C Kawai

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 acid-reactive 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.

The distribution of fibrosis 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 (1.1 (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.

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 correlated 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.

To assess the contractile state of the hypertrophied ventricle induced by long-standing systemic hypertension in 22 patients, we used echocardiography for the measurement of the ventricular diameter and posterior wall thickness, together with simultaneous recording of brachial arterial pressure. Meridional wall stress (WSt) was used for the expression of the force per unit cross-sectional area. The WSt-diameter relation obtained during dynamic responses to acute pressure reduction by nitroprusside infusion was compared with the same relation obtained in 10 normal subjects (posterior wall thickness averaged 0.7 cm [range 0.6-0.9 cm]) over a range of matched systolic pressure induced by methoxamine administration. In 15 patients in whom end-diastolic wall thickness increased to 1.1 cm (range 1.0-1.2 cm), the linear WSt-diameter relation at end-systole did not differ from the control group, indicating a normal level of inotropic state. In the seven patients with an end-diastolic wall thickness of 1.3 cm or more, the end-systolic WSt-diameter relation was clearly shifted to the right and had a less steep slope. These findings indicate that in advanced left ventricular hypertrophy induced by pressure overload, myocardial contractility may be depressed.

Diltiazem, verapamil and nifedipine suppress sinoatrial (SA) nodal function in the excised rabbit heart. Clinically, however, their suppressive effect on the SA node is modified considerably by the reflex increase in sympathetic tone as a result of the fall in blood pressure caused by the vasodilating action of the calcium antagonists. Diltiazem, verapamil and nifedipine suppress atrioventricular (AV) nodal conduction and prolong refractory periods in the excised rabbit AV node. Clinically, diltiazem and verapamil exert a similar suppressive effect on the AV node and are useful for treating and preventing AV nodal reentrant tachycardia. Nifedipine, in clinically practical doses, has no antiarrhythmic properties, probably because of reflex activation of the sympathetic system secondary to its hypotensive effect, which is greater than that of the other two calcium antagonists. Diltiazem and verapamil may sometimes worsen AV conduction, especially in patients with conduction disturbances. Nifedipine, on the other hand, can be used as a coronary vasodilator with the least untoward effect on AV conduction.