Q J Med 2002; 95: 339-341
© 2002 Association of Physicians
Editorial |
Reducing cholesterol and atherosclerosis
University Hospital Aintree, Liverpool
The oxidative modification of low-density lipoprotein (LDL) is an important pre-requisite for macrophage uptake and accumulation of cellular cholesterol ester in the arterial wall. This is a key component to the development of the atherosclerotic lesion.
Patients with coronary artery disease (CHD), i.e. stable and unstable angina and acute myocardial infarction, have significantly elevated levels of oxidized LDL when compared with age-matched controls; however, at any given concentration of plasma cholesterol, there is considerable variability in the clinical expression of CHD. This reflects the diversity in the reaction of the arterial wall to hypercholesterolaemia and the associated changes in endothelial function, immunological effects, smooth muscle cell proliferation and coagulation. Despite the complexity of these responses, opinion is generally united that LDL-cholesterol lowering is essential to achieve a reduction in CHD mortality and clinical event rates.
The strong positive relationship between cholesterol and CHD and the role of other risk factors can be derived from several lines of evidence. The large cohort studies carried out between populations1,2 and within single and migrating populations,3,4 have helped us to understand the association of low- and high-density lipoprotein, and the correlation between CHD and all the primary risk factors. Although total cholesterol does not appear to differ greatly among ethnic groups, high-density lipoprotein (HDL) cholesterol is lowest, and serum triglycerides highest, among South Asians.
This pattern of dyslipidaemia is also common in obese patients and non-insulin-dependent diabetics. Reduced HDL cholesterol and increased triglycerides constitute two of the key features of the insulin resistance syndrome,5 and may confer an additional risk for other development of cardiovascular disease, which is not accounted for in many of the epidemiological studies.
Convincing evidence that atheromatous plaque development can be slowed or prevented with lipid lowering came initially from animal studies on cholesterol-fed primates, and histological measurement of plaque size following dietary restriction.6,7
Methods to detect regression of atheroma in patients with CHD have included subjective assessment of the improvement of the severity of angina. Although this may indicate plaque regression, it may also occur by other mechanisms, including the development of collateral vessels, exercise conditioning or even myocardial necrosis. Myocardial perfusion imaging has some of the same limitations, and cannot reliably show changes in mild obstructive lesions.
The coronary arteriogram remains the principal method for accurately assessing change in the severity of luminal narrowing. By measuring and comparing the changes per segment in a series of arterial segments in each individual, a relatively small number of patients can provide a great deal of information, and the use of computerized, quantitative angiography avoids the imprecision and the subjectivity of visual assessment. A series of randomized trials has documented the magnitude of regression, its frequency and the conditions under which it can occur in patients. Despite the diversity among these studies in clinical presentation, lipid entry requirements, treatment regimens and methods of arteriographic analysis, their outcomes are surprisingly consistent.8–10 The published data strongly support the hypothesis that lipid-lowering therapy selectively depletes those lesions containing a large lipid core, and therefore reduces or slows atheromatous plaque development.
These ‘regression’ trials had three main purposes: firstly to test the effects of reducing lipid levels on the course of atherosclerosis, secondly to compare the effects using different methods of lipid-lowering, e.g. weight reduction, exercise or drugs, and finally to study the influence of genetic and familial factors on the progression of atherosclerosis.11–13
Significant reduction in the incidence of clinical coronary events has been shown even with relatively modest changes in LDL cholesterol using various lipid-lowering drug regimens. This is probably a consequence of reducing the high lipid content of atheromatous lesions, thereby rendering them more stable and less prone to disruption. There is remarkable unanimity among investigators who have conducted meta-analyses of the trials of cholesterol reduction, that there is a reduction in the incidence of both fatal and non-fatal coronary events.14–16 This appears to be the case irrespective of whether the decrease in cholesterol levels was achieved by diet or drugs, or whether the studies were primary or secondary prevention trials of long or short duration. It seems likely that other cardiovascular risk factors such as smoking, hypertension and diabetes interact to heighten arterial wall damage and increase the likelihood of plaque disruption, therefore treatment strategies should encompass the control of all risk factors to maximize benefit.
The improvement in cardiovascular end points is incompletely explained by the treated LDL cholesterol levels, and other mechanisms of action of lipid-lowering drugs, particularly the statins, have been studied.17 These include modification of endothelial function, inflammatory responses, effects on plaque stability and thrombus formation. Although experimental animal models have suggested that statins may increase the stability of atheromatous plaque through reduction in macrophage and cholesterol ester content, the effect of cholesterol-lowering therapy in patients is probably more complex. A review of the data from several angiographic studies suggests that the main actions of lipid-lowering therapy may include plaque stabilization as well as regression of atheroma.18 It has been noted that the plaques most prone to fissuring or rupture are usually small- to medium-sized, and lipid-lowering therapy appears to decrease the lipid pool within those plaques.19
Statin therapy may also ameliorate endothelial dysfunction,20 and this may in turn be due to its LDL-cholesterol-lowering and anti-oxidant properties. The benefits of cholesterol lowering on endothelium-dependent vascular relaxation have been demonstrated both in animal models and in patient studies, and the improvement in endothelial function with statin therapy may be explained by their effect on endothelium-derived relaxing factor (nitric oxide) and possibly the synthesis of other vasoactive factors such as endothelin 1.21
The effects of statins in animal models and on cultured human smooth-muscle cells, fibroblasts and endothelial cells, and the anti-proliferative effects of these drugs, have been studied by measuring cell number and mitochondrial dehydrogenase activity. The results indicate that statins are potent inhibitors of arterial smooth muscle proliferation and migration, indicating a potential mechanism beyond that of cholesterol reduction in stabilizing atheromatous plaque.22
Finally, it is thought that statin treatment may influence the thrombogenic response of the vessel wall by interaction with tissue factor release platelet aggregation, plasma viscosity and fibrinolytic components.
These are all possible advantages of statin therapy that, in combination with cholesterol lowering, may help to reduce cardiovascular clinical events, and stabilize the atheromatous plaque.
Even patients considered to be at increased risk of vascular disease, regardless of initial cholesterol levels, may benefit from statin therapy. The Heart Protection Study results presented at the American Heart Association's recent meeting provided clear evidence of benefit not only amongst patients with prior myocardial infarction or other evidence of CHD, but also in patients without a prior history of CHD and those with diabetes, cerebrovascular and peripheral vascular disease. Elderly patients (i.e. aged >75 years) benefitted to the same extent as younger patients, and the reduction in vascular mortality and both coronary and non-coronary events was achieved without reaching pre-specified target cholesterol levels.
Previous results from studies such as WOSCOPS, CARE and LIPID23–25 suggest that moderate reduction in cholesterol levels by 20–25% leads benefits similar to lowering cholesterol further. Therefore, pushing treatment strategies to obtain the lowest possible cholesterol level may not be desirable, and could expose patients to an increased risk of drug side-effects. However, appropriate lowering of cholesterol in the context of the clinical history and other risk factors should be the aim of every physician, with all the accumulated evidence that this effectively prevents the progression of coronary heart disease.
References
1. Keys A. Coronary heart disease—the global picture. Atherosclerosis1975; 22:149–92.[Web of Science][Medline]
2. Simons LA. Interrelations of lipids and lipoproteins with coronary artery disease mortality in 19 countries. Am J Cardiol1986; 57:5–10G.
3.
Andersen KM, Castelli WP, Levy D. Cholesterol and mortality: 30 years of follow-up from the Framingham study. JAMA1987; 257:2176–80.
4. Nichamen MZ, et al. Epidemiological studies of coronary heart disease and stroke in Japanese men living in Japan, Hawaii, and California: distribution of biochemical risk factors. Am J Epidemiol1975; 102:424.
5. McKeigue PM, Shah B, Marmot MG. Relation of central obesity and insulin resistance with high diabetes prevalence and cardiovascular risk in South Asians. Lancet1991; 337:382–6.[Web of Science][Medline]
6. Wissler RW, Vesselinovitch D. Can atherosclerotic plaques regress? Anatomic and biochemical evidence from nonhuman animal models. Am J Cardiol1990; 65:33–40.
7.
Armstrong ML, Megan MB. Lipid depletion in atheromatous coronary arteries in rhesus monkeys after regression diets. Circ Res1972; 30:675–80.
8.
Brensike JF, Levy RI, Kelsey SF, et al. Effects of therapy with cholesyramine on progression of coronary atherosclerosis: results of the NHLBI Type II coronary intervention study. Circulation1984; 69:313–24.
9. Buchwald H, Varco RL, Matts JP, Long JM, Fitch LL, Campbell GS, et al. Effect of partial ileal bypass on mortality and morbidity from coronary heart disease in patients with hypercholesterolemia—Report of the Program on Surgical Control of the Hyperlipidemias (POSCH). N Engl J Med1990; 323:946–55.[Abstract]
10. Brown BG, Albers JJ, Fisher LD, et al. Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. N Engl J Med1990; 323:1289–98.[Abstract]
11. Watts GF, Lewis B, Brunt JNH, Lewis ES, et al. Effects on coronary artery disease of lipid-lowering diet, or diet plus cholestyramine, in the St. Thomas’ Atherosclerosis Regression Study (STARS). Lancet1992; 339:563–9.[Web of Science][Medline]
12.
The Lipid Research Clinics Program: The Lipid Research Clinics Coronary Primary Prevention Trial results: I. Reduction in incidence of coronary heart disease. JAMA1984; 251:351–64.
13.
Manninen V, Elo MO, Frick MH, et al. Lipid alterations and decline in the incidence of coronary heart disease in the Helsinki Heart Study. JAMA1988; 260:641–51.
14. Keech A. Does cholesterol lowering reduce total mortality? Postgrad Med J1992; 68:870–1.
15.
Holme I. An analysis of randomised trials evaluating the effect of cholesterol reduction on total mortality and coronary heart disease incidence. Circulation1990; 82:1916–24.
16. Muldoon MF, Manuck SB, Matthews KA. Lowering cholesterol concentrations and mortality: a quantitative review of primary prevention trials. Br Med J1992; 304:431–4.
17. Wheeler DC. Are there potential non-lipid-lowering uses of statins? Drugs1998; 56:517–22.[Web of Science][Medline]
18. Waters D. Plaque stabilization: a mechanism for the beneficial effect of lipid-lowering therapies in angiography studies. Prog Cardiovasc Dis1994; 37(3):107–120.[Web of Science][Medline]
19. Gutstein DE, Fuster V. Pathophysiology and clinical significance of atherosclerotic plaque rupture. Cardiovasc Res1994; 41(2):323–333.
20.
Rosenson RS, Tangney CC. Antiatherothrombotic properties of statins: implications for cardiovascular event reduction JAMA1998; 279:1643–50.
21. Brown BG, Zhao X. Importance of endothelial function in mediating the benefits of lipid-lowering therapy. Am J Cardiol1998; 279:1643–50.
22.
Ross R. Atherosclerosis—an inflammatory disease. N Eng J Med1999; 340(2):115–26.
23.
Shepherd J, Cobbe SM, Ford I, et al. for the West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med1995; 333:1301–7.
24. Pfeffer MA, Sacks FM, Moye LA, et al. for the CARE Investigators. Cholesterol and Recurrent Events: a secondary prevention trial for normolipidemic patients. Am J Cardiol1995; 76:98–106C.
25. Tonkin AM for the LIPID Study Group. Management of the Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) Study after the Scandinavian Simvastatin Survival Study (4S). Am J Cardiol1995; 76:107–12C.[Web of Science][Medline]
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