The Cholesterol hypothesis: Time for the obituary?

Abstract The cholesterol hypothesis links cholesterol intake and blood levels to cardiovascular disease. It has had enormous impact on health care and society during decades, but has little or no scientifi c backing that is relevant for the human species. Apparently, the hypothesis is false and should be buried. The historical background to the hypothesis of a causal relationship between the level of serum cholesterol and the development of atherosclerosis began with Rudolf Virchow ' s description (1856) of the atherosclerotic plaque with its cholesterol deposits. Nikolai Anitchkov' s experiment with rabbits in St Petersburg (1913) was a key publication. He fed rabbits with cholesterol from egg yolks and found that they developed atherosclerotic plaques containing cholesterol. When he tried with other animalscarnivores -it was not possible to reproduce the results. They didn ' t get atherosclerosis. Two publications by Ancel Keys had a tremendous impact on the general belief of the cholesterol hypothesis. In 1953 he reported that the dietary intake of fat was signifi cantly correlated to the serum cholesterol level and the incidence of cardiovascular death in six countries (1). It appeared very convincing but the problem was that these six countries were selected from all together 22 countries. There was no correlation whatsoever if all the countries were included. The study was obviously a falsifi cation. The other publication came 1986 -the Seven-countries study (2). Keys followed 12000 middle-aged men and recorded their diet and cholesterol values for many years. With statistical maneuvers he " showed" that saturated fat was the culprit. The idea that cholesterol is dangerous took root with the well-known Framingham study (3). It was found that the cholesterol level had been slightly increased after a heart attack in previously healthy men. Therefore, it was claimed that high cholesterol was a risk factor for myocardial infarction. Amazingly, very little attention was taken when the 30 years follow-up of the Framingham project was published (4). It turned out that high cholesterol was not a risk factor for men older than 47 years and not for women at all. Further, it was found that more men had died of a heart attack among those whose cholesterol had decreased over the years. The authors wrote : " For every milligram percent cholesterol had decreased, cardiovascular mortality and total mortality increased by fourteen and eleven percent " . Other studies have strongly supported this conclusion. Sachdeva and coworkers These studies showed clearly that there is no causal relationship between the cholesterol level in blood and the risk of dying from a myocardial infarction but the so-called cholesterol hypothesis is still alive. The most momentous arguments for keeping the idea alive are the reported benefi cial effects of cholesterol-lowering drugs -the statins. But how valid are the arguments? To answer that question, one must consider the pivotal role powerful dru

Heparin-binding protein (HBP/CAP37): A missing link in neutrophil-evoked alteration of vascular permeability

Polymorphonuclear leukocyte infiltration into tissues in host defense and inflammatory diseasecauses increased vascular permeability and edema formation through unknown mechanisms.Here, we report the involvement of a paracrine mechanism in neutrophil-evoked alteration inendothelial barrier function. We show that upon neutrophil adhesion to the endothelial lining,leukocytic 2 integrin signaling triggers the release of neutrophil-borne heparin-binding protein(HBP), also known as CAP37/azurocidin, a member of the serprocidin family of neutrophilcationic proteins. HBP induced Ca++-dependent cytoskeletal rearrangement and intercellular gapformation in endothelial-cell monolayers in vitro, and increased macromolecular efflux in microvesselsin vivo. Moreover, selective inactivation of HBP prevented the neutrophils from inducingendothelial hyperpermeability. Our data suggest a fundamental role of neutrophil-derivedHBP in the vascular response to neutrophil trafficking in inflammation. Targeting this moleculein inflammatory disease conditions offers a new strategy for prevention of endothelial barrierdysfunction caused by misdirected leukocyte activation

ICAM-1 and VCAM-1 expression following aneurysmal subarachnoid hemorrhage and their possible role in the pathophysiology of subsequent ischemic deficits

BACKGROUND: The pathophysiology of ischemic cerebral lesions following aneurysmal subarachnoid hemorrhage (SAH) is poorly understood. There is growing evidence that inflammatory reactions could be involved in the pathogenesis of such delayed occurring ischemic lesions. The aim of this study was to evaluate adhesion molecules with regard to these lesions following SAH. METHODS: Serum and cerebrospinal fluid (CSF) samples were taken daily from 15 patients up to day 9 after SAH and evaluated for intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1). RESULTS: CSF and serum samples correlated well during nearly the whole time course (p 0.0001 and p < 0.007) but not to a delayed lesion in the CT scan. CONCLUSION: We believe that inflammatory processes are involved in the pathogenesis of cerebral vasospasm but they might only be a part of a multifactorial pathogenesis