Relation of High-Density Lipoproteins to Coronary Artery Disease BARRY LEWIS, MD, PhD, FRCP, FRCPath Low mean concentrations of high-density lipoprotein (HDL) cholesterol have long been recognized as a characteristic of patients with coronary heart dis- ease, and the measurement of this fraction is a relatively strong discriminator between patients with coronary heart disease and those without. When subjects are ranked by the severity of coronary atherosclerosis determined angiographically, levels of HDL cholesterol, particularly of its HDLl subclass, are consistently lower in subjects with extensive disease than in those with minimal atheroma. HDL cholesterol is derived from a number of sources, mobilization from peripheral tissues being but one. Generally, longitudinal studies have confirmed that a low HDL cholesterol level is potently and inde- pendently predictive of a high risk of coronary heart disease, one exception being a study of subjects with hypercholesterolemia. Despite the strength of these epidemiologic associations, there is no evi- dence from experimental studies or clinical trials to establish that low HDL levels are causally important in atherogenesis. An inverse relation between high-density lipoprotein (HDL) cholesterol levels and coronary heart disease was recognized 30 years ago. lr2 This report reviews recent findings on this relation and lists 3 questions concerning its basis. The first is, how consistent is the inverse relation between HDL levels and coronary heart dis- ease? Second, does thi:s inverse relation reflect a causal interaction between this lipoprotein and atherogenesis? Third, how should such a relation influence current clinical practice? In case-control data from a multicenter study in 4 European cities, mean HDL levels were shown to be consistently low in patients with ischemic heart disease. In all participating groaps, HDL cholesterol was lower than that in matched controls, and in most or all centers, low-density (LDL) and very low density lipoprotein (VLDL) lipids were elevated (Table I). When the Lon- don data were segregated according to the patient’s age, the low mean levels of HDL cholesterol were most pronounced in patients in whom ischemic heart disease developed earlier in life, and the trend did not reach statistical significance in older patients.8 To date, 5 longitudinal epidemiologic studies have been performed. The first of these was the study of more than 6,000 men in Tromso, Norway.4,s Lipoproteins were measured in persons in whom myocardial infarc- tion subsequently developed and in twice as many matched controls. The HDL cholesterol concentration was substantially lower in those in whom ischemic heart disease developed than in the controls. Triglyceride From the Department of Chemical Pathology and Metabolic Disorders at St. Thomas’ Hospital Medical School, London, SE1 7EH England. Address for reprints: Barry Lewis, MD, Department of Chemical Pathology and Metabolic Disorders, St. Thomas’ Hospital Medical School, London SE1.7EH, England. levels were not significantly higher, whereas cholesterol levels were significantly higher in those in whom the disease developed (Table II). In brief, similar observations were made in the Framingham study8 and in the Israeli Heart Study (Table IID However, in a prospective study in Gothenberg, Sweden, the HDL cholesterol level was not predictive of ischemic heart disease in a series of subjects with hypercholesterolemia.* An informative form of case-control study was used by several groups of investigators in which patients were ranked according to the severity of the atheroma on coronary arteriograms, and the atheroma score was re- lated to plasma lipoprotein levels.8 A study by Jenkins et ali0 was especially attractive in that it used multi- variate analysis to control for the effects of age, smoking and blood pressure. In patients with the severest ath- eroma, VLDL lipids were higher than in those with minimal coronary atherosclerosis; LDL cholesterol was higher and HDL cholesterol strikingly lower in those with the severest coronary artery disease (Table IV). We used a similar design. In a consecutive series of more than 100 men who underwent coronary arteriog- raphy, we compared lipoprotein patterns in those in the lowest and highest quintiles and the middle 3 quintiles of a score of coronary atherosclerosis (Table V). HDL cholesterol was lowest in those with the severest disease. This effect was confined to the HDLs subclass. The mean HDLs cholesterol level was little more than half that of persons with minimal or no disease. There was a direct relation between LDL cholesterol level and the severity of coronary disease. The last 2 entries in Table V reflect indexes of the concentration of remnant par- ticles in plasma, that is, of partly metabolized VLDL and chylomicrons. We found no difference in the ratio of cholesterol to triglyceride in lipoproteins with a density <1.019; this index did not discriminate between 58
Transcript
Relation of High-Density Lipoproteins to Coronary Artery Disease
BARRY LEWIS, MD, PhD, FRCP, FRCPath
Low mean concentrations of high-density lipoprotein (HDL) cholesterol have long been recognized as a characteristic of patients with coronary heart dis- ease, and the measurement of this fraction is a relatively strong discriminator between patients with coronary heart disease and those without. When subjects are ranked by the severity of coronary atherosclerosis determined angiographically, levels of HDL cholesterol, particularly of its HDLl subclass, are consistently lower in subjects with extensive disease than in those with minimal atheroma. HDL
cholesterol is derived from a number of sources, mobilization from peripheral tissues being but one. Generally, longitudinal studies have confirmed that a low HDL cholesterol level is potently and inde- pendently predictive of a high risk of coronary heart disease, one exception being a study of subjects with hypercholesterolemia. Despite the strength of these epidemiologic associations, there is no evi- dence from experimental studies or clinical trials to establish that low HDL levels are causally important in atherogenesis.
An inverse relation between high-density lipoprotein (HDL) cholesterol levels and coronary heart disease was recognized 30 years ago. lr2 This report reviews recent findings on this relation and lists 3 questions concerning its basis. The first is, how consistent is the inverse relation between HDL levels and coronary heart dis- ease? Second, does thi:s inverse relation reflect a causal interaction between this lipoprotein and atherogenesis? Third, how should such a relation influence current clinical practice?
In case-control data from a multicenter study in 4 European cities, mean HDL levels were shown to be consistently low in patients with ischemic heart disease. In all participating groaps, HDL cholesterol was lower than that in matched controls, and in most or all centers, low-density (LDL) and very low density lipoprotein (VLDL) lipids were elevated (Table I). When the Lon- don data were segregated according to the patient’s age, the low mean levels of HDL cholesterol were most pronounced in patients in whom ischemic heart disease developed earlier in life, and the trend did not reach statistical significance in older patients.8
To date, 5 longitudinal epidemiologic studies have been performed. The first of these was the study of more than 6,000 men in Tromso, Norway.4,s Lipoproteins were measured in persons in whom myocardial infarc- tion subsequently developed and in twice as many matched controls. The HDL cholesterol concentration was substantially lower in those in whom ischemic heart disease developed than in the controls. Triglyceride
From the Department of Chemical Pathology and Metabolic Disorders at St. Thomas’ Hospital Medical School, London, SE1 7EH England.
Address for reprints: Barry Lewis, MD, Department of Chemical Pathology and Metabolic Disorders, St. Thomas’ Hospital Medical School, London SE1.7EH, England.
levels were not significantly higher, whereas cholesterol levels were significantly higher in those in whom the disease developed (Table II).
In brief, similar observations were made in the Framingham study8 and in the Israeli Heart Study (Table IID However, in a prospective study in Gothenberg, Sweden, the HDL cholesterol level was not predictive of ischemic heart disease in a series of subjects with hypercholesterolemia.*
An informative form of case-control study was used by several groups of investigators in which patients were ranked according to the severity of the atheroma on coronary arteriograms, and the atheroma score was re- lated to plasma lipoprotein levels.8 A study by Jenkins et ali0 was especially attractive in that it used multi- variate analysis to control for the effects of age, smoking and blood pressure. In patients with the severest ath- eroma, VLDL lipids were higher than in those with minimal coronary atherosclerosis; LDL cholesterol was higher and HDL cholesterol strikingly lower in those with the severest coronary artery disease (Table IV).
We used a similar design. In a consecutive series of more than 100 men who underwent coronary arteriog- raphy, we compared lipoprotein patterns in those in the lowest and highest quintiles and the middle 3 quintiles of a score of coronary atherosclerosis (Table V). HDL cholesterol was lowest in those with the severest disease. This effect was confined to the HDLs subclass. The mean HDLs cholesterol level was little more than half that of persons with minimal or no disease. There was a direct relation between LDL cholesterol level and the severity of coronary disease. The last 2 entries in Table V reflect indexes of the concentration of remnant par- ticles in plasma, that is, of partly metabolized VLDL and chylomicrons. We found no difference in the ratio of cholesterol to triglyceride in lipoproteins with a density <1.019; this index did not discriminate between
58
6B HIGH-DENSITY LIPOPROTEINS AND CORONARY ARTERY DISEASE
TABLE I Lipoprotein Cholesterol in Coronary Heart TABLE IV Lipoprotein Concentrations: Associations with Disease, as Percentage of Age- and Sex- Coronary Atherosclerosis Scores by Tertile (n Matched Controls (n = 231)3 = 41)‘O
* p <O.OOl. + p <O.Ol. HDL = high-density lipoproteins; LDL = low-density lipoproteins;
VLDL = very low density lipoproteins.
l p <0.05. HDL = high-density lipoprotein; LDL = lowdensity lipoprotein; VLDL
= very low density lipoprotein.
TABLE II Tromso Heart Study: Lipids and Lipoproteins in Men Developing Coronary Heart Disease in a 2- Year Follow-Up of 6,595 Men Aged 20 to 49 Years5
Cases Matched Controls (n = 17) (n = 31)
Cholesterol (mg/dl) 248’ HDL cholesterol 25.6”
(mg/dl) Triglyceride (mg/dl) 192
l p <O.Ol. HDL = high-density lipoprotein.
229 39.4
165
TABLE Ill Israeli lschemic Heart Disease Study: Mortality Per 1,000 Men in 7 Years by Quintile of Cholesterol or High-Density Lipoprotein Cholesterol Level (n N 1000)7
Ql Q2 Q3 Q4 Q5
Ml versus total cholesterol 7.6 12.6 14.2 20.2 MI versus HDL cholesterol 12.6
2;:: 10.2 7.8
Sudden death versus 5.4 4.4 4.5 :::
5.6 total cholesterol
Sudden death versus 5.6 11.0 4.2 3.9 2.4 HDL cholesterol
those with gross disease and those with minimal disease. When we classified the data differently and looked at the distribution of atherosclerosis in persons in the highest and lowest quintiles of the distribution of the concentration of HDLs cholesterol (Table VI), patients with the highest HDLs cholesterol had little more than one third the mean coronary artery score of persons with the lowest HDLs cholesterol levels.
Another source of information on the relation be- tween HDL and atherosclerosis is found in the longi- tudinal investigation of Brooks et ali1 Using arteriog- raphy of the femoral artery tree and repeating the procedure 1 year later, they quantitated the severity of atheroma and calculated the rate of progression of the disease between the 2 arteriograms. Progression was inversely related to HDL cholesterol and directly to LDL cholesterol (Table VII). In the intervention group and controls of a regression trial in man we found a di- rect relation between mean LDL cholesterol and angi- ographic evidence of progression; although an inverse
TABLE V Lipoprotein Classes, Subclasses and Composition: Associations with Coronary Atherosclerosis (n = 104)s
l p <0.05. + p <O.Ol. d = density; HDL = high-density lipoprotein; LDL = low-density li-
poprotein.
relation between HDL and progression was seen it was weaker and not significant.
All of these studies show a connection between HDL and the atherogenic process; however, in some situations HDL does not show such a relation. In the collaborative study in which colleagues in Italy, Switzerland and Sweden and our group in London compared, by iden- tical methods, the lipoprotein concentrations in normal persons of both sexes and different ages,3 levels of both LDL and VLDL lipids were higher in the relatively high coronary heart disease areas in Sweden and in the United Kingdom than in Switzerland and in Italy. Therefore, an association exists between the mortality from ischemic heart disease in these 4 industrialized European cities and these lipoproteins. However, there were virtually no differences in HDL cholesterol. To the extent that interpopulation differences in coronary heart disease can be attributed to lipoprotein-mediated risk, such differences must be associated with LDL and perhaps with VLDL, but these interpopulation differ- ences in coronary heart disease rates could not be at- tributed to differences in HDL cholesterol levels.
The answer of the second question concerning a causal relation between HDL and atherogenesis is un- known, As discussed by Gotto in this symposium, HDL enters plasma as a discoidal particle and is derived from both the small intestine and the liver. Its subsequent metabolism is considerably more complex, and for discussion we will isolate a few aspects. Under the in- fluence of the enzyme lecithin-cholesterol acyltrans- ferase (LCAT), the free cholesterol of nascent HDL is largely converted to cholesteryl ester, which comes to form the core of a spherical HDL particle.
August 22. 1983 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 52 78
TABLE VI Frequency of Coronary Artery Disease Related to Distribution of HDLz Cholesterol (n = 104)9
HDLs Cholesterol (Quintile)
Lowest Highest P
Coronary score Mean number of stenoses Patients with stenoses (n)
‘E 10.8 <o.oo*
20’ 2.4 <o.oo*
13 <O.Ol
TABLE VII Femoral Atherosclerosis Progression Rate”
TABLE VIII Hyperalphalipoproteinemia and Cholesterol Kinetics14
Patients With Hyperalphalipo- Control
oroteinemia Subjects
Cholesterol in pool A (g/70 kg) Cholesterol in pool 6 (g/70 kg) Tissue cholesterol pools
(g/70 kg) Cholesterol turnover (mg/kg.ld)
21.0 267 21.5’ 51.5 34.6f 69.9
9.4f 15.1
HDL cholesterol is derived not only from primary secretion by the liver and gut but also from other sources. Additional cholesterol transfers to HDL from extrahepatic cells, subsequently being converted by LCAT to cholesteryl ester. This cholesteryl ester may reach the liver, at least in part, by transfer through a specific transfer protein to triglyceride-bearing lipo- proteins. These lipoproteins undergo further metabo- lism and are ultimately metabolized, at least in part, by the liver, returning their cholesterol to this organ. Therefore, HDL may play a role in initiating the uptake of cholesterol from peripheral cells rather than in transporting it to the liver for excretion in the bile.
Some HDL cholesterol, perhaps a considerable por- tion, is derived from triglyceride-rich lipoproteins (VLDL and chylomicrons) within the circulation, as a result of the action of lipoprotein lipase.
A third source of HDL cholesterol is the cholesterol derived from peripheral cells. The upshot of these processes is that HDL cholesterol is derived from multiple sources. Hence, an increase in the concen- tration plasma of HDL cholesterol does not establish that reverse cholesterol transport has been enhanced. Microsomal inducing agents, for example, increase HDL cholesterol probably by stimulating its hepatic secretion, and factors that activate lipoprotein lipase, such as certain drugs, probably increase HDL cholesterol by promoting transfer of cholesterol to HDL from VLDL and chylomicrons.
Some evidence suggests that high HDL cholesterol levels reflect an increase in reverse cholesterol transport. Miller et all3 investigated the relation between levels of HDL cholesterol in plasma and the exchangeable pools of cholesterol in extravascular spaces. In this small study, remarkably significant inverse relations were found between the amount of HDL cholesterol in plasma and the amount of exchangeable cholesterol in the tissues, findings certainly compatible with a role of HDL in centripetal transport. Evidence also exists that HDL or particles that contain HDL apoproteins and phospholipids serve as acceptors of cholesterol when cells are incubated in their presence.
In persons who have inherited high levels of HDL, the exchangeable pools of cholesterol, especially the slowly exchanging pool, are far smaller than the pools in con- trol subjects (Table VIII).14 Coronary heart disease appears to be rare in such persons.
The relation between HDL metabolism and the me- tabolism of other lipoproteins is complex, and it is dif- ficult to study variables in man that influence any single lipoprotein in isolation. For example, HDL levels are strongly correlated with the fractional catabolic rate of VLDL and with the activity of lipoprotein lipase in adipose tissue. The rate of production of VLDL is re- lated, for obscure reasons, to the rate of synthesis of HDL. It is difficult in the intact organism to isolate the determinants in the consequences of changes in any 1 lipoprotein.
In summary, HDL does function as a circulating ac- ceptor of cholesterol from peripheral cells. There is good evidence that HDL initiates the reverse transport of cholesterol from the periphery back to the liver. HDL or a subclass of HDL that contains apo E competes with LDL for receptor-mediated binding by cells, and thereby may reduce the uptake of LDL cholesterol by peripheral cells.
What are the implications of these findings for clinical practice? We have no evidence that interventions that change HDL concentration influence the risk of coro- nary heart disease. We do not have animal models; we do not have controlled trials analogous to those that have provided evidence for the beneficial effect of the reduction of total plasma cholesterol. A reasonable view is that in persons who have low HDL concentrations together with one or another form of hyperlipidemia, an optimal treatment should normalize all lipoprotein abnormalities.
References
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8B HIGH-DENSITY LIPOPROTEINS AND CORONARY ARTERY DISEASE
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