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 γ sunbunits. Mutations in PRKAG2have been associated witha cardiac syndrome including inherited ventricular preexcitation, conduction disorderand hypertrophy mimicking hypertrophic cardiomyopathy. The aim of the presentstudy was to identify PRKAG2syndrome among patients presenting with leftventricular hypertrophy (LVH).Methods and Results: Nineteen unrelated subjects with unexplained LVH wereclinically and genetically evaluated. Among4patients with bradycardia,manifestations of preexcitation were only found in a19year old male who alsodeveloped congestive heart failure3years later. Electrophysiological study of thiscase, identified the coexistence of an AV accessory pathway and AV conduction defect.Histological analysis of his ventricular tissue isolated by biopsy confirmed excessiveglycogen 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 asubstitution of a glutamic acid for lysine at residue485(p.Lys485Glu, K485E).Lys485is highly conserved among species and the mutation was absent in hisunaffected family members and in215healthy controls. To assess the role of K485inthe structure and function of the protein, computational modeling calculations andconservation analyses were performed. Electrostatic calculations indicate that K485forms a salt bridge with the conserved D248residue in the AMPK β subunit, which iscritical for proper regulation of the enzyme, and the K485E mutant disrupts theconnection.Conclusions: Our study identifies a novel de novo PRKAG2mutation in a young, inwhich progression of the disease warrants close medical attention. It also underlines the importance of molecular screening of PRKAG2gene in patients with unexplainedLVH, ventricular preexcitation, conduction defect, and/or early onset of heart failure. Background: Congenital long QT syndrome (LQTS) is a hereditary arrhythmogenicdisease characterized by a prolongation of the QT interval at basal ECG and by a highrisk of life threatening arrhythmias. Loss of function mutations in KCNH2gene whichencodes the α subunit of the rapidly activating delayed rectifier potassium current (IKr)is responsible for LQT2. Current pharmacological treatments for LQT2primarilyinclude the use of β adrenoreceptor antagonists. However, the therapeutic effects ofverapamil on LQT2remain unclear.Objective: To investigate the clinical effectiveness of verapamil on LQT2patientsand its electrophysiologic mechanism by which verapamil suppresses torsades depointes (TdP) in a developed left ventricular wedge model of LQT2.Methods: The clinical course was evaluated in a suspected LQT2proband before andafter administration of verapamil by intravenous and oral routes. Genetic screeningfor KCNH2gene was examined in the proband and her family members.Transmembrane action potentials of epicardial (Epi) and endocardial (Endo) cellswere recorded simultaneously at a basic cycle length of2000ms from an arteriallyperfused wedge of rabbit left ventricle together with a transmural ECG. E4031(0.5mol/L) was used to block IKr(LQT2model). We examined the effect of verapamilon 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 thetransmembrane pore region of KCNH2. The proband’s son carried the same mutationand showed prolonged corrected QT interval. The symptomatic ventriculararrhythmias of the proband were effectively suppressed by oral verapamil therapy. InLQT2models, E4031preferentially prolonged APD in Endo rather than Epi, therebydramatically increasing the QT interval and TDR. Spontaneous or Programmed electrical stimulation induced early afterdepolarization (EAD) was observed in Endo,and subsequent TdP occurred. Verapamil (0.5to2.5mol/L) dose dependentlyabbreviated APD in Endo more than in Epi, thereby significantly decreasing the QTinterval, TDR, and suppressing EAD and TdP.Conclusions: Our data suggest that verapamil prevents TdP in LQT2Model of theLQTS by reducing TDR. These results indicate a possible therapeutic role ofverapamil in the treatment of LQT2patients. Background: Postcardiac injury syndrome (PCIS) is a complication of a variety ofcardiac injuries, of which small heart perforation is the etiology that is oftenunrecognized. We reported a series of patients with PCIS secondary to cardiacperforation during catheter ablation procedures.Methods and Results: Out of1728radiofrequency catheter ablation procedures,21patients (1.2%) were complicated by echo defined cardiac perforation not requiringsurgical intervention. Among them,6patients (6/21,28.6%) were diagnosed withPCIS 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 wasnot significantly different (441.3±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), weremore likely accompanied by hypertension (66.7%vs.6.7%, P=0.0114) and had aprolonged hospital stay (34.2±15.8days).Conclusions: More than25%of patients with small cardiac perforation duringcatheter ablation may develop PCIS which can be masked by pericardialeffusion/tamponade. This kind of PCIS is more likely associated with elder orhypertensive patients and is usually characterized by early onset of pleural effusion.