In this study, we questioned whether in vivo probucol could prevent the progression of atherosclerosis in homozygous Watanabe heritable hyperlipidemic (WHHL) rabbits, an animal model for familial hypercholesterolemia. At 2 months of age, eight WHHL rabbits were divided into two groups. Group A (n = 4) was fed standard rabbit chow for 6 months. Group B (n = 4) was fed standard rabbit chow containing 1% probucol for 6 months. At the end of the experiments, average plasma concentrations of cholesterol were 704 ± 121 mg/dl in group A and 584 ± 61 mg/dl in group B, respectively. The percentage of surface area of total thoracic aorta with visible plaques in group A versus group B was 54.2% ± 18.8% versus 7.0% ± 6.3%, respectively. What was noteworthy was that the percentage of plaque in the descending thoracic aorta was almost negligible (0.2% ± 0.2%) in group B rabbits compared to that in group A rabbits (41.1% + 20.2%). Low density lipoproteins (LDL) isolated from WHHL rabbits under treatment with probucol (group B) were shown to be highly resistant to oxidative modification by cupric ion and to be minimally recognized by macrophages. On the contrary, LDL from group A rabbits incubated with cupric ion showed a 7.4-fold increase in peroxides (thiobarbituric acidreactive substances) and a 4.3-fold increase in the synthesis of cholesteryl ester in macrophages compared to those of LDL from group B rabbits. Thus, probucol could definitely prevent the progression of atherosclerosis in homozygous WHHL rabbits in vivo by limiting oxidative LDL modification and foam cell transformation of macrophages.Familial hypercholesterolemia (FH) is one of the most common human genetic diseases. Homozygous FH patients have inherited allelic mutations in the gene specifying the low density lipoprotein (LDL) receptor located on the cell surface (1). In these patients, few or no functional LDL receptors are synthesized in the body. As a result, not only impairment of catabolism but also overproduction of LDL occurs in FH homozygotes, subsequently leading to a 6-fold to 8-fold increase in plasma LDL levels before birth (1-3). Elevation of plasma levels of LDL leads to characteristic xanthoma formation in tendons and skin and accelerated atherosclerosis (4). Symptomatic coronary atherosclerosis typically develops before the age of 20 years in homozygous FH patients (5). To protect FH patients against atherosclerosis including coronary artery disease, it is necessary to reduce the plasma levels of LDL to as normal a level as possible. In FH homozygotes, liver transplantation is the only treatment so far (6), and plasmapheresis and the portal-caval shunt operation are partially successful (5, 7). None of the antilipidemic drugs is effective in homozygous FH patients.The foam cell has been recognized as a characteristic feature of xanthomas in skin and tendons and also of the atheromas. Many foam cells in these lesions share properties characteristic of the macrophages. Therefore, the macrophage may be the progenitor of certain foam cel...

A progression from viral myocarditis to dilated cardiomyopathy has long been hypothesized, but the actual extent of this progression has been uncertain. However, a causal link between viral myocarditis and dilated cardiomyopathy has become more evident than before with the tremendous developments in the molecular analyses of autopsy and endomyocardial biopsy specimens, new techniques of viral gene amplification, and modern immunology. The persistence of viral RNA in the myocardium beyond 90 days after inoculation, confirmed by the method of polymerase chain reaction, has given us new insights into the pathogenesis of dilated cardiomyopathy. Moreover, new knowledge of T-cell-mediated immune responses in murine viral myocarditis has contributed a great deal to the understanding of the mechanisms of ongoing disease processes. Apoptotic cell death may provide the third concept to explain the pathogenesis of dilated cardiomyopathy, in addition to persistent viral RNA in the heart tissue and an immune system-mediated mechanism. Beneficial effects of alpha1-adrenergic blocking agents, carteolol, verapamil, and ACE inhibitors have been shown clinically and experimentally in the treatment of viral myocarditis and dilated cardiomyopathy. Antiviral agents should be more extensively investigated for clinical use. The rather discouraging results obtained to date with immunosuppressive agents in the treatment of viral myocarditis indicated the importance of sparing neutralizing antibody production, which may be controlled by B cells, and raised the possibility of promising developments in immunomodulating therapy.

To clarify the pathophysiologic role of intramyocardial small artery (IMSA) diseases in hypertrophied hearts, narrowings of the IMSA were quantitatively evaluated in 39 autopsied hearts, 10 from patients with typical hypertrophic cardiomyopathy (HCM), four from patients with HCM showing features mimicking dilated cardiomyopathy (DCM-like HCM), 10 from patients with hypertension, and 15 from normal adults. The relations of narrowings of the IMSA to myocytic hypertrophy, myocardial fiber disarray, and fibrosis were also examined. The external caliber and the ratio of the luminal area to the total vascular area (percent luminal area, %lumen) were calculated by an image analyzer in 85 to 203 IMSAs from each patient. The external calibers of the IMSAs were similar among groups of hearts with HCM, hypertensive hearts, and normal hearts but were greater in those with DCM-like HCM. The mean %lumen of the IMSAs was similarly reduced in the hearts with HCM (29 + 5% in the ventricular septum and 31 5% in the left ventricular free wall) and in hypertensive hearts (30 + 8% and 31 + 7%) compared with that in normal hearts (40 5% and 38 + 5%) and was the lowest in the ventricular septum of hearts with DCM-like HCM (17 3%). The mean %lumen of the IMSA was inversely cortelated with heart weight (r = -.59), the mean size of myocytes (r = -.66 in the ventricular septum, r = -.63 in the free wall), and percent fibrotic area in the septum (r = -.68). The mean %lumen values of the IMSAs in the tissues with and without disarray in the hearts with HCM were similar. Thus IMSA disease is of pathophysiologic importance in patients with HCM, DCM-like HCM in particular, or with hypertension. Circulation 75, No. 6, 1130No. 6, -1139No. 6, , 1987 CHEST PAIN is a common symptom of patients with hypertrophic cardiomyopathy (HCM)`2 or systemic hypertension3 despite angiographically normal epicardial coronary arteries. Moreover, these patients often demonstrate abnormal findings on myocardial thallium-201 imaging6 or abnormal lactate metabolism during pacing.7 Pathologically, these hearts show a greater amount of fibrosis distributed predominantly in the subendocardium than in the subepicardium,' and myocardial infarction is sometimes evident.9 Although

SUMMARYThe distribution offibrosis was studied quantitatively in the entire left ventricular wall of a transverse slice of the heart from 10 necropsy cases of hypertrophic cardiomyopathy, 10 cases of hypertensive heart disease, and 20 normal adults. The percentage area (mean (SD)) of fibrosis in the left ventricular wall in hypertrophic cardiomyopathy (10-5 (4-3)%) was significantly greater than that in hypertensive heart disease (2-6 (1-5)%) or in normal hearts (1L1 (0-5)%). In hypertrophic cardiomyopathy the percentage area of fibrosis was greater (13 1 (4-8)%) in the ventricular septum than in the left ventricular free wall (7 7 (4-2)%) whereas in hypertensive heart disease and normal hearts values in these two areas were similar. The percentage area of fibrosis in the left ventricular free wall (where myocardial fibre disarray was not extensive even in hypertrophic cardiomyopathy) was greater in hypertrophic cardiomyopathy than in hypertensive heart disease. The percentage area of fibrosis correlated with heart weight in hypertensive heart disease, but not in hypertrophic cardiomyopathy. These results suggest that widespread fibrosis in hypertrophic cardiomyopathy cannot be explained by cardiac hypertrophy alone, and that disarray and other factors are also important in pathogenesis. The increase in the percentage area of fibrosis from the outer to the inner third of the left ventricular free wall in hypertrophic cardiomyopathy and in hypertension probably reflected transmural gradients of wall stress and myocardial fibre diameter.Although fibrosis is not specific to hypertrophic cardiomyopathy, its quantification and analysis of its regional distribution provide information that is useful in investigating the pathophysiology of the disorder. Patients and methodsForty hearts from necropsy cases were studied-10 with hypertrophic cardiomyopathy, 10 with concentric hypertrophy secondary to hypertension, and 20 normal adult hearts.

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