Clinic And Genetic Basis Of Cardiac Arrhythmias And Treatment-Related Complications

Introduction:The major structure elements of the AMP-activated protein kinase (AMPK), are α, β, and y sunbunits. Mutations in PRKAG2have been associated with a cardiac syndrome including inherited ventricular preexcitation, conduction disorder and hypertrophy mimicking hypertrophic cardiomyopathy. The aim of the present study was to identify PRKAG2syndrome among patients presenting with left ventricular hypertrophy (LVH).Methods and Results:Nineteen unrelated subjects with unexplained LVH were clinically and genetically evaluated. Among4patients with bradycardia, manifestations of preexcitation were only found in a19year old male who also developed congestive heart failure3years later. Electrophysiological study of this case, identified the coexistence of an AV accessory pathway and AV conduction defect. Histological analysis of his ventricular tissue isolated by biopsy confirmed excessive glycogen accumulation, prominent myofibrillar disarray and interstitial fibrosis. Direct sequencing of his DNA revealed a heterozygous mutation in PRKAG2consisting of an A-to-G transition at nucleotide1453(c.1453A>G), predicting a substitution of a glutamic acid for lysine at residue485(p.Lys485Glu, K485E). Lys485is highly conserved among species and the mutation was absent in his unaffected family members and in215healthy controls. To assess the role of K485in the structure and function of the protein, computational modeling calculations and conservation analyses were performed. Electrostatic calculations indicate that K485forms a salt bridge with the conserved D248residue in the AMPK β subunit, which is critical for proper regulation of the enzyme, and the K485E mutant disrupts the connection.Conclusions:Our study identifies a novel de novo PRKAG2mutation in a young, in which progression of the disease warrants close medical attention. It also underlines the importance of molecular screening of PRKAG2gene in patients with unexplained LVH, ventricular preexcitation, conduction defect, and/or early onset of heart failure. Background:Congenital long QT syndrome (LQTS) is a hereditary arrhythmogenic disease characterized by a prolongation of the QT interval at basal ECG and by a high risk of life-threatening arrhythmias. Loss of function mutations in KCNH2gene which encodes the a subunit of the rapidly activating delayed rectifier potassium current (IKr) is responsible for LQT2. Current pharmacological treatments for LQT2primarily include the use of P-adrenoreceptor antagonists. However, the therapeutic effects of verapamil on LQT2remain unclear.Objective:To investigate the clinical effectiveness of verapamil on LQT2patients and its electrophysiologic mechanism by which verapamil suppresses torsades de pointes (TdP) in a developed left ventricular wedge model of LQT2.Methods: The clinical course was evaluated in a suspected LQT2proband before and after administration of verapamil by intravenous and oral routes. Genetic screening for KCNH2gene was examined in the proband and her family members. Transmembrane action potentials of epicardial (Epi) and endocardial (Endo) cells were recorded simultaneously at a basic cycle length of2000ms from an arterially perfused wedge of rabbit left ventricle together with a transmural ECG. E-4031(0.5μmol/L) was used to block IKr (LQT2model). We examined the effect of verapamil on action potential duration (APD), transmural dispersion of repolarization (TDR) and the development of TdP in LQT2model of LQTS.Results:In the LQTS patient with TdP, we identified the D609N mutation in the transmembrane pore region of KCNH2. The proband’s son carried the same mutation and showed prolonged corrected QT interval. The symptomatic ventricular arrhythmias of the proband were effectively suppressed by oral verapamil therapy. In LQT2models, E-4031preferentially prolonged APD in Endo rather than Epi, thereby dramatically increasing the QT interval and TDR. Spontaneous or Programmed electrical stimulation-induced early afterdepolarization (EAD) was observed in Endo, and subsequent TdP occurred. Verapamil (0.5to2.5μmol/L) dose-dependently abbreviated APD in Endo more than in Epi, thereby significantly decreasing the QT interval, TDR, and suppressing EAD and TdP.Conclusions:Our data suggest that verapamil prevents TdP in LQT2Model of the LQTS by reducing TDR. These results indicate a possible therapeutic role of verapamil in the treatment of LQT2patients. Background:Postcardiac injury syndrome (PCIS) is a complication of a variety of cardiac injuries, of which small heart perforation is the etiology that is often unrecognized. We reported a series of patients with PCIS secondary to cardiac perforation during catheter ablation procedures.Methods and Results:Out of1728radiofrequency catheter ablation procedures,21patients (1.2%) were complicated by echo-defined cardiac perforation not requiring surgical intervention. Among them,6patients (6/21,28.6%) were diagnosed with PCIS secondary to cardiac perforation because they also developed pleural effusions (6/6,100%) and fever (4/6,66.7%) in addition to pericardial effusion/tamponade. Four patients with PCIS (4/6,66.7%) and four patients without PCIS (4/15,26.7%) underwent pericardial drainage but the drainage volume during the first24hours was not significantly different (441.±343.9ml vs.182.5±151.3ml, P=0.248). In the6PCIS patients, pleural effusion was detected from3hours to4days (median:2days) after ablation procedure, predominantly bilateral (66.7%) or left-sided if unilateral. Patients with PCIS were older (64.8±7.3yrs vs.45.9±14.8yrs, P=0.0078), were more likely accompanied by hypertension (66.7%vs.6.7%, P=0.0114) and had a prolonged hospital stay (34.2±15.8days).Conclusions:More than25%of patients with small cardiac perforation during catheter ablation may develop PCIS which can be masked by pericardial effusion/tamponade. This kind of PCIS is more likely associated with elder or hypertensive patients and is usually characterized by early onset of pleural effusion.