Surgical Repair of Subacute Right Ventricular Perforation after Pacemaker Implantation.

We report an 84-year-old woman who presented with right ventricular perforation 4 days after pacemaker implantation for syncope due to sick sinus syndrome. Median sternotomy revealed no pericardial effusion, but the pacing lead had penetrated the right ventricle and pericardium. When the pleura was opened, the tip of the lead was seen in the visceral pleura. The lead was cut in the pericardial cavity and extracted from the left subclavian wound together with the generator. The right ventricular perforation was sutured and a temporary pacing lead was placed on the right ventricular wall intraoperatively. Ten days after the surgery, a new pacemaker lead was placed in the ventricular septum via the right axillary vein. Right ventricular perforation is a rare complication after pacemaker implantation. Typically, it occurs at the time of implantation or within 24 hours after implantation. In the present case, the perforation of the right ventricle which needed urgent surgery occurred 4 days after implanting the pacing lead at the right ventricular apex. Great care should have been taken not to overlook this life-threatening complication even more than 24 hours after pacemaker implantation.

Efficacy and safety of flecainide for ventricular arrhythmias in patients with Andersen-Tawil syndrome with KCNJ2 mutations.

BACKGROUND: Andersen-Tawil syndrome (ATS) is an autosomal dominant genetic or sporadic disorder characterized by ventricular arrhythmias (VAs), periodic paralyses, and dysmorphic features. The optimal pharmacological treatment of VAs in patients with ATS remains unknown. OBJECTIVE: We evaluated the efficacy and safety of flecainide for VAs in patients with ATS with KCNJ2 mutations. METHODS: Ten ATS probands (7 females; mean age 27 ± 11 years) were enrolled from 6 institutions. All of them had bidirectional VAs in spite of treatment with ß-blockers (n = 6), but none of them had either aborted cardiac arrest or family history of sudden cardiac death. Twenty-four-hour Holter recording and treadmill exercise test (TMT) were performed before (baseline) and after oral flecainide therapy (150 ± 46 mg/d). RESULTS: Twenty-four-hour Holter recordings demonstrated that oral flecainide treatment significantly reduced the total number of VAs (from 38,407 ± 19,956 to 11,196 ± 14,773 per day; P = .003) and the number of the longest ventricular salvos (23 ± 19 to 5 ± 5; P = .01). At baseline, TMT induced nonsustained ventricular tachycardia (n = 7) or couplets of premature ventricular complex (n = 2); treatment with flecainide completely (n = 7) or partially (n = 2) suppressed these exercise-induced VAs (P = .008). In contrast, the QRS duration, QT interval, and U-wave amplitude of the electrocardiogram were not altered by flecainide therapy. During a mean follow-up of 23 ± 11 months, no patients developed syncope or cardiac arrest after oral flecainide treatment. CONCLUSION: This multicenter study suggests that oral flecainide therapy is an effective and safe means of suppressing VAs in patients with ATS with KCNJ2 mutations, though the U-wave amplitude remained unchanged by flecainide.

Cluster differentiation-36 deficiency type 1 and acute coronary syndrome without major cardiovascular risk factors: case report.

A 45-year-old man without major coronary risk factors, including hypertension, diabetes mellitus, smoking, hypercholesterolemia, hyperuricemia, or a family history of early cardiovascular disease, presented with acute coronary syndrome. Angiography showed thrombus formation in segment 7 of the left anterior descending coronary artery, and percutaneous coronary intervention was successful after implantation of a bare metal stent. Scintigraphy showed the absence of 123I-beta-methyl-iodophenyl pentadecanoic acid accumulation in the myocardium. Flow cytometric analysis of platelets and monocytes showed the absence of cluster differentiation (CD)-36 expression. These findings are consistent with a diagnosis of CD36 deficiency type 1, which might be associated with cardiovascular disease. The patient had no apparent major coronary risk factors except for insulin resistance and an abnormal lipoprotein profile. The findings suggest that in this case the CD36 deficiency type 1 was the pathogenic mechanism of acute coronary syndrome relative to insulin resistance and modification of the lipid profile.

Antiapoptotic activity of Akt is down-regulated by Ca2+ in myocardiac H9c2 cells. Evidence of Ca(2+)-dependent regulation of protein phosphatase 2Ac.

Cell survival signaling of the Akt/protein kinase B pathway was influenced by a change in the cytoplasmic free calcium concentration ([Ca2+]i) for over 2 h via the regulation of a Ser/Thr phosphatase, protein phosphatase 2Ac (PP2Ac), in rat myocardiac H9c2 cells. Akt was down-regulated when [Ca2+]i was elevated by thapsigargin, an inhibitor of the endoplasmic reticulum Ca(2+)-ATPase, but was up-regulated when it was suppressed by 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetra(acetoxymethyl)ester (BAPTA-AM), a cell permeable Ca2+ chelator. The inactivation of Akt was well correlated with the susceptibility to oxidant-induced apoptosis in H9c2 cells. To investigate the mechanism of the Ca(2+)-dependent regulation of Akt via the regulation of PP2A, we examined the transcriptional regulation of PP2Acalpha in H9c2 cells with Ca2+ modulators. Transcription of the PP2Acalpha gene was increased by thapsigargin but decreased by BAPTA-AM. The promoter activity was examined and the cAMP response element (CRE) was found responsible for the Ca(2+)-dependent regulation of PP2Acalpha. Furthermore, phosphorylation of CRE-binding protein increased with thapsigargin but decreased with BAPTA-AM. A long term change of [Ca2+]i regulates PP2Acalpha gene transcription via CRE, resulting in a change in the activation status of Akt leading to an altered susceptibility to apoptosis.

Oxidative modulation of NF-kappaB signaling by oxidized low-density lipoprotein.

Oxidized low-density lipoprotein (oxLDL) modifies macrophage inflammatory responses in the pathogenesis of atherosclerosis. In the present study, we focused on gamma-glutamylcysteine synthetase (gamma-GCS), a rate limiting enzyme of glutathione synthesis, and examined whether inflammatory stimulation of gamma-GCS gene in macrophages by lipopolysaccharide (LPS) is modified when the cells were exposed to oxLDL. We found that the nuclear factor-kappaB (NF-kappaB)-mediated induction of gamma-GCS by LPS (100 ng/ml) was suppressed by a 48-h pre-treatment with oxLDL (50 micro/ml), and this was due to a decrease in the DNA-binding activity of NF-kappaB. Furthermore, pre-treatment with oxLDL caused a carbonylation of NF-kappaB subunit p65. With alpha-tocopherol, the oxLDL-induced carbonylation of proteins decreased with a restoration of DNA-binding activity of NF-kappaB. Together, these indicate that oxidative modification of NF-kappaB suppresses LPS-induced expression of gamma-GCS gene in ox-LDL-treated cells, suggesting an implication of oxLDL-induced modulation of NF-kappaB signaling with atherosclerosis.

Tyrosine phosphorylation of clathrin heavy chain under oxidative stress.

In mouse pancreatic insulin-producing betaTC cells, oxidative stress due to H(2)O(2) causes tyrosine phosphorylation in various proteins. To identify proteins bearing phosphotyrosine under stress, the proteins were affinity purified using an anti-phosphotyrosine antibody-conjugated agarose column. A protein of 180kDa was identified as clathrin heavy chain (CHC) by electrophoresis and mass spectrometry. Immunoprecipitated CHC showed tyrosine phosphorylation upon H(2)O(2) treatment and the phosphorylation was suppressed by the Src kinase inhibitor, PP2. The phosphorylation status of CHC affected the intracellular localization of CHC and the clathrin-dependent endocytosis of transferrin under oxidative stress. In conclusion, CHC is a protein that is phosphorylated at tyrosine by H(2)O(2) and this phosphorylation status is implicated in the intracellular localization and functions of CHC under oxidative stress. The present study demonstrates that oxidative stress affects intracellular vesicular trafficking via the alteration of clathrin-dependent vesicular trafficking.

Nepsilon-(Carboxymethyl)lysine induces gamma-glutamylcysteine synthetase in RAW264.7 cells.

Advanced glycation end products (AGEs) play an important role in the development of angiopathy in diabetes mellitus and atherosclerosis. Here, we show that adducts of N(epsilon)-(carboxymethyl)lysine (CML), a major AGE, and bovine serum albumin (CML-BSA) stimulated gamma-glutamylcysteine synthetase (gamma-GCS), which is a key enzyme of glutathione (GSH) synthesis, in RAW264.7 mouse macrophage-like cells. CML-BSA stimulated the expression of gamma-GCS heavy subunit (h) time- and dose-dependently and concomitantly increased GSH levels. CML-BSA also stimulated DNA-binding activity of activator protein-1 (AP-1) within 3h, but the stimulatory effect decreased in 5h, and nuclear factor-kappaB (NF-kappaB) with a peak activity at 1h and the stimulatory effect diminished in 3h. Studies of luciferase activity of the gamma-GCSh promoter showed that deletion and mutagenesis of the AP-1-site abolished CML-BSA-induced up-regulation, while that of NF-kappaB-site did not affect CML-BSA-induced activity. CML-BSA also stimulated the activity of protein kinase C, Ras/Raf-1, and MEK/ERK1/2. Inhibition of ERK1/2 abolished CML-BSA-stimulated AP-1 DNA-binding activity and gamma-GCSh mRNA expression. Our results suggest that induction of gamma-GCS by CML adducts seems to increase the defense potential of cells against oxidative stress produced during glycation processes.