Impact of functional studies on exome sequence variant interpretation in early-onset cardiac conduction system diseases

Aims The genetic cause of cardiac conduction system disease (CCSD) has not been fully elucidated. Whole-exome sequencing (WES) can detect various genetic variants; however, the identification of pathogenic variants remains a challenge. We aimed to identify pathogenic or likely pathogenic variants in CCSD patients by using WES and 2015 American College of Medical Genetics and Genomics (ACMG) standards and guidelines as well as evaluating the usefulness of functional studies for determining them. Methods and Results We performed WES of 23 probands diagnosed with early-onset (<65 years) CCSD and analyzed 117 genes linked to arrhythmogenic diseases or cardiomyopathies. We focused on rare variants (minor allele frequency < 0.1%) that were absent from population databases. Five probands had protein truncating variants in EMD and LMNA which were classified as “pathogenic” by 2015 ACMG standards and guidelines. To evaluate the functional changes brought about by these variants, we generated a knock-out zebrafish with CRISPR-mediated insertions or deletions of the EMD or LMNA homologs in zebrafish. The mean heart rate and conduction velocities in the CRISPR/Cas9-injected embryos and F2 generation embryos with homozygous deletions were significantly decreased. Twenty-one variants of uncertain significance were identified in 11 probands. Cellular electrophysiological study and in vivo zebrafish cardiac assay showed that 2 variants in KCNH2 and SCN5A, 4 variants in SCN10A, and 1 variant in MYH6 damaged each gene, which resulted in the change of the clinical significance of them from “Uncertain significance” to “Likely pathogenic” in 6 probands. Conclusions Of 23 CCSD probands, we successfully identified pathogenic or likely pathogenic variants in 11 probands (48%). Functional analyses of a cellular electrophysiological study and in vivo zebrafish cardiac assay might be useful for determining the pathogenicity of rare variants in patients with CCSD. SCN10A may be one of the major genes responsible for CCSD. Translational Perspective Whole-exome sequencing (WES) may be helpful in determining the causes of cardiac conduction system disease (CCSD), however, the identification of pathogenic variants remains a challenge. We performed WES of 23 probands diagnosed with early-onset CCSD, and identified 12 pathogenic or likely pathogenic variants in 11 of these probands (48%) according to the 2015 ACMG standards and guidelines. In this context, functional analyses of a cellular electrophysiological study and in vivo zebrafish cardiac assay might be useful for determining the pathogenicity of rare variants, and SCN10A may be one of the major development factors in CCSD

Right-sided infective endocarditis as a potentially fatal complication in patients with long-term refractory severe bradyarrhythmia after cervical spinal cord injury: A case report

AbstractBradyarrhythmia is usually a spontaneously subsiding complication of cervical spinal cord injury. However, in severe cases, it can lead to cardiac arrest. We report a case of cervical spinal cord injury, complicated by right-sided infective endocarditis after the placement of a temporary pacing catheter in the right ventricle for severe bradyarrhythmia that led to cardiac arrest. Although the patient׳s condition was successfully treated by pacing catheter removal and pharmacological therapy, right-sided infective endocarditis would be a fatal complication in cases of cervical spinal cord injury where cardiac pacing is required for long-term refractory severe bradyarrhythmia

Coxsackie B2 Virus Infection Causing Multiorgan Failure and Cardiogenic Shock in a 42-Year-Old Man

Infections from coxsackie B2 viruses often cause viral myocarditis and, only rarely, multisystem organ impairment. We present the unusual case of a 42-year-old man in whom coxsackie B2 virus infection caused multiorgan infection, necessitating distal pancreatectomy, splenectomy, renal dialysis, and venoarterial extracorporeal membrane oxygenation with mechanical ventilation. In addition, the patient had a rapid-eye-movement sleep-related conduction abnormality that caused frequent sinus pauses of longer than 10 s, presumably due to myocarditis from the coxsackievirus infection. He recovered after permanent pacemaker placement and was discharged from the hospital. We discuss our aggressive supportive care and the few other reports of multiorgan impairment from coxsackieviruses

Brady- and tachyarrhythmias detected by continuous rhythm monitoring in paroxysmal atrial fibrillation

Objective: Atrial fibrillation (AF) is associated with adverse events including conduction disturbances, ventricular arrhythmias and sudden death. The aim of this study was to examine brady- and tachyarrhythmias using continuous rhythm monitoring in patients with paroxysmal self-terminating AF (PAF). Methods: In this multicentre observational substudy to the Reappraisal of Atrial Fibrillation: interaction between hyperCoagulability, Electrical remodelling and Vascular destabilisation in the progression of AF (RACE V), we included 392 patients with PAF and at least 2 years of continuous rhythm monitoring. All patients received an implantable loop recorder, and all detected episodes of tachycardia ≥182 beats per minute (BPM), bradycardia ≤30 BPM or pauses ≥5 s were adjudicated by three physicians. Results: Over 1272 patient-years of continuous rhythm monitoring, we adjudicated 1940 episodes in 175 patients (45%): 106 (27%) patients experienced rapid AF or atrial flutter (AFL), pauses ≥5 s or bradycardias ≤30 BPM occurred in 47 (12%) patients and in 22 (6%) patients, we observed both episode types. No sustained ventricular tachycardias occurred. In the multivariable analysis, age &gt;70 years (HR 2.3, 95% CI 1.4 to 3.9), longer PR interval (HR 1.9, 1.1-3.1), CHA2DS2-VASc score ≥2 (HR 2.2, 1.1-4.5) and treatment with verapamil or diltiazem (HR 0.4, 0.2-1.0) were significantly associated with bradyarrhythmia episodes. Age &gt;70 years was associated with lower rates of tachyarrhythmias. Conclusions: In a cohort exclusive to patients with PAF, almost half experienced severe bradyarrhythmias or AF/AFL with rapid ventricular rates. Our data highlight a higher than anticipated bradyarrhythmia risk in PAF. Trial registration number: NCT02726698.</p

Brady- and tachyarrhythmias detected by continuous rhythm monitoring in paroxysmal atrial fibrillation

Objective: Atrial fibrillation (AF) is associated with adverse events including conduction disturbances, ventricular arrhythmias and sudden death. The aim of this study was to examine brady- and tachyarrhythmias using continuous rhythm monitoring in patients with paroxysmal self-terminating AF (PAF). Methods: In this multicentre observational substudy to the Reappraisal of Atrial Fibrillation: interaction between hyperCoagulability, Electrical remodelling and Vascular destabilisation in the progression of AF (RACE V), we included 392 patients with PAF and at least 2 years of continuous rhythm monitoring. All patients received an implantable loop recorder, and all detected episodes of tachycardia ≥182 beats per minute (BPM), bradycardia ≤30 BPM or pauses ≥5 s were adjudicated by three physicians. Results: Over 1272 patient-years of continuous rhythm monitoring, we adjudicated 1940 episodes in 175 patients (45%): 106 (27%) patients experienced rapid AF or atrial flutter (AFL), pauses ≥5 s or bradycardias ≤30 BPM occurred in 47 (12%) patients and in 22 (6%) patients, we observed both episode types. No sustained ventricular tachycardias occurred. In the multivariable analysis, age &gt;70 years (HR 2.3, 95% CI 1.4 to 3.9), longer PR interval (HR 1.9, 1.1-3.1), CHA2DS2-VASc score ≥2 (HR 2.2, 1.1-4.5) and treatment with verapamil or diltiazem (HR 0.4, 0.2-1.0) were significantly associated with bradyarrhythmia episodes. Age &gt;70 years was associated with lower rates of tachyarrhythmias. Conclusions: In a cohort exclusive to patients with PAF, almost half experienced severe bradyarrhythmias or AF/AFL with rapid ventricular rates. Our data highlight a higher than anticipated bradyarrhythmia risk in PAF. Trial registration number: NCT02726698.</p

Diagnosis, management, and outcomes of patients with syncope and bundle branch block

Although patients with syncope and bundle branch block (BBB) are at high risk of developing atrio-ventricular block, syncope may be due to other aetiologies. We performed a prospective, observational study of the clinical outcomes of patients with syncope and BBB following a systematic diagnostic approach. Patients with ≥1 syncope in the last 6 months, with QRS duration ≥120 ms, were prospectively studied following a three-phase diagnostic strategy: Phase I, initial evaluation; Phase II, electrophysiological study (EPS); and Phase III, insertion of an implantable loop recorder (ILR). Overall, 323 patients (left ventricular ejection fraction 56 ± 12%) were studied. The aetiological diagnosis was established in 267 (82.7%) patients (102 at initial evaluation, 113 upon EPS, and 52 upon ILR) with the following aetiologies: bradyarrhythmia (202), carotid sinus syndrome (20), ventricular tachycardia (18), neurally mediated (9), orthostatic hypotension (4), drug-induced (3), secondary to cardiopulmonary disease (2), supraventricular tachycardia (1), bradycardia-tachycardia (1), and non-arrhythmic (7). A pacemaker was implanted in 220 (68.1%), an implantable cardioverter defibrillator in 19 (5.8%), and radiofrequency catheter ablation was performed in 3 patients. Twenty patients (6%) had died at an average follow-up of 19.2 ± 8.2 months. In patients with syncope, BBB, and mean left ventricular ejection fraction of 56 ± 12%, a systematic diagnostic approach achieves a high rate of aetiological diagnosis and allows to select specific treatment