THE ASSOCIATION OF LOW LEVELS OF HDL CHOLESTEROL AND ARTERIOGRAPHICALLY DEFINED CORONARY ARTERY DISEASE 1

Transcription

1 AjtCRICAN JOUKNAI. OF EPIDEMIOLOGY Vl. 109, N. 3 Cpyright 1979 by The Jhns Hpkins University Schl f Hygiene and Public Health Printed in U.SA. All rights reserved THE ASSOCIATION OF LOW LEVELS OF HDL CHOLESTEROL AND ARTERIOGRAPHICALLY DEFINED CORONARY ARTERY DISEASE 1 T. A. PEARSON, 1 B. H. BULKLEY, 5 S. C. ACHUFF, 3 P. O. KWTTEROVICH 1 AND L. GORDIS 1 Pearsn, T. A., B. H. Bulkley (Jhns Hpkins U. Schl f Medicine, Baltimre, MD 21205), S. C. Achuff, P. O. Kwltervlch and L. Grdis. The assciatin f lw levels f HDL chlesterl and arterigraphically defined crnary artery disease. Am J Epidemil 109: , Epidemilgic studies have fund assciatins between lw levels f high density llpprtein (HDL) chlesterl and increased risk f crnary artery disease, using mycardlal infarctin r angina pectris as endpints. Hwever, since mst studies have nt crrelated HDL chlesterl with the presence, severity, r lcatin f anatmically prven crnary disease, the present study measured HDL chlesterl levels In 483 men and wmen underging crnary arterigraphy. Cnsistent and statistically significant trends f decreasing mean HDL chlesterl levels with increasing numbers f diseased crnary arteries were bserved in bth men and wmen and in yunger and lder age grups. Althugh wmen withut crnary disease had much higher levels f HDL chlesterl than men withut crnary disease, the differences between men and wmen with similar degrees f crnary disease were small. Lw levels f HDL chlesterl were assciated with left main crnary disease; patients with bth triple vessel disease and left main disease had lwer levels f HDL chlesterl than did patients with triple vessel disease withut left main disease. These results were nt explained by the pssible assciatins f lw density llpprtein chlesterl r trlglycerides with HDL chlesterl. These findings suggest that lw levels f HDL chlesterl are Imprtant risk factrs fr the develpment f athersclersis and that they may be useful fr identifying patients at high risk f certain anatmic patterns f crnary artery disease. arterigraphy; arterisclersis, crnary; crnary disease; high density llpprteins mst predictive f the knwn cardivascu- lar risk factrs (14). There is evidence that HDL may inhibit chlesterl accu- mulatin in tissues (16, 17), and thus may prevent the frmatin f athersclertic lesins. Hwever, there is little infrma- tin assciating HDL chlesterl levels A number f epidemilgic studies have fund a strng assciatin between lw levels f high density lipprtein (HDL) chlesterl and mrbidity and mrtality frm athersclertic crnary artery disease (CAD) (1-15). In sme studies, lw levels f HDL chlesterl appear t be the Received fr publicatin September 28, 'Cardilgy Divisin, Department f Medicine, Abbreviatins: CAD, crnary artery disease; The Jhns Hpkins Schl f Medicine, Baltimre, HDL, high density lipprtein; LDL, lw density li- MD (Reprint requests t Dr. Bulkley at this pprtein. Presented by Dr. PearBn as the Student Prize address.) * Lipid Research Labratry, Departments f Paper at the 11th Annual Meeting f the Sciety fr Medicine and Pediatrics, The Jhns Hpkins Schl Epidemilgic Research, Iwa City, LA, June 14 16, f Medicine, Baltimre, MD This wrk was supprted in part by Lipid Re- Department f Epidemilgy, The Jhns Hp- search Clinic Cntract NO 1-HV L frm the kins Schl f Hygiene and Public Health, Balti- Natinal Institutes f Health, mre, MD. 285

2 286 PEARSON ET AL. with the actual anatmic lesins f CAD and the single knwn previus study shwed n crrelatin between HDL chlesterl and angigraphically defined CAD (18). The demnstratin f lw levels f HDL chlesterl in persns with anatmically denned CAD is imprtant in linking the findings frm ppulatin studies with thse studies n the cellular level. Furthermre, it remains t be shwn whether certain anatmic patterns f CAD can be assciated with abnrmalities in lipid and lipprtein levels. There is sme evidence t suggest that the distributin f CAD with the wrst prgnsis, namely that f the left main crnary artery, may be assciated with specific lipid and lipprtein abnrmalities, especially Type II hyperlipprteinemia (19, 20), but the relatinship t HDL chlesterl level is unexplred. The purpse f this study was t determine whether r nt lw levels f HDL chlesterl are assciated with anatmically prven CAD in general, and with left main CAD in particular. T d this, we measured HDL chlesterl levels in men and wmen underging crnary arterigraphy and crrelated levels f HDL chlesterl with the severity and lcatin f crnary arterial lesins. METHODS Bld samples were cllected frm 483 patients (342 white men and 141 white wmen) wh underwent cardiac catheterizatin and crnary arterigraphy ver a tw-year perid ( ) at The Jhns Hpkins Hspital. Black patients were nt included because f their small numbers. The indicatin fr crnary arterigraphy was chest pain in 94 per cent f the men and 82 per cent f the wmen. Patients came t the catheterizatin labratry after fasting vernight. At the beginning f the catheterizatin prcedure, and prir t systemic heparinizatin, 15 ml f venus bld were cllected in an evacuated tube cntaining sdium EDTA anticagulant. All blds were refrigerated and red cells separated frm plasma within several hurs. Plasma lipid and lipprtein levels were determined in the labratry f The Jhns Hpkins Lipid Research Clinic. Plasma chlesterl and triglyceride levels were determined with a Technicn Aut Analyzer II (Technicn Instruments Crp., Tarrytwn, NY) using mdified Lieberman Burchard and flurmetric techniques, respectively (21). HDL chlesterl was determined n the supernatant after heparin-manganese precipitatin f ther plasma lipprteins (21). Lw density lipprtein (LDL) chlesterl was calculated using the Friedewald frmula (22). Plasma lipid and lipprtein determinatins are expressed in mg/100 ml. Fr the purpses f this study, the crnary arterigrams were reviewed several mnths after each patient's catheterizatin by a team f three physicians including tw cardilgists, ne f whm is an angigrapher. The presence and severity f crnary lesins were determined by cnsensus within the team, nne f whm had prir knwledge f the patient's lipid and lipprtein levels r clinical histry. The results f the arterigram reading were cmpared with thse riginally recrded at the time f catheterizatin and anther review was perfrmed if any discrepancies existed. Patients were classified int disease categries accrding t the number f diseased crnary arteries. Patients with nrmal crnary arteries (n diseased crnary arteries) were defined as having n narrwings f greater than 50 per cent f any crnary arterial lumen visible n the arterigram. The remainder f the patients were divided int thse with ne, tw, r three vessel disease, defined as the narrwing f 50 per cent r greater f the three majr crnary arteries r their branches, i.e., right, left circumflex, r left anterir descending crnary arteries as defined by the American Heart Assciatin (23). Left main crnary disease was defined as the presence f a narrwing f greater than

3 CORONARY ARTERY DISEASE AND LOW HDL CHOLESTEROL per cent f the left main crnary artery. The presence f left main disease was nt included in the determinatin f ne, tw and three vessel disease. The reprducibility f the arterigram readings was determined by selecting 50 arterigrams at randm and re-reading them in a way identical t that dne previusly. The intra-bserver agreement was calculated between the first and secnd readings fr the presence r absence f any crnary disease, the number f diseased crnary arteries (0 vs. 1 vs. 2 vs. 3 vessels diseased), and the presence vs. the absence f left main disease. Fr statistical analysis, the patient ppulatin was divided int fur grups by sex and age (30-49 years and years, respectively). Mean lipid and lipprtein values fr each grup were calculated. Statistical significance was tested using ne way analysis f variance r Student's t test. Multiple linear regressin analysis was perfrmed t examine the relatinship between HDL chlesterl and ther plasma lipids (24). Grups in which a significant assciatin existed were stratified by the plasma lipid level f ther plasma lipids. The risk assciated with certain patterns f CAD was determined by calculatin f dds ratis fr arbitrary levels f HDL chlesterl (25). RESULTS Reprducibility f crnary arterigram readings. Fifty crnary arterigrams were selected at randm fr a secnd reading t determine the intra-bserver variatin f the reading methds. The agreement between the first and secnd readings was 94 per cent when the results were divided int arterigrams shwing zer, ne, tw, and three diseased crnary arteries (table 1). When the readings were divided int thse with n crnary disease versus any crnary disease, perfect agreement was bserved. Furthermre, 96 per cent agreement was bserved in the readings f arterigrams divided as t whether left main disease was present r nt. Study ppulatin. The study ppulatin cnsisted f 342 men and 141 wmen (table 2). The prprtin f patients with severe CAD (tw and three diseased arteries) was higher in males and in lder age grups. The prprtin f patients with nrmal crnary arteries was highest in wmen, and n CAD was detected in ver ne-half f all the wmen underging arterigraphy. Althugh 18 per cent f wmen had clinical indicatins fr catheterizatin ther than chest pain TABLE 1 Intra-bserver variability in reading 50 crnary arterigrams Secnd reading N. f diseased arteries: First reading N. f diseased arteries' N. f diseased arteries Ttals TABLE 2 Distributin by number f diseased crnary arteries, sex, and age f 483 white patients underging crnary arterigraphy years N. % Men years N. % years N. % Wmen years N. %

4 288 PEARSON ET AL. (valvular heart disease r cardimypathy), in cntrast t 6 per cent f men having these ther indicatins, almst nehalf f wmen with chest pain still had nrmal crnary arteries. Due t the large number f wmen with nrmal crnary arteries, sme disease categries in wmen cntained small numbers f subjects. HDL and arterigraphically defined crnary disease. The mean HDL chlesterl levels were determined in the tw age grups f men fr each subgrup classified by the number f diseased crnary arteries (figure 1). In bth yearld and year-ld men, decreasing mean levels f HDL chlesterl were bserved in patients with increasing numbers f diseased crnary arteries. Analysis f variance shwed these differences t be significant in the lder age grup but nt in yunger men. Hwever, fr year-lds, the mean HDL chlesterl level f men with three diseased crnary arteries was significantly lwer than the ^ 50 E 40 CO UJ _l Q I E 30 UJ FM.I9 N.S. mean HDL chlesterl f men with n crnary disease if = 2.06, p <.05). Similar trends in mean HDL chlesterl were bserved in wmen (figure 2). In bth age grups, wmen with tw and three diseased crnary arteries had lwer mean HDL chlesterl levels than wmen with n crnary disease and with ne diseased crnary artery. The differences between the grups were significant fr bth age grups. The exceptin t the relatively cnsistent trend f decreasing mean HDL chlesterl with increasing numbers f diseased crnary arteries was bserved in year-ld wmen with ne diseased artery, but this increase may be an artifact f the small size (five patients) f this grup. Mean HDL chlesterl levels were cmpared in men and wmen with the same number f diseased crnary arteries (table 3). Wmen with nrmal crnary arteries cnsistently had higher mean HDL chlesterl levels (>5 mg/100 ml) than men with nrmal arteries, regardless f p<.025 < UJ Naf Arteries Diseased Age years years FIGURE 1. Mean plasma HDL chlesterl (± 1 standard errr f the mean) in white men by age and number f diseased crnary arteries.

5 CORONARY ARTERY DISEASE AND LOW HDL CHOLESTEROL 289 i 5 CP E rr LJ UJ _1 I 60 r F«3.27 p<.05 p<.05 N. f Arteries I Diseased Age years years FIGURE 2. Mean plasma HDL chlesterl (± 1 standard errr f the mean) in white wmen by age and number f diseased crnary arteries. age grup. In year-lds, these differences were statistically significant (p <.025). The small grup f year-ld wmen with single crnary disease was the nly ther age-disease grup with mean HDL chlesterl levels significantly higher than men f similar age and with the same number f diseased cr- TABLE 3 Cmparisn f mean HDL chlesterl levels f men and wmen by age and number f diseased crnaries N. f diseased arteries years Men Wmen 39.1* * years Men Wmen * * * p <.025 by Student's Mest fr the cmparisn between men and wmen gruped by age and number f diseased arteries. nary arteries. Between grups f men and wmen with tw and three vessel crnary disease, wmen had slightly higher HDL chlesterl levels in mst grups, but the differences were small in cntrast t differences in mean HDL chlesterl levels between nrmal men and wmen. Yunger wmen with tw diseased crnary arteries actually had lwer HDL chlesterl levels than men f similar age and degree f disease. The assciatin f lw HDL chlesterl and left main disease. The assciatin between lw HDL chlesterl and left main disease was investigated by cmparing HDL chlesterl levels f patients with and withut left main disease (table 4). Of the 53 patients with left main disease, 39 (74 per cent) als had disease in the three ther crnary arteries. Cmparing patients with lesins in all three arteries withut left main disease t patients with

6 290 PEARSON ET AL year men year men Wmen triple crnary disease and left main disease, the mean HDL chlesterl levels were bserved t be lwer in all three agesex grups fr thse with left main disease. Wmen f bth age grups were cmbined t allw statistical analysis. In year-ld men, these differences were significant (p <.05). The number f patients with less than three diseased crnary arteries and left main disease was t small t allw meaningful statistical analysis. HDL chlesterl and ther plasma lipids. The relatinship between HDL chlesterl and ther plasma lipids and lipprteins was explred t determine if the assciatins between HDL chlesterl and crnary disease culd be explained by these ther ptential risk factrs. Multiple linear regressin analysis was perfrmed fr the fur age-sex grups using HDL chlesterl as the dependent variable (table 5). N cnsistent r significant relatinship between LDL chlesterl and HDL chlesterl was bserved, since nne f the regressin cefficients was significantly different frm zer. Hwever, cnsistent and significant relatinships were bserved between HDL chlesterl and triglycerides fr all fur age-sex grups. Since HDL chlesterl and triglycerides were crrelated, the age-sex grups were stratified by triglyceride levels t determine if the inverse relatinship between HDL chlesterl and crnary disease persisted. The ppulatin was arbitrarily stratified int subgrups with lw and high triglycerides (less than r greater than 150 mg/100 ml, respectively). The trends f decreasing mean HDL chlesterl levels with increasing number f diseased crnary arteries generally persisted, althugh sme subgrups cntained t small numbers fr statistical TABLE 4 Assciatin f left main disease (LMD) and HDL chlesterl in patients with triple vessel disease by age and sex N With LMD Mean HDL* 30.00t * Plasma levels in mg/100 ml. t Significantly different than withut LMD by Student's f-test (p <.05). N Withut LMD Mean HDL* TABLE 5 Relatinship between plasma HDL chlesterl and ther lipids and Upprteins: Multiple linear regressin analysis by sex and age Sex and age (years) Men Wmen Regressin cefficient* between HDL and LDL chlesterl and triglycerides LDL chlesterl * Unstandardized. t Significantly different frm 0 (p <.005) after adjustment fr LDL chlesterl. Triglycerides It t t t

7 e CORONARY ARTERY DISEASE AND LOW HDL CHOLESTEROL 50 i F = 2.96 p<.05 FM.79 N.S <r LJ i 20 i < LJ N. f Arteries Q Diseased Triglyceride Level 2 3 <l5omg/iooml > 150 mg/100 ml FIGURE 3. Mean plasma HDL chlesterl (± 1 standard errr f the mean) in year-ld men by number f diseased arteries and by level f plasma triglycerides. significance t be reached. The results f stratificatin fr year-ld men, fr example, shwed HDL chlesterl levels in men with triglycerides less than 150 mg/100 ml t be significantly lwer in thse with diseased crnary arteries than in thse with n diseased crnary arteries (figure 3). The trends in men with the higher levels f triglycerides were less cnsistent, but the mean levels f HDL chlesterl als tended t decrease with increasing crnary disease in these patients, with sme subgrups cntaining relatively small numbers. Risk f patterns f CAD fr specific levels f HDL chlesterl. The strength f assciatin between lw levels f HDL chlesterl and specific patterns f crnary disease was determined by calculatin f dds ratis as estimates f risk fr arbitrary levels f HDL chlesterl in men and wmen (table 6). The HDL chlesterl level f 35 mg/100 ml was used fr men. Fr year-ld men with this level f HDL chlesterl there existed dds ratis significantly different frm ne fr any crnary disease and fr three diseased crnary arteries. Odds ratis assciated with this HDL chlesterl level fr left main disease and fr lder men were all greater than ne, but nt significantly s. Fr wmen, higher dds ratis were bserved even when a higher arbitrary level f HDL chlesterl was used (40 mg/100 ml) (table 6). Fr any crnary disease, this level f HDL chlesterl was assciated with a significant dds rati f 4.5 fr yunger wmen and 2.7 fr lder wmen. Relatively large and significant dds ratis were als bserved in year-ld wmen fr disease in three crnary arteries and fr left main disease. DISCUSSION. Epidemilgic studies have prvided the bulk f evidence that lw HDL chlesterl levels are assciated with ischemic heart disease (1-15). Althugh these assciatins have been recgnized since the 1950's (1), they have becme f increasing

8 292 PEARSON ET AL. TABLE 6 Risk f crnary disease in men and wmen fr arbitrary levels f HDL chlesterl Age grup (years) Any crnary artery disease 3 diseased crnary arteries Left main disease Odds ratis in men fr HDL Chlesterl 35mgll00 ml 4.42* 2.09t Odds ratis in wmen fr HDL chlesterl 40 mglloo ml 4.50* * 3.42* * Significantly different frm 1 (p <.025). t Significantly different frm 1 (p <.05). t Difference frm 1 marginally significant (.10 >p >.05). recent interest as studies using multivariate statistical techniques have fund that the level f HDL chlesterl is the strngest predictr f ischemic heart disease in men and wmen ver the age f 50 years (14). The assciatin f lw levels f HDL and crnary disease als prvides a mechanism by which a number f ther established factrs may cause disease. Grups at lw risk f crnary disease have high levels f HDL chlesterl. These include blacks (26), physically active men (27, 28), and users f mderate amunts f alchl (29, 30). In cntrast, grups at high risk f crnary disease, such as whites, patients with renal failure (31, 32), cigarette smkers (33), patients with diabetes mellitus (34), and wmen using ral cntraceptives cntaining prgestins (35) have lw levels f HDL chlesterl. The differences in ccurrence f crnary artery disease bserved between men and wmen have als been attributed t differences in HDL chlesterl levels. Administratin f estrgen and teststerne have been shwn t elevate and depress, respectively, the level f HDL chlesterl (1). In ur study, all patients regardless f sex but with similar degrees f disease had similar abslute levels f HDL chlesterl, a finding which supprts the hypthesis that HDL is ne pssible mechanism by which wmen are prtected frm crnary athersclersis t That wmen with left main disease and ther frms f crnary artery disease have male-like HDL chlesterl levels has at least tw implicatins. First, these wmen with disease, particularly thse in the premenpausal ages, may have a hrmnal basis fr their increased risk. Secndly, since wmen have, n the average, significantly higher HDL chlesterl levels than men, a lw HDL chlesterl level in yung wmen may be particularly useful in identifying wmen at risk fr crnary artery disease, and may be f greater predictive value than a lw level f HDL chlesterl wuld be in a similar age grup f men. The bservatin that wmen had generally higher dds ratis fr extensive crnary disease assciated with lw HDL chlesterl levels is cnsistent with this latter implicatin. Bichemical studies f the mechanism f actin f HDL have suggested that HDL acts by preventing the accumulatin f chlesterl in cells by mbilizing intracellular chlesterl fr transprt back t the liver fr excretin (16), r by blcking LDL chlesterl's entrance int the cell by cmpetitive binding with the cell receptr (17). This preventin f chlesterl accumulatin in tissues is assumed t prevent the frmatin f athermatus lesins. In ur study we shw a crrelatin between the extent f athersclertic disease in the crnary arteries and lw HDL chlesterl levels. This suggests

9 CORONARY ARTERY DISEASE AND LOW HDL CHOLESTEROL 293 that lw levels f HDL chlesterl are assciated with acceleratin f the athersclertic prcess itself, but, f curse, des nt suggest the mechanism whereby the athersclertic prcess prgresses. We are aware f ne ther previus study which has investigated the relatinship between HDL chlesterl and anatmically defined athersclersis (18), and it failed t detect a relatinship between HDL chlesterl and crnary lesins. Hwever, the number f patients in this latter study was relatively small, patients were nt stratified by sex r age, and the methd f HDL chlesterl determinatin was different than the ne used here. A number f previus studies have crrelated high levels f plasma chlesterl r triglyceride with the degree f crnary athersclersis, defined either angigraphically r by autpsy (36-40). Mrever, left main disease has been assciated with Type II hyperlipprteinemia, characterized by high levels f LDL chlesterl (19, 20). In this study, levels f HDL chlesterl and LDL chlesterl were independent f each ther, thus high LDL chlesterl levels and lw HDL chlesterl levels may bth be imprtant in the frmatin f crnary lesins in general and left main lesins in particular. HDL chlesterl and triglyceride levels were significantly crrelated in this study. After stratificatin by triglyceride level, the assciatin between left main disease and lw HDL chlesterl generally persisted. We were unable t determine frm ur data whether lw HDL chlesterl levels cntribute a significant independent risk fr crnary athersclersis at all levels f plasma triglycerides. Hwever, a number f prspective studies f larger ppulatins, fllwing adjustment fr multiple variables, have demnstrated that it is the HDL chlesterl level, and nt the triglyceride level, which is predictive f crnary artery disease (11, 14). The crrelatin f left main disease with lw levels f HDL chlesterl culd als be viewed as a functin f extent f crnary disease. In ur study as in thers, left main disease was assciated with disease in all three ther crnary arteries. In ur study, hwever, the mean HDL levels were lwer fr patients with left main disease cmpared t thse withut, but with cmparable narrwings f the rest f the crnary tree. The findings fr patients with three diseased crnary arteries suggest that the assciatin f left main disease with lw HDL chlesterl cannt be explained merely by mre diffuse crnary disease ccurring in patients with lw HDL chlesterl. In certain grups f patients, the identificatin f thse at highest risk fr left main disease r triple vessel disease thrugh the characterizatin f risk factrs, particularly plasma lipid levels, appears prmising. Patients with these patterns f crnary disease can nly be identified at this time by arterigraphy. Fr left main disease, findings f angina pectris, markedly psitive exercise tests, and calcificatin f the left main crnary artery suggest that a patient has a greater chance f having left main disease, but these criteria identify nly a minrity f patients with left main disease (41). Yet, the early identificatin f patients at high risk fr left main disease is imprtant, since patients with these crnary lesins have a pr prgnsis (40-50 per cent mrtality in three years) (42, 43), tend t die suddenly, and derive significant benefit frm crnary bypass surgery (43). Our results suggest that, amng patients with chest pain, HDL chlesterl may have sme predictive value fr left main disease and ther frms f crnary disease. This is further supprted by the findings f ther investigatrs, that a lw HDL chlesterl is a strnger predictr f sudden cardiac death than f mycardial infarctin (44). Our findings f an assciatin f lw HDL chlesterl and left main disease, a disease distributin frequently

10 294 PEARSON ET AL. leading t sudden death, are in keeping with these ther results. This study explres the relatinship f HDL chlesterl and artergraphically defined crnary disease. Since the study is crss-sectinal in design, the assciatins between risk factrs and disease at the time f the study may be different frm thse at the time f the prductin f the disease. Furthermre, ther ptentially imprtant risk factrs as cigarette smking, lack f physical exercise, and use f alchl have nt yet been adjusted fr. Therefre, it remains t be determined whether HDL levels will be useful in the identificatin f patients with crnary disease when these additinal analyses are dne in a larger scale. Hwever, these results d supprt the ntin that lw levels f HDL chlesterl are imprtant risk factrs fr the prductin f athersclersis and that they may be useful in the identificatin f patients at high risk f certain patterns f crnary artery disease. REFERENCES 1. Barr DP: Sme chemical factrs in the pathgenesis f athersclersis. Circulatin 8: , Oliver MF, Byd, GS: Serum lipprtein patterns in crnary sclersis and assciated cnditins. Br Heart J 17: , Jencks WP, Hyatt MR, Jettn MR, et al: A study f serum lipprteins in nrmal and athersclertic patients by paper electrphretic techniques. J Clin Invest 35: , Brunner D, Lbl K: Serum chlesterl, electrphretic lipid pattern, diet and crnary artery disease: A study in crnary patients and in healthy men f different rigin and ccupatins in Israel. Ann Intern Med 49: , Carlsn LA: Serum lipids in men with mycardial infarctin. Acta Med Scand 167: , Brunner D, Altman S, Lbl K, et al: Alphachlesterl percentages in crnary patients with and withut increased ttal serum chlesterl levels and in healthy cntrls. J Atherscler Res 2: , Rsenman RH, Friedman M, Jenkins CD, et al: Recurring and fatal mycardial infarctin in the Western Cllabrative Grup Study. Am J Cardil 19: , Medalie JH, Kahn HA, Neufeld HN, et al: Five year mycardial infarctin incidence II. Assciatin f single variables t age and f birthplace. J Chrnic Dis 26: , Carlsn LA, Ericssn M: Quantitative and qualitative serum lipprtein analysis. Part 2. Studies in male survivrs f mycardial infarctin. Athersclersis 21: , Rhads GG, Gulbrandsen CL, Kagan A: Serum lipprteins and crnary heart disease in a ppulatin study f Hawaii Japanese men. N Engl J Med 294: , Castelli WP, Dyle JT, Grdn T, et al: HDL chlesterl and ther lipids in crnary heart disease. The Cperative Lipprtein Phentyping Study. Circulatin 55: , Grdn T, Castelli WP, Hjrtland MC, et al: High density lipprtein as a prtective factr against crnary heart disease. Am J Med 62: , Grdn T, Castelli WP, Hjrtland MC, et al: Predicting crnary heart disease in middleaged and lder persns. JAMA 238: , Grdn T, Castelli WP, Hjrtland MC, et al: Diabetes, bld lipids, and the rle f besity in crnary heart disease risk fr wmen. Ann. Intern Med 87: , Albers JJ, Cheung MC, Hazzard WR: Highdensity lipprteins in mycardial infarctin survivrs. Metablism 27: , Miller GT, Miller NE: Plasma-high-densitylipprtein cncentratin and develpment f ischemic heart disease. Lancet 1:16-19, Carew TE, Kschinsky T, Hayes SB, et al: A mechanism by which high-density lipprteins may slw the athergenic prcess. Lancet 1: , Berensn GS, Turner M, O'Meallie LP, et al: A study f serum lipprteins and angigraphic evidence f crnary artery disease. Suth Med J 68: , Blch A, Dinsmre RE, Lees RS: Crnary arterigraphic findings in type II and type IV hyperlipprteinemia. Lancet 1: , Bulkley BH, Rberts WC: Athersclertic narrwing f the left main crnary artery. A necrpsy analysis f 152 patients with fatal crnary heart disease and varying degrees f left main narrwing. Circulatin 53: , Natinal Heart and Lung Institute, Natinal Institutes f Health, Manual f Labratry Operatins, Lipid Research Clinics Prgram. Vl 1. Bethesda, MD, Natinal Heart and Lung Institute, Friedewald WT, Levy RI, Fredricksn DS: Estimatin f the cncentratin f lw density lipprtein chlesterl in plasma withut use f the preparative ultracentrifuge. Clin Chem 18: , Ad Hc Cmmittee fr Grading Crnary Artery Disease, Cuncil n Cardivascular Surgery, American Heart Assciatin, AHA Cmmittee Reprt, Snedecr GW, Cchran WG: Statistical Methds. (6th Editin.) Ames, Iwa, Iwa State Press, Fleiss JL: Statistical Methds fr Rates and Prprtins. New Yrk, Jhn Wiley and Sns, 1973

11 CORONARY ARTERY DISEASE AND LOW HDL CHOLESTEROL Tyrler HA, Hames CG, Krishan I, et al: Blackwhite differences in serum lipids and lipprteins in Evans Cunty. Prev Med 4: , Wd PD, Haskell W, Klein H, et al: The distributin f plasma lipprteins in middle-aged male runners. Metablism 25: , Enger SC, Herbjrnsen K, Erikssen J, et al: High density lipprteins (HDL) and physical activity: The influence f physical exercise, age and smking n KDL-chlesterl and the HDL- /ttal chlesterl rati. Scand J Clin Lab Invest 37: , Yan K, Rhads GG, Kagan A: Cffee, alchl and risk f crnary heart disease amng Japanese men living in Hawaii. N Engl J Med 297: , Castelli WP, Dyle JT, Grdn T, et al: Alchl and bld lipids The Cperative Ldpprtein Phentyping Study. Lancet 2:153, Bagdade JD, Albers JJ: Plasma high-density lipprtein cncentratins in chrnic-hemdialysis and renal-transplant patients. N Engl J Med 296: , Brunzell JD, Albers JJ, Haas LB, et al: Prevalence f serum lipid abnrmalities in chrnic hemdialysis. Metablism 26: , Garrisn RJ, Kannel WB, Feinleib M, et al: Cigarette smking and HDL chlesterl: The Framingham Offspring Study. Athersclersis 30:17-25, Hward BV, Savage PJ, Bennin LJ, et al: Lipprtein cmpsitin in diabetes mellitus. Athersclersis 30: , Bradley DD, Wingerd J, Petitti DB, et al: Serum high-density-lipprtein chlesterl in wmen using ral cntraceptives, estrgens and prgestins. N Engl J Med 299:17-20, Cramer K, Paulin S, Werk L: Crnary angigraphic findings in crrelatin with age, bdy weight, bld pressure, serum lipids, and smking habits. Circulatin 33: , Heinle RA, Levy RI, Fredricksn DS, et al: Lipid and carbhydrate abnrmalities in patients with angigraphically dcumented crnary artery disease. Am J Cardil 24: , Banks DC, Raftery EB, Oram S: Clinical significance f the crnary arterigram. Br Heart J 33: , Murray RG, Tweddel A, Third JLHC, et al: Relatin between extent f crnary artery disease and severity f hyperlipprteinaemia. Br Heart J 37: , Gtt AM, Grry GA, Thmpsn JR, et al: Relatinship between plasma lipid cncentratins and crnary artery disease in 496 patients. Circulatin 56: , DeMts H, Bncheck LJ, Rsch J, et al: Left main crnary artery disease: Risks f angigraphy, imprtance f cexisting disease in ther crnary arteries and effects f revascularizatin. Am J Cardil 36: , Lim JS, Prudfit WL, Snes FM Jr: Left main crnary arterial bstructin: Lng-term fllwup f 141 nnsurgical cases. Am J Cardil 36: , Takar T, Hultgren HN, Liptn MJ, et al: The VA Cperative Randmized Study f Surgery fr Crnary Arterial Occlusive Disease. II. Subgrup with significant left main lesins. Circulatin 54 (Suppl 3): , Medalie JH: Persnal cmmunicatin, 1978