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Introduction Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically determined heart disease characterized by fibrofatty infiltrations in the myocardium, right and/or left ventricular involvement, and ventricular tachyarrhythmias. Although ten genes have been associated with ARVC, only about 40% of the patients have an identifiable disease-causing mutation. In the present study we aimed at investigating the involvement of the genes SCN1B - SCN4B , FHL1 , and LMNA in the pathogenesis of ARVC. Methods Sixty-five unrelated patients (55 fulfilling ARVC criteria and 10 borderline cases) were screened for variants in SCN1B - 4B , FHL1 , and LMNA by direct sequencing and LightScanner melting curve analysis. Results A total of 28 sequence variants were identified: seven in SCN1B , three in SCN2B , two in SCN3B , two in SCN4B , four in FHL1 , and ten in LMNA . Three of the variants were novel. One of the variants was non-synonymous. No disease-causing mutations were identified. Conclusions In our limited sized cohort the six studied candidate genes were not associated with ARVC.

Evaluation of: Huang M, Zhang X, Chen S et al. The effect of carvedilol treatment on chronic heart failure in pediatric patients with dilated cardiomyopathy: a prospective, randomized-controlled study. Pediatr. Cardiol. 34, 680–685 (2013). A role for β-blockers in children with heart failure has not been established. Huang et al. conducted a randomized trial of oral carvedilol in children with dilated cardiomyopathy treated with conventional therapy for a minimum of 1 month. The primary end points were Ross score, echocardiographic parameters, brain natriuretic peptide levels and a composite clinical end point. Of the subjects assessed at 6 months, 41 had received carvedilol (up to 0.8 mg/kg/day) and 37 had not (control group). Carvedilol had favorable effects on Ross score, left ventricular function and brain natriuretic peptide levels. However, improvement was also seen in the control group, although this was not as pronounced. Composite end points were similar in the carvedilol-treated and control groups. Only one serious adverse event was observed. The results suggest a possible beneficial effect of carvedilol when added to conventional therapy, but a number of limitations of study design restrict the conclusions that can be drawn.

The two-pore domain potassium channel, K2P3.1 (TASK-1) modulates background conductance in isolated human atrial cardiomyocytes and has been proposed as a potential drug target for atrial fibrillation (AF). TASK-1 knockout mice have a predominantly ventricular phenotype however, and effects of TASK-1 inactivation on atrial structure and function have yet to be demonstrated in vivo. The extent to which genetic variation in KCNK3, that encodes TASK-1, might be a determinant of susceptibility to AF is also unknown. To address these questions, we first evaluated the effects of transient knockdown of the zebrafish kcnk3a and kcnk3b genes and cardiac phenotypes were evaluated using videomicroscopy. Combined kcnk3a and kcnk3b knockdown in 72 hour post fertilization embryos resulted in lower heart rate (p0.001), marked increase in atrial diameter (p0.001), and mild increase in end-diastolic ventricular diameter (p=0.01) when compared with control-injected embryos. We next performed genetic screening of KCNK3 in two independent AF cohorts (373 subjects) and identified three novel KCNK3 variants. Two of these variants, present in one proband with familial AF, were located at adjacent nucleotides in the Kozak sequence and reduced expression of an engineered reporter. A third missense variant, V123L, in a patient with lone AF, reduced resting membrane potential and altered pH sensitivity in patch-clamp experiments, with structural modeling predicting instability in the vicinity of the TASK-1 pore. These in vitro data suggest that the double Kozak variants and V123L will have loss-of-function effects on ITASK. Cardiac action potential modeling predicted that reduced ITASK prolongs atrial action potential duration, and that this is potentiated by reciprocal changes in activity of other ion channel currents. Our findings demonstrate the functional importance of ITASK in the atrium and suggest that inactivation of TASK-1 may have diverse effects on atrial size and electrophysiological properties that can contribute to an arrhythmogenic substrate.

Arrhythmogenic right ventricular cardiomyopathy is an inherited disease of the cardiomyocyte. The disease is diagnosed as a syndrome based on criteria that include ventricular arrhythmias, electrocardiographic findings, imaging, tissue characteristics and family history. An implantable cardioverter-defibrillator is generally recommended. Novel insight into the molecular genetic background has established that the disease may be associated with mutation in the genes encoding desmosomal proteins. Genetic testing is expected to facilitate the diagnostic workup and treatment of patients and their families.

A single report has associated mutations in TMEM43 (LUMA) with a distinctive form of arrhythmogenic right ventricular cardiomyopathy (ARVC). We aimed at performing mutational analysis of the gene and characterizing the associated immunohistochemical features. Sixty-five unrelated patients (55 fulfilling Task Force criteria and 10 borderline cases) were screened for mutations in TMEM43. Immunohistochemistry with anti-TMEM43, anti-plakoglobin, anti-plakophilin-2, anti-connexin-43, and anti-emerin antibodies was performed on myocardium from TMEM43-positive patients (n = 3) and healthy controls (n = 3). The genetic screening identified heterozygous variants in two families: one reported mutation (c.1073C> T; in two related patients) and one novel variant (c.705+ 7G> A; in one patient) of unknown significance. All three patients fulfilled Task Force criteria and did not carry mutations in any other ARVC-related gene. Immunostaining with TMEM43 antibody showed intense staining of the sarcolemma. The signal level was reduced in all the three TMEM43-positive patients. Immunostaining with plakoglobin-specific antibody also showed reduced signal levels in the three carriers. All patients displayed a similar immunoreactive signal for plakophilin-2, connexin-43, and emerin. In conclusion, two TMEM43 sequence variants were identified in this Danish ARVC cohort. Evaluation of the expression of TMEM43 showed a unique cardiac localization. The immunoreactive signal for the desmosomal protein plakoglobin was reduced in mutation carriers. The TMEM43 gene underlies a distinctive form of ARVC which may share a final common pathway with desmosome-associated ARVC.

INTRODUCTION: Structural right atrial abnormalities have been described in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). However, little is known about electrocardiographic signs of atrial involvement in ARVC because no systematic studies have been conducted. METHODS: P-wave-triggered signal-averaged orthogonal electrocardiogram from 40 ARVC patients (46 ± 15 years, 16 females) was compared with recordings from age- and sex-matched healthy control subjects for assessment of P-wave duration and morphology. P-wave morphology was classified with regard to the P-wave polarity in leads X, Y, and Z. RESULTS: P-wave duration was longer in patients (135 ± 18 vs 124 ± 12 milliseconds; P = .003). Two typical P-wave morphologies were identified in the controls: positive in X and Y and negative (45%) or biphasic (55%) in Z. In patients with ARVC , typical P waves were seen in only 60%, whereas 15 patients (37%) had atypical P-wave positive in all 3 leads (P < .0001). The presence of atypical P waves in the ARVC group was not associated with the presence of either structural or functional right ventricular abnormality. CONCLUSIONS: Patients with ARVC commonly demonstrate deteriorated atrial activation expressed either as prolonged P-wave duration or abnormal P-wave morphology. The P-wave abnormalities were not secondary to right ventricular dilatation. These findings show that atrial involvement is common in ARVC and may represent yet another manifestation of the disease to be considered for inclusion in ARVC diagnostic workup. (Less)

The aim of this study was to investigate the age, sex, etiology, frequency of implantable cardioverter-defibrillator (ICD) and previous cardiac arrest among patients discharged from the Department of Cardiology, Rigshospitalet (Copenhagen University Hospital), Denmark, due to ventricular tachyarrhythmias.We conducted a retrospective review of 993 patients discharged from Rigshospitalet over 6 years and 5 months with the diagnostic codes ventricular tachycardia, ventricular fibrillation or premature ventricular contractions.The population had an average age of 59 years (ranging 15-95 years) with a majority of males (76%). Among the patients with known etiology ischemic heart disease (60%), dilated cardiomyopathy (6%) and arrhythmogenic right ventricular cardiomyopathy (6%) were the most frequent. A substantial number of the patients (15%) had unknown etiology; 492 (50%) of the patients overall had an ICD implanted, the majority of whom had been categorized as having ventricular tachycardia (92%); 168 patients had previous cardiac arrest, 127 of whom did not have a potential reversible cause. Of this group 75 (59%) had an ICD implanted.Ischemic heart disease is the most common cause of ventricular tachyarrhythmias. Approximately half the patients admitted with ventricular tachyarrhythmias had an ICD implanted, the majority of whom did not have previous cardiac arrest.

The purpose of this study was to determine the number and distribution of cardiomyopathies as the aetiology of ventricular tachyarrhythmias among patients discharged from the Department of Cardiology, Rigshospitalet.The study was a retrospective review of patients discharged with the diagnostic codes ventricular tachycardia, ventricular fibrillation or premature ventricular contractions with cardiomyopathy as the presumed aetiology. Patients discharged during a period of 6 years and 5 months were included in the study. The patients were characterized by disease, gender, age, previous cardiac arrest and treatment with implantable cardioverter-defibrillator (ICD).993 patients were screened and 128 patients with cardiomyopathy were identified, corresponding to 13% of the screened patients. 58 (45%) of the patients had dilated cardiomyopathy (DCM), 57 (45%) patients had arrhythmogenic right ventricular cardiomyopathy (ARVC) and 13 (10%) had hypertrophic cardiomyopathy (HCM). The average age was 44 years for HCM, 41 years for ARVC and 58 years for DCM. The majority of the patients were male. ICD treatment was used in 95% of the patients with ARVC, 70% of the patients with HCM and 59% of the patients with DCM. Only 5 patients had previous cardiac arrest without reversible cause.The study shows that cardiomyopathies are relatively frequent causes of ventricular tachyarrhythmias in patients discharged from a specialised cardiology department. Implantation of an ICD device has a central position in the treatment of patients with cardiomyopathy and ventricular tachyarrythmias and is primarily used as a prophylactic treatment.

I. Martin , A. Christensen , M. Soka , D. Fatkin 1,2 Molecular Cardiology Division, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia Faculty of Medicine, University of New South Wales, Kensington, New South Wales, Australia Corresponding author. Background: Two-pore domain K (K2P) channels are key determinants of background K conductance in cardiomyocytes, providing dynamic regulation of cellular membrane potential. As these channels are highly expressed and functionally active in human atria they may play a role in the pathogenesis of atrial fibrillation and could be novel drug targets. We have recently shown that genetic alterations in a member of the K2P family, TASK-1, cause atrial remodeling and electrophysiological abnormalities. However, very little is known about another K2P channel, TWIK-1. Methods and Results: We initially evaluated the loss of TWIK-1 function in vivo utilising a zebrafish model. Individual morpholino-mediated knockdown of the two zebrafish TWIK-1 orthologues, kcnk1a and kcnk1b, resulted in atrial dilation and bradycardia by 72 hours post fertilisation, which were aggravated when both genes were targeted simultanously (all p < 0.05). Subsequent genetic screening of KCNK1 in 165 unrelated human probands with familial atrial fibrillation resulted in the identification of 3 gene variants of interest; one common variant (p.R171H) significantly overrepresented in affected vs unaffected individuals, one rare (p.G236S), and one novel variant (p.I198M). Electrophysiological evaluation of these variants is ongoing. Conclusion: Our in vivo findings demonstrate the importance of TWIK-1 in the function and development of the atrium and the conduction system. Our mutation screening suggests that genetic variants in TWIK-1 may contribute to atrial arrhythmogenesis.

We have read with interest the paper by Pieroni et al. ([1][1]) addressing myocarditis as a common differential diagnosis to arrhythmogenic right ventricular cardiomyopathy (ARVC). Among 30 patients noninvasively fulfilling Task Force criteria ([2][2]) for ARVC, they found that 15 patients actually

Background Congenital heart diseases (CHDs) are the most common type of birth defects and account for a significant proportion of infant mortality. Previous studies have shown an increased prevalence of CHD among children born of women ≥35 years. During the last decades women in the Western world have been giving birth at an increasing age. This might affect the newborns cardiac electrical system. Purpose To investigate the effect of maternal age on the newborns electrocardiogram (ECG). Methods Electrocardiograms from 17,489 newborns (aged 0–30 days) consecutively included in a large, prospective general population study were analyzed. All tracings were acquired digitally and ECG intervals, amplitudes, axis, etc. were automatically analyzed with extensive manual validation. Results Among the 17,489 newborns the median age was 11 days and 52% were boys. The median maternal age was 31 years (range 16–54 years). Dividing the mothers into four age quartiles we had 840 ECG's from newborns with a maternal age between 15–24 years, 12,072 between 25–34 years, 4,525 between 35–44 years, and 52 between 45–54 years. Comparing the youngest and oldest mothers we found the ECG parameters (median values, age group 15–24 vs. 45–54 years) neonatal heart rate (143 vs. 147 beats per minute), PR-interval (98 vs. 96 ms), QRS-duration (54 vs. 56 ms), QT (274 vs. 277 ms), QTcB (419 vs. 423 ms), QRS axis (115 vs. 112 degrees), max V1 R-amplitude (1257 vs. 966μV), max V6 R-amplitude (825 vs. 937μV), max V1 S-amplitude (634 vs. 649 μV) and max V6 S-amplitude (654 vs. 615 μV) were not affected by maternal age (all p>0.05). The same was found when only analyzing the subgroup of newborns aged 0–7 days (all parameters p>0.05). Conclusion We provide data from a large general population study including a wide range of maternal ages. Our findings indicate that maternal age does not affect the newborns hearts electrical system. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): This work was supported by the Danish Children Heart Foundation, Snedkermester Sophus Jacobsen and wife Astrid Jacobsen's foundation (Grant 19-R112-A5248-26048), the Research Council at Herlev-Gentofte Hospital and Toyota-Fonden, Denmark.

Background The accessory electrical pathway in Wolff-Parkinson-White (WPW) syndrome predisposes to tachycardia and may increase risk of sudden cardiac death. Studies investigating the prevalence of this condition in newborns are few. Purpose To describe the prevalence of WPW syndrome and assess the localization of the accessory pathway and associated structural heart disease in newborns from a large general population study. Methods Electrocardiograms (ECG's) and echocardiograms of 17.489 newborns (aged 0–30 days) from a large, prospective general population study were included. WPW cases were identified through manual evaluation of outliers in measurements of PR-interval, QRS-duration, QTcB interval and QRS axis. Newborns suspected for WPW syndrome were offered a secondary echocardiogram and ECG recording. Localization of the accessory pathway was assessed based on a QRS polarity algorithm. The control group consisted of 5,000 randomly selected newborns with a normal echocardiogram. Results Among the 17,489 ECG's we manually analyzed 5,166 and found 15 newborns (80% boys) with WPW syndrome (secondary confirmatory ECG's will be available at ESC 2020) consistent with prevalence of WPW syndrome of 0.1%. The median values of the PR-interval, QRS-duration and QTcB in cases and controls were 80 vs 98 ms, 74 vs 56 ms, and 449 vs 420 ms, respectively (all p Conclusion The prevalence of WPW syndrome in our cohort was 0.1%. The syndrome was more frequent in boys, and the accessory pathways were mainly left-sided. All but one of the affected newborns had structurally normal hearts. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): This work was supported by the Danish Children Heart Foundation, Snedkermester Sophus Jacobsen and wife Astrid Jacobsen's foundation (Grant 19-R112-A5248-26048), the Research Council at Herlev-Gentofte Hospital and Toyota-Fonden, Denmark.