Plaque stabilization: A mechanism for the beneficial effect of lipid-lowering therapies in...

Progress in

Cardiovascular Diseases VOL XXXVII, NO 3 NOVEMBER/DECEMBER 1994

Plaque Stabilization: A Mechanism for the Beneficial Effect of Lipid-Lowering Therapies in Angiography Studies

David Waters

E XCESSIVELY high levels of serum cholesterol, especially the low-density lipopro-

tein (LDL) fraction, have been shown conclu- sively to be a primary risk factor for atherosclerotic vascular disease. The relationship between cholesterol and atherosclerotic coronary heart disease (CHD) is regarded as causal and, in the opinion of some authorities, is decisive? Moreover, there is evidence that assertive intervention to reduce serum total and LDL cholesterol, ideally in association with an increase in the high-density lipoprotein (HDL) fraction, is associated with a very substantial reduction in morbidity, is attributable to CHD, and may reduce mortality in specific circum- stances. This conclusion is a centerpiece of various national and supranational initiatives to reduce the numbers of people killed per annum by atherosclerotic disease. 2-4

Early clinical trials of lipid-lowering interventions dealt with the effect on clinical outcomes. In more recent years, however, there has been a movement toward studies based on quantitative angiography. Various pragmatic reasons have been identified for this trend, 5,6 including the ability to generate statistically robust data from relatively small numbers of patients in a relatively short period of time. 7 The rationale underlying these studies may be summarized as follows: (1) raised cholesterol causes atherosclerosis; (2) progression of atherosclerosis causes clinical CHD events now and increases the risk for such events in the future; (3) halting progression of atherosclerosis is a surrogate for preventing CHD events; and (4) if elevated serum cholesterol causes CHD by promoting the growth of atheromatous plaques, it ought to be possible to show that lowering serum choles-

terol levels halts the growth of plaques and may lead to a reduction in their size, so-called regression. Implicit in this hypothesis is the belief that the likelihood of a plaque giving rise to clinical CHD is proportional to the size of the plaque.

Recent developments in histology, micros- copy, and pathology have initiated a reappraisal of the relationship between plaque size, vessel occlusion, and CHD and, in doing so, have permitted a reinterpretation of the results of angiography studies. This reappraisal has confirmed and strengthened the link between high levels of cholesterol and CHD and has shown more of the mechanisms by which lipid-lowering therapies may exert their beneficial effects. As a result, emphasis has shifted away from the original notion of regression, perceived as an improvement of luminal narrowing caused by a plaque, towards the concept of stabilization, which is envisaged as the consolidation of a subgroup of small- or medium-sized lipid-rich plaques that act as loci for the occlusive atherothrombotic events of clinical CHD.

ANGIOGRAPHY STUDIES

Numerous angiography studies have been conducted, not all of which satisfy the criteria relevant to a discussion of plaque stabilization. These criteria are that (1) the coronary vascula- ture should be the object of the study; (2) serial

From the Division of Cardiology, Hartford Hospital and the University of Connecticut School of Medicine, Hartford, CT.

Address reprint requests to David Waters, MD, Director of Cardiology, Division of Cardiology, Hartford Hospital, 70 Seymour St, Hartford, CT 06102.

Copyright �9 1994 by W.B. Saunders Company 0033-0620/94/3703-000155.00/0

Progress in Cardiovascular Diseases, Vol XXXVlI, No 3 (November/December), 1994: pp 107-120 107

108 DAVID WATERS

Table 1. Entry Requirements, Treatment Regimens, and Lipid Responses to Treatment in Nine Angiography Studies

Eligibility Treatment LDL Response HDL Response Follow-Up Study Criteria Regimen (%)* (%) (yr)

NHLBI 8 CAD, LDL E + R -31 +8 5 CLAS 19 CAB D + R + N -43 +37 2 CLAS II 1~ CAB D + P + N -40 +37 4 POSCH ~ MI, CHOL >5.7 mmol/L D + PIB + R -42 +5 9.71" FATS (N + C) s CAD, Apo B D + R + N -32 +43 2.5 FATS (L + C) s CAD, Apo B D + R + L -46 +15 2.5 SCOR 12 FH D + R + N -+ L -39 +25 2 STARS (D only) 13 CAD, CHOL > 6 mmol/L D -16 0 3 STARS (D + R) ~3 CAD, CHOL > 6 mmol/L D + R 36 - 4 3 Ornish et al TM CAD V + M + E -37 - 3 1 SCRIP TM CAD D + (R/N/L/F) + E, BP -21 +13 4 Heidelberg~ CAD D + E - 8 +3 1 MARS ~7 CAD D + L -38 +8.5 2.2 CCAIT TM CAD, CHOL 5.7-7,8 mmol/L D + L -29 +7.3 2

Abbreviations: CAB, coronary artery bypass graft; CHOL, serum total cholesterol; LDL, LDL cholesterol greater than the 90th percentile; Apo B, apolipoprotein B greater than 125 mg/dL; FH, familial hypercholesterolemia; D, diet; V, vegetarian diet; R, bile acid sequestrant (resin); L, Iovastatin; N, nicotinic acid; F, fibrate-type drugs; PIB, partial ileal bypass; M, mediation techniques; E, exercise program; BP, blood pressure therapy.

*Mean LDL response to control therapy was -7%. tFollow-up has been extended beyond the formal conclusion of this study. Modified and reprinted with permission. 2~ @ Copyright 1993 American Heart Association.

angiography should be used; (3) the study must incorporate a suitable control group; and (4) the lipid-modifying therapy must effect a favorable alteration in the serum lipid profile (princi- pally, a reduction in LDL cholesterol accompanied, ideally, by a decrease in triglyceride and an increase in HDL cholesterol).

Eleven studies meet these requirements: the National Heart, Lung, and Blood Institute type II trial (NHLBI); s the Cholesterol-Lowering Atherosclerosis Study (CLAS; including the extended follow-up designated CLAS-II); 9,t~ the Program on the Surgical Control of the Hyper- lipidemias (POSCH); 1] the Familial Atheroscle- rosis Treatment Study (FATS); 4 the San Fran- cisco Arteriosclerosis Specialized Center of Research (SCOR) study; ]2 the St. Thomas' Atherosclerosis Regression Study (STARS); ~3 the Lifestyle Heart Trial; 14 the Stanford Coro- nary Risk Intervention Project (SCRIP); 15 the Heidelberg study; 16 the Monitored Atheroscle- rosis Regression Study (MARS); 17 and the Ca- nadian Coronary Atherosclerosis Intervention Trial (CCAIT). is It is instructive to review these trials briefly (see Tables I and 2).

The NHLBI study involved 143 men with coronary artery disease (CAD) and LDL cholesterol in the uppermost 10% of the populationdis- tribution. Five years of therapy with a lipid- lowering diet plus the bile acid sequestrant,

cholestyramine (target dose, 24 g/d), was associated with a 28% reduction in LDL cholesterol (P < .001 v placebo-treated controls). Definite plus probable CAD progressed in 49% of pa-

Table 2. Angiographic and Clinical Outcomes in Nine Angiography Studies

Study

Control Patients Treated Patients Event

Progres- Regres- Progrea- Regres- Reduction sion (%) sion (%) sion (%) sion(%) (%)*

NHLBI 8 49 7 32 7 33 CLASP 61 2 39 16 25 CLAS II l~ 83 6 30 18 43 POSCH 11 65 6 37 14 351" FATS (N + C) 5 46 11 25 39 80$ FATS (L + C) 5 22 32 70 SCOR 12 41 13 20 33 1 v 05 STARS

(D only) 13 15 38 691" 46 4

STARS (D + R) 13 12 33 89

Ornish et al TM 32 32 14 41 0 v I t SCRIP rs NA 10 NA 21 50 Heidelberg TM 42 4 20 30 27 MARS 17 41 12 29 23 24 CCAIT TM 50 7 33 1 O 25

*The nature of the clinical events recorded varies from study to study (see original reports for details).

tStudies in which the reduction in clinical events was statistically significant by the criteria adopted for that study.

:~Results expressed as number of events rather than as a percentage because the total number of events was very small. Data are presented in the order "control group v treated group."

Modified and reprinted with permission. 21 �9 Copyright 1993 American Heart Association.

LIPID LOWERING AND PLAQUE STABILIZATION 109

tients in the placebo group and in 32% of the treated patients (P < .05). Increases in HDL cholesterol during therapy also correlated with a reduced progression of coronary atheroma.

CLAS studied 162 nonsmoking men (aged 40 to 59 years) who had undergone coronary artery bypass grafting. After baseline angiographic assessment by an expert panel, patients were randomized to diet therapy plus placebo or to diet plus colestipol and nicotinic acid for 2 years. Repeat angiograms were undertaken at the conclusion of the study. Lipid-lowering therapy was associated with a 26% reduction in plasma total cholesterol, a 43% reduction in LDL cholesterol, and a 37% increase in HDL cholesterol. These changes in lipid profile were accompanied by angiographic evidence of slowed progression of established disease in both native and grafted vessels. A small degree of regression of atheroma was recorded in 16.2% of treated patients compared with 3.6% of patients in the placebo group (P < .007). Four- year follow-up data on 113 patients involved in CLAS have subsequently been published (CLAS-II). These data confirm that the lipid response to drug therapy is sustained over the longer term and is associated with continued favorable effects on coronary atherosclerosis.

POSCH is the most extensive angiographic study of nonpharmacologic intervention against serum lipids. Nearly 900 survivors of a first myocardial infarction (MI) were randomized to either partial ileal bypass surgery or diet therapy. At the 5-year follow-up, serum total cholesterol in the surgery group was 23.3% lower than that in the control group (P < .0001), and LDL cholesterol was 37.7% lower (P < .001). A small, but significant (4.7%, P < .02), increase in HDL cholesterol was also observed. Compari- son of baseline angiograms with those taken at 3, 5, 7, and 10 years of follow-up confirmed that surgery was consistently associated with reduced progression of coronary atheroma (P < .001). In addition, lipid-lowering surgery was associated with a statistically significant reduction in the combined clinical end points of death caused by CHD and of confirmed nonfatal MI (125 events v 82 events; P < .001) and was also associated with a large reduction in the number of coronary bypass procedures (52 v 137; P < .0001). The POSCH investigators also reported reductions in overall mortality and deaths from

CHD in the surgery group. These reductions were not statistically significant at that time; however, patient follow-up and analysis are continuing, and the difference between the two groups of patients is now approaching signifi- cance at the 5% level.

In FATS, angiographically measured changes in coronary artery stenosis were related to clinical events. A total of 146 men with established CAD, familial history of coronary disease, and serum apolipoprotein B in excess of 125 mg/dL were enrolled in this study and randomized to diet therapy plus placebo (or low-dose colestipol, for ethical reasons), to colestipol (30 g three times per day) and the reductase inhibitor lovastatin (20 to 40 mg, twice per day), or to colestipol (30 g three times per day) and nicotinic acid (4 g four times per day). Quantitative angiography conducted before and at the conclusion of the 2.5-year trial established that both treatment regimens re- tarded the progression of atheromatous lesions; the overall change was in the direction of regression, with minimum lumen diameter in- creasing in both treatment groups but decreas- ing in the placebo group (P < .01). These favorable angiographic findings were accompanied by reductions in the number of clinical coronary events in both treatment groups.

STARS evaluated the impact of a lipid- lowering diet, alone or in combination with cholestyramine (8 g twice per day), on coronary atherosclerosis in 90 men with established CHD. Patients were assigned to usual therapy (U), diet therapy (D), or diet plus cholestyramine (D+C). Seventy-four patients completed the study (U, 24; D, 26; D+C, 24). Baseline lipid and lipoprotein parameters were very similar in all three groups. In the U group, little variation in lipids or lipoproteins occurred during the trial; net progression of atherosclerosis was recorded in this group.

In patients assigned to diet therapy, total cholesterol decreased by 14.2% and LDL cholesterol by 16.2% (bothP < .001). The correspond- ing reductions in the D+C group were 25.3% and 35.7%, respectively, (also both P < .001). Substantial reductions in the LDL:HDL ratio were recorded in both treatment groups (D, 17.6% and D+C, 34.6%; bothP < .001). These changes in lipid and lipoprotein profiles were accompanied by angiographic evidence of over-

110 DAVID WATERS

all regression of coronary disease in both treatment groups.

Women are underrepresented in angiographic studies, as is the case with clinical trials in general. The SCOR trial is an exception to this rule; 41 of the 72 patients involved were women. All participants had heterozygous familial hypercholesterolemia and angiographic evidence of coronary atherosclerosis. Over the course of 2 years, lipid-lowering therapy consist- ing of a recommended diet plus colestipol, nicotinic acid, and (in some cases) lovastatin resulted in highly statistically significant reductions in total and LDL cholesterol (both P < .01) and in significant increments in HDL cholesterol (P < .01). These changes were associated with a mean change of -1.53 in the percentage of area stenosis; the mean change in percentage of area stenosis among controls was +0.80 (P < .039; two-tailed test). A separate analysis of the results for women showed that the mean percentage of change in area stenosis was -2.06 (P < .05).

Ornish et a114 have reported success in the use of lifestyle changes to reverse CAD in patients with existing atheromatous plaques. Over the course of 1 year, intensive efforts at smoking cessation, regular structured exercise protocols, strict lipid-lowering diets, and stress management resulted in regression of existing lesions in 18 of 22 patients.

In SCRIP, a 4-year program of risk reduction directed at hyperlipidemia, hypertension, cigarette smoking, and obesity was associated with favorable alterations in serum lipid profile, retardation of atherosclerosis progression, and a reduction in the number of cardiac events in 145 patients aged 75 years or less.

The Heidelberg study (n = 113) has reported retardation of atherosclerosis progression in response to rigorous dietary control plus a program of regular physical exercise.

MARS, one of the most recent of these angiography studies to be completed, examined the impact of monotherapy with the hepatic hydroxymethyl glutaryl coenzyme A reductase inhibitor, lovastatin (40 mg twice a day), on coronary atherosclerosis in patients with angiographic evidence of disease in at least two segments including at least one segment with a minimum 50% diameter stenosis. A total of 270

patients aged less than 70 years were enrolled in the 2-year, placebo-controlled trial; two-thirds of patients had total cholesterol less than 240 mg/dL (6.2 mmol/L).

The overall change in percent diameter stenosis, measured by quantitative coronary angiography, was similar in both groups (lovastatin, +1.6% _+ 6.7%; placebo, +2.2% -+ 6.8%; P > .20), but lovastatin was associated with a reduction in percent diameter stenosis in lesions greater than 50% at baseline (-4.1% _+ 11.0%). This reduction was statistically significant compared with the increase of +0.9% _+ 11.0% observed in the placebo group (P < .01). Lovastatin therapy was also accompanied by increased minimum lumen diameter (+0.13 mm _+ 0.35 mm) in lesions greater than 50% at baseline, whereas progressive reduction in lumen occurred this category of lesions in the placebo group (-0.04 mm + 0.36 mm; P < .01). Comparison of the secondary end point of global changes score provided evidence of significantly less progression of CAD in patients treated with lovastatin (+0.41 _+ 1.14 v +0.88 _+ 1.12 in placebo group; P < .01). These angiographic responses to lovastatin therapy were accompanied by the expected large reductions in total cholesterol (-32%), LDL cholesterol (-45%), and apolipoprotein B (-26%) and by a modest increase in HDL cholesterol (+8.5%).

kovastatin monotherapy (in conjunction with diet) was also the intervention used in the latest of these 11 studies, CCAIT. The 331 enrolled patients, aged 21 to 70 years, were selected on the basis of diffuse but not necessarily severe coronary atherosclerosis accompanied by serum total cholesterol in the range 220 to 300 mg/dL (5.7 to 7.8 mmol/L).A total of 165 patients was assigned to diet plus lovastatin, and 166 patients were allocated to diet plus placebo. Lovastatin dosage was titrated against LDL cholesterol during the first 16 weeks of the trial with the objective of achieving LDL cholesterol less than 130 mg/dL (3.4. mmol/L).

The primary angiographic end point in CCAIT was a coronary change score (expressed in millimeters) that represented the net difference between minimum lumen diameter at baseline and after 2 years. Secondary end points in- cluded proportion of patients showing progression only, regression only, and appearance of


new lesions. Progression and regression were defined as widening or narrowing of at least 0.4 mm, and a new lesion was defined as one that was not apparent at baseline or that caused no more than 25% diameter stenosis, which nar- rowed by at least 0.4 mm during the study.

Mean lovastatin dosage during the trial was 36 rag/d; this was associated with a mean reduction of 29% _+ 11% in LDL cholesterol (P < .001). Owing to the dose titration protocol adopted for CCAIT, the mean dose consumed by patients with baseline LDL cholesterol greater than the group median of 176 mg/dL (4.6 mmol/L) was greater than that taken by patients with baseline LDL cholesterol less than the median (43 mg/d v 28 mg/d).

Mean coronary change score in the Iovastatin group was -0.05 mm _+ 0.13 mm, compared with -0.09 mm + 0.16 mm in the placebo group (P < .01). Subgroup analysis showed that this overall benefit was attributable to a reduced rate of progression among lesions causing stenosis of less than 50% at baseline (-0.06 mm _+ 0.14 mm v -0.11 mm _+ 0.18 mm; P < .014). No significant difference in coronary change scores was registered in lesions causing more than 50% stenosis at baseline.

Progression only was a significantly less fre- quent outcome in patients treated with lovastatin (33% v 50%; P < .03), but the proportion of patients showing regression only was similar in both groups (lovastatin ,10%; placebo, 7%; no significant difference). One or more new lesions developed in 23 of 146 patients treated with lovastatin compared with 49 of 153 patients in the placebo group (P = .001). New total occlusions were recorded in 10% of patients in the lovastatin group and in 12% of patients assigned to placebo (difference not significant).

Multiple variable regression analysis established that better coronary change scores were associated with higher baseline LDL cholesterol level, wider baseline minimum lumen diam- eters, lovastatin therapy, greater numbers of lesions causing more than 25% stenosis at baseline, and hypertension. Cigarette smoking emerged as a major determinant of a worse coronary change score.

Two patients in each group of the CCAIT died during the study; both deaths in the lovastatin group and 1 death in the placebo group

were classified as cardiac deaths (the fourth patient died in an air accident). In addition, there were five episodes of M] in the lovastatin group and 8 episodes of unstable angina. A total of 6 episodes of MI and 13 episodes of unstable angina occurred in the placebo group. The differences in event rates were not statistically significant.

In the CCAIT, most lesions examined caused less than 50% diameter stenosis at baseline, and most instances of progression occurred in lesions of these modest baseline dimensions (progression was shown in only 14 of 339 lesions rated as causing more than 50% stenosis at baseline). Even among the smaller lesions, the overall rate of progression was low; 59 of 865 lesions progressed in the lovastatin group (6.8%), and 108 of 965 lesions progressed in the placebo group (11.2%; P = .005 between groups). Prescription of alternate-day aspirin (325 rag) to all patients enrolled in CCAIT has been nominated as a possible explanation for the lack of progression among larger lesions. 18 The natural history of atherosclerosis as shown in this study (ie, the apparent dormancy of many atherosclerotic lesions with substantial alterations [either progression of regression] occur- ring in only a small proportion of lesions, the concentration of progression among lesions of small to intermediate size, and the postulated involvement of platelets in progression of some lesions) is pertinent to the debate about plaque stabilization and will be considered in greater detail later in this review.

A NEW PERSPECTIVE ON ANGIOGRAPHY

Formal meta-analysis of these trials is hin- dered by differences in methodology and definition of outcome. Moreover, as critics have noted, 19,2~ angiography is not without its deficien- cies and should be regarded as the best available technique for evaluating coronary atherosclerosis, not the best per se. (Proposals have been made that, if adopted generally, would help optimize the reliability, reproducibility, and variability of angiographic data. 7) However, what these studies may lack in homogeneity, they make up for in consistency. Regardless of the intervention used, lipid lowering was associated with a lesser degree of progression of atherosclerosis and a greater propensity to

112 D A V I D W A T E R S

plaque shrinkage. Moreover, this trend was associated with statistically significant reductions in the number of clinical CHD events (howsoever defined) in several trials in which elevated cholesterol or lipoprotein cholesterol was an entry criterion (FATS, POSCH, and STARS).

Therefore, in the aggregate, the results of these trials support the proposition that lipid- lowering therapy will prevent, delay, or even reverse (partially) the development of atherosclerotic lesions. However, as Brown et a121 have pointed out, the clinical impact of lipid-lowering therapies in some of these trials has been out of all proportion to the effect on plaque size. In FATS, for instance, only 12% of lesions were deemed to have undergone regression in response to therapy, and the average difference in lumen diameter between actively treated patients and controls was less than 0.1 ram. These trifling changes were nevertheless associated with a 70% to 80% reduction in cardiovascular events.5,21 In seeking to explain this apparent paradox, stress needs to be laid on the average- ness of the angiographic changes reported. The greater majority of plaques, probably in the region of 90%, do not change in response to lipid-lowering therapy. However, those that do change change quite a lot, probably enough to explain the reduction in clinical events.

Two additional observations from FATS are informative. First, aggressive lipid-lowering therapy had little influence on the progression of severely stenotic lesions (ie, those causing 70% to 90% stenosis at baseline), but decreased several-fold the likelihood of progression of smaller lesions (Fig 1). Second, 8 of 9 clinical events to occur in the control group of FATS were related to the progression of lesions designated mild or moderate in extent at baseline (Fig 2). Conversely, only I of 4 clinical events in the actively treated groups was associated with such a lesion (Fig 2). These data are supple- mented by findings from another angiographic study in which it was reported that severely stenotic lesions were more likely than smaller plaques to progress to complete occlusion of the vessel but less likely to cause MI. 22 Taeymans et al, 23 in a small retrospective study, have confirmed that lesions at high risk for occlusion are relatively modest proportions (causing approxi-

25%-

% of 20%- Lesions that 15O/o - Progress (_> 10%S) 10%-

5%-

Progression

:-,#i CONV N N I L+C I I N+C

NI 10-40%' 40-70% ' 70-98% (785) (312) (52)

Regression

% of Lesions that Regress (< -10%S

(785) (312) (100)

Baseline Stenosis Severity (% Stenosis)

Fig 1. The effect of lipid-lowering therapy in the FATS trial on progression and regression of lesions is shown according to percent baseline stenosis. Intensive lipid-lowering therapy substantially reduces the likelihood of progression of mild or moderate lesions but has little effect on the progression of lesions classified as severe at baseline. * P < .05; +P < .02;

** P < .005; ++P < .001 (versus conventional [CONV] group); see text for further details. (Adapted and reprinted with permissionY 1 [Circulation.] Copyright 1993 American Heart Association.)

mately 50% stenosis at the last pre-event angio- gram). These researchers also reported that lesions that progressed to occlusion were more likely to be located at sites of flow division and to be steeply angled, 23 findings that reaffirm the influence of high shear stresses in plaque rupture and thrombotic occlusion.

PLAQUE RUPTURE AND THROMBOSIS

These observations are compatible with the linked hypotheses that unstable angina, acute MI, and ischemic sudden death are the result of abrupt progression of small or moderately sized


CAD Progression to Events

Fig 2. Clinical events in FATS are shown according to baseline status of causal lesions. Eight of the nine clinical events recorded in the control group (n = 46) were associated with progression of lesions that caused mild or moderate stenosis at baseline. Only one of four events in the two treatment groups (n = 59) was attributable to progression of such a lesion. Numbers in lower left corner of each box indicate the total number of lesions of each type at baseline. Abbreviations: d, death; m, MI; p, progressive angina; u, unstable angina; N+C, nicotinic acid plus colestipol; N+L, nicotinic acid plus Iovastatin; CONV, conventional therapy (control group); %S, percent diameter stenosis. See text for further details. (Adapted and reprinted with permissionY 1 [Circulation.] Copy- right 1993 American Heart Asso- ciation.)

N + C

L + C

CONV

n=27

32

Mild Moderate Severe

235 103 18 , , , , ,

2 3 7 108 18 e - ' (

i --4 . [ ] ni- ,-pa

hi---,, . O]

53 313 101 ~ 16

10 40 70 100 Stenosis Severity

(Baseline-- Event)(%S)

m .

B-

plaques, and that the value of lipid-lowering therapy as shown in angiographic trials lies in its ability to stabilize a subpopulation of lipid-rich plaques which have a propensity to rupture and which, once ruptured, become sites for the propagation of thrombi that create critical stenosis or total occlusion of the affected vessel.

Plaque rupture with subsequent thrombosis as a critical factor in the genesis of acute coronary syndromes is a well-established concept. Results of recent studies indicate that rapidly evolving atherothrombotic lesions are the rule rather than the exception in patients who suffer fatal coronary events and have provided more detailed information on the factors that dispose towards plaque rupture. 21,24,25

CHARACTERISTICS OF CRITICAL CORONARY PLAQUES

Atherothrombotic occlusion of a coronary vessel is most frequently the result of deep tears in the fibrous cap of the atherosclerotic plaque 26 and of the resultant exposure of platelets to proaggregatory factors such as collagen, ne- crotic debris, yon Willebrand factor, and throm-

boxanes. Small- to medium-sized plaques with the potential for such abrupt, deep fissuring are characterized by21.27-29: (1) a core of extracellu- lar lipid, perhaps including crystalline cholesterol, that occupies more than 40% of the plaque volume; (2) a relative paucity of connective tissue in the fibrous cap overlying the lipid pool; (3) a relative paucity of smooth muscle cells in the fibrous cap overlying the centre of the lipid pool and an excess of lipid-filled macrophages in the same region; and (4) an eccentric position around the lumen of the vessel.

The physical frailties of such a plaque are evident. The substantial lipid pool, which is believed to be semiliquid at body temperature, is highly susceptible to deforming pressures that the weak fibrous cap is ill-suited to resist. The points of insertion of the fibrous cap into the surrounding normal intima are regions of high stress, 3~ at which rupture occurs frequently. Circumferential shear stresses in the fibrous cap are high in plaques with a large lipid pool. Loss from the cap of smooth muscle cells, some which have been transformed from the contrac-

114 DAVID WATERS

tile to the synthetic state, 27 may also contribute to the weakness of the fibrous cap by diminish- ing the capacity to manufacture connective tissue.

The ingress of lipid-filled macrophages to the weakest regions of the cap, first reported by Constantinides, 32 has been confirmed in several studies, but it is not clear if these cells contribute to the creation of an unstable plaque or are merely markers for such a lesion. It is known, however, that macrophages release proteases capable of degrading the connective tissue ma- trix of the fibrous cap, and that they elaborate several thrombogenic factors. Therefore, they have the potential to contribute to plaque rupture and thrombosis.

The distribution of types of atheromatous plaques in individuals is heterogeneous, and lipid-rich plaques often represent only a small proportion. In one series of patients with stable angina, lipid-rich, eccentric plaques occupying more than 50% of coronary artery diameter accounted for only 12% of all plaques of this size. 33 Others have asserted that this subpopulation of atherosclerotic plaques represents only 10% to 20% of the total plaque population but accounts for 80% to 90% of acute coronary atherosclerotic events. 21 By contrast, Waller 34 has reported that eccentric plaques represent a much larger proportion of the total plaque population.

CONSEQUENCES OF PLAQUE RUPTURE

Plaque rupture may have one of two outcomes (Fig 3). First, thrombosis within the plaque and ensuing fibrotic organization may reseal the plaque. Repeated cycles of rupture, thrombosis, and consolidation could lead to the creation of a larger, but more fibrous and stable, plaque that is less prone to rupture than its precursors and that, by virtue of the high-grade stenosis it creates, may give rise to stable angina pectoris (Fig 3). Although this scenario envis- ages plaque growth as a series of explosive bursts during which embolization may cause acute ischemic damage, the progression from initial fatty streak to a highly fibrotic plaque causing severe stenosis may extend over several decades and may be asymptomatic throughout. Compensatory development of collateral circulation during this time has been advanced as one reason why this type of plaque may totally occlude a vessel but cause only minor or silent MI or even no infarction at all. (Vos and colleagues 19 have criticized the design of some trials cited in support of this theory.)

The alternative outcome is the rapid evolu- tion of an occlusive (or critically stenotic) intraluminal thrombus over the site of plaque rupture, with the consequent development of an acute coronary syndrome (Fig 3). In its early stages, such a thrombus may generate platelet emboli, which are responsible for the symptoms

Sudden death ] Crescendo angina

Sudden death Acute infarction

Plaque fissure

Intraintimal thrombus

Reseal

0rganise

Mural intraluminal thrombus ~ 0rganise

Occlusive luminal Recanalise thrombus ~ organise ---'e

Stable 1 angina

Plaque growth

Fig 3. Possible outcomes of plaque fissuring are shown. (Adapted and reprinted with permission from the British Heart Journal, 1985, 53:363-367, Davies and Thomas 2s [published by BMJ Publishing Group].)


of unstable angina and for sudden ischemic death in susceptible patients; lipid emboli released from the ruptured plaque may also contribute to this process. Maturation of the thrombus into a fibrin-rich mass containing large numbers of red blood ceils creates a persisting occlusion and causes MI.

IMPACT OF LIPID LOWERING ON CRITICAL PLAQUES

Depletion of the lipid pool of critical atherosclerotic plaques is perhaps one of the most important effect of sustained lipid-lowering therapy. Reference to Fig 2 shows that therapy with a bile acid sequestrant plus either lovastatin or nicotinic acid almost entirely pre- vented catastrophic progression of medium- sized lesions in FATS. Of 683 lesions designated as causing mild-to-moderate stenosis at the start of the study, only 1 was subsequently linked to a clinical event (P < .005 per patient and P < .02 per lesion). By contrast, 8 of 414 such lesions were associated with clinical events in the control group. This difference in outcomes has been ascribed to removal of lipid from the plaque secondary to the correction of an atherogenic serum lipid profile.

This explanation represents the atherosclerotic plaque as a sort of intravascular boil, with removal of the lipid content relieving the me- chanical forces that dispose to rupture. How- ever, lipid-lowering therapy may well have additional favorable effects on these critical plaques, some of which are outlined below.

OXIDIZED LDL AND ENDOTHELIAL DYSFUNCTION

Oxidation, or similar modification, of LDL has been proposed as a key step in atherogenesis. 35-37 In the context of the critical atherosclerotic plaque, a decrease of the native LDL substrate by lipid-lowering therapy may have several potentially favorable effects. Specifi- cally, oxidized LDL is chemotactic for monocyte/ macrophages; it also inhibits the motility of resident macrophages. In addition, oxidized LDL is preferentially phagocytosed by macrophages (via the acetyl-LDL receptor) and, thereby, promotes the development of foam cells. As noted earlier, the amassing of macrophages in the fibrous cap is one of the hallmarks

of a critical atherosclerotic lesion. Oxidized LDL may play a crucial role in this process.

In addition, oxidized LDL is cytotoxic and stimulates the release of growth factors and cytokines. These actions also may contribute to the weakening of the fibrous cap in critical lesions. Cholesterol-lowering therapies have been associated with a reduction in the numbers of lipid-laden intimal macrophages in atherosclerotic plaques. A reduction in the amount of substrate LDL available for oxidation may be partly responsible for this.

The possibility of supplementing lipid-lowering measures with antioxidant therapy has at- tracted much attention, and two recent studies in the United States have provided strong evidence of an epidemiologic association between a high intake of vitamin E and a lower incidence of CHD in both men and women. 38,39 It is premature to consider antioxidant therapy as having a confirmed role in the prevention of CHD, but interim data are encouraging.

Oxidized LDL particles may also be implicated in a second pathologic process, namely vascular endothelial dysfunction. Extensive data have been amassed which indicate that hypercholesterolemia is associated with dysfunction of the vascular endothelium, and that this dysfunction leads to the development of a proaggregatory state. In addition, the response to vaso- constrictor stimuli is enhanced, whereas that to vasodilators is attenuated or transformed into a paradoxical vasoconstriction. 4~

Alterations of vascular sensitivity are detectable before there is visible evidence of atheromatous lesions. There are persuasive reasons to regard endothelial dysfunction as the first mani- festation of diffuse atherosclerotic vascular disease. It has been reported recently that early signs of endothelial dysfunction are evident at branch points in the human coronary vascula- ture43; these are recognized as sites especially prone to the development of atherosclerosis. Taeymans and colleagues 23 have concluded that plaques located at such sites are at particular risk for progressing to occlusion. The same group has reported a correlation between paradoxical vasoconstriction to acetylcholine and the presence of known risk factors, including serum total cholesterol.

There is ample evidence that the principal

116 DAVID WATERS

cause of the tendency toward vasoconstriction in hypercholesterolemia is impaired synthesis or release of endothelium-derived relaxant factor. The vasodilator response observed when endothelium-dependent (ie, receptor-dependent) vasodilators such as acetylcholine or serotonin are applied to normal endothelium is attenuated, abolished, or reversed when these compounds are applied to the blood vessels of hypercholesterolemic animals or humans, whereas the response to sodium nitroprusside (a nonendothe- lium-dependent vasodilator) is preserved. Treatment with lovastatin or lipid-lowering diets is associated with a substantial restitution of normal vasodilator responsiveness in hypercholesterolemic rabbits, suggesting a causal relationship between high serum lipid levels and endothelial dysfunction. 47 Lovastatin therapy has also been shown to reduce the extent of ischemic damage in a model of M! in hypercholesterolemic rabbits, 48 an effect attributed to improved vasodilator responsiveness.

Recent studies at two US centers have extended these findings to humans. Treasure et a149 have reported improvement of endothelial dysfunction in patients with established CAD treated with lovastatin (40 mg twice per day) for 6 months. Anderson et aP ~ have reported similar findings in patients with established coronary disease and elevated cholesterol (mean baseline total cholesterol, 220 _+ 33 mg/dL [5.7 -+ 0.85 mmol/L]). These patients were assigned to lipid-lowering therapy with diet only or diet plus lovastatin plus cholestyramine or probucol for 1 year. At the end of this time, paradoxical vasoconstriction induced by acetylcholine was significantly attenuated in patients treated with diet plus drugs compared with those treated with diet alone (P < .05), and the improvement in endothelial function correlated with the extent of the reduction in serum cholesterol (P = .03). 5~

As well as producing endothelium-derived relaxant factor, functioning endothelium pro- duces prostacyclin and tissue plasminogen acti- vator, which prevent platelet aggregation and thrombus formation. Endothelial cells are also the loci of action of thrombomodulin and hepa- ran sulphate, which inhibit the powerful platelet agonists, thrombin and adenosine diphosphate. The equilibrium between these influences may

be disturbed in hypercholesterolemia-induced endothelial dysfunction, leading to the creation of a proaggregatory state.

CLINICAL CONSEQUENCES OF ENDOTHELIAL DYSFUNCTION

The clinical correlates of altered vascular sensitivity and a proaggregant condition are spasm and thrombosis, respectively. It is un- likely that spasm plays a significant role in the development of fatal acute coronary syndromes in patients with no visible obstruction of coronary vessels. However, it may have a contribu- tory role in the development of exercise- induced angina in patients with fixed obstruction and may increase the susceptibility of some patients to MI or sudden ischemic death. The characteristics of the critical coronary plaque (notably those of eccentric situation and a deformable, lipid-rich core) are compatible with vasoconstriction in the functioning, nonathero- sclerotic region of the blood vessel media. 33 Serotonin released from aggregating platelets may also contribute to coronary spasm at foci of endothelial dysfunction. Therefore, plausible mechanisms exist whereby vasospasm may contribute to the development of a critical coronary obstruction.

The possible contribution of platelet-rich thrombi to acute ischemic episodes in patients with no angiographic evidence of atherosclerosis is hard to determine. However, the evidence, now incontrovertible, that antiplatelet therapy is capable of preventing a large number of cardiovascular events in patients with CHD 51 is supportive of a pathologic role for platelet-rich thrombi at sites of organic stenosis. Platelet emboli lodged in coronary microvessels down- stream from a ruptured coronary plaque may play a role in unstable angina or ischemic sudden death in a proportion of patients, 52 and interactions between aggregating platelets and areas of endothelial dysfunction have been implicated in the development of angiographically visible plaques.

Endothelial dysfunction may also have implications for the development of clinical investiga- tive techniques. Angiography might be extended to evaluating the function of vascular endothelium in patients at high risk for the development of overt atherosclerosis. This would


enable appropriate therapy to be initiated at an early stage in the development of the disease. Intravascular ultrasound may also have applica- tions in the detection of atheromatous changes.53,54

CRITICAL PLAQUES AND CORONARY EVENTS

The relationship of endothelial dysfunction and atherosclerotic plaques to coronary events has been summarized by Vos et al (Fig 4). 19 Acute coronary events may arise from plaque fissure, thrombosis, and occlusion at any stage in the development of atherosclerosis, including (albeit probably only rarely) the angiographically undetectable phase of endothelial dysfunction. The extent of thrombosis associated with plaque rupture is not always directly proportional to the magnitude of the exposure of lipid in the plaque; therefore, thrombosis at a diffuse,

early-stage lesion may explain the phenomenon of acute coronary events in patients with anglo- graphically normal vessels. However, a majority of events may be explained in terms of rupture, thrombosis, and occlusion at unstable, lipid-rich lesions of intermediate size.

IMPLICATIONS OF ATHEROTHROMBOSIS

So far as is known, the rupture of plaques is a random or arbitrary event. However, it may reasonably be assumed that the rules of probabil- ity apply and that the more unstable plaques a patient possesses, the more likely one is to fissure and give rise to a clinical event. There- fore, a case may be advanced for the use of all reasonable measures to improve the serum lipid profile to minimize the number of critical plaques that develop. These measures (ie, lipid- lowering diet, other lifestyle modifications, and

diameter stenosla

100%

80%

60%

40%

20%

40% 0%

0% plaque

area

t - O Q

0 0 0 A

Q

0 .D

E e

i

, (

n <

1 �9 o e = / = = . / = =

/ / ,V-,m,alred,,o. = ~ / intraluminal

i plaque

~ gra.phlcally de tectab le extraluminal

p l a q u e I: endothel ia l dysfunot lon

I: not d iseased t ime -)

Fig 4. The relationship between progression of atherosclerotic plaque, plaque rupture and thrombosis, and the development of a clinical coronary event is shown. The diagonal line represents the (presumed) linear growth of a plaque. Rupture of the plaque fol lowed by thrombosis and the development of a clinical coronary event may occur at any point along the line from the development of endothelial dysfunction onwards. The horizontal line represents the lower limit of detection by angiography and indicates that endothelial dysfunction (less than 40% of internal elastic lamina occupied by atheroma) does not cause angiographically detectable stenosis of the affected vessel. See text for further details, (Adapted and reprinted with permission. TM)

118 DAVID WATERS

appropriate drug therapy) are not guaranteed to eliminate the risk to individuals; a patient with only one such lesion may still be unlucky enough to have that plaque rupture. Applied consistently, however, such measures should reduce the risk of acute coronary events in a population.

The studies described earlier involved patients with angiographic evidence of coronary atherosclerosis. Elevated cholesterol is a powerful and often neglected risk factor in the secondary prevention of CHD. 55,56 The concept of plaque rupture and its prevention by lipid- lowering interventions provides a mechanism to explain the discrepancy between the angiographic changes observed in these trials and the clinical outcomes. In doing so, this mechanism provides a rationale for more decisive action in lowering elevated cholesterol in patients with established heart disease. 1 Recent reports that abnormal vasoconstriction is a predictor of coronary artery restenosis are consistent with the reported connection between endothelial dysfunction and atherosclerosis and reinforce the importance of vigorous intervention against established risk factors in patients who undergo coronary artery bypass and other revasculariza- tion procedures.

Similar considerations apply to primary prevention of CHD. That lipid lowering reduces clinical CHD events has been shown in large-

scale trials. Although angiographic data are not available from those trials, there is no reason to believe that the pathophysiologic processes of atherosclerosis in patients with no history of CHD differ from those in patients who have already experienced a clinical event. Indeed, the phenomenon of endothelial dysfunction in patients with no overt atherosclerosis suggests that patients free of CHD but with hypercholesterolemia and abnormal vasomotor responses represent a distinct patient population in which early and assertive measures to correct the lipid profile may be highly beneficial.

The traditional definition of regression is closely circumscribed. Angiography data sug- gest that probably the greatest single contribution of intensive lipid lowering is to reduce the likelihood of rupture among lipid-rich lesions of small to moderate dimensions by depleting these high-risk lesions of part of their lipid content. Rupture of these lesions with ensuing thrombosis is perceived increasingly as the principal cause of overt CHD events. Therefore, in clinical terms, stabilization of critical plaques is a more important goal than reduction of the size of large atherosclerotic lesions. Indeed, it may be that, in terms of hard end points such as death and disability, regression, in the original sense of the term, is neither realistic nor relevant, whereas stabilization is both.

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