IMPORTANCETruncating variants in the gene encoding filamin C (FLNCtv) are associated with arrhythmogenic and dilated cardiomyopathies with a reportedly high risk of ventricular arrhythmia.OBJECTIVE To determine the frequency of and risk factors associated with adverse events among FLNCtv carriers compared with individuals carrying TTN truncating variants (TTNtv). DESIGN, SETTING, AND PARTICIPANTSThis cohort study recruited 167 consecutive FLNCtv carriers and a control cohort of 244 patients with TTNtv matched for left ventricular ejection fraction (LVEF) from 19 European cardiomyopathy referral units between 1990 and 2018. Data analyses were conducted between June and October, 2020. MAIN OUTCOMES AND MEASURESThe primary end point was a composite of malignant ventricular arrhythmia (MVA) (sudden cardiac death, aborted sudden cardiac death, appropriate implantable cardioverter-defibrillator shock, and sustained ventricular tachycardia) and end-stage heart failure (heart transplant or mortality associated with end-stage heart failure). The secondary end point comprised MVA events only. RESULTSIn total, 167 patients with FLNCtv were studied (55 probands [33%]; 89 men [53%]; mean [SD] age at baseline evaluation, 43 [18] years). For a median follow-up of 20 months (interquartile range, 7-60 months), 29 patients (17.4%) reached the primary end point (19 patients with MVA and 10 patients with end-stage heart failure). Eight (44%) arrhythmic events occurred among individuals with baseline mild to moderate left ventricular systolic dysfunction (LVSD) (LVEF = 36%-49%). Univariable risk factors associated with the primary end point included proband status, LVEF decrement per 10%, ventricular ectopy (Ն500 in 24 hours) and myocardial fibrosis detected on cardiac magnetic resonance imaging. The LVEF decrement (hazard ratio [HR] per 10%, 1.83 [95% CI, 1.30-2.57]; P < .001) and proband status (HR, 3.18 [95% CI, 1.12-9.04]; P = .03) remained independent risk factors on multivariable analysis (excluding myocardial fibrosis and ventricular ectopy owing to case censoring). There was no difference in freedom from MVA between FLNCtv carriers with mild to moderate or severe (LVEF Յ35%) LVSD (HR, 1.29 [95% CI,]; P = .64). Carriers of FLNCtv with impaired LVEF at baseline evaluation (n = 69) had reduced freedom from MVA compared with 244 TTNtv carriers with similar baseline LVEF (for mild to moderate LVSD: HR, 16.41 [95% CI,]; P < .001; for severe LVSD: HR, 2.47 [95% CI, 1.04-5.87]; P = .03). CONCLUSIONS AND RELEVANCEThe high frequency of MVA among patients with FLNCtv with mild to moderate LVSD suggests that higher LVEF values than those currently recommended should be considered for prophylactic implantable cardioverter-defibrillator therapy in FLNCtv carriers.

twitter: @dr_pavia // @fernidom Tweet: "Natural history study of PRKAG2 syndrome reveals high rates of AF, conduction disease, advanced HF and life-threatening arrhythmias." ABSTRACT Background: PRKAG2 gene variants cause a syndrome characterised by cardiomyopathy, conduction disease and ventricular preexcitation. Only a small number of cases have been reported to date, and the natural history of the disease is poorly understood. Objectives: To describe phenotype and natural history of PRKAG2 variants in a large multicenter European cohort. Methods: We retrospectively studied clinical, electrocardiographic and echocardiographic data from 90 individuals with PRKAG2 variants (53% males, median 33 years (IQR: 15-50) recruited from 27 centers. Results: At first evaluation, 93% of patients were in NYHA functional class I or II. Maximum left ventricular (LV) wall thickness was 18±8 mm and LV ejection fraction was 61±12%. LV hypertrophy (LVH) was present in 60 (67%) subjects at baseline. Thirty patients (33%) had ventricular preexcitation or had undergone an accessory pathway ablation; 17 (19%) had a pacemaker (median age at implantation 36 years (IQR: 27-46)) and 16 (18%) had atrial fibrillation (AF) (median age 43 years (IQR: 31-54)). After a median follow-up of 6 years (IQR:2.3-13.9), 71% of individuals had LVH, 29% had AF, 21% a de novo pacemaker (median age at implantation 37 years (IQR: 29-48)), 14% required admission for heart failure (HF), 8% experienced sudden cardiac death or equivalent, 4% required a heart transplant and 13% died. Conclusions: PRKAG2 syndrome is a progressive cardiomyopathy characterized by high rates of AF, conduction disease, advanced HF and life-threatening arrhythmias. Classical features of preexcitation and severe LVH are not uniformly present and diagnosis should be considered in patients with LVH who develop AF or require a PPM at a young age.

Aims Dilated cardiomyopathy (DCM) associated with dystrophin gene (DMD) mutations in individuals with mild or absent skeletal myopathy is often indistinguishable from other DCM forms. We sought to describe the phenotype and prognosis of DMD associated DCM in DMD mutation carriers without severe skeletal myopathy. Methods and results At 26 European centres, we retrospectively collected clinical characteristics and outcomes of 223 DMD mutation carriers (83% male, 33 ± 15 years). A total of 112 individuals (52%) had DCM at first evaluation [n = 85; left ventricular ejection fraction (LVEF) 34 ± 11.2%] or developed DCM (n = 27; LVEF 41.3 ± 7.5%) after a median follow‐up of 96 months (interquartile range 5–311 months). DCM penetrance was 45% in carriers older than 40 years. DCM appeared earlier in males and was independent of the type of mutation, presence of skeletal myopathy, or elevated serum creatine kinase levels. Major adverse cardiac events (MACE) occurred in 22% individuals with DCM, 18% developed end‐stage heart failure and 9% sudden cardiac death or equivalent. Skeletal myopathy was not associated with survival free of MACE in patients with DCM. Decreased LVEF and increased left ventricular end‐diastolic diameter at baseline were associated with MACE. Individuals without DCM had favourable prognosis without MACE or death during follow‐up. Conclusions DMD‐associated DCM without severe skeletal myopathy is characterized by incomplete penetrance but high risk of MACE, including progression to end‐stage heart failure and ventricular arrhythmias. DCM onset is the major determinant of prognosis with similar survival regardless of the presence of skeletal myopathy.

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