alive for that period. Figures were similar for subjects with HDL cholesterol >0nm. l~' or HDL cholesterol <0mM. l~', at 89 and 38%, respectively. Only 28% of the patients with the combination triglycerides >20 mm. l~' and HDL cholesterol <0mM. l~' were alive 0 years after surgery. These data suggest that dyslipidaemia, especially the combination of high serum triglycerides and low HDL cholesterol, is an important factor influencing long-term clinical outcome after coronary bypass surgery. Introduction Coronary artery bypass surgery (CABG) is now an established method for treatment of severe angina pectoris due to coronary atherosclerosis. However, recurrence of angina is more common the longer the period after surgery. Follow-up coronary angiograms 5 years after CABG show high rates of stenosis both in vein grafts and native coronary arteries' '. Although many angiographic studies have shown a significant correlation between dyslipidaemia and the presence and degree of coronary atherosclerosis' 2 " 4 ', very few studies report on the relationship between serum lipids and outcome following CABG. In one study of saphenous vein grafts, atherosclerosis was mainly related to high levels ofapobcontaining lipoproteins' 5. In another large cohort of bypass patients, serum cholesterol and triglycerides correlated significantly to cardiac events during 0 years of follow-up' 6. Furthermore, serum cholesterol' 7 ' and triglycerides' 8 ' have been reported to be predictors of the need for reoperation after myocardial revascularization. We have studied the relationship between preoperative serum lipid levels and clinical outcome during postoperative follow-up in a group of 83 patients who underwent CABG between 979 and 985. Submitted for publication on 30 April 993, and in revised 25 November 993. form Correspondence: Tomas Linden MD PhD, Wallenberg Laboratory, Sahlgren's Hospital S Gothenburg, Sweden. Methods STUDY POPULATION The studied population consisted of 83 patients (82 men and one woman) who underwent coronary bypass surgery (CABG) due to stable angina pectoris, NYHA function class III IV, at Sahlgren's hospital. Mean age at the time of surgery was 56-3 ± 35, range 39-75, years. The surgery was performed during the period in 78 of the patients, while five patients were operated on during 985. All patients received vein transplant grafts except one, who received an internal mammary artery graft to the left anterior descendant artery. This is a post hoc analysis of patients originally included in a biopsy study of the aortic content of apob' 9 ' or lipid' 0. Clinical characteristics at surgery of all 83 patients are summarized in Table. Seven patients were hyperlipidaemic prior to surgery. One was being treated with clofibrate, while the others had received dietary advice only. The follow-up period after operation varied between 6 and years, average 855 ± 365 months, range -33 (deaths included). For patients alive at follow-up in 992, the average follow-up time was 05 months ±33, range Deaths were checked from a central register and all living patients were contacted by means of a questionnaire sent by mail. All but four patients answered the questionnaire. Of these four, two had moved abroad and two could not be contacted. Angina pectoris was evaluated by a Downloaded from by guest on May, 206 OI95-668X/94/ $08.00/0 tj 994 The European Society of Cardiology

2 748 T. Linden et al. Table I Clinical characteristics at surgery of 83 patients undergoing coronary bypass surgery Variable n (%) Age (years) 56-3 ± 8-5 Male sex 82(99) Smoking never smoked 4(7) ex smokers 46(55) smokers 23(38) Previous MI 54(65) Hypertension (treated) 27(33) Known hyperlipidaemia 7(8) Diabetes (type II) 3(4) No of coronary arteries with significant stenosis at angiography (>50%) 2-3 Medication beta-blockers 72(87) nitrates (48) calcium-antagonists 24(29) lipid-lowering agents () questionnaire similar to the Rose's questionnaire ". Information on myocardial infarction, reoperation or percutaneous transluminal angioplasty (PTCA) was obtained from the medical records. Causes of death were taken from death certificates, medical records or, when available, autopsy protocols. BIOCHEMICAL ANALYSES Fasting serum samples were drawn in the morning of the day of surgery. Serum cholesterol, triglycerides, HDL-cholesterol, apo-b and apo-ai were determined as described elsewhere' 2. HDL cholesterol was determined on fresh serum and all other lipid measurements were made on serum frozen at C. STATISTICAL METHODS Student's t-test was used for comparisons between groups. For multivariate analysis, the Cox proportional hazard model was used and included the following variables: total cholesterol, triglycerides, HDL cholesterol, apo-b, apo-ai, the presence or absence of hypertension, age, number of coronary vessels with significant stenosis (more than 50% obstruction of the lumen), the presence or absence of myocardial infarction before surgery, number of vein grafts. Results CLINICAL EVENTS DURING FOLLOW-UP Twenty-two patients had died at follow-up. The causes of death are presented in Table 2. One patient died within one month of surgery, and 4 patients sustained fatal myocardial infarctions (63% of total deaths). Altogether, 8 patients died from cardiovascular disease (82% of total deaths). One patient was reported drowned. The clinical characteristics of patients alive at Table 2 Causes of death of 83 patients who underwent coronary bypass surgery due to severe angina pecloris, n=22. Mean follow-up period was 85-5 ± 36 5 months Causes of death n=22 Cardiac death Aortic aneurysm Cerebrovascular Tumour Postoperative Accident Number Table 3 Clinical characteristics of 57 patients alive at a mean follow-up period of 05 months Four patients could not be contacted. Figures are number of patients. Angina has been graded. representing no chest pain, 2 angina pectoris a few times weekly and 3 daily angina pectoris Variable Smoking never smoked ex smokers smokers Angina pectoris 2 3 Reoperation PTCA Hyperlipidaemia (treated) Postoperative MI Diabetes (type II) Medication beta-blockers nitrates calcium-antagonists lipid-lowering agents (% of living patients) 0(7) 39(68) 8(4) 27(47) (9) 9(33) 9(6) 3(5) 6() 2(2) 8(4) 30(53) 5(26) 9(33) 5(9) follow-up are shown in Table 3. One third of the patients had no subjective symptoms of angina pectoris, nine had undergone another revascularization and three had undergone a PTCA. Twelve patients had sustained a non-fatal myocardial infarction. Altogether 3 patients had sustained a coronary event, denned as reoperation, PTCA, fatal or non-fatal myocardial infarction during the follow-up period. At follow-up nine patients were diagnosed as hyperlipidaemic and five of those were treated with lipid-lowering agents. CARDIAC EVENTS IN RELATION TO PRE-OPERATIVE SERUM LIPID LEVELS When the pre-operative serum levels of total cholesterol, triglycerides and HDL-cholesterol were compared with a random population sample from the city of Goteborg, stratified for age and sex [l3], % of the patients had a total cholesterol above the th percentile of the population. Thirty-six percent had a triglyceride level higher than the th percentile, and 3% had HDL Downloaded from by guest on May, 206

3 ' " ;.. :.. Serum triglycerides and HDL cholesterol 749 Table 4 Total cardiac events in relation to lipid variables. (Myocardial infarction, reoperation and cardiac death are included as cardiac events). Univariate analysis was used. Four patients were lost to follow-up Variable Cholesterol (mm. ') Triglycerides (mm. l~') HDL (mm.r ) apob(g.r') apo-ai (g.r ) Event (n=3) 6-64 ± ± ± ± ±09 Event-free (n=48) 6-4 ± ± -4 0 ± ± ±0-28 /"-value ns ns ns cholesterol below the 0th percentile of the population sample. A total of 3 patients sustained 35 cardiac events during the follow-up period. The serum levels of lipids and apolipoproteins B and AI for those with or without at least one cardiac event are presented in Table 4. In a univariate analysis, patients with cardiac events had significantly higher levels of total cholesterol (/ > <005) and triglycerides (/ ) <005). In a multivariate analysis only total cholesterol remained significantly related (/ > <005) to the presence of cardiac events. There was no significant relationship between cardiac events and HDL cholesterol, apolipoproteins AI and B or any of the other studied risk factors for cardiovascular disease. TOTAL MORTALITY AND CARDIAC DEATHS Overall mortality as well as cardiac deaths (death from myocardial infarction) were analysed in relation to pre-operative lipid levels, apo-b, apo-ai, age, number of coronary arteries with significant stenosis, presence of hypertension, number of vein grafts and myocardial infarction prior to surgery. In the Cox proportional hazard analysis triglycerides and HDL cholesterol were significantly related to total mortality (/><005 and 00 r By cholesterol By triglycerides /*<00, respectively). Total cholesterol was not significantly related to total mortality. In the life-table analysis shown in Fig. total cholesterol, triglycerides and HDL cholesterol have been dichotomized. Ten year survival for subjects with triglycerides below 2-OmM.l" at operation was 85%, while it was only 48% for subjects with triglycerides over 2-0 mm. ~ '. The same survival figures for subjects with HDL cholesterol above or below -OmM.l" were 89% and 38%, respectively. Triglycerides and HDL cholesterol were significantly related to cardiac death (/ ) <005 and P<0-0\, respectively), but there was no significant relationship to total cholesterol. A life-table analysis for cardiac mortality is shown in Fig. 2. Survival when only cardiac death was considered was 92% for subjects with triglycerides below 2-OmM.r', while the same figure for subjects with triglycerides above 20 mm.i" was 59%. For subjects with HDL cholesterol higher or lower than 0 mm. ~ ', survival when cardiac death was considered was 95% and 49%, respectively. When high triglycerides and low HDL cholesterol were combined in the same subjects these differences in survival were even more pronounced, Fig. 3. Discussion The results of the present study suggest that serum triglycerides and HDL cholesterol are predictors for death after coronary artery bypass surgery. In addition, serum cholesterol appears to influence the likelihood of further coronary events. No other variable had a significant effect on clinical outcome. The patients were recruited from two previous studies at this laboratory, which examined aortic intimal content of lipids and apolipoprotein B. At follow-up, 26% of the patients had died, mostly from cardiovascular causes, while 37% had suffered at least one cardiac event. Although this was a small study, the patients seemed to be representative of bypass patients in By HDL Downloaded from by guest on May, Choi = 6-3 (n = 45) --- Choi >6-3(n = 37) Tg«20(n = 43) ---Tg>20(n = 37) 48 -HDL 3 0 (n = 46) -HDL< 0 (n = 35) I i I 0 > Years of follow-up Figure Total mortality in relation to total cholesterol, triglycerides and HDL cholesterol in 83 patients operated on for coronary bypass surgery and followed for a mean period of 85-5 ± 36-5 months. The patients were divided by the median of total cholesterol, triglycerides and HDL cholesterol levels, respectively

4 750 T. Linden et al By cholesterol ^W,_ - - Choi S 6-3 (n = 45) --- Choi > 6-3 <n = 37) i By triglycerides Tg =S 2 0 (n = 43) --- Tg> 20(n = 37) L t By HDL HDL 3 0 (n = 46) --- HDL< l-0ln = 35) L [ < > i i i i i i i i i i i i i i i Years of follow-up Figure 2 Cardiac mortality and survival when only cardiac death was considered, in relation to total cholesterol, triglycerides and HDL cholesterol in 83 patients undergoing coronary bypass surgery and followed for a mean period of 85-5 ± 36-5 months. The patients were divided according to the median of total cholesterol triglycerides and HDL cholesterol, respectively I 60 to L, Tg «2 0 and "HDL 3= 0 (n = 29) Tg > 2 0 or "HDL< 0 (n = 3) Tg > 20 and HDL< 0 (n = 20) I By Triglycerides and HDL S E I i I... Tg =S 20 and HDLS= 0 (n = 29) Tg > 2 0 or HDL< 0 (n = 3) Tg > 20 and HDL < 0 (n= 20) Years of follow-up Figure 3 Cardiac and total mortality in relation to triglycerides and HDL cholesterol in 83 patients operated on for coronary bypass surgery. The patients were divided into three groups according to the median of triglycerides and HDL cholesterol, respectively. Group with HDL cholesterol above 0mM. " ' and triglycerides below 20mM "' (n=29), group 2 with HDL cholesterol below lomm P or triglycerides above 2 0 mm. "' (n=3) and group 3 with HDL cholesterol below -0 mm. ~ ' and triglycerides above 20 mm. ' (n=20) Downloaded from by guest on May, 206 general, with comparable clinical outcome' 45, reoperation rate 6 and recurrence of anginal symptoms ' 78. Fourteen percent of the patients sustained a non-fatal myocardial infarction and 7% died of myocardial infarction, a total cumulative event rate of 3% during the follow-up period; this is similar to previous reports' 9. Thus, although the study group was small and selected, it seems to be similar to other groups of patients undergoing coronary bypass surgery. Many of the patients had serum lipid levels outside those of a reference Swedish population. The most prevalent lipid disorder was a low level of HDL cholesterol and moderately elevated triglycerides. This was recently observed in a similar population of patients undergoing bypass surgery 20. Prior to surgery only one patient was being treated with lipid-lowering therapy and at follow-up only five patients were on medication for hyperlipidaemia. A disproportionately low rate of treatment, in spite of a high prevalence of hyperlipidaemia in CABG patients, had been reported previously' 222. The Coronary Artery Surgery Study reported that CABG does not appear to act as a stimulus for patients to modify their own cholesterol levels, since the average cholesterol levels were higher 5 years after surgery than at the time of surgery' 23.

5 Serum triglycerides and HDL cholesterol 75 Risk factors predictive of long-term outcome after CABG have been studied in a number of studies. A low ejection fraction' 24 ' 25, the number of diseased vessels' 26, the location of coronary artery disease, age and severity of angina have been shown to affect prognosis several years after surgery' 23 " 25. Ejection fraction was not quantified in our study but none of the other variables were significantly related to clinical outcome. The only variables predicting coronary events during follow-up in the present study were total cholesterol and triglycerides. This is in accordance with results from a larger population of patients followed for 0 years' 6. Total cholesterol' 7 and triglycerides' 8 * 26 have also been shown to be predictors of reoperation after myocardial revascularization. In the Cox proportional hazard analysis, cardiac deaths and overall mortality were significantly related to triglycerides and HDL cholesterol. To our knowledge this has not been previously reported, although longterm survival following CABG in younger men has been related to serum cholesterol levels' 27. The combination of low HDL cholesterol and high triglycerides is a dyslipidaemia often associated with increased risk for coronary heart disease. It is one of the characteristics of familial combined hyperlipidaemia' 28, and also a component of the so-called metabolic syndrome' 29. These dyslipidaemias have also been associated with the presence of small, atherogenic, LDL particles' 30. Our data, as shown in Figsl-3, emphasize that the combination of low HDL and high triglycerides is a strong predictor of mortality after CABG. Apolipoprotein A-I, although being the main apolipoprotein of HDL cholesterol, had no influence on survival. There is no evident explanation for this. However, this is in agreement with earlier observations that HDL cholesterol is a stronger indicator for coronary risk than serum apoal' In conclusion, after long-term follow-up of 83 patients undergoing CABG due to severe stable angina pectoris, serum triglycerides and cholesterol were significantly related to subsequent cardiac events. Furthermore, high triglycerides and low HDL cholesterol were significantly related to cardiac and overall mortality. Thus, dyslipidaemia seems to be an important factor influencing long-term clinical outcome after coronary bypass surgery. We are grateful to Mrs Aira Lidell for laboratory assistance and to Dr Simon Maxwell for helpful advice. This study was supported by the Swedish Heart and Lung Foundation and the Swedish Medical Research Council (grant no. 453). References [] Bourassa G, Campeau L, Lesperence J, Solymoss BC. Atherosclerosis after coronary artery by-pass surgery: results of recent studies and recommendations regarding prevention. 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