Mortality and incidence of cardiovascular diseases and their changing patterns were studied on the basis of the results from the long-term and autopsy-based prospective population survey conducted in a Japanese rural community, Hisayama since 1961, taking pathologic characteristics of atherosclerosis and its risk profile into account. Mortality from intracerebral hemorrhage and cerebral infarction recently decreased among the Hisayama population, and this is possibly due to the reduction in the incidence of intracerebral hemorrhage and cerebral infarction. Of the specific three types of cerebral infarction (lacunar infarcts, cortical infarcts and cerebral embolism), lacunar infarcts (in the perforating arterial areas) which were most frequent among the Hisayama population, only decreased in the recent study cohort. A pathologic study revealed that the detected frequency of fibrinoid necrosis on the putamen decreased in autopsy-cases from the population in 1970's compared to those in 1960's. This can be related to the decreased prevalence and improved control of hypertension in the recent population. On the other hand, subarachnoid hemorrhage more occurred especially in aged females than expected, and its incidence increased with advanced age decade. The frequency of multiple infarcts on the cortex or deep white matter increased with advanced age-decade and were thought to give a great influence on the prognosis of the aged through impairing activity of daily life and inducing vascular dementia. This involvement seemed to be associated with aging-process and its degenerative changes rather than hypertensive vascular lesions on the brain. Ischemic heart disease (IHD) including myocardial infarction did not increase among the recent population. Risk factors for IHD were, however, hypertension, high value of serum cholesterol, cigarette-smoking and obesity. Moreover serum cholesterol was more related to myocardial infarction from the recent population than that from the initial one. Since metabolic atherogenic factors such as serum lipid profiles, glucose intolerance, obesity steadily increase among the recent Hisayama residents, atherosclerosis and its related disease are highly expected to further increase in the future.

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In 1852, Rokitansky suggested that organized fibrin on vessel walls could cause atherosclerosis. Although this so-called "thrombogenic" hypothesis of atherosclerosis was denied by Virchow, Duguid revived this hypothesis in 1946.
In 1976, Ross and Glomset emphasized the importance of intimal smooth-muscle proliferation as the key element in the development of the advanced lesions of atherosclerosis. These two hypotheses suggest that hypercoagulability in a broad sense, including an enhanced platelet function and impaired fibrinolysis, may accelerate atherosclerosis. Recently, it has been shown that many risk factors of atherogenesis, such as an increase in LDL cholesterol, lipoprotein(a) and/or fibrinogen and a decrease in HDL cholesterol, enhances the platelet function while impairing fibrinolysis. The present article reviews these papers that have recently proposed supporting evidence for the “thrombogenic” or “response-to injury” hypothesis. These papers have presented conclusion such as: increased fibrinogen content in plasma enhances platelet aggregability; Apo A-I stabilizes prostacyclin which is a physiological antiplatelet substance in plasma; hyperlipidemia causes an increase in the plasminogen activator inhibitor (PAT), which is an important inhibitor of fibrinolysis in plasma; lipoprotein(a) which belongs to supergene family of plasminogen competitively impaires fibrinolysis.
The contribution of viral infection of the vascular endothelial cells to atherogenesis has also been discussed. The present article discusses the relationship between the latent infection of vascular cells with the herpes simplex virus and the “thormbogenic” or “response-to injury” hypothesis.
Relating to aging and hypercoagulable state, an increased procoagulant activity in cultured fibroblasts from progeria and Werner's syndrome of premature aging has been reported.
Recently, papers have suggested that the Alzheimer amyloid beta-protein precursor is identical to the platelet alpha granule protein. As a result of these studies, recent observations indicating that the frequency of Alzheimer's disease decreases in patients with rheumatoid arthritis are interesting, since aspirin or non-steroidal antiinflammatory drugs, frequently used in the cases of rheumatoid arthritis, suppress the platelet function.
Although there has been no direct evidence of the effectiveness of antithrombotic agents on the prevention of atherosclerotic diseases or Alzheimer's disease in man, this possibility should be further investigated.

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For many years a great controversy raged over why arteriosclerotic changes were so accerelated in diabetics., From an epidemiological viewpoint, one can say that diabetes is a disease, characterized by a combination of a genetic predisposition to hypertension, obesity, and hyperlipidemia, all of which are known to be major risk factors for the pathogenesis of atherosclerotis. However, no genetic linkage among these risk factors has been demonstrated. Recent knowledge about the pathogenesis of atherosclerotis in type-2 diabetes indicates that the increased hepatic production of VLDL, due to hyperinsulinemia, the stagnation of VLDL-VLDL-remnant-LDL pathway, its acceleration in the presence of nephropathy, and the subsequent increase of triglyceride (TG)-rich lipoprotein(s) and glycosylated/oxidized lipoprotein(s) which are more easily recognized by the receptor(s) of modified macrophages, may play relatively important roles. A significant increase in the plasma concentration of lipoprotein(a) also seems to be responsible for the dual processes of atherosclerosis and thrombogenesis. Furthermore, regarding endothel-derived active proteins, the plasma levels of the plasminogen-activator inhibitor 1 (PAI-1) and endothelin are significantly increased in patients with diabetic macroangiopathy, while the activities of the plasminogenactivator, prostacyclin and lipoprotein lipase are decreased. These alterations of endothel-derived factors may possibly contribute to the atherogenesis via the inhibiting action on fibrinolysis, the stagnation of VLDL and the hyperaggregability of the platelets.
Next, the possible relation of sex steroids to alterations in lipid metabolism, blood coagulation and fibrinolysis is now controversial. Nevertheless, some authors have emphasized the significance of the decreased plasma levels of dehydroisoandrosterone as anti-atherosclerotic steroids in diabetes mellitus, while others have implicated the increased PAT-1 activity to the decreased level of serum testosterone.
Finally, the reason for the higher incidence of calcification in the abdominal aortic wall and for medial arterial calcification (MAC) with the appearance of railroad track-like shadows on the X-ray film of diabetics has not yet been elucidated. The only conclusion that can be made at present is that hypertension may contribute to aortic or arterial calcification, and the existence of autonomous neuropathy may augument MAC (Monckeberg).

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In the present study we attempted to quantify the sequential changes occurring in cholesterolinduced aortic and coronary lesions in normotensive and renovascular hypertensive rabbits, which were placed on a 0.5% cholesterol diet for 16 weeks and observed up to 104 weeks after being withdrawn from the diet. After measuring the degree of surface involvement, a representative section covering the whole length of the aorta was obtained, and a histometric quantitative analysis was performed using an image-processing system. Furthermore, ten continuous step sections of the left coronary artery bed were prepared from each animal, and the degree of luminal stenosis was estimated in all the arterial segments contained. The results indicated a significant reduction of aortic lesions and a reversal of the luminal narrowing of the coronary artery in normotensive, as well as hypertensive, animals. It seems likely that, even in hypertensive animals, substantial regression of both aortic and coronary atherosclerosis can be expected after normalization of hypercholesterolemia.

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Apoprotein A-I and B-100 containing particles were isolated by selective affinity columns prepared with monoclonal antibodies. The effect of age on the cholesterol and protein concentrations in these particles were studied in 56 noninsulin-dependent diabetic men and 59 nondiabetic men. Neither group was obese. In both groups, the plasma cholesterol values were less than 230mg/dl, while the plasma triglyceride values were less than 150mg/dl. The total cholesterol (Ch), free cholesterol (FC), cholesterol ester (CE), the ratio of CE/FC, protein content, and the ratio of Ch/protein content in apoprotein A-I and B-100-containing particles in each group were not significant between the 4 age groups.

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High-density lipoproteins (HDL) have been reported to be antiatherogenic. However, very recently the possibility that some patients with marked hyperHDLemia had developed complications caused by atherosclerosis has been reported. In this paper, atherogenicity was clinically and biologically assessed in a patient with marked HDLemia.
One 29-year-old female patient showed marked plasma hyperHDLemia (HDL-cholesterol, 105-181mg/dl, apolipoprotein AI & AII, also elevated) with almost normal levels of low or very low lipoproteins. Hepatic triglyceride lipase activity was low while lipoprotein lipase activity was rather high. Cholesterol ester transfer protein activity was normal. Incorporation of HDL into the patient lymphocytes was normal, suggesting that the HDL receptor of the patient's liver was intact. Because of these results the patient was classified as a type of hyperlipidemia characterized by marked hyperHDLemia with a low hepatic triglyceride lipase activity.
The patient had developed marked corneal opacity. However, there was no evidence of coronary atherosclerosis that could be assessed by clinical symptoms & signs, exercise-loaded electrocardiograms, or a coronary angiography. Moreover, no other complications arising from the atherosclerosis were discovered. This data indicates that the development of corneal opacity did not parallel that of atherosclerosis.
The HDL of the patient was rather more taken up by HepG₂ than the control HDL, and there was normal reverse transport activity from macrophages. This data suggests that patient's HDL was at least not atherogenic.
The above results indicate that the marked hyperHDLemia was not atherogenic in spite of the development of premature corneal opacity.

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In order to study the mechanism of the development of atherosclerosis in response to a cholesterol (CH) diet and smoking (SM) with reference to the function of the sympathetic nervous and adrenal systems, male rabbits fed a CH-supplemented (1.5%) diet and inhaled standard (SM-1) or nicotineless cigarette (SM-2) twice a day for 12 weeks.
A marked deposit of lipids was noted in the aorta of animals fed a CH diet, with increased CH in the plasma, liver and adrenal glands. Anemia and decubital ulcer formation were also pronounced. No combined effect of additional SM loading on these findings was noted.
Plasma dopamine-β-hydroxylase (DβH) activity and the catecholamine contents of the heart and adrenal glands increased.
The increases in the adrenal glands weight and in the plasma corticoid level were more pronounced with SM, especially with SM-1 loading. Single loading of SM-1 and SM-2 also raised the levels of plasma DβH and the tissue catecholamine.

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