regression of atherosclerosis

9 Lipoproteins and the progression/regression of atherosclerosis J A C Q U E S D. B A R T H

Progression and regression of atherosclerosis has been assessed, until recently, by a follow-up of clinical events. It has been shown that the higher the serum LDL-cholesterol the more likely will be progression of vascular disease. Atherosclerosis may develop for many decades before clinical complications such as a myocardial infarction occur. On the other hand, regression of coronary atherosclerosis has been demonstrated after only several years of dramatic lowering of fat intake/serum cholesterol. Although there are many other confounding cardiovascular risk factors, the premise of high serum LDL-blood levels inducing progression of disease remains. More accurate in vivo methods for assessing the extent of atherosclerosis had to be developed to assess more effectively the acute (such as thrombolytic therapy) or chronic (i.e. lowering of LDL-cholesterol) treatments of atherosclerosis. Trials using serial coronary angiography have become surrogates assessment of morphological change. With the introduction of quantitative (computerized) methods for measuring atherosclerosis during the last decade, several lipid intervention studies have been published using this surrogate end-point. Recently there has been a shift of focus to repeated non-invasive testing such as B-mode ultrasonography instead of evaluation of changes in arterial lumen (patency). These approaches are very promising because parameter tests, such as changes in intima-media thickness (IMT), have high accuracy and precision (Figure 1). Computerized methods of assessment of sometimes minute changes of vessel wall thickness have now been standardized. The problem of non-invasive imaging of the coronary arteries has not yet been resolved. However, there is a highly significant correlation between changes found on coronary angiography and B-mode sonography of the carotid arteries (Salonen and Salonen, 1991; Blankenhorn et al, 1993a; Adams et al, 1994). This overview of the relationship of serum lipoprotein levels to the progression/regression of atherosclerosis will be limited to human studies, D Y S L I P I D A E M I A A N D THE C O R O N A R Y ARTERY

Epidemiological studies have indicated that dyslipidaemia is strongly Baillikre's Clinical Endocrinology and Metabolism849 Vol. 9, No. 4, October 1995 ISBN 0-7020-1982-8

Copyright © 1995, by Bailli6re Tindall All rights of reproduction in any form reserved

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Figure 1. Computerized assessment of IMT of the far wall of the common carotid artery.

correlated to morbidity and mortality from coronary artery disease (CAD) (Kannel et al, 1979; Cabin and Roberts, 1982). LDL-cholesterol is positively correlated to the development of CAD, whereas HDL-cholesterol has an inverse correlation to this process (Miller et al, 1981; Keys, 1983). Clinical trials have demonstrated that the reduction of LDL-cholesterol decreases CAD morbidity and mortality. LDL-lowering seems to be associated with a slower rate of angiographic progression of mild lesion (< 50%) and regression of more severe lesions (>50%). It seems that regression of coronary lesions and the extent of atherosclerosis have become surrogates for a decline in clinical events. The relative small changes are not likely to explain the major decreases in clinical events that result from lipid lowering. Lipid lowering may alter and/or decrease the lipoprotein content of the atherosclerotic plaque, increase plaque stability and decrease the likelihood of the plaque's rupture. Reduction of circulating LDL appears to improve endothelium function and change the enzymatic endothelial response for the better. Modulators of the lipoprotein metabolism, though many, like postheparin lipase activities, are thought to play an important role. Lipoprotein lipase (LPL) and hepatic lipase (HL) are located in the endothelial cells lining the blood vessels. LPL activity modulates triglyceride-rich lipoprotein, chylomicron and very low density lipoprotein (VLDL) catabolism. Therefore, it may regulate, to a certain extent, LDL metabolism (Hamosh and Hamosh, 1983), whereas HL may be associated with the conversion of atherogenic intermediate density lipoproteins (IDL) to HDL (Murase and Itakuru, 1981). Another function may be clearing of cholesterol into bile through an intervention in HDL metabolism (Jansen and Htilsmann, 1980). In two earlier epidemiological studies (Vartianen and Kanerva, 1947; StrCm and Jensen, 1951) done during the Second World War a dramatic and rapid decline of complications of atherosclerosis was found, implicating

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that reversal of complications of atherosclerosis, e.g. myocardial infarction, does not necessarily have to follow a similar long path of progression of disease. Table 1 lists important trials dealing with regression of atherosclerosis. Table 1. Overview of randomized angiographic studies regression/progression trials. Lipids in the intervention group (mmol/1) Study (number of patients)

Intervention mode

NHLBI (143) CLAS I (188) CLAS II (69) FATS (74)

Cotestipol/niacin/

UC-SF (41) LHT (22)

Colestipol/niacin Behavioural

Heidelberg (29)

Exercise and diet Diet/maximal drug Diet/cholestyramine

Duration of study (years)

LDL A---~B

HDL A--->B

Progression (%)/ regression (%)

5 2 2 2.5

6.3--->4.6 4.4-->2.5 5.2--->3.6 5.1--->2.6

0.98-->1.06 1.16--->1.58 1,16--->1.55 0.90-->1.06

19/4 39/16" 30/18' 25/39*

7.3--~4.4 3.9---~2.5 5.1---~4.4 4.1--->3.1 5.3--->3.6 4.5-->3.2 4.0--~2.2 4.4-->3.0 4.6-->2.7 3.6---~2.2

1.21--->1.52 1.01--->1.00 0,92---~0.91 1.19-~1.33 1.13---->1.13 1.07--->1.12 1.09-~1.19 1.t0--~1.18 1.03--->1.08 1.08--->1.22

19/32 14/82" 10/28 29/14" 12/33" 33/10 29/23 23/19 37/13' 23/13

4.4---~3.3

1.06-->1.14

29/17'

Cholestyramine Colestipol/niacin

Colestipol/niacin lovastatin

SCRIP (118) STARS (50) CCAIT (146) MARS (123) MAAS (189) POSCH (421) HARP (40)

Simvastatin Partial ileal bypass Pravastatin/niacin/

2.2 1 1 4 3 2 2 4 9.7 2.5

PLAC I (206)

cholestyramine/ gemfibrozil Pravastatin

3

Lovastatin

Lovastatin

A, value at baseline; B, value at end study. * Means significantly different (P < 0.05).

Neither the angiographic nor the sonographic outcome (B-mode carotid) is uniform, due probably to the lack of uniformity of definition and the difference in studied populations. Definite genetic markers for atherosclerosis development are still lacking, although progress has been made (Acton et al, 1992). A definite antioxidant study and a study on the effects of hormonal replacement therapy post-menopausal have to be done. ANGIOGRAPHIC TRIALS: FOCUS ON LIPOPROTEINS The following trials, using sequential coronary angiography to assess changes in morphology, were done using lipoprotein-lowering interventions. National Heart-Lung-Blood Institute (NHLBI) type II study This early trial used sequential coronary angiograms to compare the change in coronary morphology between placebo and cholestyramine-treated

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patients with LDL-cholesterol above the 90th percentile of the general population (Brensike et al, 1984). Cholestyramine decreased LDLcholesterol by 26%, whereas low-fat diet alone induced a decrease of only 5%. Cholestyramine retarded progression by 50% in comparison with the placebo population. A significant correlation was found to the level of LDL-cholesterol decrease and deceleration of progression of atherosclerosis. Triglycerides increased in both groups by 25%. A population of 116 patients with known CAD and hyperlipidaemia was followed for 5 years. No significant difference was found in total events and mortality. Angiographic change was significantly (P<0.03) progressive in the placebo group. New lesion formation and regression were essentially not different. However, in lesions initially > 50%, progression was significantly less in the intervention group. It may be concluded from this trial that a lower LDL-cholesterol in the diet and cholestyramine decelerate the progression of coronary atherosclerosis. HDL subfractions were associated with the slowing of progression and regression of disease, whereas reduction in small LDL lead to a deceleration of disease alone. Leiden Intervention Trial

This relatively small trial was the first one to use quantitative coronary angiography. Intervention consisted of a low-fat diet, increased polyunsaturated fatty acid intake and exercise (brisk walking three times for 20 minutes a week) over the 2-year duration of the trial. Changes in serum lipoproteins were moderate, with LDL-cholesterol decreasing 10% and HDL-cholesterol increasing 4%, but significant regression of coronary disease occurred. Regression was seen only in patients who had complied with the prescribed diet and who had had a significant decrease in their LDL/HDL cholesterol ratio. In a multifactorial analysis of serum only HDL-C, hepatic lipase activity (HL) and triiodothyronine (T3) were significant predictors of regression of disease (Arntzenius et al, 1985; Barth, 1986; Barth et al, 1987a). Hepatic lipase was assessed before in a study comparing coronary angiograms with and without diffuse atherosclerosis. It has been hypothesized that the level of HL, an important modulator of HDL-C, will rise before the HDL-C level in non-pharmacological lipid-lowering intervention studies (Barth and Arntzenius, 1991). The role of oestradiol and testosterone was also studied. Testosterone in itself was not associated with the progression of disease, neither was a higher oestradiol in men associated with disease regression (Barth, 1986). The most important aspect of this study may be the fact that regression of disease occurred only in patients who had shown a significant change from an initially high to a low LDL/HDL ratio. Clinical follow-up after termination of the study demonstrated that only those who had had initial further progression after 5.5 years of study had died.

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There is currently no explanation for the observation of increased conversion of thyroxine (T4 to T3 in the regression group). In addition, at the end of the study a significant correlation was established between anti-anginal medication and the progression of disease. Regression of disease was accompanied by a significant reduction of the use of anti-anginal medication (Barth, 1986).

St Thomas' Atherosclerosis Regression Study (STARS) This randomized study had a three-arm approach. The effects on progression/regression of CAD of diet alone, diet and cholestyramine and usual care were compared (Watts et al, 1992). The initial mean total cholesterol was 7.22 mmol/1 + 0.76 mmol/1 in the 50 participants. The mean plasma cholesterol levels during the 39 months trial period were 6.91, 6.16, 5.54 mmol/1 in 'usual care' controls, diet- and diet-plus-cholestyramine-treated groups, respectively. Overall progression was significantly decreased in the diet (15%) and diet-plus-cholestyramine (12%) groups. Changes in coronary artery segmental diameter were independently and significantly correlated with the LDL-cholesterol concentration and the ratio of LDL-toHDL cholesterol during the trial period. Both interventions significantly reduced the frequency of cardiovascular events. LDL and HDL are heterogeneous lipoproteins. Both consist of subsets with distinct properties (Krauss and Burke, 1982; Fruchart, 1991). In normal subjects up to four major LDL subfractions, distinguished in density and size, have been identified; LDL~ is the largest and least dense, LDL4 is the smallest and most dense. In most healthy people, the major subfractions are LDL~ and LDL2, while the smaller denser subfractions LDL 3 and LDL4 are present in very small amounts. In addition, coronary arteriographic evidence indicated that a lack of progression of angiographic coronary atherosclerosis had significantly greater reductions in IDL and dense LDL compared with subjects who exhibited progression (Krauss et al, 1987). In a univariate analysis it became apparent in STARS that only changes in atherosclerosis were correlated with IDL (d= 1.006-1.019 kg/1, LDL2 (d = 1.019-1.040 kg/1), LDL3 (d = 1.040-1.063 kg/1) and HDL 3 (d= 1.1251.210kg/1). In a multivariate analysis, correlations between changes in coronary luminal dimensions and LDL3 were independent of age, smoking, weight and blood pressure. Most patients showing regression of disease had an LDL3 cholesterol level of less than 1.8 mmol/1 indicating that subfraction LDL 3 may be the single most powerful effect on the course of coronary atherosclerosis (Watts et al, 1993). Angiographic regression was significantly more prevalent in the dietary intervention group. Change was significantly (P < 0.05) more prevalent in the intervention groups in lesions that were initially > 50%.

Lifestyle Heart Trial The Lifestyle Heart Trial applied non-pharmacological intervention to

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patients with symptomatic coronary atherosclerosis (Ornish et al, 1990). The intervention consisted of a strict very-low-fat diet, exercise, yoga and behavioural modification. In the intervention group a significant decrease of LDL-cholesterol was attained, whereas HDL-cholesterol hardly changed during the 2-year study. Positron emission tomography (PET) scanning was used to assess the change in myocardial perfusion. Although most patients were suffering from angina at the start of the study, the most apparent observation was a rapid decrease in anginal symptoms. This was confirmed by an increase in myocardial perfusion which was significantly changed for the better in some of the symptomatic patients after only 90 days (Gould et al, 1994). In the treatment group of 28 patients LDL-cholesterol decreased 37%, HDL-cholesterol 3% and ap0B 24%. apoA1 increased by 2%. The control population consisted of 20 CAD patients. The most significant effect was found in the intervention in the lesions that were initially < 50% (P = 0.03). This study confirmed the earlier finding that behavioural modification may decelerate progression and induce regression of disease.

The Heidelberg Study This study consisted Of a combination of exercise and diet to induce regression of coronary atherosclerosis in men suffering from coronary artery disease (Hambrecht et al, 1993). After only 1 year a significant number of patients who participated in the intervention group showed signs of regression of disease. LDL-C decreased in the intervention group by 12% and triglycerides by 7%. HDL-C increased in the group by 2%. It was inferred from this study that at least 1500 kcal/week and probably 2000 kcal/week have to be spent exercising to induce stabilization or regression of coronary atherosclerosis (Schuler et al, 1992). The results of this study were disappointing in the sense that no regression in the regular exercise population could be attained. On the other hand, the intervention was too short to expect regression of disease.

Cholesterol Lowering Atherosclerosis Study (CLAS) and Familial Atherosclerosis Treatment Study (FATS) These randomized placebo-controlled studies used different drug combinations to attain a lower LDL-C and a higher HDL-C value. CLAS applied a combination of diet, colesfipol, a resin and nicotinic acid, a vitamin, whereas FATS had a three-arm approach: placebo, colestipol and lovastatin, a HMG-CoA reductase inhibitor, and a colestipol and nicotinic acid arm. In FATS, patients had hyperlipoproteinaemia B and a positive history. CLAS

CLAS II was a two years extension of the CLAS I study (Cashin-Hemphill et al, 1990). CLAS aimed at inducing regression of coronary atherosclerosis in normocholesterolaemic men with established coronary heart disease

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and a coronary artery bypass operation. The control population received extensive dietary counselling (Blankenhorn et al, 1987). The 2- and 4-year intervention trials showed that progression of disease was slowed down only slightly in the diet-only group. Of special interest is that, if progression of disease occurred, then this was not dependent on the initial cholesterol values but was related much more to the percentage of lipid change. Drug treatment in the CLAS study resulted in a 43% reduction in LDL-C, a 22% reduction in triglycerides and a 37% increase in HDL-C. This showed a progression of disease in the treatment group (P < 0.03) and induced regression in 16.2% of the drug-treated patients (P < 0.002). It is noteworthy that the magnitude of change in serum LDL was a better predictor of the effect of intervention than were baseline blood values. On the other hand, the ratio of apoCIII in HDL/VLDL appeared to be a more reliable indicator for the change in lesions (< 50%) (Blankenhorn et al, 1993b). FATS

This trial was conducted in 103 men with established coronary heart disease, hyper-apoB and a positive family history for CAD, who underwent sequential coronary angiograms within 2.5 years (Brown et al, 1990). Patients were randomized to three strata: placebo, lovastatin and colestipol or nicotinic acid plus colestipol. Dietary treatment decreased serum LDLcholesterol by 11% and increased HDL-cholesterol by 4%, resulting in 11% regression of disease. Lovastatin and colestipol reduced LDL-cholesterol 46%, while HDL-cholesterol increased 15%, resulting in regression of coronary atherosclerosis in 32% of the patients. Nicotinic acid and colestipol reduced LDL-cholesterol less profoundly but regression occurred in a higher percentage of patients, namely, 39%. HDL-cholesterol increased in this stratum 43%. apoB decreased by 36% in the lovastatin/ colestipol group, whereas niacin and colestipol induced a decrease in apoB of 28%. These results imply that small changes in lipoprotein values during short-course dietary intervention induce regression of coronary atherosclerosis significantly. Furthermore, the change in the drug-induced lipids strata did not correlate linearly with regression of atherosclerosis. This may imply that either the lipid parameters are poor indicators of what is really happening in the vessels or that drug-induced lipid change, by interfering with cholesterol production, is a less effective way to induce regression of coronary heart disease (Brown et al, 1993).

Pravastatin Limitation of Atherosclerosis in the Coronary Arteries I (PLAC I)/Monitored Atherosclerosis Regression Study (MARS)/Canadian Coronary Atherosclerosis Intervention Trial (CCAIT)/Multicentre Anti-atheroma Study (MAAS) These randomized studies assessed the effects of HMG-CoA reductase inhibitors alone on lipoproteins and progression/regression of coronary

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atherosclerosis (Pitt et al, 1993, 1994; Blankenhorn et al, 1993b; Waters et al, 1993; MAAS investigators and Oliver, 1994; Hodis et al, 1994). Although the different drugs induced an important decrease in LDLcholesterol and some increase in HDL-C, overall effects were less than expected. Regression of disease did not occur at all or only in either stenosis over 50% or just in lesions under 50%. The overall decrease in incidence of new lesion formation, as well as a reduction in clinical events, was present significantly more in the drug-treated groups. No clear advantage of the lipid-lowering properties of pravastatin (PLAC I), lovastatin (MARS, CCAIT) or simvastatin (MAAS) was recognized. The MAAS study indicated that when the sequential 2-year angiogram was compared to the sequential 4-year angiogram, during the second 2-year period, less effect was seen on the change in atherosclerosis. In these studies, LDLcholesterol decreased 30-48% and HDL cholesterol increased 15-40%. A reduction of 20-45% triglyceride could be established.

Pravastatin in the Limitation of Atherosclerosis in the Carotid Arteries (PLAC II)/Asymptomatic Carotid Atherosclerosis Prevention Study (ACAPS) The PLAC II was a 3-year study of 151 patients with established coronary atherosclerosis (Furberg et al, 1994a). This was the first study that used Bmode carotid intima-media thickness exclusively as the morphological endpoint. Pravastatin reduced progression of disease and was capable of inducing some regression while lipoproteins were changed. LDLcholesterol was decreased from serum LDL levels at a baseline of 4.3mmol/1 to values of 3.1 mmol/1 during the study. HI)L-cholesterol increased from 1.20 to 1.28 mmol/l. Slowing of progression of disease was significant (P < 0.01), and clinical events were reduced by 61% (P< 0.01). ACAPS, a 3-year study, demonstrated that lovastatin in combination with a lipid-lowering diet using ultrasonographically-assessed IMT measurements of the carotid artery, indicated that regression of disease was a definite possibility (Furberg et al, 1994b). In addition, a significant lower cardiovascular event rate was established (70%, P<0.001) in 229 participants.

Stanford Coronary Risk Intervention Project (SCRIP) This randomized 300-patient study had a LDL-C goal of 2.84 mmol/1. Controls were managed by their physicians, and the special intervention population received diet, exercise, weight reduction and lipid-lowering drug therapy (Haskell et al, 1994). Hypertriglyceridaemia as a cardiovascular risk factor is an aspect that remains controversial (Hulley et al, 1980). However, mild to moderate elevation of plasma triglycerides is associated with a dense LDL subclass pattern (LDL pattern B). This seems to be a heritable trait determined by a single major dominant gene (Austin et al, 1990). The dense LDL subfractions are a marker for a common genetic

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trait that effects lipoprotein metabolism and increases cardiovascular risk. The pattern B is associated with elevated triglyceride levels, VLDL and IDL and a decreased HDL. The B pattern persists even when VLDL, triglyceride and HDL levels are normal; it carries a three-fold greater risk of cardiovascular disease despite no difference in LDL-cholesterol (Austin et al, 1988). The special intervention population in the SCRIP reduced triglycerides by 18%, LDL-C by 28% and increased HDL-C by 14%. Subfractionation in LDL patterns revealed a significant preference for change in pattern B versus pattern A (P < 0.01). Lipid changes in small LDL and triglycerides were significantly higher in pattern B with changes of -40 and -71% respectively (P < 0.0001, P < 0.01).

UC-SF Familial Hypercholesterolaemia Trial (SCOR) During this 26-month-long study, 72 familial hypercholesterolaemic patients were randomized and treated. Controls were given diet and colestipol, and the intervention group were given diet, colestipol, nicotinic acid and lovastatin (Kane et al, 1990). Triglyceride values declined by 21%, and LDL-C by 61% in the intervention group. HDL-C increased in the intervention group by 25%. Deceleration of progression of disease occurred.

Program on the Surgical Control of Hyperlipidaemia (POSCH) POSCH was a controlled study for assessing the effects of partial ileal bypass, as lipid-lowering intervention, on the change, mortality and morbidity in coronary atherosclerosis (Buchwald et al, 1992). LDL-cholesterol decreased during a 7-year follow-up by 59%, whereas HDL-cholesterol and triglyceride levels basically remained the same. HDL2c was significantly lower (P < 0.01) in the control group (0.22 mmol/l). Apolipoprotein B was significantly lower in the intervention group, and apoA1 significantly higher.

Harvard Atherosclerosis Reversibility Project (HARP) This randomized study in 70 patients with established coronary heart disease, focused on the maximal lipid-lowering effect of different drugs to reach a total cholesterol value of < 4.0 mmol/1 or a ratio of LDL/HDL < 2.0 (Stone et al, 1993; Sacks et al, 1994). The trial lasted for 2.5 years and the following drugs in sequence were prescribed to reach the desired lipid goal: pravastatin, niacin, cholestyramine and gemfibrozil. LDL cholesterol in the intervention group declined by 41% and HDL increased by 13%. However, the intensive pharmacological intervention of normocholesterolaemic patients (mean serum cholesterol concentration 5.5 mmol/1), had dramatic effects on lipoprotein profiles but angiographically assessed benefit could not be established.

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CLINICAL EVENTS STUDIES Focus on some lipoprotein aspects

Oslo diet and anti-smoking trial The 15-year results of this trial have been summarized and published (Betteridge and Barth, 1992). This primary prevention study enrolled over 1200 patients who were randomized to intervention (low saturated fat intake and stop-smoking advice) and control groups (Hjermann et al, 1981). The doctor-patient interaction was limited to an infrequent review of cardiovascular risk factors. This resulted in a 10% decrease in total cholesterol, and the total fat intake decreased from 40 to 27%. The polyunsaturated fat/saturated fat ratio increased from 0.3 to 0.7%, and a decrease of triglycerides of 28% HDL-C increased by 5% in those patients who had lost weight. The conclusion of the 15-year follow-up data was that this intervention led to a 5% decrease for risk of coronary heart disease for every 1% total cholesterol lowering. In addition, as may be seen in Table 2, cardiovascular death decreased by 50% in the intervention group, whereas total death decreased by 30%. This study is one of the first to demonstrate that mortality will decrease when healthy advice on the heart is given and followed. Table 2. Oslo diet and anti-smoking trial (15 years' data).*

5 years 8.5 years 15 years

CHD Total CHD Total CHD Total

death death death death death death

Intervention (n = 604)

Control (n = 628)

P

6 16 7 19 24 58

14 24 19 31 48 82

ns ns 0.037 0.055 0.004 0.027

*Adapted from Hjermann (1991) and cited in Betteridge and Barth (1992).

Scandinavian Simvastatin Survival Study

The recently published Scandinavian Simvastatin Survival Study (4S Group et al, 1994) showed that cardiovascular and total mortality could be significantly decreased by lipid lowering using simvastatin. A total of 4444 patients with established coronary heart disease and serum cholesterol values between 5.5 and 8.0 mmol/1 were followed for a median of 5.4 years. LDL-cholesterol decreased by 35% in the intervention group, whereas HDL-cholesterol increased by 8%. In the placebo group there were 189 deaths, while the simvastatin group showed 111 deaths (P < 0.001). Some 622 patients in the placebo group and 431 in the simvastatin group suffered a cardiovascular complication. No increase in non-atherosclerotic death was found. Subgroup analysis of the elderly and women indicated that a similar effect of the intervention was found (Table 3).

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LIPOPROTEINS AND ATHEROSCLEROSIS Table 3. Assessment of clinical events during lipid-lowering therapy. B-mode ultrasound studies

Years

Base during LDL (mmo/1)

Base during HDL (mmol/1)

All events

3 3

4.3 --->3.1 4.1 --->2.9

1.20 --4 1.28 1.19 ---) 1.20

-61%* -60%*

PLAC II (n = 151) pravastatin ACAPS (n = 460) lovastatin

Oslo: diet smoking (n = 604) diet 4S (n = 2221) simvastatin Pravastatin (n = 530) pravastatin Oxford (n = 414) simvastatin

5 5.4 0.5 3

6.0 4.9 4.7 4.8

~ 5.4 --->3.2 --->3.5 --> 3.0

1.18 1.18 1.14 1.16

--> 1.20 ---) 1.27 --4 1.23 ~ 1.26

Cardiovascular events -12%* -42%* -12%* -%(NA)

* Significantly different using standard t-test. NA = not available.

The Pravastatin Multinational Study The effects of pravastatin in patients with serum total cholesterol levels from 5.2 to 7.8 mmol/1 plus two additional atherosclerotic risk factors were studied for effects on clinical events (Pravastatin Multinational Study Group, 1993). In 1062 patients serum LDL-cholesterol fell by 26% during the 26 weeks of double-blind study, and HDL cholesterol increased by 7%. During the 26 weeks there were significantly more serious effects in the placebo group than in the intervention group. This study may indicate that acute lipid-lowering will have a fairly rapid effect on the decline of events. It is presumed to be unlikely that the coronary morphology would have changed that dramatically in 6 months' time (Table 3).

Oxford Cholesterol Study This study was designed to assess the effects of simvastatin on blood lipids and to assess the feasibility of a larger multicentre mortality study (Keech et al, 1994). In the 621 participants who were considered to be at high risk, LDL cholesterol fell by 41% and HDL increased by 6% on 2 0 - 4 0 m g simvastatin. Calculations from this study indicate that tens of thousands of patients would be needed to attain a decrease of a substantial risk of coronary heart disease (Table 3). DISCUSSION A sequential angiographic trial, using different lipid-lowering intervention modes, seems to be an attractive alternative to assessing regression/ reversal of coronary atherosclerosis (Barth, 1986; Moncada et al, 1993; Blankenhorn and Hodis, 1994; Superko and Krauss, 1994). Most studies, however, have been shown to induce deceleration of progression in the intervention arm of the study. Angiography, which is basically viewing the lumen and not the atherosclerotic change itself, may be used even when quantitative methods are employed in fairly advanced disease. A clear and uniform definition for the different changes, such as progression or

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regression of atherosclerosis, is still lacking and should be strived for. Interestingly, although limited data are currently available, it would appear that behavioural modification of atherogenic lifestyle seems a valuable and effective proposition in certain populations. The 'statins' seem to be very effective in changing lipoprotein profiles by dramatically lowering LDLcholesterol and slightly increasing HDL. However, morphological changes do not go in parallel with the level of lipid change. In fact, regression of disease remains a fairly rare phenomenon in established disease. The newer trials, that are using clinical events as end-points, seem to do better when 'statins' are used. One may ask, when reviewing the statin regression studies, whether these compounds should be reserved to familial diseases and combination therapy reserved for alimentary induced hypercholesterolaemia. Different predictors in different lipid-lowering studies may herald regression or slowing of progression of atherosclerosis (Table 4). Another aspect that needs further exploring concerns the fact that about 50% of the population with coronary artery disease have normal LDL values but a low HDL/high triglyceride lipoprotein pattern (Barth and Zonjre, 1992). 'Statins' seem not to be the best of therapies for this lipid pattern. In addition, it seems that change in coronary morphology does not explain the dramatic decline in cardiovascular incidents. Inferred from this, may we state that lipid lowering does the job, so why bother? Lipid lowering in a post-myocardial phase seems the prudent way to proceed (Rossouw et al, 1990). The B-mode ultrasound studies point to a newer direction in atherosclerosis assessment by trying to locate as early as possible those who are more likely to benefit from lipid-lowering therapy. Early detection and a more individualized approach seem a proper way to proceed. Therefore, it has been made clear that dietary change should not be a time-limited option but a life-long commitment to health. Radical Table 4. Predictors for stabilization/regression of plaque and atherosclerosis development. Study LHT

Heidelberg LIT SCRIP NHLBI CLAS FATS CCAIT MARS MAAS PLAC I PLAC II ACAPS POSCH HARP STARS

Oslo

Disappearence of anginal pain, level of adherence Level of exercise reached per week LDL/HDL ratio change, HL, T 4 to conversion T3 increase HDL increase and LDL decrease LDL decrease, smaller LDL decrease, HDLz~ and HDLr~more progression HDL increase, ratio of apo CIII in HDL/VLDL in lesions < 50% HDL increase LDL lowering LDL lowering LDL lowering HDL increase and LDL decrease LDL decrease LDL decrease and HDL increase LDL decrease None LDL 3 level Weight loss, adherence to diet

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dietary changes are possible as may be inferred from the Lifestyle heart trial and the Leiden intervention trial, if health professionals participating in the trial have a positive attitude to dietary intervention. Studies that have examined a small number of arterial segments report a higher initial stenosis than do trials that follow a large number of segments. Since lesions causing greater stenosis are more likely to regress, the reported regression in different trials is in part inversely proportional to the number of vessel segments followed (Brown et al, 1993; Sniderman and Ghezzo, 1994). It seems that significant lesions (> 50%) most readily regress with LDL lowering, whereas lesion stabilization seems to be a more frequent occurrence in smaller lesions (<50%). This process may be more dependent on HDL levels (Assmann and Funke, 1990; Arntzenius and Barth, 1991). Nevertheless, angiographic or sonographic changes are clearly predictive of ensuing cardiovascular events. The CLAS study indicated that a 10% change in mean stenosis per patient resulted in an over two-fold difference in the relative risk for cardiovascular events. Both the POSCH and MARS studies demonstrated a rate of morphological change for the rate of clinical events. From the results of the CLAS trial, it appears that it is less important at what lipid level intervention starts as long as significant changes are made. It is quite remarkable to see that during a reassessment 3.5 years after termination of the LIT, without further proper dietary re-inforcement, diet could be adhered to. FATS re-states again the importance of dietary change for inducing regression of coronary atherosclerosis, even in dyslipidaemic patients. FATS also indicates that the majority of acute events arise from lesions that are less that 70% stenotic. In principle, three mechanisms may stabilize plaque and reduce the risk of clinical events: 1.

2. 3.

Lipid lowering affects endothelial dysfunction directly. Different lipoprotein modulators are located in endothelial lining, e.g. LPL, HL, thromboxane A2 and EDRF. A higher lipid level influences them adversely. Lowering of LDL increases their function. Vasoconstriction reduces vasomotor tone and contributes even more to lesion obstruction. Impaired vasodilatory responses and stimulators of endotheliumdependent vasodilation are seen in early atherosclerosis (exercise and stress) in the presence of hypercholesterolaemia or elevated levels of Lp(a). Changes in coronary artery diameter due to lipoprotein modification are in part due to mobilization of cholesterol esters in macrophages, lipoproteins and droplets resulting in a small decrease in plaque size. A fissure of a lipid-rich atherosclerotic plaque is recognized as a precipating factor in sudden occlusion. Plaques at highest risk for fissuring are those with a large core lipid component and a weak cap. An intramural haemorrhage and thrombus formation may occur, resulting in a complete occlusion. The clinical results are frequently most devastating when mild to moderate lesions are involved since high-grade stenotic lesions are more often associated with collateral formation.

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LDL lowering is associated with decreased progression of mild and moderate lesions and regression of moderate to severe lesions assessed by sequential coronary angiography. Regression of coronary atherosclerosis may be used as a surrogate marker for a decrease in clinical events. The relatively small changes in lumen diameter are unlikely to explain the significant decreases in clinical events in the majority of lipidlowering studies. A reduction in serum LDL-cholesterol and/or an increase in serum HDL-cholesterol results in a decrease in the lipid content of the atherosclerotic plaque, increased plaque stability and reduced likelihood of plaque rupture. In addition, reduction of circulating LDL appears to improve the vasodilatory response of the endothelium and the endothelial dysfunction in general. Specific factors that are predictive of a recognized and positive outcome in terms of regression, and hence decrease of coronary events, are an LDL-cholesterol lowering and an HDL-cholesterol increase (Table 4) (Schwartz et al, 1992). LDL pattern B and triglyceride levels appear also to play a prognostic role. Lp(a) is an independent risk factor, but results from FATS demonstrated that the risk associated with high levels of Lp(a) are attenuated once LDL-cholesterol was lowered below 2.5 mmol/1. In MARS, an LDL level below 2.5 mmol/1 and the LDL/HDL ratio were the best predictors for change in lesions > 50%. VLDL and LDL apolipoprotein C-III, which are markers for triglyceride-rich lipoprotein metabolism, were the best predictors of change in lesions < 50%. CLAS indicated that triglyceride levels predict progression, particularly when LDL levels are aggressively lowered. This finding supports the fact that triglyceride-rich lipoproteins are atherogenic. To summarize, regression of atherosclerosis is possible but there is no consensus on the most effective therapy, let alone which lipoprotein changes would be the most favourable ones to strive for. Early detection of atherosclerosis using ultrasound methods and early intervention with an individualized therapeutic approach should be beneficial. SUMMARY

Lipoproteins and the impact of lipid lowering on progression and regression of coronary artery disease are discussed. Angiographically assessed regression studies are reviewed (NHLBI, LIT, LHT, CLAS I and II, FATS, POSCH, Heidelberg, STARS, SCRIP, MAAS, PLAC I, HARP, UC-SF), as are B-mode ultrasound studies (ACAPS, PLAC II) and survival studies (Oslo diet-smoking study, SSSS, Pravastatin, Oxford). Although study populations and the interventions are different in the studies, I have come to the following conclusions. Regression of atherosclerosis correlates well with reduction in LDL cholesterol and an increase in HDL cholesterol. Although overall improvement in the severity and extent of the disease was modest, reduction of clinical events was impressive. Lipid modulation may stabilize existing lesions by improving the stability of the lesion cap and/or promoting loss of cholesterol content from within the plaque. Survival studies

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indicate that lipid lowering lowers morbidity and increases longevity in patients with established coronary heart disease. The B-mode ultrasound studies using the carotid artery as surrogate for the change in atherosclerosis in the coronary seems extremely promising. The atherosclerotic process as well as complications may be studied at an early stage using noninvasive methods. Acknowledgements I am indebted to J. J. Frohlich MD, FRCP(C), Director of the University of British Columbia's Lipid Clinic in Vancouver B.C. for his editorial help and great insight in this matter.

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