Stretch of the papillary insertion triggers reentrant arrhythmia: an in silico patient study.

Background: The electrophysiological mechanism connecting mitral valve prolapse (MVP), premature ventricular complexes and life-threatening ventricular arrhythmia is unknown. A common hypothesis is that stretch activated channels (SACs) play a significant role. SACs can trigger depolarizations or shorten repolarization times in response to myocardial stretch. Through these mechanisms, pathological traction of the papillary muscle (PM), as has been observed in patients with MVP, may induce irregular electrical activity and result in reentrant arrhythmia. Methods: Based on a patient with MVP and mitral annulus disjunction, we modeled the effect of excessive PM traction in a detailed medical image-derived ventricular model by activating SACs in the PM insertion region. By systematically varying the onset of SAC activation following sinus pacing, we identified vulnerability windows for reentry with 1 ms resolution. We explored how reentry was affected by the SAC reversal potential ( E SAC ) and the size of the region with simulated stretch (SAC region). Finally, the effect of global or focal fibrosis, modeled as reduction in tissue conductivity or mesh splitting (fibrotic microstructure), was investigated. Results: In models with healthy tissue or fibrosis modeled solely as CV slowing, we observed two vulnerable periods of reentry: For E SAC of -10 and -30 mV, SAC activated during the T-wave could cause depolarization of the SAC region which lead to reentry. For E SAC of -40 and -70 mV, SAC activated during the QRS complex could result in early repolarization of the SAC region and subsequent reentry. In models with fibrotic microstructure in the SAC region, we observed micro-reentries and a larger variability in which times of SAC activation triggered reentry. In these models, 86% of reentries were triggered during the QRS complex or T-wave. We only observed reentry for sufficiently large SAC regions ( > = 8 mm radius in models with healthy tissue). Conclusion: Stretch of the PM insertion region following sinus activation may initiate ventricular reentry in patients with MVP, with or without fibrosis. Depending on the SAC reversal potential and timing of stretch, reentry may be triggered by ectopy due to SAC-induced depolarizations or by early repolarization within the SAC region.

Highly malignant disease in childhood-onset arrhythmogenic right ventricular cardiomyopathy.

AIMS: This study aimed to explore the incidence of severe cardiac events in paediatric arrhythmogenic right ventricular cardiomyopathy (ARVC) patients and ARVC penetrance in paediatric relatives. Furthermore, the phenotype in childhood-onset ARVC was described. METHODS: Consecutive ARVC paediatric patients and genotype positive relatives ≤18 years of age were followed with electrocardiographic, structural, and arrhythmic characteristics according to the 2010 revised Task Force Criteria. Penetrance of ARVC disease was defined as fulfilling definite ARVC criteria and severe cardiac events were defined as cardiac death, heart transplantation (HTx) or severe ventricular arrhythmias. Childhood-onset disease was defined as meeting definite ARVC criteria ≤12 years of age. RESULTS: Among 62 individuals [age 9.8 (5.0-14.0) years, 11 probands], 20 (32%) fulfilled definite ARVC diagnosis, of which 8 (40%) had childhood-onset disease. The incidence of severe cardiac events was 23% (n = 14) by last follow-up and half of them occurred in patients ≤12 years of age. Among the eight patients with childhood-onset disease, five had biventricular involvement needing HTx and three had severe arrhythmic events. Among the 51 relatives, 6% (n = 3) met definite ARVC criteria at time of genetic diagnosis, increasing to 18% (n = 9) at end of follow-up. CONCLUSIONS: In a paediatric ARVC cohort, there was a high incidence of severe cardiac events and half of them occurred in children ≤12 years of age. The ARVC penetrance in genotype positive paediatric relatives was 18%. These findings of a high-malignant phenotype in childhood-onset ARVC indicate a need for ARVC family screening at younger age than currently recommended.

Lamin A/C cardiomyopathy: young onset, high penetrance, and frequent need for heart transplantation.

Aims: Lamin A/C (LMNA) mutations cause familial dilated cardiomyopathy (DCM) with frequent conduction blocks and arrhythmias. We explored the prevalence, cardiac penetrance, and expressivity of LMNA mutations among familial DCM in Norway. Furthermore, we explored the risk factors and the outcomes in LMNA patients. Methods and results: During 2003-15, genetic testing was performed in patients referred for familial DCM. LMNA genotype-positive subjects were examined by electrocardiography, Holter monitoring, cardiac magnetic resonance imaging, and echocardiography. A positive cardiac phenotype was defined as the presence of atrioventricular (AV) block, atrial fibrillation/flutter (AF), ventricular tachycardia (VT), and/or echocardiographic DCM. Heart transplantation was recorded and compared with non-ischaemic DCM of other origin. Of 561 unrelated familial DCM probands, 35 (6.2%) had an LMNA mutation. Family screening diagnosed an additional 93 LMNA genotype-positive family members. We clinically followed up 79 LMNA genotype-positive [age 42 ± 16 years, ejection fraction (EF) 45 ± 13%], including 44 (56%) with VT. Asymptomatic LMNA genotype-positive family members (age 31 ± 15 years) had a 9% annual incidence of a newly documented cardiac phenotype and 61% (19/31) of cardiac penetrance during 4.4 ± 2.9 years of follow-up. Ten (32%) had AV block, 7 (23%) AF, and 12 (39%) non-sustained VT. Heart transplantation was performed in 15 of 79 (19%) LMNA patients during 7.8 ± 6.3 years of follow-up. Conclusion: LMNA mutation prevalence was 6.2% of familial DCM in Norway. Cardiac penetrance was high in young asymptomatic LMNA genotype-positive family members with frequent AV block and VT, highlighting the importance of early family screening and cardiological follow-up. Nearly 20% of the LMNA patients required heart transplantation.