Keiji Yoneya

Angiotensinogen gene polymorphism in Japanese patients with hypertrophic cardiomyopathy

To examine the contribution of the renin-angiotensin system to hypertrophic cardiomyopathy (HCM), we studied 96 patients with HCM (mean age 50 years, 55% male), 105 of their unaffected siblings and offspring, and 160 healthy subjects without known hypertension and left ventricular hypertrophy (LVH) who were frequency matched to cases by age and sex. Patients were divided into familial or sporadic HCM (FHCM or SHCM) groups with or without affected members of their family. The region of interest in the angiotensinogen (AGT) gene, the missense mutation with methione-to-threonine amino acid substitution at codon 235 in angiotensinogen (M235T), was amplified by polymerase chain reaction with the use of allele-specific oligonucleotide primers flanking the polymorphic region of the AGT gene to amplify template deoxyribonucleic acid prepared from peripheral leukocytes. The T allele frequency was higher in the SHCM group than in unaffected siblings and offspring (88% vs 78%, X2 = 4.6, p < 0.05). The M allele frequency was higher in unaffected siblings and offspring than in patients with SHCM (23% vs 12%, X2 = 4.6, p < 0.05). The T allele frequency among unaffected siblings and offspring was similar to that observed in healthy subjects (78% vs 78%). We conclude that HCM, especially in sporadic cases, is partially determined by genetic disposition. The molecular variant of angiotensinogen T235 seems to be a predisposing factor for cardiac hypertrophy in HCM and carries an approximately twofold increased risk.

Beneficial effect of myocardial angiogenesis on cardiac remodeling process by amlodipine and MCI-154

The present study examined the effect of long-term treatment with amlodipine and MCI-154 (a Ca2+ sensitizer) on progressive cardiac dysfunction and microvasculature in the dilated cardiomyopathic (DCM) hamster heart. After treatment of DCM hamsters (Bio 53.58) with amlodipine or MCI-154 for 15 wk from the age of 5 wk, amlodipine and MCI-154 were found to cause an increase in left ventricular percent fractional shortening and decreases in left ventricular diastolic dimension and isovolumic relaxation time in echocardiograms ( P < 0.01). A hemodynamic study showed that the diastolic time constant decreased in the amlodipine-treatment group ( P < 0.05). In a morphometric study employing a double-staining method that discriminated arteriolar and venular capillaries, amlodipine and MCI-154 caused increases in total capillary density ( P < 0.05) and the proportion of venular capillaries ( P < 0.05). Moreover, Northern blot analysis showed that the expression of mRNA for vascular endothelial growth factor was significantly increased by amlodipine and MCI-154. They preserve coronary microvasculature in the DCM hamster and might induce angiogenesis of small vessels, thereby contributing to preservation of cardiac systolic and diastolic function.The present study examined the effect of long-term treatment with amlodipine and MCI-154 (a Ca2+ sensitizer) on progressive cardiac dysfunction and microvasculature in the dilated cardiomyopathic (DCM) hamster heart. After treatment of DCM hamsters (Bio 53.58) with amlodipine or MCI-154 for 15 wk from the age of 5 wk, amlodipine and MCI-154 were found to cause an increase in left ventricular percent fractional shortening and decreases in left ventricular diastolic dimension and isovolumic relaxation time in echocardiograms (P < 0.01). A hemodynamic study showed that the diastolic time constant decreased in the amlodipine-treatment group (P < 0.05). In a morphometric study employing a double-staining method that discriminated arteriolar and venular capillaries, amlodipine and MCI-154 caused increases in total capillary density (P < 0.05) and the proportion of venular capillaries (P < 0.05). Moreover, Northern blot analysis showed that the expression of mRNA for vascular endothelial growth factor was significantly increased by amlodipine and MCI-154. They preserve coronary microvasculature in the DCM hamster and might induce angiogenesis of small vessels, thereby contributing to preservation of cardiac systolic and diastolic function.

Effects of doxazosin on orthostatic blood pressure in hypertensive patients with and without diabetes mellitus

Abstract Alpha 1 -blockers are thought to cause the orthostatic hypotension frequently observed in patients with hypertension. We studied the degree to which doxazosin reduced the blood pressure in hypertensive patients with diabetes mellitus (HDM [+]) and without diabetes mellitus (HDM [−]), when they were placed in a standing position. Seven HDM (−) patients and eight HDM(+) patients were included in this study. After diagnosis, a blood pressure—monitoring system for ambulatory patients was attached to each patient. Blood pressure was measured, first with patients in a supine position and again 2 and 4 minutes after standing. The same procedure was performed on each patient after 12 weeks of doxazosin treatment. The mean dose of doxazosin was 2.1 ± 1.5 mg for HDM(−) patients and 2.4 ± 2.5 mg for HDM(+) patients. Treatment with doxazosin resulted in a significant sitting blood pressure reduction as measured by the ordinary cuff method. Doxazosin caused no statistically significant orthostatic systolic blood pressure reduction at 2 minutes after standing for HDM(−) patients (15 ± 5 mm Hg [control] vs 16 ± 4 mm Hg [treatment]) and for HDM(+) patients (7 ± 15 mm Hg [control] vs 8 ± 14 [treatment]), respectively). We concluded doxazosin did not have a statistically significant effect on the orthostatic blood pressure reduction for both HDM(−) patients and HDM(+) patients with respect to the doses used.

Cardiac remodeling: Role of neovascularization in heart failure

Abnormalities in microvasculature and neovascular formation in the process of cardiac remodeling, and the relationship between angiogenesis and cardiac remodeling have not been elucidated, in dilated cardiomyopathy (DCM) and heart failure. To clarify the alterations in capillary microvasculature and the role of angiogenesis in cardiac remodeling, we examined the myocyte density, fibrous tissue volume, expression of genes relating to fibrosis, capillary density, and the expression of the genes for vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) at the ages of 5, 13, and 20 weeks and also investigated the effects of long-term treatment with amlodipine, nifedipine, and MCI-154 on capillary microvasculature and cardiac angiogenesis in hearts of the TO2 strain of cardiomyopathic hamster. Cardiomyopathic hamsters showed decreases in capillary density and proportion of venular capillaries concomitantly with a decrease in numerical myocyte density and enhanced expression of the genes for collagen I, collagen III, and transforming growth factor-β1, (TGF-β1,) leading to cardiac fibrosis. Long-term treatment with amlodipine and MCI-154 suppressed decreases in capillary density and the proportion of venular capillaries concomitantly with induction of VEGF and bFGE In conclusion, alterations in capillary microvasculature may be involved in the process of cardiac remodeling during dilated cardiomyopathy. Suppression of angiogenesis may be related to alterations in capillary microvasculature. Induction of cardiac angiogenesis may be a new strategy for the treatment of the remodeling process in dilated cardiomyopathy.