Genetic causes of many familial arrhythmia syndromes remain elusive. In this study, whole‐exome sequencing (WES) was carried out on patients from three different families that presented with ...life‐threatening arrhythmias and high risk of sudden cardiac death (SCD). Two French Canadian probands carried identical homozygous rare variant in TECRL gene (p.Arg196Gln), which encodes the trans‐2,3‐enoyl‐CoA reductase‐like protein. Both patients had cardiac arrest, stress‐induced atrial and ventricular tachycardia, and QT prolongation on adrenergic stimulation. A third patient from a consanguineous Sudanese family diagnosed with catecholaminergic polymorphic ventricular tachycardia (CPVT) had a homozygous splice site mutation (c.331+1G>A) in TECRL. Analysis of intracellular calcium (Ca2+i) dynamics in human induced pluripotent stem cell‐derived cardiomyocytes (hiPSC‐CMs) generated from this individual (TECRLHom‐hiPSCs), his heterozygous but clinically asymptomatic father (TECRLHet‐hiPSCs), and a healthy individual (CTRL‐hiPSCs) from the same Sudanese family, revealed smaller Ca2+i transient amplitudes as well as elevated diastolic Ca2+i in TECRLHom‐hiPSC‐CMs compared with CTRL‐hiPSC‐CMs. The Ca2+i transient also rose markedly slower and contained lower sarcoplasmic reticulum (SR) calcium stores, evidenced by the decreased magnitude of caffeine‐induced Ca2+i transients. In addition, the decay phase of the Ca2+i transient was slower in TECRLHom‐hiPSC‐CMs due to decreased SERCA and NCX activities. Furthermore, TECRLHom‐hiPSC‐CMs showed prolonged action potentials (APs) compared with CTRL‐hiPSC‐CMs. TECRL knockdown in control human embryonic stem cell‐derived CMs (hESC‐CMs) also resulted in significantly longer APs. Moreover, stimulation by noradrenaline (NA) significantly increased the propensity for triggered activity based on delayed afterdepolarizations (DADs) in TECRLHom‐hiPSC‐CMs and treatment with flecainide, a class Ic antiarrhythmic drug, significantly reduced the triggered activity in these cells. In summary, we report that mutations in TECRL are associated with inherited arrhythmias characterized by clinical features of both LQTS and CPVT. Patient‐specific hiPSC‐CMs recapitulated salient features of the clinical phenotype and provide a platform for drug screening evidenced by initial identification of flecainide as a potential therapeutic. These findings have implications for diagnosis and treatment of inherited cardiac arrhythmias.
Synopsis
Mutations in the novel TECRL gene were identified in patients with malignant exercise‐induced arrhythmias. Increased triggered electrical activity upon stimulation in patient‐specific hiPSC‐CMs was rescued by the antiarrhythmic drug flecainide.
Trans‐2,3‐enoyl‐CoA reductase‐like (TECRL) is preferentially expressed in the heart.
Mutations in TECRL cause lethal arrhythmias in humans.
Cardiac defects in TECRL patients are characterized by overlapping features of long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT).
Cardiomyocytes differentiated from patient‐specific human induced pluripotent stem cells (hiPSCs) recapitulate the electrical abnormalities observed in TECRL patients.
Mutations in the novel TECRL gene were identified in patients with malignant exercise‐induced arrhythmias. Increased triggered electrical activity upon stimulation in patient‐specific hiPSC‐CMs was rescued by the antiarrhythmic drug flecainide.
Calmodulin (CaM) mutations are associated with cardiac arrhythmia susceptibility including congenital long QT syndrome (LQTS).
The purpose of this study was to determine the clinical, genetic, and ...functional features of 2 novel CaM mutations in children with life-threatening ventricular arrhythmias.
The clinical and genetic features of 2 congenital arrhythmia cases associated with 2 novel CaM gene mutations were ascertained. Biochemical and functional investigations were conducted on the 2 mutations.
A novel de novo CALM2 mutation (D132H) was discovered by candidate gene screening in a male infant with prenatal bradycardia born to healthy parents. Postnatal course was complicated by profound bradycardia, prolonged corrected QT interval (651 ms), 2:1 atrioventricular block, and cardiogenic shock. He was resuscitated and was treated with a cardiac device. A second novel de novo mutation in CALM1 (D132V) was discovered by clinical exome sequencing in a 3-year-old boy who suffered a witnessed cardiac arrest secondary to ventricular fibrillation. Electrocardiographic recording after successful resuscitation revealed a prolonged corrected QT interval of 574 ms. The Ca(2+) affinity of CaM-D132H and CaM-D132V revealed extremely weak binding to the C-terminal domain, with significant structural perturbations noted for D132H. Voltage-clamp recordings of human induced pluripotent stem cell-derived cardiomyocytes transiently expressing wild-type or mutant CaM demonstrated that both mutations caused impaired Ca(2+)-dependent inactivation of voltage-gated Ca(2+) current. Neither mutant affected voltage-dependent inactivation.
Our findings implicate impaired Ca(2+)-dependent inactivation in human cardiomyocytes as the plausible mechanism for long QT syndrome associated with 2 novel CaM mutations. The data further expand the spectrum of genotype and phenotype associated with calmodulinopathy.
Abstract Background Suppression of frequent premature ventricular contractions (PVCs) does not systematically lead to an expected reversal of PVC-induced cardiomyopathy and determinants of left ...ventricular ejection fraction (LVEF) recovery (reverse remodeling) after ablation remain largely unknown. Methods Ninety-six consecutive patients with a suspicion of PVC induced-cardiomyopathy were retrospectively included. Parameters potentially related to reverse remodeling (> 10% increase in LVEF) were analyzed in patients w/wo long-term success (decrease in PVC burden > 80%). Results Over a mean follow-up of 24 ± 21 months, long-term ablation success was obtained in 76 patients (79%). In these, reverse remodeling was observed in 63 (83%) (LVEF 39 ± 8 to 56 ± 8%, p < 0.0001). In multivariate analysis, only an older age (and marginally a lower PVC QRS amplitude) was independently associated with the lack of reverse remodeling. Only 10 of the 35 patients who initially should have received an ICD for primary prevention remained candidates for implantation after ablation. Lack of reverse remodeling was significantly linked to a higher mortality. Conclusion Reverse remodeling was observed in 83% of patients with frequent PVC and unexplained cardiomyopathy undergoing long-term successful ablation of the PVC. A younger age was independently correlated with the occurrence of reverse remodeling.
Introduction: The complete circuit of reentrant left atrial tachycardias (LATs) occurring after ablation for atrial fibrillation (AF) has not been well described. Identifying discrete isthmuses ...critical to these LATs may simplify their elimination by catheter ablation.
Methods and Results: Fifteen patients (all male, 56 ± 8 years) with 15 reentrant LATs following AF ablation underwent activation and entrainment mapping. Eleven patients (11 LATs) had a single localized site with low amplitude (0.16 ± 0.05 mV), fractionated long duration (131 ± 23 msec) electrograms coinciding with an isoelectric interval of 106 ± 24 msec between flutter waves on all 12 ECG leads. Three‐dimensional mapping and entrainment revealed this site to be a narrow markedly slowly conducting isthmus adjacent to ablated left (n = 8) or right (n = 3) pulmonary vein (PV) ostia, and critical to nine small diameter (15 ± 3 mm) and two large diameter (49 ± 2 mm) circuits. One radiofrequency (RF) application on this isthmus eliminated LAT in all 11 patients. Four patients (four LATs) with large circuits around the mitral annulus and/or PV ostia lacked isoelectric ECG intervals and slow‐conducting isthmuses and required multiple RF applications across anatomically wide, rapidly conducting isthmuses.
Conclusion: Focally ablatable narrow isthmuses of slow conduction are critical for the majority of reentrant LAT occurring after ablation for AF. The role and presence of these isthmuses can be anticipated by observing significant isoelectric intervals between flutter waves on all 12‐surface ECG leads. Their distinctive electrophysiological characteristics allow their identification and elimination by simple RF ablation.
Objective: The surgical Maze III procedure remains the gold standard in treating atrial fibrillation (AF); however due to clinical difficulties and higher risks, less invasive ablation alternatives ...are clinically investigated. The present study aims to define more efficient ablation patterns of the modified maze procedure using a biophysical model of human atria with chronic AF. Methods: A three-dimensional model of human atria was developed using both MRI-imaging and a one-layer cellular model reproducing experimentally observed atrial cellular properties. Sustained AF could be induced by a burst-pacing protocol. Ablation lines were implemented in rendering the cardiac cells non-conductive, mimicking transmural lines. Lines were progressively implemented respectively around pulmonary veins (PV), left atrial appendage (LAA), left atrial isthmus (LAI), cavo-tricuspid isthmus (CTI), and intercaval lines (SIVC) in the computer model, defining the following patterns: P1 = PV, P2 = P1 + LAA, P3 = P2 + LAI, P4 = P3 + CTI, P5 = P3 + SIVC, P6 = P5 + CTI. Forty simulations were done for each pattern and proportion of sinus rhythm (SR) conversion and time-to-AF termination (TAFT) were assessed. Results: The most efficient patterns are P5, P6, and Maze III with 100% success. The main difference is expressed in decreasing mean TAFT with a correlation coefficient R = −0.8. There is an inflexion point for 100% success rate at a 7.5 s TAFT, meaning that no additional line is mandatory beyond pattern P5. Conclusions: Our biophysical model suggests that Maze III could be simplified in his right atrial pattern to a single line joining both vena cavae. This has to be confirmed in clinical settings.
Objective: To determine the adequacy of ‘in silico’ biophysical models of atrial fibrillation (AF) in the design of different ablation line patterns. Background: Permanent AF is a severe medical ...problem for which (surgical) ablation is a possible treatment. The ideal ablation pattern remains to be defined. Methods: Forty-six consecutive adult patients with symptomatic permanent drug refractory AF underwent mitral surgery combined with non-transmural, (n = 20) and transmural (n = 26) radiofrequency Minimaze. The fraction of ‘in vivo’ conversions to sinus rhythm (SR) in both groups was compared with the performance of the fraction of ‘in silico’ conversions observed in a biophysical model of permanent AF. The simulations allowed us to study the effectiveness of incomplete and complete ablation patterns. A simulated, complete, transmural Maze III ablation pattern was applied to 118 different episodes of simulated AF set-up in the model and its effectiveness was compared with the clinical results reported by Cox. Results: The fraction of conversions to SR was 92% ‘in vivo’ and 88% ‘in silico’ (p = ns) for transmural/complete ablations, 60% respectively 65% for non-transmural/incomplete Minimaze (p = ns) and 98% respectively 100% for Maze III ablations (p = ns). The fraction of conversions to SR ‘in silico’ correlated with the rates ‘in vivo’ (r2 = 0.973). Conclusions: The fraction of conversions to SR observed in the model closely corresponded to the conversion rate to SR post-surgery. This suggests that the model provides an additional, non-invasive tool for optimizing ablation line patterns for treating permanent AF.
Factors associated with premature ventricular contraction-induced cardiomyopathy (PVCi-CMP) remain debated.
The purpose of this study was to test the correlation of various factors to the presence ...PVCi-CMP in a large multicenter population.
One hundred sixty-eight consecutive patients referred for ablation of frequent premature ventricular contractions (PVCs) were included. Patients were divided into 2 groups: group 1 with suspected PVCi-CMP (96 patients, ejection fraction 38% ± 10%, left ventricular end-diastolic diameter 62 ± 8 mm, with or without additional structural heart disease); and group 2 (control group, 72 patients with normal ejection fraction and left ventricular dimensions). Various clinical and electrophysiologic parameters were compared between groups.
In univariate analysis, left ventricular origin of PVC, lack of palpitations, long PVC coupling interval, epicardial origin of the focus, long sinus beat QRS duration, male gender, high PVC burden, presence of polymorphic PVCs, high PVC QRS duration, and older age were significantly related to the presence of PVCi-CMP. In multivariate analysis, only lack of palpitations, PVC burden, and epicardial origin remained significantly and independently correlated with the presence of cardiomyopathy. Even if sinus QRS duration or PVC left ventricular origin were also found independently linked to PVCi-CMP in the whole population, they were no longer correlated when patients with additional heart disease were excluded.
Lack of palpitations, PVC burden, and epicardial origin are independent factors that identify patients prone to developing PVCi-CMP.
Surgical ablation procedures for treating atrial fibrillation have been shown to be highly successful. However, the ideal ablation pattern still remains to be determined. This article reports on a ...systematic study of the effectiveness of the performance of different ablation line patterns.
This study of ablation line patterns was performed in a biophysical model of human atria by combining basic lines: (i) in the right atrium: isthmus line, line between vena cavae and appendage line and (ii) in the left atrium: several versions of pulmonary vein isolation, connection of pulmonary veins, isthmus line, and appendage line. Success rates and the presence of residual atrial flutter were documented. Basic patterns yielded conversion rates of only 10-25 and 10-55% in the right and the left atria, respectively. The best result for pulmonary vein isolation was obtained when a single closed line encompassed all veins (55%). Combination of lines in the right/left atrium only led to a success rate of 65/80%. Higher rates, up to 90-100%, could be obtained if right and left lines were combined. The inclusion of a left isthmus line was found to be essential for avoiding uncommon left atrial flutter.
Some patterns studied achieved a high conversion rate, although using a smaller number of lines than those of the Maze III procedure. The biophysical atrial model is shown to be effective in the search for promising alternative ablation strategies.
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