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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.

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Aims Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is characterized by fibrofatty infiltration of the myocardium and ventricular arrhythmias that may lead to sudden cardiac death. It has been observed that male patients develop the disease earlier and present with more severe phenotypes as compared to females. Thus, we hypothesized that serum levels of sex hormones may contribute to major arrhythmic cardiovascular events (MACE) in patients with ARVC/D. Methods and results The serum levels of five sex hormones, sex hormone-binding globulin, high sensitivity troponin T, pro-brain natriuretic peptide, cholesterol, triglycerides, insulin, and glucose were measured in 54 ARVC/D patients (72% male). Twenty-six patients (48%) experienced MACE. Total and free testosterone levels were significantly increased in males with MACE as compared to males with a favourable outcome, whereas estradiol was significantly lower in females with MACE as compared to females with a favourable outcome. Increased testosterone levels remained independently associated with MACE in males after adjusting for age, body mass index, Task Force criteria, ventricular function, and desmosomal mutation status. Furthermore, an induced pluripotent stem cell-derived ARVC/D cardiomyocyte model was used to investigate the effects of sex hormones. In this model, testosterone worsened and estradiol improved ARVC/D-related pathologies such as cardiomyocyte apoptosis and lipogenesis, strongly supporting our clinical findings. Conclusions Elevated serum testosterone levels in males and decreased estradiol levels in females are independently associated with MACE in ARVC/D, and directly influence disease pathology. Therefore, determining the levels of sex hormones may be useful for risk stratification and may open a new window for preventive interventions.

Background-Ventricular tachycardia (VT) isthmuses can be defined by fixed or functional block. During sinus rhythm, pace mapping near the exit of an isthmus should produce a QRS similar to that of VT. Pace mapping at sites proximal to the exit may produce a similar QRS with a longer stimulus-to-QRS interval (S-QRS). The aim of the study was to determine whether a VT isthmus could be identified and followed by pace mapping. Methods and Results-Left ventricular pace mapping during sinus rhythm was performed at 819 sites in 11 patients with VT late after infarction, and corresponding CARTO maps were reconstructed. An isthmus site was defined by entrainment and/or VT termination by ablation. Pace-mapping data were analyzed from the identified isthmus site and from sites at progressively increasing distances from this initial isthmus site. Sites where pace mapping produced the same QRS with different S-QRS delays were identified to attempt to trace the course of the isthmus. In 11 patients, 13 confluent low-voltage infarct regions were present. In all these regions, parts of VT isthmuses were identified by pace mapping. In 11 of 13 of the identified isthmus parts, the QRS morphology of the pace map matched a VT QRS. In 10 of 11 patients, radiofrequency ablation rendered clinical VTs noninducible. Successful ablation sites were localized within an isthmus identified by pace mapping in all of these 10 patients. Conclusions-VT isthmuses can be identified and part of their course delineated by pace mapping during sinus rhythm.This method could help target isthmus sites for ablation during stable sinus rhythm.

Background: Myocardial contractility can be altered using voltage clamp techniques by modulating amplitude and duration of the action potential resulting in enhanced calcium entry in the cell of isolated muscle strips (Non-Excitatory Currents; NEC). Extracellular electrical stimuli delivered during the absolute refractory period (Cardiac Contractility Modulation; CCM) have recently been shown to produce inotropic effects in-vivo. Aim: Understanding the cellular mechanism, underlying the CCM effect, is essential for evaluating its clinical potential. We tested the hypothesis that NEC and CCM modulate contractility via similar cellular mechanisms. Methods: Square wave electric currents were applied in the organ bath to isometrically contracting rabbit RV papillary muscle and human failing trabecular muscle during the absolute refractory period (ARP). Results: These currents, which did not initiate new action potentials or contractions, modulated action potential duration (shortened or lengthened) and contractility (enhanced or depressed) in a manner that depended upon their amplitude, duration and delay from the pacing stimulus. The contractility modulation effect in the rabbit RV papillary muscle was markedly blunted after exposure to ryanodine, indicating that the sarcoplasmic reticulum plays an important role in the contractility modulation. Conclusion: Like voltage clamping, extracellular currents applied during the ARP can similarly modulate action potential duration in-vitro and modulate myocardial contractility by similar intracellular mechanisms. This concept provides the potential of a therapeutic strategy in patients with heart failure to enhance contractility.