The discovery of the pathophysiological aspects of atherosclerosis--a review.

Considering the morphological findings in egyptian mummies at the beginning of the 20th century, atherosclerotic lesions were also apparent in pharaoh mummies more than 3500 years ago. Hippokrates (469-377 b.c.) described the sudden (cardiac) death, whereas Erasistratos had documented the typical claudication intermittens symptoms of peripheral arterial disease approximately 300 b.c. Later on in 1575, Fallopius observed severe pathological findings in arteries which he has characterized as a 'degeneration to bones', suggesting the presence of calcified atherosclerotic lesions. The relation between coronary lesions and the symptoms of angina pectoris was postulated in 1799 by Parry, however, only more than 80 years later angina pectoris was interpreted as a result of myocardial ischemia by Potain. During that time, the term 'arteriosclerosis' was firstly created by Lobstein in his 'Lehrbuch der pathologischen Anatomie', published in 1835. With the beginning of the last century, the pathophysiological aspects of plaque development were investigated in more detail by a number of researchers. In this context, people such as Saltykow, Chalatow and Anitschkow are important to notice. In 1914, Anitschkow firstly described the role of cholesterol accumulation in the vessel wall for the development of atherosclerosis. He used a cholesterol-fed rabbit model, which is the most important model of experimental atherosclerosis up to now. He also firstly described the 'Cholesterinesterphagozyten', which today commonly are known as foam cells, derived from macrophages. Using the cholesterol-fed rabbit model as well, already in 1942, Ludden et al. could demonstrate the atheroprotective effect of estrogen experimentally, a finding, which got later confirmed in the primate model and epidemiological studies. In the last three decades our knowledge has expanded by a large number of findings, based on morphological, immunohistological and molecular methods. In this context, one major contribution was the discovery of the LDL-receptor and its importance for the development of atherosclerosis by Brown and Goldstein, and the setting up of the 'response to injury hypothesis' by Ross and Glomset. At the present, we understand atherosclerosis as a complex (and at least in part as a physiological) phenomenon, beginning in the early childhood. The pathological aspect, making it to a disease, is depending on individual growth dynamics and plaque localization. The following key processes during the development of atherosclerosis are identified: 1) Endothelial injury, 2) intimal cholesterol accumulation and monocyte invasion with subsequent foam cell formation, 3) migration and proliferation of smooth muscle cells with expression of extracellular matrix 4) local thrombus formation with secondary organization 5) calcification and/or plaque rupture 6) final occlusion due to plaque rupture/thrombus formation. The classical concept of cardiovascular risk factors does only partially explain the origin of atherosclerosis. For the future, further mechanism(s) need to be identified and studied (genomic pathways, hormonal aspects, infective components, etc.) probably opening an effective therapeutical strategy to prevent and treat atherosclerotic diseases.