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Background: Genetic variants in calsequestrin-2 ( CASQ2 ) cause an autosomal recessive form of catecholaminergic polymorphic ventricular tachycardia (CPVT), although isolated reports have identified arrhythmic phenotypes among heterozygotes. Improved insight into the inheritance patterns, arrhythmic risks, and molecular mechanisms of CASQ2 -CPVT was sought through an international multicenter collaboration., Methods: Genotype-phenotype segregation in CASQ2 -CPVT families was assessed, and the impact of genotype on arrhythmic risk was evaluated using Cox regression models. Putative dominant CASQ2 missense variants and the established recessive CASQ2-p.R33Q variant were evaluated using oligomerization assays and their locations mapped to a recent CASQ2 filament structure., Results: A total of 112 individuals, including 36 CPVT probands (24 homozygotes/compound heterozygotes and 12 heterozygotes) and 76 family members possessing at least 1 presumed pathogenic CASQ2 variant, were identified. Among CASQ2 homozygotes and compound heterozygotes, clinical penetrance was 97.1% and 26 of 34 (76.5%) individuals had experienced a potentially fatal arrhythmic event with a median age of onset of 7 years (95% CI, 6-11). Fifty-one of 66 CASQ2 heterozygous family members had undergone clinical evaluation, and 17 of 51 (33.3%) met diagnostic criteria for CPVT. Relative to CASQ2 heterozygotes, CASQ2 homozygote/compound heterozygote genotype status in probands was associated with a 3.2-fold (95% CI, 1.3-8.0; P =0.013) increased hazard of a composite of cardiac syncope, aborted cardiac arrest, and sudden cardiac death, but a 38.8-fold (95% CI, 5.6-269.1; P <0.001) increased hazard in genotype-positive family members. In vitro turbidity assays revealed that p.R33Q and all 6 candidate dominant CASQ2 missense variants evaluated exhibited filamentation defects, but only p.R33Q convincingly failed to dimerize. Structural analysis revealed that 3 of these 6 putative dominant negative missense variants localized to an electronegative pocket considered critical for back-to-back binding of dimers., Conclusions: This international multicenter study of CASQ2 -CPVT redefines its heritability and confirms that pathogenic heterozygous CASQ2 variants may manifest with a CPVT phenotype, indicating a need to clinically screen these individuals. A dominant mode of inheritance appears intrinsic to certain missense variants because of their location and function within the CASQ2 filament structure.

Background: High-level exercise has been associated with a malignant phenotype in desmosomal and genotype-negative forms of arrhythmogenic right ventricular cardiomyopathy (ARVC). This is the first study to examine this issue with ARVC secondary to the TMEM43 p.S358L mutation., Objective: The purpose of this study was to evaluate the impact of exercise on arrhythmic risk and cardiac death in TMEM43 p.S358L ARVC., Methods: Individuals with the TMEM43 p.S358L mutation enrolled in a prospective registry who had received a primary prevention implantable cardioverter-defibrillator (ICD) were invited to complete the modified Paffenbarger Physical Activity Questionnaire to assess their physical activity in the year before their ICD implantation. Time-to-event analyses using unadjusted and adjusted Cox proportional hazards models evaluated associations between physical activity and first appropriate ICD discharge secondary to malignant ventricular arrhythmia or cardiac death., Results: In 80 subjects with the TMEM43 p.S358L mutation, exercise ≥9.0 metabolic equivalent of task (MET)-hours/day (high level) in the year before ICD implantation was associated with an adjusted 9.1-fold increased hazard of first appropriate ICD discharge (there were no deaths) relative to physical activity <9.0 MET-hours/day (moderate level) (95% confidence interval [CI] 3.3-24.6 MET-hours/day; P < .001). The median age from birth to first appropriate ICD discharge was 58.5 years (95% CI 56.5-60.5 years) vs 35.8 years (95% CI 28.2-43.4 years) (P < .001) in subjects in moderate- and high-level exercise groups, respectively., Conclusion: Exercise ≥9.0 MET-hours/day is associated with an increased risk of malignant ventricular arrhythmias in the TMEM43 p.S358L subtype of ARVC. Extrapolating these data, we suggest molecular testing be offered in early childhood to inform exercise choices reflective of the genotype., (Copyright © 2020 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

We report a case of a 61 year old female with disappearance of anteroseptal Q waves following an anterior STEMI. At presentation a 12 lead ECG revealed frank anteroseptal Q waves and T wave inversion (V1-V3). The patient underwent percutaneous coronary intervention (PCI) with drug eluting stenting to a critically stenosed left anterior descending artery. At a five month follow-up visit a 12 lead ECG demonstrated the complete resolution of anteroseptal Q waves and normal R wave progression was seen in the precordial leads. Here we discuss this observation with a review of the literature regarding Q wave resolution., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: Arrhythmogenic right ventricular cardiomyopathy caused by a TMEM43 p.S358L mutation is a fully penetrant autosomal dominant cause of sudden cardiac death where prophylactic implantable cardioverter defibrillator therapy significantly reduces mortality by returning lethal cardiac rhythms to normal. This qualitative study assessed the psychological ramifications of the implantable cardioverter defibrillator on recipients, their spouses and their mutation negative siblings., Design: Qualitative interview study., Participants: Twenty-one individuals (nine mutation positive, eight mutation negative and four spouses) from 15 families completed semi-structured interviews., Results: No theoretical assumptions about the data were made: inductive sub-coding was accomplished with the constant comparison method and cohesive themes across all respondent interviews were determined. All interviewees had a family history of sudden cardiac death and appropriate implantable cardioverter defibrillator therapy in themselves or family members. Average length of time with an implantable cardioverter defibrillator was 10 years. Major themes included: (1) acceptance and gratitude, (2) grudging acceptance, (3) psychological effects (on emotional and psychological well-being; functioning of the broader family unit; and relationships), and (4) practical concerns (on clothes, travel, loss of driving licence and the effects of an implantable cardioverter defibrillator discharge). These affected all family members, regardless of mutation status., Conclusions: Despite the survival advantage of implantable cardioverter defibrillator therapy, the intervention carries psychological and practical burdens for family members from kindreds manifesting p.S358L TMEM43 ARVC that does not appear to dissipate with time. A move towards integrating psychology services with the cardiac genetics clinic for the extended family may provide benefit., (© The European Society of Cardiology 2017.)

Objectives: This study sought to investigate for an underlying genetic etiology in cases of apparent idiopathic bundle branch re-entrant ventricular tachycardia (BBRVT)., Background: BBRVT is a life-threatening arrhythmia occurring secondary to macro-re-entry within the His-Purkinje system. Although classically associated with dilated cardiomyopathy, BBRVT may also occur in the setting of isolated, unexplained conduction system disease., Methods: Cases of BBRVT with normal biventricular size and function were recruited from 6 North American centers. Enrollment required a clinically documented wide complex tachycardia and BBRVT proven during invasive electrophysiology study. Study participants were screened for mutations within genes associated with cardiac conduction system disease. Pathogenicity of identified mutations was evaluated using in silico phylogenetic and physicochemical analyses and in vitro biophysical studies., Results: Among 6 cases of idiopathic BBRVT, each presented with hemodynamic compromise and 2 suffered cardiac arrests requiring resuscitation. Putative culprit mutations were identified in 3 of 6 cases, including 2 in SCN5A (Ala1905Gly [novel] and c.4719C>T [splice site mutation]) and 1 in LMNA (Leu327Val [novel]). Biophysical analysis of mutant Ala1905Gly Na v 1.5 channels in tsA201 cells revealed significantly reduced peak current density and positive shifts in the voltage-dependence of activation, consistent with a loss-of-function. The SCN5A c.4719C>T splice site mutation has previously been reported as disease-causing in 3 cases of Brugada syndrome, whereas the novel LMNA Leu327Val mutation was associated with a classic laminopathy phenotype. Following catheter ablation, BBRVT was noninducible in all cases and none experienced a clinical recurrence during follow-up., Conclusions: Our investigation into apparent idiopathic BBRVT has identified the first genetic culprits for this life-threatening arrhythmia, providing further insight into its underlying pathophysiology and emphasizing a potential role for genetic testing in this condition. Our findings also highlight BBRVT as a novel genetic etiology of unexplained sudden cardiac death that can be cured with catheter ablation., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: We previously showed a survival benefit of the implantable cardioverter defibrillator (ICD) in males with arrhythmogenic right ventricular cardiomyopathy caused by a p.S358L mutation in TMEM43. We present long-term data (median follow-up 8.5 years) after ICD for primary (PP) and secondary prophylaxis in males and females, determine whether ICD discharges for ventricular tachycardia/ventricular fibrillation were equivalent to an aborted death, and assess relevant clinical predictors., Methods and Results: We studied 24 multiplex families segregating an autosomal dominant p.S358L mutation in TMEM43. We compared survival in 148 mutation carriers with an ICD to 148 controls matched for age, sex, disease status, and family. Of 80 male mutation carriers with ICDs (median age at implantation 31 years), 61 (76%) were for PP; of 68 females (median age at implantation 43 years), 66 (97%) were for PP. In males, irrespective of indication, survival was better in the ICD groups compared with control groups (relative risk 9.3 [95% confidence interval 3.3-26] for PP and 9.7 [95% confidence interval 3.2-29.6] for secondary prophylaxis). For PP females, the relative risk was 3.6 (95% confidence interval 1.3-9.5). ICD discharge-free survival for ventricular tachycardia/ventricular fibrillation ≥ 240 beats per minute was equivalent to the control survival rate. Ectopy (≥ 1000 premature ventricular complexes/24 hours) was the only independent clinical predictor of ICD discharge in males, and no predictor was identified in females., Conclusions: ICD therapy is indicated for PP in postpubertal males and in females ≥ 30 years with the p.S358L TMEM43 mutation. ICD termination of rapid ventricular tachycardia/ventricular fibrillation can reasonably be considered an aborted death., (© 2016 American Heart Association, Inc.)

In many patients with atrial fibrillation, the most appropriate strategy is 'rate control', designed to slow down the rapid ventricular rates often seen with atrial fibrillation. Based on the hypothesis that symptoms, especially palpitations and exercise intolerance, are due to rapid ventricular rates with activity, optimum rate control usually requires reducing ventricular rates at rest and during activity. Beta-blockers and nondihydropyridine calcium channel blockers are likely more effective than digoxin alone, and the adequacy of rate control is best assessed with heart rate measurement during activity or with ambulatory electrocardiographic monitoring. Taking a patient's symptoms into account, reasonable target ventricular rates are less than 80 beats/min at rest and less than 100 beats/min, on average, over 24 h.

Objectives: We sought to determine the impact of implantable cardioverter-defibrillator (ICD) therapy in patients with familial arrhythmogenic right ventricular cardiomyopathy (ARVC)., Background: Arrhythmogenic right ventricular cardiomyopathy is a cause of sudden cardiac death, which may be prevented by ICD., Methods: We studied 11 families in which a 3p25 deoxyribonucleic acid (DNA) haplotype at locus ARVD5 segregated with disease and compared mortality in subjects who received an ICD with that in control subjects who were matched for age, gender, ARVC status, and family. Subjects (n = 367) at 50% a priori risk of inheriting ARVC were classified as high risk (HR) (n = 197), low risk (n = 92), or unknown (n = 78) on the basis of clinical events, DNA haplotyping, and/or pedigree position. Forty-eight HR subjects (30 males, [median age 32 years] and 18 females [median age 41 years]) were followed after ICD (secondary to ventricular tachycardia [VT] in 27%). Survival was compared with 58 HR control subjects who were alive at the same age to-the-day at which the ICD subject received the device., Results: In the HR group, 50% of males were dead by 39 years and females by 71 years: relative risk of death was 5.1 (95% confidence interval 3 to 8.5) for males. The five-year mortality rate after ICD in males was zero compared with 28% in control subjects (p = 0.009). Within five years, the ICD fired for VT in 70% and for VT >240 beats/min in 30%, with no difference in discharge rate when analyzed by ICD indication., Conclusions: The unknown mutation at the ARVD5 locus causing ARVC results in high mortality. Risk stratification using genetic haplotyping and ICD therapy produced improved survival for males.

Biatrial pacing is a promising new therapy for drug refractory AF. This article reports two studies. First, an initial 14-patient experience with a novel technique for biatrial pacing. The authors attempted to pace from the LA vein branches of the proximal CS for LA stimulation. LA vein pacing would potentially offer the advantages of greater interatrial synchronization and possibly greater reduction in AF burden and also of lesser far-field R wave sensing and greater lead stability. Second, a postmortem series examining the number, size, and site of LA veins draining into the proximal CS is described. LA vein pacing was successful in 9 of 14 patients. LA vein electrode parameters have been stable during a median follow-up of 580 days. There were three early lead dislodgments but no other complications. In the second study, a postmortem analysis of 43 human hearts was performed. The study found that 38 (88.4%) of 43 hearts had at least one LA vein draining into the proximal 5 cm of the CS. In addition, 81.2% (33/43) had at least one vein greater than 4 Fr caliber. Thus, pacing in a greater proportion of patients might be achieved by the development and use of smaller (3, 4, and 5 Fr) electrodes. Furthermore, these smaller leads would obviously allow deeper advancement into the LA veins with the potential advantages of greater interatrial synchronization and lead stability and lesser far-field R wave sensing.

Atrial tachycardia (AT) originating in the triangle of Koch is reported rarely and presents a potential risk of atrioventricular (AV) block during radiofrequency (RF) catheter ablation. Eight patients with AT in the triangle of Koch undergoing RF ablation are presented. There were five women and three men, ranging in age from 32 to 74 years. One patient had bicuspid aortic valve disease, and the other seven patients had no structural heart disease. At electrophysiological study, AT was inducible in all eight patients. In one patient, AV nodal re-entrant tachycardia was also inducible. The site of AT was located by recording the earliest atrial activation during AT and successful RF ablation. Fluoroscopy confirmed the corresponding site to the region of the triangle of Koch. The earliest atrial activation was 35+/-9 ms before the surface P wave, and was recorded at the apex of the triangle of Koch near the bundle of His in six patients and midway between the bundle of His and coronary sinus os in two patients. At the successful RF application site, His potential was not recorded in any patient. The mean AV ratio was 5:1 (range 1:1 to 12:1). RF ablation at the successful site resulted in accelerated junctional rhythm in four of the eight patients and successfully terminated AT in all eight patients, with first-degree AV block in one patient. In conclusion, AT from the triangle of Koch is a distinct entity and RF ablation can be successfully performed; however, a potential risk of AV block remains.

1. Compound II is a novel analogue of sotalol which has been reported to be free of beta-adrenoceptor and L-type calcium channel blocking actions. The effects of compound II on the contraction of guinea-pig papillary muscles (at 2 microM) and single ventricular myocytes (at 100 nM) were investigated. 2. Exposure to compound II caused a significant increase in the contraction of both preparations. 3. Compound II prolonged the action potential of the single myocytes and increased the magnitude of the Ca-activated current which was used as a qualitative indicator of the intracellular calcium transient. 4. The ratio of first/steady state Ca-activated currents evoked by short action potentials was not modified. This may indicate that compound II does not influence the normal functioning of the sarcoplasmic reticulum stores. 5. The observations are consistent with the hypothesis that action potential prolongation by compound II reduces Ca2+ extrusion via the Na-Ca exchange. This in turn allows increased uptake of calcium into the sarcoplasmic reticulum stores so that more calcium is available for release by subsequent action potentials, leading to an increase in intracellular calcium transients and contractions.

1. The actions and mechanisms of action of novel analogues of sotalol which prolong cardiac action potentials were investigated in guinea-pig and rabbit isolated ventricular cells. 2. In guinea-pig and rabbit cells the compounds significantly prolonged action potential duration at 20% and 90% repolarization levels without affecting resting membrane potential. In guinea-pig but not rabbit cells there was an increase in action potential amplitude and in rabbit cells there was no change in the shape or position of the 'notch' in the action potential. 3. Possible mechanisms of action were studied in more detail in the case of compound II (1-(4-methanesulphonamidophenoxy)-3-(N-methyl 3,4 dichlorophenylethylamino)-2-propanol). Prolongation of action potential duration continued to occur in the presence of nisoldipine, and calcium currents recorded under voltage-clamp conditions were not reduced by compound II (1 microM). Action potential prolongation by compound II was also unaffected in the presence of 10 microM tetrodotoxin. 4. Compound II (1 microM) did not influence IK1 assessed from the current during ramp changes in membrane potential (20 mV s-1) over the range -90 to -10 mV. 5. Compound II (1 microM) blocked time-dependent delayed rectifier potassium current (IK) activated by step depolarizations and recorded as an outward tail following repolarization. When a submaximal concentration (50 nM) was applied there was no change in the apparent reversal potential of IK.6. Submaximal concentrations of compound II were without effect on activation of IK with time at a membrane potential of + 40 mV, and no changes were detected in the time constants of the two components of IK decay over the range of potentials - 60 to 0 mV. Compound 11 (50 nM) appeared to cause a small shift in the activation of IK with membrane potential (an apparent shift of approximately 10mV in the depolarizing direction at the mid-point of the curve).7. Log dose-response curves for action potential prolongation and for blockade of IK by compound II were similar. The IC50 for compound II was approximately 30 nM.8. It is concluded that this novel series of compounds prolongs action potential duration, and that in the case of compound II the evidence supports a potent selective effect on the time-dependent potassium current IK, an effect which can account for this prolongation.

The synthesis of 22 (4-methanesulfonamidophenoxy)propanolamines and their testing on isolated guinea pig cardiac myocytes, on isolated preparations from guinea pig atria, and on rat blood pressure are described. Secondary amines in the series (11a-f) showed residual beta-blocking activity, whereas incorporation of N-methyl phenylalkyl and 4-phenyl alicyclic amine groups abolished beta-blocking activity but led to enhanced ability to block the channel conducting the delayed rectified potassium current, and hence produced an increase in the cardiac action potential duration (APD). Incorporation of hydrophobic Cl and CF3 groups further enhanced potassium channel blocking activity. Compounds 81 and 8m produced a significant increase in APD at nanomolar concentrations, with no effect on cardiac muscle conduction velocity, and hence merit further investigation as Class III antiarrhythmic agents. Methylation of the methanesulfonamido group abolished channel-blocking activity; 4-carboxy and 3-methanesulfonamido analogues retained activity but at a reduced level.