Jasvinder Sidhu

Transgenic mouse model of ventricular preexcitation and atrioventricular reentrant tachycardia induced by an AMP-activated protein kinase loss-of-function mutation responsible for Wolff-Parkinson-White syndrome

Background—We identified a gene (PRKAG2) that encodes the &ggr;-2 regulatory subunit of AMP-activated protein kinase (AMPK) with a mutation (Arg302Gln) responsible for familial Wolff-Parkinson-White (WPW) syndrome. The human phenotype consists of ventricular preexcitation, conduction abnormalities, and cardiac hypertrophy. Methods and Results—To elucidate the molecular basis for the phenotype, transgenic mice were generated by cardiac-restricted expression of the wild-type (TGWT) and mutant(TGR302Q) PRKAG2 gene with the cardiac-specific promoter &agr;-myosin heavy chain. ECG recordings and intracardiac electrophysiology studies demonstrated the TGR302Q mice to have ventricular preexcitation (PR interval 10±2 versus 33±5 ms in TGWT, P<0.05) and a prolonged QRS (20±5 versus 10±1 ms in TGWT, P<0.05). A distinct AV accessory pathway was confirmed by electrical and pharmacological stimulation and substantiated by induction of orthodromic AV reentrant tachycardia. Enzymatic activity of AMPK in the mutant heart was significantly reduced (0.009±0.003 versus 0.025±0.001 nmol · min−1 · g−1 in nontransgenic mice), presumably owing to the mutation disrupting the AMP binding site. Excessive cardiac glycogen was observed. Hypertrophy was confirmed by increases in heart weight (296 versus 140 mg in TGWT) and ventricular wall thickness. Conclusions—We have developed a genetic animal model of WPW that expresses a mutation responsible for a familial form of WPW syndrome with a phenotype identical to that of the human, including induction of supraventricular arrhythmia. The defect is due to loss of function of AMPK. Elucidation of the molecular basis should provide insight into development of the cardiac conduction system and accessory pathways.

Differential interactions of thin filament proteins in two cardiac troponin T mouse models of hypertrophic and dilated cardiomyopathies

AIM Mutations in a sarcomeric protein can cause hypertrophic cardiomyopathy (HCM) or dilated cardiomyopathy (DCM), the opposite ends of a spectrum of phenotypic responses of the heart to mutations. We posit the contracting phenotypes could result from differential effects of the mutant proteins on interactions among the sarcomeric proteins. To test the hypothesis, we generated transgenic mice expressing either cardiac troponin T (cTnT)-Q92 or cTnT-W141, known to cause HCM and DCM, respectively, in the heart. METHODS AND RESULTS We phenotyped the mice by echocardiography, histology and immunoblotting, and real-time polymerase chain reaction. We detected interactions between the sarcomeric proteins by co-immunoprecipitation and determined Ca2+ sensitivity of myofibrillar protein ATPase activity by Carter assay. The cTnT-W141 mice exhibited dilated hearts and decreased systolic function. In contrast, the cTnT-Q92 mice showed smaller ventricles and enhanced systolic function. Levels of cardiac troponin I, cardiac alpha-actin, alpha-tropomyosin, and cardiac troponin C co-immunoprecipitated with anti-cTnT antibodies were higher in the cTnT-W141 than in the cTnT-Q92 mice, as were levels of alpha-tropomyosin co-immunoprecipitated with an anti-cardiac alpha-actin antibody. In contrast, levels of cardiac troponin I co-immunoprecipitated with an anti-cardiac alpha-actin antibody were higher in the cTnT-Q92 mice. Ca2+ sensitivity of myofibrillar ATPase activity was increased in HCM but decreased in DCM mice compared with non-transgenic mice. CONCLUSION Differential interactions among the sarcomeric proteins containing cTnT-Q92 or cTnT-W141 are responsible for the contrasting phenotypes of HCM or DCM, respectively.

Ethanol infusion in the vein of Marshall

BACKGROUND The vein of Marshall (VOM) is a left atrial (LA) vein that contains autonomic innervation and triggers of AF. Its location coincides with areas usually ablated during pulmonary vein (PV) antral isolation (PVAI). OBJECTIVE This study sought to delineate the safety and ablative effects of ethanol infusion in the VOM during catheter ablation of atrial fibrillation (AF). METHODS Patients undergoing PVAI (n = 14) gave consent for adjunctive VOM ethanol infusion. In 10 of 14 patients, the VOM was cannulated with an angioplasty wire and balloon. Echocardiographic contrast was injected in the VOM under echocardiographic monitoring. Two infusions of 100% ethanol (1 ml each) were delivered via the angioplasty balloon in the VOM. LA bipolar voltage maps were created before and after ethanol infusion. Radiofrequency ablation times required to isolate each PV and other procedural data were compared with those of 10 age-, sex-, AF type- and LA size-matched control subjects undergoing conventional PVAI. RESULTS The VOM communicated with underlying myocardium, as shown by echocardiographic contrast passage into the LA. There were no acute complications related to VOM ethanol infusion, which led to the creation of a low-voltage area in the LA measuring 10.6 +/- 7.6 cm(2) and isolation of the left inferior PV in 4 of 10 patients. Radiofrequency ablation time required to achieve isolation of the left inferior PV was reduced (2.2 +/- 4 min vs. 11.4 +/- 10.3 min in control subjects, P <.05). CONCLUSION VOM ethanol infusion is safe in humans, decreases radiofrequency ablation time in the left inferior PV, and may have a role as an adjunct to PVAI.

Retrograde Ethanol Infusion in the Vein of MarshallCLINICAL PERSPECTIVE: Regional Left Atrial Ablation, Vagal Denervation, and Feasibility in Humans

Background— The vein of Marshall (VOM) is an attractive target during ablation of atrial fibrillation because of its autonomic innervation, its location anterior to the left pulmonary veins, and its drainage in the coronary sinus. Methods and Results— We studied 17 dogs. A coronary sinus venogram showed a VOM in 13, which was successfully cannulated with an angioplasty wire and balloon. In 5 dogs, electroanatomical maps of the left atrium were performed at baseline and after ethanol infusion in the VOM, which demonstrated a new crescent-shaped scar, extending from the annular left atrium toward the posterior wall and left pulmonary veins. In 4 other dogs, effective refractory periods (ERP) were measured at 3 sites in the left atrium, before and after high-frequency bilateral vagal stimulation. The ERP decreased from 113.6±35.0 to 82.2±25.4 ms ( P <0.05) after vagal stimulation. After VOM ethanol infusion, vagally-mediated ERP decrease was eliminated (from 108.6±24.1 to 96.4±16.9 ms, P =NS). The abolition of vagal effects was limited to sites near the VOM (ERP, 104±14 versus 98.6±12.2 ms postvagal stimulation; P =NS), as opposed to sites remote to VOM (ERP, 107.2±14.9 versus 78.6±14.7 ms postvagal stimulation; P <0.05). To test feasibility in humans, 6 patients undergoing pulmonary vein antral isolation had successful VOM cannulation and ethanol infusion; left atrial voltage maps demonstrated new scar involving the inferoposterior left atrial wall extending toward the left pulmonary veins. Conclusions— Ethanol infusion in the VOM achieves significant left atrial tissue ablation, abolishes local vagal responses, and is feasible in humans. Received August 29, 2008; accepted November 24, 2008.Background—The vein of Marshall (VOM) is an attractive target during ablation of atrial fibrillation because of its autonomic innervation, its location anterior to the left pulmonary veins, and its drainage in the coronary sinus. Methods and Results—We studied 17 dogs. A coronary sinus venogram showed a VOM in 13, which was successfully cannulated with an angioplasty wire and balloon. In 5 dogs, electroanatomical maps of the left atrium were performed at baseline and after ethanol infusion in the VOM, which demonstrated a new crescent-shaped scar, extending from the annular left atrium toward the posterior wall and left pulmonary veins. In 4 other dogs, effective refractory periods (ERP) were measured at 3 sites in the left atrium, before and after high-frequency bilateral vagal stimulation. The ERP decreased from 113.6±35.0 to 82.2±25.4 ms (P<0.05) after vagal stimulation. After VOM ethanol infusion, vagally-mediated ERP decrease was eliminated (from 108.6±24.1 to 96.4±16.9 ms, P=NS). The abolition of vagal effects was limited to sites near the VOM (ERP, 104±14 versus 98.6±12.2 ms postvagal stimulation; P=NS), as opposed to sites remote to VOM (ERP, 107.2±14.9 versus 78.6±14.7 ms postvagal stimulation; P<0.05). To test feasibility in humans, 6 patients undergoing pulmonary vein antral isolation had successful VOM cannulation and ethanol infusion; left atrial voltage maps demonstrated new scar involving the inferoposterior left atrial wall extending toward the left pulmonary veins. Conclusions—Ethanol infusion in the VOM achieves significant left atrial tissue ablation, abolishes local vagal responses, and is feasible in humans.

Retrograde Ethanol Infusion in the Vein of MarshallCLINICAL PERSPECTIVE

Background— The vein of Marshall (VOM) is an attractive target during ablation of atrial fibrillation because of its autonomic innervation, its location anterior to the left pulmonary veins, and its drainage in the coronary sinus. Methods and Results— We studied 17 dogs. A coronary sinus venogram showed a VOM in 13, which was successfully cannulated with an angioplasty wire and balloon. In 5 dogs, electroanatomical maps of the left atrium were performed at baseline and after ethanol infusion in the VOM, which demonstrated a new crescent-shaped scar, extending from the annular left atrium toward the posterior wall and left pulmonary veins. In 4 other dogs, effective refractory periods (ERP) were measured at 3 sites in the left atrium, before and after high-frequency bilateral vagal stimulation. The ERP decreased from 113.6±35.0 to 82.2±25.4 ms ( P <0.05) after vagal stimulation. After VOM ethanol infusion, vagally-mediated ERP decrease was eliminated (from 108.6±24.1 to 96.4±16.9 ms, P =NS). The abolition of vagal effects was limited to sites near the VOM (ERP, 104±14 versus 98.6±12.2 ms postvagal stimulation; P =NS), as opposed to sites remote to VOM (ERP, 107.2±14.9 versus 78.6±14.7 ms postvagal stimulation; P <0.05). To test feasibility in humans, 6 patients undergoing pulmonary vein antral isolation had successful VOM cannulation and ethanol infusion; left atrial voltage maps demonstrated new scar involving the inferoposterior left atrial wall extending toward the left pulmonary veins. Conclusions— Ethanol infusion in the VOM achieves significant left atrial tissue ablation, abolishes local vagal responses, and is feasible in humans. Received August 29, 2008; accepted November 24, 2008.Background—The vein of Marshall (VOM) is an attractive target during ablation of atrial fibrillation because of its autonomic innervation, its location anterior to the left pulmonary veins, and its drainage in the coronary sinus. Methods and Results—We studied 17 dogs. A coronary sinus venogram showed a VOM in 13, which was successfully cannulated with an angioplasty wire and balloon. In 5 dogs, electroanatomical maps of the left atrium were performed at baseline and after ethanol infusion in the VOM, which demonstrated a new crescent-shaped scar, extending from the annular left atrium toward the posterior wall and left pulmonary veins. In 4 other dogs, effective refractory periods (ERP) were measured at 3 sites in the left atrium, before and after high-frequency bilateral vagal stimulation. The ERP decreased from 113.6±35.0 to 82.2±25.4 ms (P<0.05) after vagal stimulation. After VOM ethanol infusion, vagally-mediated ERP decrease was eliminated (from 108.6±24.1 to 96.4±16.9 ms, P=NS). The abolition of vagal effects was limited to sites near the VOM (ERP, 104±14 versus 98.6±12.2 ms postvagal stimulation; P=NS), as opposed to sites remote to VOM (ERP, 107.2±14.9 versus 78.6±14.7 ms postvagal stimulation; P<0.05). To test feasibility in humans, 6 patients undergoing pulmonary vein antral isolation had successful VOM cannulation and ethanol infusion; left atrial voltage maps demonstrated new scar involving the inferoposterior left atrial wall extending toward the left pulmonary veins. Conclusions—Ethanol infusion in the VOM achieves significant left atrial tissue ablation, abolishes local vagal responses, and is feasible in humans.