Saireitoh is a traditional Chinese medicine that is often given to patients with nephrotic syndrome or glomerulonephritis. Studies have reported that Saireitoh stimulates intrinsic steroid secretion in rats and suppresses the proliferation of fibroblasts in vitro. We examined the effects of Saireitoh on vascular smooth muscle cell proliferation and migration in vitro and experimental atherosclerosis in vivo. Saireitoh rabbit serum obtained from New Zealand White rabbits which were given a diet containing 2% Saireitoh for 3 days significantly inhibited [3H] -thymidine incorporation by smooth muscle cells, which were isolated from thoracic aorta explants of rabbits. The addition of 10% Saireitoh rabbit serum to a culture medium containing smooth muscle cells inhibited DNA synthesis by 50% as compared with a control culture to which 10% normal rabbit serum was added. We also found that the number of smooth muscle cells in the culture containing Saireitoh rabbit serum was decreased. When PDGF was used as a chemoattractant, we demonstrated that Saireitoh rabbit serum slightly inhibits the migration of smooth muscle cells. In in vivo experiments, Saireitoh did not suppress the development of atherosclerosis but tended to reduce the damage. We concluded that although Saireitoh inhibited the proliferation of smooth muscle cells, the effect of prevention on the development of atherosclerosis is weak in the in vivo condition.
To clarify whether acute medial necrosis of the aorta induces aneurysms and intimal thickening at a later stage, we first attempted to induce acute aortic medial necrosis in 47 normal rabbits by the administration of Russell's viper venom intraperitoneally and of angiotensin II intravenously as used in a previous study and then followed the rabbits for 1 and 2 months respectively. As a control, 18 adult normal rabbits were used. Six control and 20 treated rabbits were sacrificed after aortagraphy at the end of one month, while the remaining 12 control and 27 treated rabbits were sacrificed at the end of 2 months. We evaluated the aortic lesions by gross observations and both light and electron microscopic examinations. In addition, at the end of one month, aortagraphy was performed to measure the luminal diameter of the aorta of the 6 control and 20 treated rabbits. We macroscopically found the saccular lesions to be surrounded by small crater like lesions mainly at the thoracic aortas in 18 out of 47 treated rabbits. These lesions consisted of the necrosis and calcification of the aortic media and the destruction of the elastic fiber along with intimal thickening. However, no aneurysmal dilatation was found in the aortagraphy findings. We thus conclude that acute medial necrosis produced saccular and crater like lesions but these lesions were not confirmed by aortagraphy.
Agents which inhibit the oxidative modification of low density lipoprotein (LDL) have been thought to be helpful in preventing the formation of atherosclerotic lesions ; the so-called “oxidation hypothesis”. To test this hypothesis, we examined the antioxidative activities of 127 Kampo medicines in vitro and their inhibitory effects on the development of atheromatous plaque formation in KHC rabbits, a model of spontaneous familial hypercholesterolemia. Some of the 127 Kampo medicines showed scavenging or antioxidative effects equal to or stronger than those of probucol in vitro. Choi-joki-to, which had the strongest antioxidative effects on LDL in vitro, was chosen for a study in vivo. After 24 weeks, 1 g/kg of Choi-joki-to successfully inhibited the progression of atherosclerotic lesions in KHC rabbits (P<0.01). Further investigations regarding the antioxidative effects of Kampo medicines are expected.
We histologically examined the coronary arteries of 52 autopsied cases of the youths (3 to 39 years of age, mean 28.5 years) in Kyushu island, Japan, without clinical events of coronary artery diseases. The coronary artery specimens were taken from the proximal portions of the right coronary artery (Seg. 1), the left anterior descending artery (Seg. 6), and the macroscopically most stenotic region (ST). Atherosclerotic lesions were histologically classified into four types : concentric fibrous, eccentric fibrous, concentric lipid-rich, or eccentric lipid-rich type. The degrees of stenosis (< 25%, 25-50%, 50-75%, > 75%) were morphometrically evaluated. The majority of coronary arteries with under 50% stenosis were of the concentric fibrous type. Lipid-rich types of coronary atherosclerosis increased in the coronary arteries with over 50% stenosis and were observed in the Seg. 6 and ST, while 70% of Seg. 1 lesions with over 50% stenosis were of a fibrous type. Serum cholesterol levels of patients with a lipid-rich type of coronary atherosclerosis were significantly higher than those with a fibrous type. These results suggested that the early stage of coronary atherosclerosis in Japanese youths is mainly of a concentric fibrous type, which later develops to a lipid-rich type. Hypercholesterolemia would promote the progression of atherosclerosis.
The Framingham Study was initiated in 1948 to investigate an epidemic of coronary disease in the USA, using a prospective epidemiological approach. Insights were provided into the prevalence, incidence, full clinical spectrum and predisposing factors. The major “risk factors” (a term coined by the Framingham Study) for coronary disease, stroke, peripheral artery disease and heart failure were identified and clinical misconceptions dispelled about isolated systolic hypertension, left ventricular hypertrophy, dyslipidemia, atrial fibrillation and glucose intolerance. Average values for blood lipids, blood pressure, body weight, glucose and fibrinogen were shown to be dangerously suboptimal and to have a continuous graded relationship to cardiovascular disease without critical values. Dyslipidemia, glucose intolerance and elevated fibrinogen were shown to have smaller hazard ratios in the elderly, but this was offest by a higher absolute risk. Diabetes was shown to operate more strongly in women, eliminating their advantage over men. Serum total cholesterol was shown to derive its atherogenic potential from its LDL component and also to reflect cholesterol being removed in the HDL fraction. The total/HDL-cholesterol ratio was demonstrated to be the most efficient lipid profile for predicting coronary disease. LDL was shown to be correlated with hemostatic factors, suggesting that there would be additional benefits to lowering LDL. High triglyceride associated with reduced HDL, indicating insulin resistance and small-dense LDL, was shown to be associated with excess coronary disease. All the risk factors tended to cluster, and this was shown to be promoted by insulin resistance induced by weight gain. Multivariate risk profiles were produced to facilitate risk stratification of candidates for coronary disease, stroke, peripheral artery disease and heart failure. The Framingham Study is now engaged in quantifying the independent contributions of homocysteine Lp (a), insulin resistance, small-dense LDL, C-reactive protein, clotting factors and genetic determinants of cardiovascular disease. We are now able to estimate the lifetime risk of all the atherosclerotic cardiovascluar diasease outcomes.