Haruo Hirayama

Prediction of Genetic Risk for Hypertension

Abstract—Although genetic epidemiological studies have suggested that several genetic variants increase the risk for hypertension, the genes that underlie genetic susceptibility to this condition remain to be identified definitively. Large-scale association studies that examine many gene polymorphisms simultaneously are required to predict genetic risk for hypertension. The population of the present study comprised 1940 unrelated Japanese individuals, including 1067 subjects with hypertension (574 men, 493 women) and 873 controls (533 men, 340 women). The genotypes for 33 single nucleotide polymorphisms of 27 candidate genes were determined with a fluorescence- or colorimetry-based allele-specific DNA primer-probe assay system. Multivariate logistic regression analysis with adjustment for age, body mass index, and the prevalence of smoking, diabetes mellitus, hypercholesterolemia, and hyperuricemia revealed that 2 polymorphisms (825C→T in the G protein &bgr;3 subunit gene and 190G→A in the CC chemokine receptor 2 gene) were significantly associated with hypertension in men and that one polymorphism (−238G→A in the tumor necrosis factor &agr; gene) was significantly associated with hypertension in women. These results suggest that 2 and 1 genes may be susceptibility loci for hypertension in Japanese men and women, respectively, and that genotyping of these polymorphisms may prove informative for prediction of the genetic risk for hypertension.

Arterial remodeling influences the development of intimal hyperplasia after stent implantation

OBJECTIVES We examined whether preinterventional arterial remodeling influenced the interventional results after stenting. BACKGROUND Arterial remodeling is seen in atherosclerotic lesions, and it may play an important role in the early stage of atherosclerosis. METHODS We examined 113 lesions that underwent elective stenting using tubular slotted stents under intravascular ultrasound guidance. The lesions were divided into three groups--adequate, intermediate and inadequate remodeling group--according to preinterventional arterial remodeling. The patients were subjected to coronary angiography and intravascular ultrasound evaluation on average 6.4 months after stenting. RESULTS At baseline and immediately after stenting, there were no differences in quantitative angiographic analysis among remodeling groups. However, the plaque cross-sectional area (CSA) in the minimal lumen CSA at preintervention and intimal hyperplasia CSA at follow-up were significantly larger in the adequate remodeling group than in the inadequate remodeling group. The restenosis rate of stenting for the lesions with inadequate arterial remodeling was very low (9.4%). A significant positive correlation was found between preinterventional plaque CSA and intimal hyperplasia CSA at follow-up (r = 0.47, p < 0.0001). Moreover, remodeling index significantly correlated with relative intimal hyperplasia CSA (r = 0.28, p < 0.01). CONCLUSIONS Preinterventional arterial remodeling influenced the development of intimal hyperplasia after stenting.

Antiarrhythmic Efficacy of Dipyridamole in Treatment of Reperfusion Arrhythmias Evidence for cAMP-Mediated Triggered Activity as a Mechanism Responsible for Reperfusion Arrhythmias

BACKGROUND Intracellular calcium overload is believed to play an important role in development of reperfusion arrhythmias. Dipyridamole, an inhibitor of cellular uptake of adenosine, may prevent or terminate reperfusion arrhythmias by reducing intracellular calcium overload. METHODS AND RESULTS First, we tested for a preventive effect of dipyridamole. Sixty-one patients who underwent primary PTCA for treatment of acute anterior wall myocardial infarction were enrolled in this prospective study. Patients were divided into dipyridamole (DP) and nondipyridamole (non-DP) groups. The 2 groups had similar baseline characteristics. In the DP group, dipyridamole 0.5 mg/kg was infused intravenously for 3 minutes immediately before reperfusion during primary PTCA. Arrhythmias after reperfusion were analyzed from continuous ECG recordings. None of the patients in the DP group (n=23) had accelerated idioventricular rhythms (AIVR) or ventricular tachycardia (VT). In contrast, 7 (18.4%) had AIVR and 3 (7.9%) had VT in the non-DP group (n=38; P<0.01). Second, we tested for a termination effect of dipyridamole. Dipyridamole 0.5 mg/kg was infused intravenously while continuous ECG recordings were obtained in 9 patients who had either sustained AIVR (n=7) or sustained VT (n=2) after reperfusion of occluded coronary artery. Arrhythmias were terminated in all patients. CONCLUSIONS These results indicate that administration of dipyridamole can prevent and terminate reperfusion arrhythmias such as AIVR and VT. cAMP-mediated triggered activity may, at least in part, be responsible for reperfusion-induced AIVR and VT.

Body surface distribution of abnormally low QRST areas in patients with Wolff-Parkinson-White syndrome. Evidence for continuation of repolarization abnormalities before and after catheter ablation.

BackgroundWhether the Wolff-Parkinson-White syndrome (WPW) is associated with repolarization abnormalities is controversial. The QRST isointegral map (I-map) is theoretically independent of the activation sequence and dependent on repolarization properties. There have been no reports concerning the effects of radiofrquency (RF) catheter ablation of accessory pathway (AP) on repolarization properties analyzed by I-mapping. Methods andResults. I-maps were constructed from data recorded in 38 patients with WPW to investigate repolarization properties and their body surface distribution in a physiological state, without pharmacological influences, and in 13 ablated patients to elucidate the effects of RF ablation on repolarization properties. Patients were divided into three groups: group A, 15 patients with type AWPW (left-sided AP); group B, 10 patients with type B (right-sided AP); and group C, 13 patients who were successfuly ablated. Group C consisted of three subgroups: subgroup CA, 7 patients with type A WPW; subgroup CB, 3 patients with type B WPW; and subgroup Cc, 3 patients with concealed WPW. Controls consisted of 608 normals. Although I-maps ofWPWwere highly (r=.87) correlated with the mean normal I-map, the location of the minimum in groups A and B differed significantly from that in normals. The minimum was located over the upper right anterior chest in normal subjects, over the back in 82% of 22 patients with type A WP1W including ablated patients (groups A±CA), and over the mid to lower right anterior chest in 62% of 13 patients with type B WPW including ablated patients (groups B±CJ). Groups A±CA and B±CB had an abnormally low QRST area (“-2SD area”) over the back and right anterior chest, respectively. The abnormally located minimum and the “-2SD area” were present in 7 of 10 ablated patients with manifest WPW (groups CA±CB). After RF ablation, the distribution of the minimum, initially abnormal, became normal over a period of days or weeks, and the “-2SD area” disappeared over 1 week in all 7 patients. Correlation coefficients between I-maps and the mean normal I-map increased after RF ablation. Conclusions(1) WPW is often associated with abnormalities in repolarization properties. (2) Repolarization abnormalities were located over the back in type A WPW and over the right mid to lower chest in type B WPW. (3) The abnormalities remain immediately after RF ablation and gradually normalize. These findings support the concept that ST-T abnormalities in 12-lead ECGs following RF ablation are attributable to “cardiac memory.”

Lack of Association of Angiotensin Converting Enzyme Gene Polymorphism or Serum Enzyme Activity With Coronary Artery Disease in Japanese Subjects

The association of an insertion/deletion (I/D) polymorphism in the angiotensin converting enzyme (ACE) gene or the serum activity of ACE with coronary artery disease (CAD) was investigated in Japanese men and women. The ACE genotype of 947 CAD subjects who underwent coronary angiography and of 893 control subjects was determined by polymerase chain reaction analysis. No association of the DD genotype or the D allele with CAD was observed in men or women. In a low risk group (defined by a body mass index below the median value and the absence of a history of hypertension, diabetes mellitus, and hypercholesterolemia), there was also no association between the ACE gene polymorphism and CAD. No significant difference in serum ACE activity was detected between CAD subjects and controls of all genotypes or of the same genotype, whereas a significant association was apparent between serum ACE activity and ACE genotype for both CAD subjects and controls among both men and women. These results indicate that the ACE I/D polymorphism and genotype associated variation in serum ACE activity are not risk factors for CAD in Japanese men or women.

Maximum Derivative of Left Ventricular Pressure Predicts Cardiac Mortality After Cardiac Resynchronization Therapy

Cardiac resynchronization therapy (CRT) has been reported to improve cardiac performance. However, CRT in patients with advanced heart failure is not always accompanied by an improvement in survival rates. We investigated the association between hemodynamic studies and long‐term prognosis after CRT.

Lack of association between variants of the angiotensinogen gene and the risk of coronary artery disease in middle-aged Japanese men ☆ ☆☆ ★

The renin-angiotensin system is important in cardiovascular remodeling. Although a variant of the angiotensinogen gene is associated with an increased generation of angiotensinogen, it is unclear how this genetic variant might influence the activity of the renin-angiotensin system and thereby contribute to the predisposition to coronary artery disease (CAD). The relation between genetic polymorphisms in the gene-encoding angiotensinogen and the risk of CAD in middle-aged Japanese men was investigated. Two polymorphisms in exon 2 of the angiotensinogen gene, M235T and T174M, were analyzed in 327 patients with CAD and 352 matched control subjects. The genotype distribution of both polymorphisms did not differ between patients with CAD and control subjects. No combination of genotypes of the two polymorphisms was associated with CAD. Results indicate that the M235T and T174M variants of the angiotensinogen gene are not associated with CAD in Japanese men.

Association of a Deletion Polymorphism of the Angiotensin-Converting Enzyme Gene with Left-Ventricular Hypertrophy in Japanese Women with Essential Hypertension; Multicenter Study of 1,919 Subjects

The relationship of an insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene to left-ventricular hypertrophy in individuals with essential hypertension (EH) was investigated in a large population of Japanese men and women. The ACE genotype of 762 subjects with EH (425 men and 337 women) and 1,157 healthy controls (604 men and 553 women) was determined by polymerase chain reaction analysis. The distribution of ACE genotypes did not differ significantly between patients with EH and control in both men and women. For women with EH, the DD genotype was positively associated with the thickness of the interventricular septum and inversely associated with the left ventricular end-diastolic dimension, both determined by echocardiography. In contrast, the DD genotype was not associated with any echocardiographic parameter in men with EH. These results indicate that the DD genotype is a risk factor for left-ventricular hypertrophy in Japanese women with EH, but not for Japanese men.

Procedural sedation with dexmedetomidine during ablation of atrial fibrillation: a randomized controlled trial.

AIMS Procedural sedation by non-anaesthesiologists with GABAergic anaesthetics has the potential risk of fatal respiratory depression. Dexmedetomidine works its sedative action via α2-adrenergic receptors, and is less associated with respiratory depression. We tested the usability of dexmedetomidine as a procedural sedative during ablation of atrial fibrillation (AF). METHODS AND RESULTS Consecutive patients were randomized to be treated with dexmedetomidine (n = 43) or thiamylal (n = 44) as sedatives during AF ablation. Apnoeic and body movement events were monitored using a novel portable respiratory monitor, the SD-101, during the procedure. Although the majority of the patients receiving dexmedetomidine required rescue sedations with thiamylal, the respiratory disturbance index (RDI) defined as the total number of sleep-disordered breathing events divided by the recording time (10.4 ± 5.1 vs. 18.2 ± 8.1 events/h; P < 0.0001) and movement index defined as the number of body movement events per hour (7.6 ± 6.1 vs. 11.0 ± 5.5 events/h; P = 0.0098) were both significantly lower in the dexmedetomidine arm than in the thiamylal arm. A multivariate linear regression analysis including potential factors revealed that dexmedetomidine vs. thiamylal was solely and independently associated with the RDI (β = -0.62; P = 0.0031). The occurrence of hypotension [9 (21%) vs. 4 (9%); P = 0.14] and bradycardia [4 (9%) vs. 4 (9%); P = 1.0] were similar in the patients with dexmedetomidine and thiamylal. CONCLUSION Procedural sedation with dexmedetomidine may assure safety and patient immobility during AF ablation, and therefore may be a potential alternative for that with GABAergic anaesthetics.

Incremental predictive value of myocardial scintigraphy with 123I-BMIPP in patients with acute myocardial infarction treated with primary percutaneous coronary intervention

PurposeIt is unclear whether 123I-labelled β-methyl iodophenyl pentadecanoic acid (123I-BMIPP) myocardial scintigraphy adds further predictive value for future cardiac events compared with the variables obtained during cardiac catheterisation in patients with acute myocardial infarction (AMI) treated with primary percutaneous coronary intervention (PCI). We therefore investigated whether 123I-BMIPP imaging in patients with AMI treated by primary PCI was useful in predicting future cardiac events.MethodsOne hundred and fifty-nine patients with AMI who were treated with primary PCI and underwent left ventriculography (LVG) on admission underwent 201Tl and 123I-BMIPP myocardial scintigraphy. Scintigrams were visually classified, and the total defect score (TDS) was calculated. Major adverse cardiac events (MACE) were defined as cardiac death including sudden death, congestive heart failure and recurrence of acute coronary syndrome. Patients were followed up for a mean of 34.5 months (12–63 months).ResultsTwenty-six patients had MACE. Kaplan-Meier analysis indicated that patients with the top 50% of 123I-BMIPP TDSs had a significantly higher rate of MACE (P=0.007). Patients with mismatch between 201Tl and 123I-BMIPP images also had significantly more MACE (P=0.02). In the prediction of MACE, the global chi-square value was 5.2 (P=0.001) based on LVEF (<45%) and the number of diseased vessels (two or three). Adding 123I-BMIPP TDS and the mismatch improved the global chi-square value (χ2=7.2)Conclusion Myocardial scintigraphy using 201Tl and 123I-BMIPP predicts future cardiac events in patients with AMI treated with primary PCI, and provides additional predictive value compared with the variables obtained with cardiac catheterisation alone.