For several decades, the prevention of CHD (including the prevention of ischaemic recurrence after a prior AMI) has focused on the reduction of the traditional risk factors: smoking, HBP, hypercholesterolaemia. Priority was given to the prevention (or reversion) of vascular atherosclerotic stenosis. As discussed above, it has become clear in secondary prevention that clinical efficiency needs to primarily prevent the fatal complications of CHD such as SCD. This does not mean, however, that we should not try slowing down the atherosclerotic process, and in particular plaque inflammation and rupture. Indeed, it is critical to prevent the occurrence of new episodes of myocardial ischaemia whose repetition in a recently injured heart can precipitate SCD or CHF. Myocardial ischaemia is usually the consequence of coronary occlusion caused by plaque rupture and subsequent thrombotic obstruction of the artery.
Recent progress in the understanding of the cellular and biochemical pathogenesis of atherosclerosis suggests that, in addition of the traditional risk factors of CHD, there are other very important targets of therapy to prevent plaque inflammation and rupture. In this regard, the most important question is: how and why does plaque rupture occur?
Most investigators agree that atherosclerosis is a chronic low-grade inflammation disease.29 Pro-inflammatory factors (free radicals produced by cigarette smoking, hyperhomocysteinaemia, diabetes, peroxidised lipids, hypertension, elevated and modified blood lipids) contribute to injure the vascular endothelium, which results in alterations of its antiatherosclerotic and antithrombotic properties. This is thought to be a major step in the initiation and formation of arterial fibrostenotic lesions.29 From a clinical point of view, however, an essential distinction should be made between unstable, lipid-rich and leucocyte-rich lesions and stable, acellular fibrotic lesions poor in lipids, as the propensity of these two types of lesion to rupture into the lumen of the artery, whatever the degree of stenosis and lumen obstruction, is totally different.
In 1987, we proposed that inflammation and leucocytes play a role in the onset of acute CHD events. This has recently been confirmed. - It is now accepted that one of the main mechanisms underlying the sudden onset of acute CHD syndromes, including unstable angina, myocardial infarction and SCD, is the erosion or rupture of an atherosclerotic lesion,32'33 which triggers thrombotic complications and considerably enhances the risk of malignant ventricular arrhythmias.34,35 Leucocytes have been also implicated in the occurrence of ventricular arrhythmias in clinical and experimental settings,84 85 and they contribute to myocardial damage during both ischaemia and reperfusion.86 Clinical and pathological studies showed the importance of inflammatory cells and immune mediators in the occurrence of acute CHD events,29,86 and prospective epidemiological studies showed a strong and consistent association between acute CHD and systemic inflammation markers.88,89 A major question is to know why there are macrophages and activated lymphocytes29 in atherosclerotic lesions and how they get there. Issues such as local inflammation, plaque rupture and attendant acute CHD complications follow.
Steinberg et al. proposed in 1989 that oxidation of lipoproteins causes accelerated atherogenesis.90 Elevated plasma levels of low-density lipoproteins (LDL) are a major factor of CHD, and reduction of blood LDL levels (for instance by drugs) results in less CHD. However, the mechanism(s) behind the effect of high LDL levels is not fully understood. The concept that LDL oxidation is a key characteristic of unstable lesions is supported by many reports.29 Two processes have been proposed. First, when LDL particles become trapped in the artery wall, they undergo progressive oxidation and are internalised by macrophages, leading to the formation of typical atherosclerotic foam cells. Oxidised LDL is chemotactic for other immune and inflammatory cells and up-regulates the expression of monocyte and endothelial cell genes involved in the inflammatory reaction.29,89 The inflammatory response itself can have a profound effect on LDL,29 creating a vicious circle of LDL oxidation, inflammation and further LDL oxidation. Second, oxidised LDL circulates in the plasma for a period sufficiently long to enter and accumulate in the arterial intima, suggesting that the entry of oxidised lipoproteins within the intima may be another mechanism of lesion
inflammation, in particular in patients without hyperlipidaemia. " " Elevated plasma levels of oxidised LDL are associated with CHD, and the plasma level of malondialdehyde-modified LDL is higher in patients with unstable CHD syndromes (usually associated with plaque rupture) than in patients with clinically stable CHD.30 In the accelerated form of CHD typical of posttransplantation patients, higher levels of lipid peroxidation92-94 and of oxidised LDL95 were found as compared to the stable form of CHD in non-transplanted patients. Reactive oxygen metabolites and oxidants influence thrombus formation (see reference 95 for a review), and platelet reactivity is significantly higher in transplanted patients than in non-transplanted CHD patients.97
The oxidised LDL theory is not inconsistent with the well-established lipid-lowering treatment of CHD, as there is a positive correlation between plasma levels of LDL and markers of lipid peroxidation93,98 and a low absolute LDL level results in reduced amounts of LDL available for oxidative modification. LDL levels can be lowered by drugs or by reducing saturated fats in the diet. Reduction of the oxidative susceptibility of LDL was reported when replacing dietary fat with carbohydrates. Pharmacological/quantitative (lowering of cholesterol) and nutritional/qualitative (high antioxidant intake) approaches of the prevention of CHD are not mutually exclusive but additive and complementary. An alternative way to reduce LDL concentrations is to replace saturated fats with polyunsaturated fats in the diet. However, diets high in polyunsaturated fatty acids increase the polyunsaturated fatty acid content of LDL particles and render them more susceptible to oxidation28 which would argue against use of such diets (see above the section on SCD and n-6 PUFA). In the secondary prevention of CHD, such diets failed to improve the prognosis of the patients (for a review see de Lorgeril et al.36). In that context, the traditional Mediterranean diet, with low saturated fat and polyunsaturated fat intakes, appears to be the best option. Diets rich in oleic acid increase the resistance of LDL to oxidation independent of the content in antioxidants99 100 and results in leucocyte inhibition.101 Thus, oleic acid-rich diets decrease the pro-inflammatory properties of oxidised LDL. Constituents of olive oil other than oleic acid may also inhibit LDL oxidation.102 Various components of the Mediterranean diet may also affect LDL oxidation. For instance, alpha-tocopherol or vitamin C, or a diet combining reduced fat, low-fat dairy products and a high intake of fruits and vegetables, was shown to favourably affect either LDL oxidation itself or/and the cellular consequences of LDL oxidation86,103
Finally, significant correlation was found between certain dietary fatty acids and the fatty acid composition of human atherosclerotic plaques,104,105 which suggests that dietary fatty acids are rapidly incorporated into the plaques. This implies a direct influence of dietary fatty acids on plaque formation and the process of plaque rupture. It is conceivable that fatty acids that stimulate oxidation of LDL (n-6 fatty acids) induce plaque rupture, whereas those that inhibit LDL oxidation (oleic acid), inhibit leucocyte function (n-3 fatty acids)106 or prevent 'endothelial activation' and the expression of pro-inflammatory proteins (oleic acid and n-3
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