Ryosuke Kametani

Pleiotropic Effects of the β-Adrenoceptor Blocker Carvedilol on Calcium Regulation during Oxidative Stress-Induced Apoptosis in Cardiomyocytes

Carvedilol is a nonselective β-adrenoceptor blocker with multiple pleiotropic actions. A recent clinical study suggested that carvedilol may be superior to other β-adrenoceptor blockers in the treatment of heart failure. Despite numerous investigations, the underlying mechanisms of carvedilol on improving heart failure are yet to be fully established. The purpose of this study is to clarify the pleiotropic effect of carvedilol on cytosolic and mitochondrial calcium regulation during oxidative stress-induced apoptosis in cardiomyocytes. Carvedilol (10 μM), but not metoprolol (10 μM), reduced H2O2 (100 μM)-induced apoptosis in neonatal rat cardiomyocytes. During the process, changes in cytosolic calcium concentration ([Ca2+]i) and mitochondrial calcium concentration ([Ca2+]m) and mitochondrial membrane potential (ΔΨm) were measured by fluorescent probes [Fluo-3/acetoxymethyl ester (AM), Rhod-2/AM, and tetramethylrhodamine ethyl ester, respectively] and imaged by laser confocal microscopy. The results showed that H2O2 caused [Ca2]m overload first, followed by [Ca2+]i overload, leading to ΔΨm dissipation and the induction of apoptosis. Carvedilol (10 μM) significantly delayed these processes and reduced apoptosis. These effects were not observed with other β-adrenoceptor blockers (metoprolol, atenolol, and propranolol) or with a combination of the α (phentolamine)- and the β-adrenoceptor blocker. The antioxidant N-acetyl-l-cysteine (NAC, 5 mM) and the combination of NAC and propranolol (10 μM) showed an effect similar to that of carvedilol. Therefore, the effect of carvedilol on H2O2-induced changes in [Ca2+]m, [Ca2+]i, and ΔΨm is independent of α- and β-adrenoceptors but is probably dependent on the antioxidant effect.

NO donor-activated PKC-delta plays a pivotal role in ischemic myocardial protection through accelerated opening of mitochondrial K-ATP channels.

Nitric oxide (NO) can activate protein kinase C (PKC) and the activation of mitochondrial ATP-sensitive potassium (K-ATP) channels is cardioprotective. However, interactions among NO, PKC, and mitochondrial K-ATP channels remain vague. To clarify the cardioprotective mechanism induced by nicorandil, we compared its ability to activate PKC isoforms with that of the mitochondrial K-ATP channel opener, diazoxide. We induced myocardial infarction in rats by 30 minutes of ischemia followed by reperfusion, then assessed the infarct size 3 weeks later. We also examined the translocation of PKC isoforms in the isolated perfused rat heart. Nicorandil and diazoxide reduced infarct size, and the effect of nicorandil, but not of diazoxide attenuated by the PKC inhibitor, chelerythrine, or by the NO quencher, carboxy PTIO. Immunoblotting revealed that nicorandil translocated PKC-δ to the mitochondria, and that this was inhibited by carboxy PTIO. The protective effect of nicorandil against myocardial infarction partly depended on the translocation of PKC-δ to the mitochondria, which we attributed to the NO donor effect of nicorandil. The PKC-δ- dependent activation of mitochondrial K-ATP channel opening might be synergistic with its direct effect, making nicorandil an efficient opener of such channels.

Respiratory failure and pulmonary hypertension associated with Klippel-Feil syndrome

A 28-year-old woman with a deformed thorax and kyphoscoliosis associated with Klippel-Feil syndrome developed respiratory failure with pulmonary hypertension. Pulmonary133Xe ventilation and99mTc-MAA perfusion scintigraphies showed maldistributions of lung ventilation and perfusion, and noticeably delayed133Xe washout from the lungs. Dynamic breathing MR imaging showed poor and/or asynchronous respiratory movements of the chest wall and diaphragm. These findings indicate that the perfusion-ventilation imbalance, the decreased ventilatory turnover, and expiratory flow from the alveolar space partly derived from the impaired respiratory mechanics may be responsible for the respiratory complications in this patient.

Successful ethanol injection into the anterior interventricular cardiac vein for ventricular premature contractions arising from the left ventricular summit

Introduction Ventricular premature contractions (VPCs) without structural heart disease arising from an outflow tract are amenable to treatment with radiofrequency (RF) catheter ablation, but may not always be cured successfully because of the characteristic structure. Most of themmay not be life threatening but can sometimes annoy patients. Recently, retrograde coronary venous ethanol infusions have been reported as an alternative method in patients with refractory ventricular arrhythmias (VAs) to RF ablation originating from various sites. In those papers, all experienced ventricular tachycardias and had comorbidities or structural heart disease with a reduced ejection fraction. This report describes the first case without structural heart disease to undergo an ethanol injection into the anterior interventricular cardiac vein (EIAIV) via the great cardiac vein (GCV) for VPCs arising from the left ventricular (LV) summit region that all other RF approaches could not eliminate.

Fistula between the Thoracic Duct and an Unusual Vessel Aneurysm Branching Off the Abdominal Aorta Revealed by Aneurysm Rupture: A Case Report

Fistulas between an aneurysm branching off the abdominal aorta and the thoracic duct are rare. We report a case of aneurysmal-thoracic duct fistula diagnosed by angiography when aneurysm ruptured, and we successfully treated by catheter embolization. A 42-year-old man was referred to our hospital with a chief complaint of sudden back and chest pain. Computed tomography showed both post-mediastinal and retroperitoneal hematomas, with the aneurysm from the aorta being connected to the thoracic duct. After confirming the aneurysmal-thoracic duct fistula by angiography, we performed embolization of the aneurysm. The patient has remained well for 3 postoperative months, to date.

Ethanol injection into the Marshall vein provoking a pericardial effusion resulting in a fatal complication in a patient with persistent atrial fibrillation

An EIM (ethanol infusion into the vein of Marshall [VOM]) provoked a fatal complication in a chronic hemodialysis patient. Autopsy revealed a lacerated VOM covered with thrombi as the only potential cause. The EIM caused vascular damage and clots resulting in myocardial necrosis and interstitial bleeding around the lacerated VOM.