Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy.

AIMS: The aim of this study was to determine the frequency of heterozygous truncating ALPK3 variants (ALPK3tv) in patients with hypertrophic cardiomyopathy (HCM) and confirm their pathogenicity using burden testing in independent cohorts and family co-segregation studies. METHODS AND RESULTS: In a discovery cohort of 770 index patients with HCM, 12 (1.56%) were heterozygous for ALPK3tv [odds ratio(OR) 16.11, 95% confidence interval (CI) 7.94-30.02, P = 8.05e-11] compared to the Genome Aggregation Database (gnomAD) population. In a validation cohort of 2047 HCM probands, 32 (1.56%) carried heterozygous ALPK3tv (OR 16.17, 95% CI 10.31-24.87, P < 2.2e-16, compared to gnomAD). Combined logarithm of odds score in seven families with ALPK3tv was 2.99. In comparison with a cohort of genotyped patients with HCM (n = 1679) with and without pathogenic sarcomere gene variants (SP+ and SP-), ALPK3tv carriers had a higher prevalence of apical/concentric patterns of hypertrophy (60%, P < 0.001) and of a short PR interval (10%, P = 0.009). Age at diagnosis and maximum left ventricular wall thickness were similar to SP- and left ventricular systolic impairment (6%) and non-sustained ventricular tachycardia (31%) at baseline similar to SP+. After 5.3 ± 5.7 years, 4 (9%) patients with ALPK3tv died of heart failure or had cardiac transplantation (log-rank P = 0.012 vs. SP- and P = 0.425 vs. SP+). Imaging and histopathology showed extensive myocardial fibrosis and myocyte vacuolation. CONCLUSIONS: Heterozygous ALPK3tv are pathogenic and segregate with a characteristic HCM phenotype.

Formin Homology 2 Domain Containing 3 (FHOD3) Is a Genetic Basis for Hypertrophic Cardiomyopathy.

BACKGROUND: The genetic cause of hypertrophic cardiomyopathy remains unexplained in a substantial proportion of cases. Formin homology 2 domain containing 3 (FHOD3) may have a role in the pathogenesis of cardiac hypertrophy but has not been implicated in hypertrophic cardiomyopathy. OBJECTIVES: This study sought to investigate the relation between FHOD3 mutations and the development of hypertrophic cardiomyopathy. METHODS: FHOD3 was sequenced by massive parallel sequencing in 3,189 hypertrophic cardiomyopathy unrelated probands and 2,777 patients with no evidence of cardiomyopathy (disease control subjects). The authors evaluated protein-altering candidate variants in FHOD3 for cosegregation, clinical characteristics, and outcomes. RESULTS: The authors identified 94 candidate variants in 132 probands. The variants' frequencies were significantly higher in patients with hypertrophic cardiomyopathy (74 of 3,189 [2.32%]) than in disease control subjects (18 of 2,777 [0.65%]; p < 0.001) or in the gnomAD database (1,049 of 138,606 [0.76%]; p < 0.001). FHOD3 mutations cosegregated with hypertrophic cardiomyopathy in 17 families, with a combined logarithm of the odds score of 7.92, indicative of very strong segregation. One-half of the disease-causing variants were clustered in a small conserved coiled-coil domain (amino acids 622 to 655); odds ratio for hypertrophic cardiomyopathy was 21.8 versus disease control subjects (95% confidence interval: 1.3 to 37.9; p < 0.001) and 14.1 against gnomAD (95% confidence interval: 6.9 to 28.7; p < 0.001). Hypertrophic cardiomyopathy patients carrying (likely) pathogenic mutations in FHOD3 (n = 70) were diagnosed after age 30 years (mean 46.1 ± 18.7 years), and two-thirds (66%) were males. Of the patients, 82% had asymmetric septal hypertrophy (mean 18.8 ± 5 mm); left ventricular ejection fraction <50% was present in 14% and hypertrabeculation in 16%. Events were rare before age 30 years, with an annual cardiovascular death incidence of 1% during follow-up. CONCLUSIONS: FHOD3 is a novel disease gene in hypertrophic cardiomyopathy, accounting for approximately 1% to 2% of cases. The phenotype and the rate of cardiovascular events are similar to those reported in unselected cohorts. The FHOD3 gene should be routinely included in hypertrophic cardiomyopathy genetic testing panels.

Yield of atrial fibrillation detection with Textile Wearable Holter from the acute phase of stroke: Pilot study of Crypto-AF registry.

BACKGROUND: We describe the feasibility of monitoring with a Textile Wearable Holter (TWH) in patients included in Crypto AF registry. METHODS: We monitored cryptogenic stroke patients from stroke onset (<3days) continuously during 28days. We employed a TWH composed by a garment and a recorder. We compared two garments (Lead and Vest) to assess rate of undiagnosed Atrial Fibrillation (AF) detection, monitoring compliance, comfortability (1 to 5 points), skin lesions, and time analyzed. We describe the timing of AF detection in three periods (0-3, 4-15 and 16-28days). RESULTS: The rate of undiagnosed AF detection with TWH was 21.9% (32 out of 146 patients who completed the monitoring). Global time compliance was 90% of the time expected (583/644h). The level of comfortability was 4 points (IQR 3-5). We detected reversible skin lesions in 5.47% (8/146). The comfortability was similar but time compliance (in hours) was longer in Vest group 591 (IQR [521-639]) vs. Lead 566 (IQR [397-620]) (p=0.025). Also, time analyzed was more prolonged in Vest group 497 (IQR [419-557]) vs. Lead (336h (IQR [140-520]) (p=0.001)). The incidence of AF increases from 5.6% (at 3days) to 17.5% (at 15th day) and up to 20.9% (at 28th day). The percentage of AF episodes detected only in each period was 12.5% (0-3days); 21.7% (4-15days) and 19% (16-28days). CONCLUSIONS: 28days Holter monitoring from the acute phase of the stroke was feasible with TWH. Following our protocol, only five patients were needed to screen to detected one case of AF.

Impact of Chronic Total Coronary Occlusion on Recurrence of Ventricular Arrhythmias in Ischemic Secondary Prevention Implantable Cardioverter-Defibrillator Recipients (VACTO Secondary Study): Insights From Coronary Angiogram and Electrogram Analysis.

OBJECTIVES: This study sought to evaluate the incidence and clinical effect of coronary chronic total occlusions (CTOs) in patients with ischemic cardiomyopathy receiving an implantable cardioverter-defibrillator (ICD) for secondary prevention of sudden cardiac death (SCD). BACKGROUND: CTOs are common in patients with ischemic cardiomyopathy, which is the major cause of SCD. However, the impact of CTO in SCD survivors receiving an ICD is unknown. METHODS: A total of 425 patients who had survived an episode of ventricular arrhythmias and underwent ICD implantation for secondary prevention in 8 centers were included. Coronary angiogram, CTO angiographic characteristics, and ventricular arrhythmia pattern were centrally analyzed. Primary and secondary endpoints were appropriate ICD therapies and mortality during a median follow-up of 4.1 years, according to the presence of CTO in the baseline angiogram. RESULTS: Appropriate ICD therapies were higher in patients with CTO (51.7% vs. 36.3%; p = 0.001 at 4 years). Left ventricular ejection fraction (LVEF) (p = 0.015) and CTO (p = 0.001) were independent predictors of appropriate ICD therapy. Ventricular arrhythmia onset was associated to a shorter coupling interval and lower prematurity index in CTO patients. Defibrillator therapies were independently associated with worse LVEF (p = 0.046) and renal dysfunction (p = 0.023) among patients with CTO, and a tendency was observed in patients with better collateral flow (p = 0.093). Patients with poorer renal function (p = 0.029), LVEF (p = 0.041), and CTO (p = 0.033) experienced higher mortality rate. CONCLUSIONS: Among ICD recipients for secondary prevention of SCD, coronary CTO conferred a higher risk of VA recurrence and mortality in long-term follow-up. Angiographic and VA patterns could provide insights into the mechanisms of SCD and may have implications for the use of interventions designed to limit ICD shocks in this high-risk population.

Usefulness of multidetector computed tomography before and after pulmonary vein isolation. / Utilidad de la tomografía computarizada multidetector en la evaluación previa y el seguimiento de los pacientes sometidos a ablación de venas pulmonares.

OBJECTIVE: To analyze the usefulness of multidetector computed tomography (MDCT) in the preprocedural evaluation and follow-up of patients undergoing radiofrequency ablation of pulmonary veins and the impact of the MDCT findings on the approach to treatment. METHOD: We retrospectively analyzed 92 consecutive MDCT studies done in 80 patients between January 2011 and June 2013; 70 (76%) studies were done before a first ablation procedure and 22 (24%) were done in patients who had undergone an ablation procedure. RESULTS: Findings were useful in 34% of the patients who underwent MDCT before the first ablation procedure and in 68% of the studies done after a procedure. The incidence of stroke associated with the ablation procedure was 3%, similar to the incidence recorded in our center before we started to use MDCT to evaluate the anatomy of the left atrium. All symptomatic patients had some pulmonary vein stenosis, and 80% had significant stenosis. Furthermore, the stenoses progressed very rapidly; treatment with balloon angioplasty was associated with early restenosis. Stenting was an alternative in cases of failed angioplasty. CONCLUSION: In the preprocedural evaluation and postprocedural follow-up of patients undergoing pulmonary vein isolation, MDCT is useful for guiding treatment and detecting complications.

[High performance of an implantable Holter monitor in the detection of concealed paroxysmal atrial fibrillation in patients with cryptogenic stroke and a suspected embolic mechanism]. / Altorendimiento del holter implantable en la detecciónde fibrilación auricular paroxística oculta en pacientescon ictus criptogénico y sospecha de mecanismo embólico.

INTRODUCTION: Implantable loop recorders (ILR) may allow detection of occult paroxysmal atrial fibrillation (PAF) in patients with cryptogenic ischemic stroke. However, optimal selection algorithm and ideal duration of monitoring remain unclear. AIM. To determine the incidence and time-profile of PAF in patients with cryptogenic ischemic stroke studied with Reveal XT ILR, who were selected based on a high suspicion of cerebral embolism. SELECTION CRITERIA: absence of stroke etiology after complete study including vascular imaging, transesophageal echocardiography and at least 24 hours of cardiac rhythm monitoring, and confirmation of acute embolic occlusion of intracranial artery by transcranial duplex or characteristics of acute ischemic lesion on neuroimaging suggesting embolic mechanism of ischemia. After implanting Reveal XT ILR, patients were trained to perform transmissions monthly or when symptoms occurred. We reviewed the information online each month and patients underwent clinical visits at 3rd and 6th month and then every six months. RESULTS: We included 101 patients with cryptogenic ischemic stroke and at least one month of follow-up after ILR implant. Mean age was 67 years, 54 women (53.5%). Mean follow-up after implantation was 281 ± 212 days. Occult PAF was detected in 34 patients (33.7%). Frequency of false positives: 22.8%. Median time from implant to arrhythmia detection was 102 days (range: 26-240 days). 24 (70%) patients with PAF had several arrhythmic episodes detected with ILR. The majority of events (75%) were detected during the first six months of monitoring. CONCLUSIONS: In our patients with probably embolic cryptogenic ischemic stroke, PAF was detected by Reveal XT ILR in 33.7%. One in four events occurred after the first six months of monitoring.

TITLE: Alto rendimiento del holter implantable en la deteccion de fibrilacion auricular paroxistica oculta en pacientes con ictus criptogenico y sospecha de mecanismo embolico.Introduccion. El holter implantable permite detectar fibrilacion auricular paroxistica (FAP) oculta en pacientes con ictus criptogenico, pero se desconoce que algoritmo de seleccion tiene un mayor rendimiento y la duracion optima de monitorizacion. Objetivo. Conocer la frecuencia y el tiempo hasta detectar la FAP mediante un holter implantable Reveal XT ® en pacientes con ictus criptogenico seleccionados por sospecha elevada de embolismo cerebral. Pacientes y metodos. Criterios de seleccion: ausencia de etiologia del ictus tras el estudio completo incluyendo un ecocardiograma transesofagico, monitorizacion ECG y holter de 24 horas, asi como confirmacion de oclusion aguda embolica de la arteria intracraneal por duplex transcraneal o bien alta sospecha de embolismo por caracteristicas de neuroimagen. Tras implantar el holter Reveal XT se formo a los pacientes para que emprendieran transmisiones todos los meses o ante sintomas. Se reviso la informacion online mensualmente y se realizaron visitas clinicas en las unidades de Neurologia y Cardiologia. Resultados. Se incluyeron 101 pacientes con ictus criptogenico y al menos un mes de seguimiento: edad media de 67 años, 54 mujeres (53,5%). Tiempo medio de seguimiento: 281 ± 212 dias. Se detecto FAP oculta en 34 pacientes (33,7%) y falsos positivos en 23 (22,8%). Mediana desde el implante hasta la deteccion de la arritmia: 102 dias (rango: 26-240 dias). En un 70% de los pacientes se registraron multiples episodios de FAP. El 75% de los eventos se detectaron durante los primeros seis meses de monitorizacion. Conclusiones. El algoritmo de seleccion de pacientes con ictus criptogenico segun sospecha de embolismo cerebral se asocio a una elevada frecuencia (33,7%) de FAP oculta con holter implantable. Uno de cada cuatro eventos sucedio tras los primeros seis meses de monitorizacion.