Ali Erdogan

Pulmonary Vein Diameter Reduction After Radiofrequency Catheter Ablation for Paroxysmal Atrial Fibrillation Evaluated by Contrast-Enhanced Three-Dimensional Magnetic Resonance Imaging

Background—Radiofrequency catheter ablation (RFCA) is a promising intervention to treat atrial fibrillation. However, pulmonary vein (PV) stenosis after RFCA has been reported. The aim of this study was to investigate the incidence and time course of pulmonary vein stenosis after RFCA within a period of 3 months. Contrast-enhanced magnetic resonance angiography (MRA) was used to visualize pulmonary veins and was compared with radiographic angiography. Methods and Results—Forty-six consecutive patients with symptomatic paroxysmal atrial fibrillation had RFCA in the orifice of 138 pulmonary veins. Comparison of diameters measured in 44 untreated vessels either by radiographic angiography or with MRA established the reliability of MRA (r =0.934). MRA measurements revealed an incidence of relevant diameter reductions of ≥25% or stenosis of ≥50% after RFCA of 25 of 138 (18.1%) treated vessels 1 day and/or 3 months after ablation. A progression of diameter reduction after RFCA was observed in 8.3% (maximum 75%), whereas a regression was observed in 6.3% of treated PVs. Ablation at a radial angle of >180° of a pulmonary vein orifice increased the risk of diameter reduction significantly compared with ablation at a radial angle ≤180° (P =0.002). Conclusions—The occurrence and progression of PV stenosis is a potential significant complication of RFCA in the orifice of pulmonary veins. These findings may have an impact on the technical performance of this intervention. In addition, long-term studies will be necessary to evaluate lumen reduction over time. MRA is a noninvasive, reproducible imaging modality for this purpose.

Interplay between Ca2+ cycling and mitochondrial permeability transition pores promotes reperfusion-induced injury of cardiac myocytes

Uncontrolled release of Ca2+ from the sarcoplasmic reticulum (SR) contributes to the reperfusion‐induced cardiomyocyte injury, e.g. hypercontracture and necrosis. To find out the underlying cellular mechanisms of this phenomenon, we investigated whether the opening of mitochondrial permeability transition pores (MPTP), resulting in ATP depletion and reactive oxygen species (ROS) formation, may be involved. For this purpose, isolated cardiac myocytes from adult rats were subjected to simulated ischemia and reperfusion. MPTP opening was detected by calcein release and by monitoring the ΔΨm. Fura‐2 was used to monitor cytosolic [Ca2+]i or mitochondrial calcium [Ca2+]m, after quenching the cytosolic compartment with MnCl2. Mitochondrial ROS [ROS]m production was detected with MitoSOX Red and mag‐fura‐2 was used to monitor Mg2+ concentration, which reflects changes in cellular ATP. Necrosis was determined by propidium iodide staining. Reperfusion led to a calcein release from mitochondria, ΔΨm collapse and disturbance of ATP recovery. Simultaneously, Ca2+ oscillations occurred, [Ca2+]m and [ROS]m increased, cells developed hypercontracture and underwent necrosis. Inhibition of the SR‐driven Ca2+ cycling with thapsigargine or ryanodine prevented mitochondrial dysfunction, ROS formation and MPTP opening. Suppression of the mitochondrial Ca2+ uptake (Ru360) or MPTP (cyclosporine A) significantly attenuated Ca2+ cycling, hypercontracture and necrosis. ROS scavengers (2‐mercaptopropionyl glycine or N‐acetylcysteine) had no effect on these parameters, but reduced [ROS]m. In conclusion, MPTP opening occurs early during reperfusion and is due to the Ca2+ oscillations originating primarily from the SR and supported by MPTP. The interplay between Ca2+ cycling and MPTP promotes the reperfusion‐induced cardiomyocyte hypercontracture and necrosis. Mitochondrial ROS formation is a result rather than a cause of MPTP opening.

Risk Stratification Using Heart Rate Turbulence and Ventricular Arrhythmia in MADIT II: Usefulness and Limitations of a 10-Minute Holter Recording

Background: We evaluated the usefulness of heart rate turbulence (HRT) parameters and frequency of ventricular premature beats (VPBs) for risk‐stratifying postinfarction patients with depressed left ventricular function enrolled in Multicenter Automatic Defibrillator Trial II (MADIT II).

Inappropriate arrhythmia detection in implantable defibrillator therapy due to oversensing of diaphragmatic myopotentials.

Nonadequate arrhythmia detection and delivery of electrical therapy is still a main problem in current implantable cardioverter defibrillator therapy. Besides supraventricular arrhythmias extra-cardiac biosignals also can cause inadequate shock delivery. The present study focuses on nonadequate arrhythmia detection due to oversensing of diaphragmatic myopotentials. Their clinical characteristics, incidence and management are presented. Three-hundred-eighty-four recipients of a transvenous cardioverter-defibrillator who were implanted and followed-up at our institution between October 1991 and June 1999 were enrolled. During a mean follow-up of 32±25 months a total number of 139 nonadequate episodes of arrhythmia detection due to oversensing of diaphragmatic myopotentials were observed in 33 patients (8.6%). In 11 patients a total of 32 high energy shock deliveries occurred. Oversensing of diaphragmatic myopotentials was primarily observed in patients implanted with defibrillator leads providing “integrated bipolar” sensing. The vast majority of nonadequate arrhythmia detection were observed during intrinsic bradycardia heart rate and/or antibradycardia pacing. Electrical lead failure was ruled out in every patient. In 90% of the patients with a cardioverter-defibrillator providing programmable maximal sensitivity (n=16), the reduction of maximum sensitivity was effective in preventing further episodes of nonadequate arrhythmia detection. In 48% of the patients with devices without programmable maximal sensitivity (n=17), surgery revision was necessary to solve the problem.

Percutaneous Pulmonary Vein Stenting for the Treatment of Severe Stenosis After Pulmonary Vein Isolation

Introduction: Pulmonary vein stenosis (PVS) is a potential complication of pulmonary vein isolation (PVI) using radiofrequency energy. The aim of our study was the evaluation of the severity and long‐term outcome of primary angioplasty and angioplasty with pulmonary vein stenting for PVS.

Hepatobiliary and Pancreatic MRI and MRCP Findings in Patients with HIV Infection

OBJECTIVE The purpose of this article is to describe the spectrum of MRI and MR cholangiopancreatography (MRCP) findings of hepatic, pancreatic, and biliary manifestations in patients with HIV infection. CONCLUSION The spectrum of MRI and MRCP findings in HIV-infected patients includes acute or chronic hepatitis (or both), pancreatitis, cholangitis, acalculous cholecystitis, and biliary strictures that may resemble primary sclerosing cholangitis. The presence of segmental extrahepatic biliary strictures is characteristic of AIDS cholangiopathy.

Dose-dependent activation of Ca2+-activated K+ channels by ethanol contributes to improved endothelial cell functions

BACKGROUND Regular moderate alcohol (EtOH) intake seems to protect against both coronary artery disease and ischemic stroke, whereas the risk increases with heavy EtOH consumption. Effects of EtOH on endothelial cell function may be relevant to these disparate effects. Potassium channels play an important role in the regulation of endothelial cell functions. Therefore, we investigated whether Ca-activated K channels (BKCa) are modulated by EtOH. Furthermore, we examined whether EtOH-induced changes of endothelial nitric oxide (NO) formation and cell proliferation are due to BKCa activation. METHODS The patch-clamp technique was used to investigate BKCa activity in cultured human umbilical vein endothelial cells (HUVEC). NO formation was analyzed by using the fluorescence dye 4,5-diaminofluorescein. Endothelial proliferation was examined by using cell counts and measuring [H]thymidine incorporation. RESULTS EtOH dose-dependently (10-150 mmol/liter) modulated BKCa-activity, with the highest increase of open-state probability at a concentration of 50 mmol/liter (n = 13; p < 0.05). Inside-out recordings revealed that this effect was due to direct BKCa activation, whereas open-state probability was not changed in cell-attached recordings after pertussis toxin preincubation. EtOH (10 and 50 mmol/liter) caused a significant increase of NO levels, which was blocked by the highly selective BKCa inhibitor iberiotoxin (100 nmol/l; n = 30; p < 0.05). Higher concentrations of EtOH (100 and 150 mmol/liter) significantly reduced NO synthesis (n = 30; p < 0.05). Both methods revealed a significant increase of HUVEC proliferation, which was inhibited by iberiotoxin (n = 30; p < 0.05). At a concentration of 150 mmol/liter, EtOH caused a significant reduction of endothelial proliferation. CONCLUSIONS EtOH directly activates BKCa in HUVEC, leading to an increase of endothelial proliferation and production of NO. These results indicate a possible beneficial effect of low-dose EtOH on endothelial function, whereas higher concentrations must be considered as harmful.

Insulin Stabilizes Microvascular Endothelial Barrier Function via Phosphatidylinositol 3-Kinase/Akt-Mediated Rac1 Activation

Objective—Insulin is a key regulator of metabolism, but it also confers protective effects on the cardiovascular system. Here, we analyze the mechanism by which insulin stabilizes endothelial barrier function. Methods and Results—Insulin reduced basal and antagonized tumor necrosis factor-&agr;-induced macromolecule permeability of rat coronary microvascular endothelial monolayers. It also abolished reperfusion-induced vascular leakage in isolated-perfused rat hearts. Insulin induced dephosphorylation of the regulatory myosin light chains, as well as translocation of actin and vascular endothelial (VE)-cadherin to cell borders, indicating a reduction in contractile activation and stabilization of cell adhesion structures. These protective effects were blocked by genistein or Hydroxy-2-naphthalenylmethylphosphonic acid tris acetoxymethyl ester (HNMPA-[AM]3), a pan-tyrosine-kinase or specific insulin-receptor-kinase inhibitor, respectively. Insulin stimulated the phosphatidylinositol 3-kinase (PI3K)/Akt pathway and NO production, and it activated Rac1. Inhibition of PI3K/Akt abrogated Rac1 activation and insulin-induced barrier protection, whereas inhibition of the endothelial nitric oxide synthase/soluble guanylyl cyclase pathway partially inhibited them. Inhibition of Rac1 abrogated the assembly of actin at cell borders. Accordingly, it abolished the protective effect of insulin on barrier function of the cultured endothelial monolayer, as well as the intact coronary system of ischemic-reperfused hearts. Conclusion—Insulin stabilizes endothelial barrier via inactivation of the endothelial contractile machinery and enhancement of cell-cell adhesions. These effects are mediated via PI3K/Akt- and NO/cGMP-induced Rac1 activation.

Clinical and arrhythmic outcomes after implantation of a defibrillator for primary prevention of sudden death in patients with post-myocardial infarction cardiomyopathy: The Survey to Evaluate Arrhythmia Rate in High-risk MI patients (SEARCH-MI)

Aims To evaluate clinical and arrhythmic outcomes in post-infarction cardiomyopathy patients implanted with a defibrillator (ICD) for primary prevention of sudden death. Methods and results The SEARCH-MI registry is a European multi-centre, prospective, observational study enrolling patients after myocardial infarction, chronic left ventricular dysfunction and an ICD implanted for primary prevention of sudden death. Data on 556 patients with at least one recorded follow-up are presented. Survey to Evaluate Arrhythmia Rate in High-risk MI (SEARCH-MI) patients were sicker than those enrolled in MADIT-II with higher New York Heart Association class and left bundle branch block. Total mortality was 10.4%. Close to one-third (30%) of patients experienced episodes of sustained ventricular arrhythmia. One-quarter (23%) received at least one appropriate therapy and 10% inappropriate therapy. Gender (25% males vs. 5% females, P = 0.0009) and history of non-sustained ventricular tachycardia (24% with vs. 18% without P = 0.037) were predictive of appropriate ventricular therapy. Conclusion SEARCH-MI represents the current clinical management of post-MI patients with left ventricular dysfunction indicated to defibrillator implant for primary prevention. European routine clinical practice was influenced by landmark trials and guidelines which impacted on the implantation of cardiac resynchronization therapy in over 25% of such patients. Non-sustained ventricular tachycardia identifies subjects with a higher incidence of appropriate ICD therapy.

Margatoxin Inhibits VEGF-Induced Hyperpolarization, Proliferation and Nitric Oxide Production of Human Endothelial Cells

Background: Vascular endothelial growth factor (VEGF) induces proliferation of endothelial cells (EC) in vitro and angiogenesis in vivo. Furthermore, a role of VEGF in K+ channel, nitric oxide (NO) and Ca2+ signaling was reported. We examined whether the K+ channel blocker margatoxin (MTX) influences VEGF-induced signaling in human EC. Methods: Fluorescence imaging was used to analyze changes in the membrane potential (DiBAC), intracellular Ca2+ (FURA-2) and NO (DAF) levels in cultured human EC derived from human umbilical vein EC (HUVEC). Proliferation of HUVEC was examined by cell counts (CC) and [3H]-thymidine incorporation (TI).Results: VEGF (5–50 ng/ml) caused a dose-dependent hyperpolarization of EC, with a maximum at 30 ng/ml (n = 30, p < 0.05). This effect was completely blocked by MTX (5 µmol/l). VEGF caused an increase in transmembrane Ca2+ influx (n = 30, p < 0.05) that was sensitive to MTX and the blocker of transmembrane Ca2+ entry 2-aminoethoxydiphenyl borate (APB, 100 µmol/l). VEGF-induced NO production was significantly reduced by MTX, APB and a reduction in extracellular Ca2+ (n = 30, p < 0.05). HUVEC proliferation, examined by CC and TI, was significantly increased by VEGF and inhibited by MTX (CC: –58%, TI –121%); APB (CC –99%, TI –187%); N-monomethyl-L-arginine (300 µmol/l: CC: –86%, TI –164%). Conclusions: VEGF caused an MTX-sensitive hyperpolarization which results in an increased transmembrane Ca2+ entry that is responsible for the effects on endothelial proliferation and NO production.