Kazuhiko Ogawa

RETRACTED: Valsartan in a Japanese population with hypertension and other cardiovascular disease (Jikei Heart Study): a randomised, open-label, blinded endpoint morbidity-mortality study

BACKGROUND Drugs that inhibit the renin-angiotensin-aldosterone system benefit patients at risk for or with existing cardiovascular disease. However, evidence for this effect in Asian populations is scarce. We aimed to investigate whether addition of an angiotensin receptor blocker, valsartan, to conventional cardiovascular treatment was effective in Japanese patients with cardiovascular disease. METHODS We initiated a multicentre, prospective, randomised controlled trial of 3081 Japanese patients, aged 20-79 years, (mean 65 [SD 10] years) who were undergoing conventional treatment for hypertension, coronary heart disease, heart failure, or a combination of these disorders. In addition to conventional treatment, patients were assigned either to valsartan (40-160 mg per day) or to other treatment without angiotensin receptor blockers. Our primary endpoint was a composite of cardiovascular morbidity and mortality. Analysis was by intention to treat. The study was registered at clintrials.gov with the identifier NCT00133328. FINDINGS After a median follow-up of 3.1 years (range 1-3.9) the primary endpoint was recorded in fewer individuals given valsartan than in controls (92 vs 149; absolute risk 21.3 vs 34.5 per 1000 patient years; hazard ratio 0.61, 95% CI 0.47-0.79, p=0.0002). This difference was mainly attributable to fewer incidences of stroke and transient ischaemic attack (29 vs 48; 0.60, 0.38-0.95, p=0.028), angina pectoris (19 vs 53; 0.35, 0.20-0.58, p<0.0001), and heart failure (19 vs 36; 0.53, 0.31-0.94, p=0.029) in those given valsartan than in the control group. Mortality or tolerability did not differ between groups. INTERPRETATION The addition of valsartan to conventional treatment prevented more cardiovascular events than supplementary conventional treatment. These benefits cannot be entirely explained by a difference in blood pressure control.

Effects of efonidipine, an L- and T-Type dual calcium channel blocker, on heart rate and blood pressure in patients with mild to severe hypertension: an uncontrolled, open-label pilot study

BACKGROUND Dihydropyridines (DHPs), a type of calcium channel blocker (CCB), are commonly prescribed for the treatment of hypertension and angina pectoris. DHPs act mainly on L-type calcium channels, essentially causing reflex tachycardia (elevated heart rate [HR]), which negatively affects cardiac function. Because T-type calcium channels in the sinoatrial node attenuate reflex tachycardia, a dual L- and T-type CCB (eg, efonidipine hydrochloride) may favorably affect cardiac pacing, thereby reducing reflex tachycardia. The effect of efonidipine as a DHP on HR deserves special consideration with regard to reflex tachycardia. OBJECTIVE The aim of this study was to determine whether the L- and T-type CCB efonidipine can decrease the elevated HR induced by prior treatment using traditional DHPs. METHODS This uncontrolled, open-label pilot study was conducted at the Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine (Tokyo, Japan). Patients aged 48 to 80 years with mild to severe hypertension and angina pectoris and who were receiving therapy with a DHP other than efonidipine were eligible. During an 8-week observation period, patients continued therapy with their DHP. After those 8 weeks, therapy was switched to oral efonidipine (40-mg tablet once daily) in patients whose blood pressure (BP) was stable and well controlled and whose HR was >80 bpm. BP and HR were monitored every 4 weeks of treatment with efonidipine. RESULTS Eighteen patients (12 men, 6 women; mean [SD] age, 62.6 [12] years) were enrolled. After the switch to efonidipine, mean (SD) HR decreased significantly, from 94 (7) bpm to 86 (11) bpm at 12 weeks (P<0.05). The antihypertensive effect of efonidipine was similar to that of the DHPs used before the switch to efonidipine therapy, and reflex tachycardia was attenuated. CONCLUSION In this study of a small sample of patients with mild to severe essential hypertension and angina pectoris, efonidipine was as effective as other DHPs. Moreover, the drug attenuated the reflex tachycardia that occurred with traditional DHPs.

Effect of captopril on isoproterenol-induced myocardial ornithine decarboxylase activity

Polyamines are thought to play an essential role in cellular hypertrophy and proliferation. Ornithine decarboxylase (ODC) catalyzes the first and probably the rate-limiting step in biosynthesis of polyamines. In this study, we evaluated the pathophysiological role of the renin-angiotensin system in isoproterenol-induced cardiac hypertrophy, using myocardial ODC activity as an indicator of cardiac hypertrophy. Isoproterenol caused an eight-fold increase of myocardial ODC activity in normotensive Wistar rats within 4 h after injection. Captopril suppressed the induction of ODC by isoproterenol to two-thirds of the control level. These results indicate that the renin-angiotensin system may participate in the induction of myocardial hypertrophy by isoproterenol.

Evaluation of the timing of flecainide administration and ischemia-induced ventricular arrhythmias in rats

Abstract Ischemia-induced arrhythmias are major complications of acute myocardial infarction; therefore, understanding the proper use of antiarrhythmic drugs in this situation is important. The goal of the present study was to determine how the timing of flecainide administration influenced ischemia-induced arrhythmias in an isolated rat heart model. Ischemia-induced arrhythmia was produced by ligating the left coronary artery. The effect of flecainide (10 −6 M) on ischemia-induced arrhythmia varied depending on the time of drug administration in relation to the time of coronary artery ligation. Drug administration both before and after (group 5) coronary artery ligation was most effective, followed by administration before (group 4) and then by administration after (group 3). At the end of each experiment, the left and right ventricular walls of each heart were separated, and drug concentration in each part was measured. Drug concentration in the left ventricular wall differed significantly between the group in which coronary artery ligation was not performed (group 1) and group 3 or 4. No correlation between drug concentration in the right ventricular wall and antiarrhythmic effect was observed. These differences in antiarrhythmic effect depending on the timing of drug administration may be caused by the difference in drug concentration in the ischemic zone and the effect of coronary artery occlusion on the speed of drug dispersion within this zone. This myocardial infarction model is useful for studying the correlation between antiarrhythmic effect and regional drug distribution.