Nobuyuki Ohmichi

DD genotype of the angiotensin-converting enzyme gene is a risk factor for left ventricular hypertrophy.

BackgroundThe cardiac renin-angiotensin system has been suggested to be involved in the development of left ventricular hypertrophy. In humans, a strong correlation has been found between plasma angiotensin I-converting enzyme (ACE) activity and the insertion/deletion (I/D) polymorphism of the ACE gene, which has been reported to be associated with myocardial infarction, ischemic and idiopathic dilated cardiomyopathy, sudden death in hypertrophic cardiomyopathy, and restenosis after percutaneous transluminal coronary angioplasty. In the present study, we examined the possibility that the genotype of the ACE gene might influence the development of left ventricular hypertrophy. Methods and ResultsThe study population consisted of 268 subjects randomly selected from our outpatient clinic. In 142 subjects, left ventricular mass (LVM) was determined by echocardiogram. The genotype of the ACE gene was determined by the polymerase chain reaction. ANCOVA revealed that the genotype of the ACE gene had no effect on blood pressure. The percentage of the explained variance of LVM with variables including diastolic blood pressure (DBP, P = .0001), body mass index (BMI, P = .0001), sex (P = .0009), and the genotype of the ACE gene (P = .0017) was 34.61%. Significant differences in the effects of the genotype of the ACE gene on LVM were observed between the II and DD (P = .0004) and between the ID and DD (P = .0077) genotypes. The percentage of the explained variance of the LVM/ht ratio with variables including sex (P = .134), age (P = .3655), the genotype of the ACE gene (P = .0014), BMI (P = .0001), and DBP (P = .0001) was 31.25%. Significant differences in the effects of the genotype of the ACE gene on LVM/ht were observed between the II and DD genotypes (P = .0003) and between the ID and DD genotypes (P = .0091). ConclusionsIn addition to BMI and DBP, the genotype of the ACE gene was a significant predictor of LVM and LVM/ht in our study population.

Angiotensinogen Gene and Blood Pressure in the Japanese Population

A molecular variant of the angiotensinogen gene with threonine instead of methionine at position 235 (ie, with M235T polymorphism) has been shown to be associated with essential hypertension in Caucasian populations. The purpose of the present study was to assess whether the M235T polymorphism was associated with essential hypertension in the Japanese population. The study population consisted of 347 subjects selected in our outpatient clinic. The clinical data included in the analyses were sex, age, body mass index, cholesterol level, genotype of the angiotensinogen gene, genotype of the angiotensin-converting enzyme gene, and systolic and diastolic blood pressure. Multiple regression analysis revealed that only body mass index was a predictor of both diastolic and systolic blood pressure in these 347 subjects, but the genotype of the angiotensinogen gene was identified as a predictor of both diastolic and systolic blood pressure in a subpopulation less than 50 years of age. However, in a subpopulation more than 50 years of age, body mass index was the only predictor of both systolic and diastolic blood pressure. Of the 347 subjects, 189 had a technically excellent echocardiogram at the initial observation period. Multiple regression analysis revealed that sex, body mass index, diastolic blood pressure, and genotype of the angiotensin-converting enzyme gene were predictors of left ventricular mass. Although subjects with the TT angiotensinogen genotype had significantly greater left ventricular mass than those with either the TM or the MM genotype, the effects of the genotype of the angiotensinogen gene on left ventricular mass were mainly due to effects on blood pressure.

Renin Is Expressed in Rat Macrophage/Monocyte Cells

The cardiac renin-angiotensin system has been suggested to be involved in various pathological conditions, including hypertrophy and remodeling. However, direct evidence that renin synthesized in situ is really involved in the putative angiotensin II generation is still lacking because of the relatively low abundance of renin mRNA in cardiac tissues. We evaluated renin mRNA expression levels in the ventricles under various pathological conditions and found that renin gene expression was markedly increased in the ventricles of isoproterenol-treated rats. Renin mRNA expression levels in the ventricles of rats that had been injected with isoproterenol (150 mg/kg SC) were transiently and markedly increased to 6-, 90-, and 4-fold compared with control expression levels at 24, 72, and 120 hours, respectively, after isoproterenol administration, Immunohistochemical analysis revealed that some of the OX-42-positive macrophage/monocyte cells had a reninlike immunoreactivity. An in vitro experiment indicated that rat peritoneal macrophage/monocyte cells expressed renin mRNA in abundance. The present study confirmed that a subpopulation of macrophage/monocyte cells could express renin. Macrophage/monocyte cells may be a source of tissue renin in some pathological conditions.

Relationship between the response to the angiotensin converting enzyme inhibitor imidapril and the angiotensin converting enzyme genotype.

Insertion (I)/deletion (D) polymorphism of the angiotensin converting enzyme (ACE) gene has been reported to be involved in various cardiovascular diseases. We investigated prospectively whether the response to the ACE inhibitor imidapril varied according to the ACE genotype or plasma ACE activity in Japanese hypertensive patients. The study population consisted of 57 hypertensive patients. After a 4-week observation period, imidapril was administered at a dose of 5 mg/day and blood pressure was measured every 2 weeks for 6 weeks. The plasma ACE activity in patients with the DD or ID genotype was significantly higher than that in patients with the II genotype. Neither the reduction nor the percent reduction in systolic blood pressure was significantly different between patients with either the DD or ID genotype and patients with the II genotype (DD or ID v II, 18.8 +/- 2.4 v 20.2 +/- 3.3 mm Hg; P = NS, 10.9 +/- 1.4 v 11.7 +/- 1.9%; P = NS, respectively). However, both the reduction and the percent reduction in diastolic blood pressure tended to be higher in patients with the II genotype (DD or ID v II, 7.9 +/- 1.2 v 12.4 +/- 2.2 mm Hg; P = .0669, 8.1 +/- 1.2 v 12.4 +/- 2.2%; P = .0569, respectively). The reduction in diastolic blood pressure was inversely correlated with plasma ACE activity (r = 0.301, P = .0253). In conclusion, the response to imidapril in hypertensive patients is determined at least in part by the ACE genotype.

Human SA gene locus as a candidate locus for essential hypertension.

We have recently identified a candidate gene for rat genetic hypertension by identifying an mRNA species that shows markedly higher expression in the kidneys of spontaneously hypertensive rats than in those of Wistar-Kyoto rats. By using a restriction fragment length polymorphism, we carried out cosegregation analyses between the genotype of the SA gene and blood pressure in three F2 cohorts and observed significant effects of the SA gene on blood pressure in all of those cohorts. In the present study, we have isolated a human counterpart of the rat SA gene to investigate the possible association between the human SA gene and human essential hypertension. The deduced amino acid sequence from the isolated human SA cDNA consisted of 578 amino acid residues and had slight homology to a bacterial enzyme, acetyl-coenzyme A synthase. The human gene was mapped to the human chromosome 16 with the use of a rodent/human somatic hybrid cell panel. A restriction fragment length polymorphism was found with the restriction enzyme Pst I, and the allele frequencies were compared between hypertensive and control groups. The hypertensive group consisted of 89 individuals, and the Pst I rare allele (A2 allele) frequency in this group was 0.270. The control group consisted of 81 healthy normotensive individuals whose precise clinical data were available; the A2 allele frequency in this group was 0.09. Significant differences in the frequency of the A2 allele were observed between the hypertensive and control groups (P = .0001). The present findings provide favorable evidence that the SA gene is a candidate gene for human essential hypertension and also provide a starting point for future studies.

Genetic basis of left ventricular remodeling after myocardial infarction

The purpose of the present study was to assess whether the insertion (I)/deletion (D) polymorphism of the angiotensin converting enzyme (ACE) gene, and the polymorphism of angiotensinogen (AGT) gene with threonine (T) instead of methionine (M) at amino acid 235 in exon 2 (M235T) were associated with left ventricular dilatation after myocardial infarction. In 103 patients with myocardial infarction, the left ventricular (LV) end-diastolic volume index (EDVI) and the end-systolic volume index (ESVI) were assessed by echocardiography at two time points, namely at 7 +/- 4 days and at 3.9 +/- 1.3 months (mean +/- S.D.) after the infarction. The increases in the LVEDVI and LVESVI on the second echocardiogram were significantly higher in subjects with the DD and ID genotypes than in patients with the II genotype (P < 0.05 and P < 0.005, respectively). Multiple regression analysis revealed that the LVESVI at the first echocardiographic examination and the ACE I/D genotype were significant predictors of the LVEDVI and LVESVI at the second echocardiographic examination. However, the AGT M235T genotype was eliminated. In conclusion, the DD and ID genotypes of the ACE gene were significantly associated with the progression of the LVEDVI and LVESVI after myocardial infarction. The presence of the deletion allele of the ACE gene may be a risk factor of congestive heart failure after a myocardial infarction.

The Genotype of the Angiotensin- Converting Enzyme Gene and Global left Ventricular Dysfunction After Myocardial Infarction

We examined the relation between the genotype of the angiotensin-converting enzyme (ACE) gene and the development of left ventricular dysfunction, as assessed by biplane left ventriculograms, after myocardial infarction. Seventy-nine patients (deletion homozygote [DD] = 13; insertion/deletion heterozygote [ID] = 38; insertion homozygote [II] = 28) underwent cardiac catheterization twice for reevaluation of percutaneous transluminal coronary angioplasty. Subjects who had their first cardiac catheterization within 2 months from the onset of myocardial infarction were enrolled. The second cardiac catheterization was performed from 4 to 7 months after the first cardiac catheterization. ACE genotypes were determined by using the polymerase chain reaction. Ejection fraction, and end-diastolic and end-systolic volume indexes at the first cardiac catheterization were not significantly different among the 3 groups. The end-diastolic volume index at the second cardiac catheterization was not significantly different among the 3 groups. Ejection fractions (mean +/- SD) at the second catheterization in the 3 groups were 0.51 +/- 0.15 (DD), 0.56 +/- 0.12 (ID), and 0.62 +/- 0.09 (II) (p = 0.02), and were significantly lower in the DD group than in the II group. The end-systolic volume indexes (mean +/- SD) were 46 +/- 21 (DD), 43 +/- 24 (ID), and 30 +/- 14 (II) ml/m2 (p = 0.01), and were significantly greater in the DD and ID groups than in the II group.(ABSTRACT TRUNCATED AT 250 WORDS)

Variant of the β3-adrenergic receptor gene and coronary atherosclerosis in Japanese subjects

In the present study, we assessed the significance of the Trp64Arg mutation in the beta3-adrenergic receptor gene in 428 Japanese subjects, including 198 subjects who underwent coronary angiography for possible ischemic heart diseases (IHD group) and 230 non-IHD subjects (control group). We conclude that the Trp64Arg polymorphism of the beta3-adrenergic receptor gene did not appear to have any pathophysiological significance in Japanese subjects.

The II Genotype of the Angiotensin-Converting Enzyme Gene Delays the Onset of Acute Coronary Syndromes

The DD genotype of the angiotensin-converting enzyme (ACE) gene has been reported to be a risk factor for myocardial infarction. However, this association has not been confirmed in some populations. We hypothesized that the discrepancies between these studies may be due to their definition of ischemic heart diseases. According to the genotype of the ACE gene, we analyzed the profiles of 320 patients who underwent coronary angiography for possible ischemic heart diseases. Of these, 23 patients had no significantly diseased vessels and no acetylcholine-induced vasospasm (normal acetylcholine responder [NAR]) (II, 7; ID, 14; DD, 2), 34 patients had no significantly diseased vessels and acetylcholine-induced vasospasm (paradoxical acetylcholine responder: [PAR]) (II, 15; ID, 18; DD, 1), 80 angina pectoris (AP) patients had significantly diseased vessels (II, 41; ID, 37; DD, 2), and 183 patients demonstrated myocardial infarction (MI) (II, 67; ID, 91; DD, 25). The frequency of the DD genotype was significantly lower in PAR and AP patients than in those with MI (P = .0344). Next we analyzed the length of time between the first anginal pain and the onset of myocardial infarction in the MI group. We obtained reliable information regarding this period in 149 of the 183 patients. This period was significantly shorter in the ID and DD groups than in the II group (P = .0022). Multiple regression analyses revealed that this period was significantly determined (P = .0003, R = .324) by the genotype of the ACE gene (II = 1, ID + DD = 2, P = .0003) and age (P = .034). The D allele of the ACE gene and lower age were associated with a shorter period. On the other hand, the genotype of the ACE gene had no significant effect on the number of significantly diseased (> 50%) lesions. The frequency of the D allele in subjects with a rapid progression of MI was significantly higher than that in subjects with a prolonged history of stable AP (P < .0001). In summary, the II genotype of the ACE gene was associated with a longer period of time between the first anginal pain and the onset of myocardial infarction than the ID and DD genotypes of the ACE gene.

Expression of angiotensin converting enzyme and chymase in human atria.

Background A cardiac angiotensin II-generating system has been suspected to be involved in various cardiac pathological conditions. Both angiotensin converting enzyme and human chymase can convert angiotensin I to angiotensin II. Objective To clarify the relative contributions of these two enzymatic pathways to angiotensin II generation in vivo. Methods We assessed the expression levels of messenger RNA (mRNA) for collagen type Iα, transforming growth factor-β1, brain natriuretic peptide, angiotensin converting enzyme and chymase in right atrial appendages by competitive polymerase chain reaction and Northern blot analyses. Correlations among the concentrations of these mRNA were analysed to obtain insight that might be important in understanding the formation of angiotensin II in atrial tissue. Results The collagen type Ia and brain natriuretic peptide mRNA concentrations were correlated significantly to the mean pulmonary arterial pressure. Multivariate regression analysis revealed that the collagen type Iα mRNA concentration could be explained in terms of the brain natriuretic peptide (P = 0.0005) and angiotensin converting enzyme (P = 0.0084) mRNA concentrations (r = 0.598, P <0.0001). The chymase mRNA concentration had no significant correlation to the collagen type Ia mRNA concentration. Moreover, multiple regression analysis revealed that the transforming growth factor-β1 mRNA concentration could be explained in terms of the angiotensin converting enzyme mRNA concentration alone (r = 0.424, P = 0.014). Conclusions The present results suggest that the level of angiotensin converting enzyme affects the tissue angiotensin II level in human atria; however, we could obtain no evidence that chymase is important in determining the tissue angiotensin II level.