[All mortality by cause of death. The challenge of coronary prevention]

Much debate on the benefits and risks of cholesterol lowering to prevent coronary heart disease has focused on excess non-CHD mortality rates reported in some trials. Because of the wide variation in design of cholesterol-lowering trials and because the non-CHD mortality rate was not a controlled endpoint of statistical power in most published studies, it has been difficult to determine whether any excess mortality was due to certain therapies, to other mechanisms, or to chance. As a result, some investigators have performed retrospective analyses of pooled trial data in order to augment statistical power. Some investigators have hypothesized that the human brain is dependent on a constant supply of cholesterol from the circulation and that cholesterol loss in neuronal membranes, with the possible consequences of behavioral disorders and increased risk of accident and violent death. Indeed Weidner and Griffin suggest that low cholesterol is a marker for poor underlying health; physical illnesses are likely to cause depression and other negative emotional states, which are often accompanied by suppressed appetite and weight loss causing reduction in cholesterol levels. Such mental states may also increase the risk of non-CHD death, for example suicide. Rossouw reviews the evidence concerning non-CHD mortality in cholesterol-lowering trials and reports metaanalyses carried out for all trials combined. The findings indicated a significant (15%) increase in non-CHD mortality in all trials combined. However, this was not related to cholesterol lowering itself, because there was no increased risk in trials with > 10% cholesterol reduction, whereas there was a significant (22%) increase in trials with lesser degrees of cholesterol lowering. The publication of a large secondary prevention trial (4S) employing Simvastatin for cholesterol lowering supports the idea that cholesterol reduction itself does not have adverse effects on non-CHD mortality. The overview of all published trials demonstrates their effectiveness in reducing cholesterol and provides clear evidence of benefits on stroke and total mortality. A 10% reduction in cholesterol yielded about a 20% decrease in CHD mortality, which would be expected to result in about a 6% reduction in total mortality. Endothelium-dependent relaxations are reduced in hyperlipidemia and atherosclerosis. Exogenous L-arginine improves or restores the reduced endothelium-dependent relaxations. Moreover inflammation is associates with the initiation and progression of atherosclerosis. The fact of the matter is the Cardiovascular drugs already in clinical use or in development are able to interfere with certain aspects of endothelial function and may be useful in protecting the vessels and, hence, in preventing the development of cardiovascular disease.