Mitsuyuki Shimizu

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.

Down-regulation of sarcolipin mRNA expression in chronic atrial fibrillation

Background  Abnormal intracellular Ca2+ homeostasis is an important modulator of chronic atrial fibrillation. Sarcolipin, a homologue of phospholamban, is specifically expressed in the atria, and may play an important role in modulating intracellular Ca2+ homeostasis in the atria. The aim of this study was to investigate the expression of sarcolipin mRNA in the atrial myocardium of patients with chronic atrial fibrillation.

Post‐transcriptional downregulation of sarcolipin mRNA by triiodothyronine in the atrial myocardium

Thyroid hormone‐mediated positive cardiotropic effects are differently regulated between the atria and ventricles. This regulation is, at least in part, dependent on sarcoplasmic reticulum (SR) proteins. Sarcolipin, a homologue of phospholamban, has been recently identified as an atrium‐specific SR protein. The expression of sarcolipin mRNA was significantly decreased in the atria of mice with hyperthyroidism and in 3,5,3′‐triiodo‐l‐thyronine‐treated neonatal rat atrial myocytes. Promoter activity and mRNA stability analyses revealed that thyroid hormone post‐transcriptionally downregulated the expression of sarcolipin mRNA. The atrium‐specific effect of thyroid hormone may occur in part through the regulation of atrial sarcolipin gene expression.

JIKEI HEART study: A morbi-mortality and remodeling Study with valsartan in Japanese patients with hypertension and cardiovascular disease

AbstractBackground: Several recent clinical trials have demonstrated that angiotensin II receptor blockers (ARBs) have cardiovascular as well as renal protective effects. Asian patients including Japanese were under-represented in these trials, however, and no large-scale clinical trials of ARBs have yet been performed in Japan. It is therefore important to verify that the results of these studies are also valid for Japanese patients. The JIKEI HEART Study has been designed to investigate whether concomitant treatment with valsartan, an angiotensin II receptor blocker, in addition to conventional treatment, will improve the prognosis of Japanese patients with cardiovascular diseases (hypertension, ischemic heart disease, congestive heart failure). Method and Evaluation of Results: Around 3,000 patients with hypertension, ischemic heart disease and/or congestive heart failure will be randomized to receive either additional treatment with valsartan (80 mg/day) or conventional therapy. The follow-up period will be three years. The primary endpoint will be the onset of any cardiovascular event. Secondary endpoints will include death from any cause, changes in left ventricular size and function, renal function, changes in neuro-hormonal levels and quality-of-life assessments. Sub-studies will explore the effect in patients with diabetes mellitus, hyperlipidemia and the effects of combination of drugs. Conclusion: Improved prognosis would confirm the role of angiotensin II receptor blockers in the treatment of the cardiovascular disease in Japanese patients.

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.

A case of CTO treated with minimum use of contrast media

The retrograde approach is a novel technique for improving the success rate of guidewire passage through chronic total occlusion (CTO). In addition, this technique, especially when intravascular ultrasound‐guided reverse controlled antegrade and retrograde subintimal tracking is employed, may help the operator to save on the contrast media used. In the case reported here, only 10 ml of contrast media was used in percutaneous coronary intervention for CTO.

Gender Differences in the Effects of Angiotensin Receptor Blockers on Cardiovascular Disease

Women tend to develop hypertension later as they transition into menopause, and during and after menopause the development of hypertension in women is independent of age and body mass index (BMI) but is related to menopause itself. One of the mechanisms of hypertension development in postmenopausal women is believed to be the lack of estrogen leading to vasoconstriction due to both renin-angiotensin-aldosterone (RAA)-sensitive and sodium-sensitive pathways. Nowadays, we have many medications of antihypertensive therapy, including angiotensin converting enzyme (ACE) inhibitor and angiotensin receptor blocker (ARB) in addition to diuretics, beta-blockers, calcium channel blockers. The present review summarizes gender differences in the effects of ARB on blood pressure lowering and cardiovascular outcomes from the published reports of large-scaled, randomized clinical trials and its substudy on sex-specific difference. Many antihypertensive drugs have been developed, and the benefit of blood pressure lowering therapy for the prevention of cardiovascular disease would be expected not only in men but also in women as indicated in the large-scaled clinical studies with ARB.

A novel technique for catheter engagement of protruding aorto-ostial stent.

We present a case of stenoses in the right coronary artery with a previously deployed stent showing gross protrusion into the aorta. Despite difficulty in cannulation of a guiding catheter into the coronary artery, percutaneous intervention was accomplished using a novel technique to engage the protruding stent.

Sex differences in effects of valsartan administration on cardiovascular outcomes in hypertensive patients: Findings from the Jikei Heart Study

OBJECTIVES The randomized Jikei Heart Study has demonstrated that the addition of valsartan to conventional treatments prevents more cardiovascular events in Japanese patients with hypertension. This substudy analyses the sex difference in cardiovascular disease risk reduction in the Jikei Heart Study. METHODS Treatment effects were evaluated by sex (1038 women and 2043 men) as hazard ratios with 95% confidence intervals (CIs) using Cox regression models adjusted for age, BMI, smoking, dyslipidemia, diabetes, antihypertensives, and statin use at baseline. RESULTS Women were older, had higher SBP, total and low-density lipoprotein cholesterol but were less frequently smokers or diabetics, and had a lower DBP and incidence of coronary artery disease. A greater incidence of primary endpoint, a composite of cardiovascular events, occurred in men versus women [hazard ratio 1.37 (95% CI 1.02-1.85)]. Men in the valsartan group had a significant reduction in the primary endpoint [hazard ratio 0.6 (95% CI 0.44-0.82), P = 0.001], whereas a nonsignificant effect was found in women [hazard ratio 0.64 (95% CI 0.39-1.06), P = 0.075]. However, statistical heterogeneity of this valsartan effect was not found between sexes, and women of at least 55 years of age, mostly after menopause, in the valsartan group showed a significant risk reduction for the primary endpoint [hazard ratio 0.60 (95% CI 0.36-0.99)]. CONCLUSION The valsartan effect was significant in men and in elderly women but consistent in both sexes. A potential cardiovascular protection by valsartan therapy might be attributed to the cardiovascular risk level but not to the sex difference.

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.