Atsushi Shindo

A haplotype of the CYP4A11 gene associated with essential hypertension in Japanese men

Objective CYP4A11, a member of the cytochrome P450 family, acts mainly as an enzyme that converts arachidonic acid to 20-hydroxyeicosatetraenoic acid, a metabolite involved in blood pressure regulation in humans. Disruption of the murine cyp4a14 and cyp4a10 genes, homologues of human CYP4A11, was reported recently to cause hypertension. The gene-disrupted male mice had higher blood pressure than the gene-disrupted female mice. The present study aimed to assess the association between the human CYP4A11 gene and essential hypertension, using a haplotype-based case–control study including separate analysis of the gender groups. Methods The 304 essential hypertension patients and 207 age-matched control individuals were genotyped for three single-nucleotide polymorphisms of the human CYP4A11 gene (rs2269231, rs1126742, rs9333025). Data were assessed for three separate groups: total participants, men and women. Results For total participants, the genotypic distribution of rs1126742 differed significantly between the two groups (P = 0.005). For total participants, men and women, the recessive model (CC versus TC + TT) of rs1126742 differed significantly between the two groups (P = 0.007, P = 0.043, and P = 0.045, respectively). Logistic regression analysis showed the TC + TT genotype was significantly higher in essential hypertension patients than in control individuals for total participants and men (P = 0.022 and P = 0.043, respectively). The A-T-G haplotype frequency (established by rs2269231, rs1126742, rs9333025) was significantly higher in essential hypertension men than in control men (P = 0.043). Conclusions Essential hypertension is associated with the TC + TT genotype of rs1126742 in the human CYP4A11 gene. The A-T-G haplotype appears a useful genetic marker of essential hypertension in Japanese men.

A Haplotype of the CYP4F2 Gene is Associated With Cerebral Infarction in Japanese Men

BACKGROUND CYP4F2, a member of the cytochrome P450 family, acts mainly as an enzyme and is involved not only in the metabolism of leukotriene B4, but also in that of arachidonic acid. It converts arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE), a metabolite involved in the regulation of the vascular tone in the brain. The aim of this study was to assess the association between the human CYP4F2 gene and cerebral infarction (CI), using a haplotype-based case-control study with separate analyses of data from the gender groups. METHODS A total of 175 CI patients and 246 control subjects were genotyped for five single-nucleotide polymorphisms (SNPs) of the human CYP4F2 gene (rs3093105, rs3093135, rs1558139, rs2108622, rs3093200). For data analysis, three separate groups were assessed: all subjects, men, and women. RESULTS In the male subjects, the G allele frequency for rs2108622 was significantly higher in CI patients as compared to control subjects (P = 0.025). The overall distribution of the haplotypes in the men was significantly different between the CI patients and the control subjects (P = 0.027). Additionally, the frequency of the T-C-G haplotype for men was significantly higher in the CI patients than in the control subjects (P = 0.008). Multiple logistic regression analysis also revealed the significance of the T-C-G haplotype in men, even after adjustment for confounding factors. CONCLUSIONS The results of this study indicate that, in Japanese men, CI is associated with the G allele of rs2108622 and, in addition, that the T-C-G haplotype appears to be a useful genetic marker for CI.

Prediction of the efficacy of pulmonary vein isolation for the treatment of atrial fibrillation by the signal-averaged P-wave duration

Background: The noninvasive methods for predicting a successful pulmonary vein isolation (PVI) have not been well described. The aim of this study was to assess the usefulness of the P‐wave signal‐averaged electrocardiogram (P‐SAECG) in predicting the chance of a successful PVI in patients with atrial fibrillation (AF).

A haplotype of the CYP4F2 gene associated with myocardial infarction in Japanese men

This study assessed associations between the CYP4F2 gene and myocardial infarction (MI), using a haplotype-based case-control study of 234 MI patients and 248 controls genotyped for 5 single-nucleotide polymorphisms (rs3093105, rs3093135, rs1558139, rs2108622, rs3093200). For men, G allele frequency of rs2108622 and frequency of the T-C-G haplotype were significantly higher, and frequency of the T-C-A haplotype was significantly lower for MI patients than for controls (P=0.006, P=0.001 and P=0.002, respectively).

Haplotype-based case-control study of the human CYP4F2 gene and essential hypertension in Japanese subjects.

CYP4F2 acts primarily as an enzyme that converts arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE), a metabolite involved in the regulation of blood pressure in humans. The aim of the present study was to assess the association between the human CYP4F2 gene and essential hypertension (EH) using a haplotype-based case-control study that included separate analysis of the two gender groups. The 249 EH patients and 238 age-matched controls were genotyped for 5 single-nucleotide polymorphisms (SNPs) of the human CYP4F2 gene (rs3093105, rs3093135, rs1558139, rs2108622, rs3093200). Data were analyzed for 3 separate groups: all subjects, and men and women separately. For the total population and for male subjects, the distribution of the dominant model of rs1558139 (CC vs. CT+TT) differed significantly between the EH patients and control subjects (p=0.037 and p=0.005, respectively), with a higher percentage of EH patients showing the CC genotype. Logistic regression showed that, for men, the CC genotype of rs1558139 was more prevalent in the EH patients than in the control subjects (p=0.026), while, for the total population, the difference disappeared (p=0.247). For men, the overall distribution of the haplotypes was significantly different between the EH patients and the control subjects (p=0.042), and the frequency of the T-T-G haplotype was also significantly lower for EH patients than for control subjects (p=0.009). In conclusion, the present results indicate that rs1558139 might be a genetic marker for EH and the T-T-G haplotype might be a protective genetic marker for EH in Japanese men.

Haplotype‐based case‐control study of CYP4A11 gene and myocardial infarction

CYP4A11, which is a member of the cytochrome P450 family, acts mainly as an enzyme that converts arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE), a metabolite involved in the maintenance of cardiovascular health. Recently, it was reported that many subfamilies of CYP genes have an association with myocardial infarction (MI). The aim of the present study was to assess the association between the human CYP4A11 gene and MI, using a haplotype-based case-control study with a separate analysis of the gender groups. A total of 239 MI patients and 285 controls were genotyped for 3 single-nucleotide polymorphisms (SNPs) of the human CYP4A11 gene (rs2269231, rs1126742, rs9333025). The data obtained via haplotype-based case-control studies were assessed for 3 separate groups: total subjects, men, and women. For the total, men and women groups, the distribution of the genotypes and alleles of the 3 SNPs did not show any significant difference between the MI patients and the control subjects. For the total and the men groups, the overall distribution of the haplotypes constructed with the 3 SNPs significantly differed between the MI patients and control subjects (P < 0.001). Also, for the total and for the men, the frequency of the T-T-A haplotype constructed with the 3 SNPs was significantly lower for the MI patients than for the control subjects (both P < 0.001). The T-T-A haplotype constructed with the 3 SNPs appears to be a protective genetic marker for MI in Japanese men.

Anatomic and Electrophysiologic Differences between Chronic and Paroxysmal Atrial Flutter: Intracardiac Echocardiographic Analysis

Background : It remains unknown why atrial flutter (AFL) occurs as either a chronic or paroxysmal arrhythmia.

Frequency-dependent electrophysiological effect of ibutilide on human atrium and ventricle

Most of the class III antiarrhythmic agents developed in recent years blocks the rapid component of delayed rectifier potassium current (IKr). IKr blocker shows reverse use-dependency and also may cause torsades de pointes at slower heart rate. Ibutilide fumarate, a novel class III antiarrhythmic agent, increases window Na+ current at the action potential plateau phase. We studied the rate-dependent effect of ibutilide on the electrophysiological parameters of human atrium and ventricle. Franz catheter and a pacing catheter were placed closely in the high right atrium and right ventricular apex to record monophasic action potentials (MAP) during pacing at cycle length (PCL) of 600[emsp4 ]ms and 350[emsp4 ]ms in eight patients who underwent electrophysiological study. MAP duration of right atrium (RA-MAPD) and right ventricle (RV-MAPD), effective refractory period of RA and RV (RA-ERP and RV-ERP), intra-atrial conduction time (IACT) and intra-ventricular conduction time (IVCT) were measured before and after intravenous administration of ibutilide (0.01[emsp4 ]mg/kg up to 1[emsp4 ]mg). A conduction time from RA pacing spike to distal coronary sinus potential was used to measure IACT, while QRS duration of surface ECG during RV pacing was used to measure IVCT. Ibutilide prolonged RA-MAPD by 60[emsp4 ]ms at PCL 600[emsp4 ]ms and by 53[emsp4 ]ms at PCL 350[emsp4 ]ms; RV-MAPD by 48[emsp4 ]ms at PCL 600[emsp4 ]ms and by 55[emsp4 ]ms at PCL 350[emsp4 ]ms. Ibutilide did not affected RA and RV-ERP/MAPD ratio, IACT, and IVCT. Ibutilide prolongs MAPD and ERP of human atrium and ventricle without reverse use-dependency.

Usefulness of the polarity in high-density wide range-filtered bipolar mapping to detect isthmus block during radiofrequency ablation of typical atrial flutter.

Background: The atrial activation sequence around the tricuspid annulus (TA) cannot always be used to establish whether complete block has been achieved across the cavotricuspid isthmus (CTI) during radiofrequency ablation (RFCA) for typical counterclockwise atrial flutter (CCW-AFL).Aim: We examined whether a change in the polarity of the atrial high-density wide range-filtered bipolar electrograms recorded near the ablation line is an accurate indicator of complete CTI block.Methods: Nineteen patients with CCW-AFL underwent RFCA. Electrograms were recorded around the TA with duodecapolar conventional (2mm × 8mm × 2mm spacing) and high-density (2-mm spacing) Halo catheters. The bipolar electrograms on the high-density Halo catheter recorded from a series of adjacent electrode pairs positioned just lateral to the ablation line were filtered at a bandpass setting of 0.05–500 Hz. The activation sequence on the conventional Halo catheter during coronary sinus pacing (CSp) and inferolateral TA pacing, and the bipolar electrograms on the high-density Halo catheter during CSp were determined before and after RFCA. The final complete CTI block was verified by the presence of widely split double electrograms ≥100 msec along the ablation line.Results: The final complete CTI block was achieved in all the 19 patients. Before RFCA, the polarity of bipolar electrograms was predominantly negative during CCW-AFL and positive during CSp. In 18 of the 19 patients, the bipolar electrograms exhibited the CCW activation and a negative polarity during CSp only after complete CTI block. In one of those 18 patients, additional applications of RFCA changed the polarity of bipolar electrograms positive to negative although the conventional Halo electrogram activation sequence suggested complete CTI block during CSp. In seven patients, who had transverse conduction across the crista terminalis during CSp, the conventional Halo electrogram activation sequence suggested an incomplete CTI block. However, in six of those seven patients, the CCW activation had a predominantly negative polarity of the bipolar electrograms. In one of those seven patients, complete CTI block was unable to be detected even using the high-density Halo catheter.Conclusions: These data demonstrate that the high-density wide range-filtered mapping can identify the CTI block in undetectable cases of complete CTI block or incomplete CTI block by the conventional method. The polarity of the bipolar electrograms recorded just lateral to the ablation line during CSp after RFCA of AFL may be used as a simple and an accurate indicator of complete CTI block.

Effect of IKr Blocker Nifekalant on Atrial Action Potential Duration After Successful Internal Cardioversion of Chronic Atrial Fibrillation

Background: Chronic atrial fibrillation (AF) is characterized by a marked decrease in the atrial effective refractory period (ERP) and in the ERP adaptation to rate as well as a decrease in the atrial conduction velocity. Little information is available about the ionic mechanisms underlying AF in humans.