Anti-DSG2 antibodies are a sensitive and specific biomarker for ARVC. The development of autoimmunity as a result of target-related mutations is unique. Anti-DSG2 antibodies likely explain the cardiac inflammation that is frequently identified in ARVC and may represent a new therapeutic target.

BackgroundThe cardiovascular complications of cancer therapeutics are the focus of the burgeoning field of cardio‐oncology. A common challenge in this field is the impact of cancer drugs on cardiac repolarization (ie, QT prolongation) and the potential risk for the life‐threatening arrhythmia torsades de pointes. Although QT prolongation is not a perfect marker of arrhythmia risk, this has become a primary safety metric among oncologists. Cardiologists caring for patients receiving cancer treatment should become familiar with the drugs associated with QT prolongation, its incidence, and appropriate management strategies to provide meaningful consultation in this complex clinical scenario.Methods and ResultsIn this article, we performed a systematic review (using Preferred Reporting Items of Systematic Reviews and Meta‐Analyses (PRISMA) guidelines) of commonly used cancer drugs to determine the incidence of QT prolongation and clinically relevant arrhythmias. We calculated summary estimates of the incidence of all and clinically relevant QT prolongation as well as arrhythmias and sudden cardiac death. We then describe strategies to prevent, identify, and manage QT prolongation in patients receiving cancer therapy. We identified a total of 173 relevant publications. The weighted incidence of any corrected QT (QTc) prolongation in our systematic review in patients treated with conventional therapies (eg, anthracyclines) ranged from 0% to 22%, although QTc >500 ms, arrhythmias, or sudden cardiac death was extremely rare. The risk of QTc prolongation with targeted therapies (eg, small molecular tyrosine kinase inhibitors) ranged between 0% and 22.7% with severe prolongation (QTc >500 ms) reported in 0% to 5.2% of the patients. Arrhythmias and sudden cardiac death were rare.ConclusionsOur systematic review demonstrates that there is variability in the incidence of QTc prolongation of various cancer drugs; however, the clinical consequence, as defined by arrhythmias or sudden cardiac death, remains rare.

Atrial fibrillation (AF), the most common arrhythmia, is a growing epidemic with substantial morbidity and economic burden. Mechanisms underlying vulnerability to AF remain poorly understood, which contributes to the current lack of highly effective therapies. Recognizing mechanistic subtypes of AF may guide an individualized approach to patient management. Here, we describe a family with a previously unreported syndrome characterized by early-onset AF (age <35 years), conduction disease and signs of a primary atrial myopathy. Phenotypic penetrance was complete in all mutation carriers, although complete disease expressivity appears to be age-dependent. We show that this syndrome is caused by a novel, heterozygous p.Glu11Lys mutation in the atrial-specific myosin light chain gene MYL4. In zebrafish, mutant MYL4 leads to disruption of sarcomeric structure, atrial enlargement and electrical abnormalities associated with human AF. These findings describe the cause of a rare subtype of AF due to a primary, atrial-specific sarcomeric defect.

Background: Hypertrophic cardiomyopathy (HCM) is considered a leading cause of sudden cardiac death (SCD) in younger people. The incidence of HCM-related SCD and its relationship to exercise have not been well studied in large comprehensive studies outside of tertiary care settings. This study sought to estimate the incidence of HCM-related SCD and its association with exercise in a large unselected population. Methods: Using the Office of the Chief Coroner of Ontario database encompassing all deaths attended by the coroner, we identified all HCM-related SCDs in individuals 10 to 45 years of age between 2005 and 2016 (70 million person-years). Confirmation of HCM was based on typical macroscopic and microscopic features (definite HCM-related SCD). Sudden deaths with a prior clinical diagnosis of HCM but no autopsy were considered probable HCM-related SCDs. Cases with typical features but no myofiber disarray were considered possible HCM. The completeness of data was verified in a subset of patients in the Toronto area with the use of a registry of all emergency medical services–attended cardiac arrests, with an autopsy rate of 94%. To estimate the number of HCM-related aborted cardiac arrests and lives potentially saved by implantable cardioverter-defibrillators, all de novo implantations for secondary prevention and all implantations and appropriate shocks for primary prevention in patients with HCM 10 to 45 years of age, respectively, were identified with the use of a registry containing data on implantable cardioverter-defibrillator implantations from all implanting sites throughout Ontario. Results: Forty-four, 3, and 6 cases of definite, probable, and possible HCM-related SCDs, respectively, were identified, corresponding to estimated annual incidence rates of 0.31 per 1000 HCM person-years (95% CI, 0.24–0.44) for definite HCM-related SCD, 0.33 per 1000 HCM person-years (95% CI, 0.34–0.62) for definite or probable HCM-related SCD, and 0.39 per 1000 HCM person-years (95% CI, 0.28–0.49) for definite, probable, or possible HCM-related SCD (estimated 140 740 HCM person-years of observation). The estimated annual incidence rate for HCM-related SCD plus aborted cardiac arrest and HCM-related life-threatening arrhythmia (SCD, aborted cardiac arrest, and appropriate implantable cardioverter-defibrillator shocks) was 0.84 per 1000 HCM person-years (95% CI, 0.70–1.0). The majority (70%) of SCDs occurred in previously undiagnosed individuals. Most SCDs occurred during rest (64.8%) or light activity (18.5%). Conclusions: The incidence of HCM-related SCD in the general population 10 to 45 years of age is substantially lower than previously reported, with most cases occurring in previously undiagnosed individuals. SCDs are infrequently related to exercise.

By using a bipolar ablation technique, we have demonstrated the creation of significantly deeper lesions without increasing the lesion width, compared with standard ablation. Further clinical trials are warranted to detail the risks of this technique.

Arrhythmogenic cardiomyopathy (ACM) is an inherited arrhythmia syndrome characterized by severe structural and electrical cardiac phenotypes, including myocardial fibrofatty replacement and sudden cardiac death. Clinical management of ACM is largely palliative, owing to an absence of therapies that target its underlying pathophysiology, which stems partially from our limited insight into the condition. Following identification of deceased ACM probands possessing ANK2 rare variants and evidence of ankyrin-B loss of function on cardiac tissue analysis, an ANK2 mouse model was found to develop dramatic structural abnormalities reflective of human ACM, including biventricular dilation, reduced ejection fraction, cardiac fibrosis, and premature death. Desmosomal structure and function appeared preserved in diseased human and murine specimens in the presence of markedly abnormal β-catenin expression and patterning, leading to identification of a previously unknown interaction between ankyrin-B and β-catenin. A pharmacological activator of the WNT/β-catenin pathway, SB-216763, successfully prevented and partially reversed the murine ACM phenotypes. Our findings introduce what we believe to be a new pathway for ACM, a role of ankyrin-B in cardiac structure and signaling, a molecular link between ankyrin-B and β-catenin, and evidence for targeted activation of the WNT/β-catenin pathway as a potential treatment for this disease.

Aims Brugada syndrome (BrS) is characterized by a unique electrocardiogram (ECG) pattern and life-threatening arrhythmias. However, the Type 1 Brugada ECG pattern is often transient, and a genetic cause is only identified in &lt;25% of patients. We sought to identify an additional biomarker for this rare condition. As myocardial inflammation may be present in BrS, we evaluated whether myocardial autoantibodies can be detected in these patients. Methods and results For antibody (Ab) discovery, normal human ventricular myocardial proteins were solubilized and separated by isoelectric focusing (IEF) and molecular weight on two-dimensional (2D) gels and used to discover Abs by plating with sera from patients with BrS and control subjects. Target proteins were identified by mass spectrometry (MS). Brugada syndrome subjects were defined based on a consensus clinical scoring system. We assessed discovery and validation cohorts by 2D gels, western blots, and ELISA. We performed immunohistochemistry on myocardium from BrS subjects (vs. control). All (3/3) 2D gels exposed to sera from BrS patients demonstrated specific Abs to four proteins, confirmed by MS to be α-cardiac actin, α-skeletal actin, keratin, and connexin-43, vs. 0/8 control subjects. All (18/18) BrS subjects from our validation cohorts demonstrated the same Abs, confirmed by western blots, vs. 0/24 additional controls. ELISA optical densities for all Abs were elevated in all BrS subjects compared to controls. In myocardium obtained from BrS subjects, each protein, as well as SCN5A, demonstrated abnormal protein expression in aggregates. Conclusion A biomarker profile of autoantibodies against four cardiac proteins, namely α-cardiac actin, α-skeletal actin, keratin, and connexin-43, can be identified from sera of BrS patients and is highly sensitive and specific, irrespective of genetic cause for BrS. The four involved proteins, along with the SCN5A-encoded Nav1.5 alpha subunit are expressed abnormally in the myocardium of patients with BrS.

Automated T-wave morphology analysis accurately discriminates patients with pathogenic LQTS mutations from control subjects and between the 2 most common LQTS subtypes. Mutation carriers without baseline QTc prolongation were also identified. This may be a useful tool for screening families of LQTS patients, particularly when the QTc interval is subthreshold and genetic testing is unavailable.