Abstract-Connexin43 (Cx43), the predominant ventricular gap junction protein, is critical for maintaining normal cardiac electrical conduction, and its absence in the mouse heart results in sudden arrhythmic death. The mechanisms linking reduced Cx43 abundance in the heart and inducibility of malignant ventricular arrhythmias have yet to be established. In this report, we investigate arrhythmic susceptibility in a murine model genetically engineered to express progressively decreasing levels of Cx43. Progressively older cardiac-restricted Cx43 conditional knockout (CKO) mice were selectively bred to produce a heart-specific Cx43-deficient subline ("O-CKO" mice) in which the loss of Cx43 in the heart occurs more gradually. O-CKO mice lived significantly longer than the initial series of CKO mice but still died suddenly and prematurely. At 25 days of age, cardiac Cx43 protein levels decreased to 59% of control values (PϽ0.01), but conduction velocity was not significantly decreased and no O-CKO mice were inducible into sustained ventricular tachyarrhythmias. By 45 days of age, cardiac Cx43 abundance had decreased in a heterogeneous fashion to 18% of control levels, conduction velocity had slowed to half of that observed in control hearts, and 80% of O-CKO mice were inducible into lethal tachyarrhythmias. Enhanced susceptibility to induced arrhythmias was not associated with altered invasive hemodynamic measurements or changes in ventricular effective refractory period. Thus, moderately severe reductions in Cx43 abundance are associated with slowing of impulse propagation and a dramatic increase in the susceptibility to inducible ventricular arrhythmias. Key Words: connexin43 Ⅲ arrhythmia Ⅲ electrophysiology Ⅲ heart Ⅲ mice V entricular tachyarrhythmias are a frequent cause of sudden cardiac death in ischemic and nonischemic heart disease. Despite intense investigation, molecular mechanisms underlying the propensity of diseased myocardium to initiate and propagate lethal arrhythmias are incompletely understood. In recent years, a number of genetically engineered murine models have been developed to explore the pathophysiology of arrhythmogenesis. Although many such mice display increases in the frequency of spontaneous or inducible ventricular ectopy, in almost all cases this activity is self-limited and has not been shown to be the proximate cause of death. 1-4 Several other mutant mouse models are able to support sustained ventricular arrhythmias, but these require provocative stimuli, such as anesthesia or exercise with administration of adrenergic agents. [5][6][7][8] To date, only the heartspecific connexin43 (Cx43) conditional knockout (CKO) mouse has been shown to die prematurely from spontaneous sustained ventricular tachyarrhythmias. 9 Because of the arrhythmic propensity of the Cx43 CKO mouse and the ease of inducible sustained arrhythmias, 10 it has served as an ideal model for the study of basic mechanisms of arrhythmia.In myopathic hearts, abnormal expression of Cx43 (gap junction remodeling) may contri...

Background— Although routinely administered, definitive evidence for the benefits of prophylactic antibiotics before the implantation of permanent pacemakers and implantable cardioverter-defibrillators from a large double-blinded placebo-controlled trial is lacking. The purpose of this study was to determine whether prophylactic antibiotic administration reduces the incidence of infection related to device implantation. Methods and Results— This double blinded study included 1000 consecutive patients who presented for primary device (Pacemaker and implantable cardioverter-defibrillators) implantation or generator replacement randomized in a 1:1 fashion to prophylactic antibiotics or placebo. Intravenous administration of 1 g of cefazolin (group I) or placebo (group 2) was done immediately before the procedure. Follow-up was performed 10 days, 1, 3, and 6 months after discharge. The primary end point was any evidence of infection at the surgical incision (pulse generator pocket), or systemic infection related to be procedure. The safety committee interrupted the trial after 649 patients were enrolled due to a significant difference in favor of the antibiotic arm (group I: 2 of 314 infected patients—0.63%; group II: 11 of 335 to 3.28%; RR=0.19 ; P =0.016). The following risk factors were positively correlated with infection by univariate analysis: nonuse of preventive antibiotic ( P =0.016); implant procedures (versus generator replacement: P =0.02); presence of postoperative hematoma ( P =0.03) and procedure duration ( P =0.009). Multivariable analysis identified nonuse of antibiotic ( P =0.037) and postoperative hematoma ( P =0.023) as independent predictors of infection. Conclusions— Antibiotic prophylaxis significantly reduces infectious complications in patients undergoing implantation of pacemakers or cardioverter-defibrillators.

OBJECTIVES This study sought to determine whether the extent of late gadolinium enhancement (LGE) can provide additive prognostic information in patients with a nonischemic dilated cardiomyopathy (NIDC) with an indication for implantable cardioverter-defibrillator (ICD) therapy for the primary prevention of sudden cardiac death (SCD). BACKGROUND Data suggest that the presence of LGE is a strong discriminator of events in patients with NIDC. Limited data exist on the role of LGE quantification. METHODS The extent of LGE and clinical follow-up were assessed in 162 patients with NIDC prior to ICD insertion for primary prevention of SCD. LGE extent was quantified using both the standard deviation–based (2-SD) method and the full-width half-maximum (FWHM) method. RESULTS We studied 162 patients with NIDC (65% male; mean age: 55 years; left ventricular ejection fraction [LVEF]: 26 ± 8%) and followed up for major adverse cardiac events (MACE), including cardiovascular death and appropriate ICD therapy, for a mean of 29 ± 18 months. Annual MACE rates were substantially higher in patients with LGE (24%) than in those without LGE (2%). By univariate association, the presence and the extent of LGE demonstrated the strongest associations with MACE (LGE presence, hazard ratio [HR]: 14.5 [95% confidence interval (CI): 6.1 to 32.6; p < 0.001]; LGE extent, HR: 1.15 per 1% increase in volume of LGE [95% CI: 1.12 to 1.18; p < 0.0001]). Multivariate analyses showed that LGE extent was the strongest predictor in the best overall model for MACE, and a 7-fold hazard was observed per 10% LGE extent after adjustments for patient age, sex, and LVEF (adjusted HR: 7.61; p < 0.0001). LGE quantitation by 2-SD and FWHM both demonstrated robust prognostic association, with the highest MACE rate observed in patients with LGE involving >6.1% of LV myocardium. CONCLUSIONS LGE extent may provide further risk stratification in patients with NIDC with a current indication for ICD implantation for the primary prevention of SCD. Strategic guidance on ICD therapy by cardiac magnetic resonance in patients with NIDC warrants further study.

BackgroundAtrioesophageal fistula (AEF) is a rare but serious adverse event of atrial fibrillation (AF) ablation.ObjectiveTo identify the clinical characteristics of AEF following ablation procedures for AF and determine the associated mortality.MethodsA systematic review of observational cases of AEF following ablation procedures for AF was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement protocol.Results53 cases were identified. Mean age was 54±13 years; 73% (39/53) of cases occurred in males. Mean interval between procedure and presentation was 20±12 days, ranging from 2 to 60 days. AEF was observed in 12 patients who underwent surgical radiofrequency ablation (RFA) and in 41 patients with percutaneous RFA. Fever was the most common presenting symptom (n=44) followed by neurological deficits (n=27) and haematemesis (n=19). CT of the chest (n=27) was the preferred diagnostic test. Patients who did not receive a primary esophageal repair were more likely to have a deadly outcome (34% vs 83%; p<0.05). No difference in mortality rate was found between patients who underwent surgical RFA when compared with percutaneous RFA (58% vs 56%; p=0.579). No association was found between onset of symptoms and mortality (19±10 vs 23±14 days; p=0.355).ConclusionsAEF following ablation procedures for AF is a serious complication with high mortality rates. Presenting symptoms most often include a triad of fever, neurological deficit and/or haematemesis within 60 days of procedure. The preferred diagnostic test is CT of the chest. The treatments of choice is surgical repair.

Background-Ventricular arrhythmias are life-threatening complications of heart failure and myocardial ischemia.Increased diastolic Ca 2ϩ overload occurring in ischemia leads to afterdepolarizations and aftercontractions that are responsible for cellular electric instability. We inquired whether sarcoplasmic reticulum Ca 2ϩ ATPase pump (SERCA2a) overexpression could reduce ischemic ventricular arrhythmias by modulating Ca 2ϩ overload. Methods and Results-SERCA2a overexpression in pig hearts was achieved by intracoronary gene delivery of adenovirus in the 3 main coronary arteries. Homogeneous distribution of the gene was obtained through the left ventricle. After gene delivery, the left anterior descending coronary artery was occluded for 30 minutes to induce myocardial ischemia followed by reperfusion. We compared this model with a model of permanent coronary artery occlusion. Twenty-fourhour ECG Holter recordings showed that SERCA2a overexpression significantly reduced the number of episodes of ventricular tachycardia after reperfusion, whereas no significant difference was found in the occurrence of sustained or nonsustained ventricular tachycardia and ventricular fibrillation in pigs undergoing permanent occlusion. Conclusions-We

Transgenic mice have become important experimental models in the investigation of mechanisms causing cardiac arrhythmias because of the ability to create strains with alterations in repolarizing membrane currents. It is important to relate alterations in membrane currents in cells to their phenotypic expression on the electrocardiogram (ECG). The murine ECG, however, has unusual characteristics that make interpretation of the phenotypic expression of changes in ventricular repolarization uncertain. The major deflection representing the QRS (referred to as "a") is often followed by a secondary slower deflection ("b") and sometimes a subtle third deflection ("c"). To determine whether the second or third deflections or both represent ventricular repolarization, we recorded the ventricular monophasic action potential (MAP) in open-chest mice and correlated repolarization with the ECG. There was no significant correlation by linear regression, between action potential duration to 50% or 90% repolarization (APD(50) or APD(90)), respectively, of the MAP and either the interval from onset of Q to onset of b (Qb interval) or onset of c (Qc interval). Administration of 4-aminopyridine (4-AP) significantly prolonged APD(50) and APD(90) and the Qb interval, indicating that this deflection on the ECG represents part of ventricular repolarization. After 4-AP, the c wave disappeared, also suggesting that it represents a component of ventricular repolarization. Although it appears that both the b and c waves that follow the Q wave on the ECG represent ventricular repolarization, neither correlates exactly with APD(90) of the MAP. Therefore, an accurate measurement of complete repolarization of the murine ventricle cannot be obtained from the surface ECG.

Patients with CS and ICDs are at high risk for ventricular arrhythmias. This population also has high rates of inappropriate shocks and device complications.

The clinical presentation of LAE is influenced by the time from the most recent CIED procedure. Although clinical manifestations of pocket infection are present in the majority of patients with early LAE, late LAE should be considered in any CIED patient who presents with fever, bloodstream infection, or signs of sepsis, even if the device pocket appears uninfected. Prompt recognition and management may improve outcomes.