Truncating mutations in FLNC caused an overlapping phenotype of dilated and left-dominant arrhythmogenic cardiomyopathies complicated by frequent premature sudden death. Prompt implantation of a cardiac defibrillator should be considered in affected patients harboring truncating mutations in FLNC.

Dilated cardiomyopathy (DCM) represents a particular aetiology of systolic heart failure that frequently has a genetic background and usually affects young patients with few co-morbidities. The prognosis of DCM has improved substantially during the last decades due to more accurate aetiological characterization, the red-flag integrated approach to the disease, early diagnosis through systematic familial screening, and the concept of DCM as a dynamic disease requiring constant optimization of medical and non-pharmacological evidence-based treatments. However, some important issues in clinical management remain unresolved, including the role of cardiac magnetic resonance for diagnosis and risk categorization and the interaction between genotype and clinical phenotype, and arrhythmic risk stratification. This review offers a comprehensive survey of these and other emerging issues in the clinical management of DCM, providing where possible practical recommendations.

No abstract

Aims ACE‐inhibitors, β‐blockers, implantable cardioverter–defibrillator (ICD) and cardiac resynchronization therapy (CRT) improved prognosis of heart failure. We sought to analyse the long‐term prognostic impact of evidence‐based integrated therapeutic strategies in patients with idiopathic dilated cardiomyopathy (IDCM). Methods and results From 1978 to 2007, 853 IDCM patients (45 ± 15 years, 72% males) were enrolled and classified as follows: Group 1, 110 patients (12.8%) enrolled during 1978–1987; Group 2, 376 patients (44.1%) enrolled during 1988–1997; Group 3, 367 patients (43.1%) enrolled during 1998–2007. ACE‐inhibitors/angiotensin receptor blockers were administered in 34%, 93%, and 93% (P <0.001), and β‐blockers in 11%, 82%, and 86% (P <0.001) in Groups 1, 2, and 3, respectively; ICDs were implanted in 2%, 14%, and 13% (P = 0.005); mean time to device implantation was lower in Group 3. At 8 years, heart transplant (HTx)‐free survival rates were 55%, 71%, and 87% in Groups 1, 2, and 3, respectively (P <0.001). Similar progressive improvement was found for pump‐failure death (DHF)/HTx, while survival free from sudden death (SD) was significantly improved only in Group 3. Multivariable models considering competing risk indicated early diagnosis (i.e. a baseline less advanced disease stage) and tailored medical therapy (HR 0.44, CI 95% 0.19–0.98) as independent protectors against DHF/HTx. Concerning SD, lower left ventricular ejection fraction emerged as a predictor, while ICD was the only therapy with a protective role (HR 0.08, CI 95% 0.01–0.61). Treatment with digitalis emerged as a predictor of both DHF/HTx and SD. Conclusions An effective management and evidence‐based integrated therapeutic approach progressively and significantly improved the long‐term prognosis of IDCM during the last three decades.

Left ventricular ejection fraction (EF) remains the major parameter for diagnosis, phenotyping, prognosis and treatment decisions in heart failure. The 2016 ESC heart failure guidelines introduced a third EF category for an EF of 40–49%, defined as heart failure with mid-range EF (HFmrEF). This category has been largely unexplored compared with heart failure with reduced EF (HFrEF; defined as EF <40% in this Review) and heart failure with preserved EF (HFpEF; defined as EF ≥50%). The prevalence of HFmrEF within the overall population of patients with HF is 10–25%. HFmrEF seems to be an intermediate clinical entity between HFrEF and HFpEF in some respects, but more similar to HFrEF in others, in particular with regard to the high prevalence of ischaemic heart disease in these patients. HFmrEF is milder than HFrEF, and the risk of cardiovascular events is lower in patients with HFmrEF or HFpEF than in those with HFrEF. By contrast, the risk of non-cardiovascular adverse events is similar or greater in patients with HFmrEF or HFpEF than in those with HFrEF. Evidence from post hoc and subgroup analyses of randomized clinical trials and a trial of an SGLT1–SGLT2 inhibitor suggests that drugs that are effective in patients with HFrEF might also be effective in patients with HFmrEF. Although the EF is a continuous measure with considerable variability, in this comprehensive Review we suggest that HFmrEF is a useful categorization of patients with HF and shares the most important clinical features with HFrEF, which supports the renaming of HFmrEF to HF with mildly reduced EF.

No abstract

Background: Variants in the cardiomyocyte-specific RNA splicing factor RBM20 have been linked to familial cardiomyopathy but the causative genetic architecture and clinical consequences of this disease are incompletely defined. Methods and Results: To define the genetic architecture of RBM20 cardiomyopathy, we first established a database of RBM20 variants associated with cardiomyopathy and compared these to variants observed in the general population with respect to their location in the RBM20 coding transcript. We identified two regions significantly enriched for cardiomyopathy-associated variants in exons 9 and 11. We then assembled a registry of 74 patients with RBM20 variants from 8 institutions across the world (44 index cases and 30 from cascade testing). This RBM20 patient registry revealed highly prevalent family history of sudden cardiac death (51%) and cardiomyopathy (72%) among index cases, and a high prevalence of composite arrhythmias (including AF, NSVT, ICD discharge and sudden cardiac arrest, 43%). Patients harboring variants in cardiomyopathy-enriched regions identified by our variant database analysis were enriched for these findings. Further, these characteristics were more prevalent in the RBM20 registry than in large cohorts of patients with DCM and titin (TTNtv) cardiomyopathy, and not significantly different from a cohort of patients with Lamin A/C associated (LMNA) cardiomyopathy. Conclusions: Our data establish RBM20 cardiomyopathy as a highly penetrant and arrhythmogenic cardiomyopathy. These findings underline the importance of arrhythmia surveillance and family screening in this disease and represent the first step in defining the genetic architecture of RBM20 disease causality on a population level. −/− mice demonstrate pro-arrhythmic calcium release from the sarcoplasmic reticulum 45. Parikh et al.

Background: Truncating variants in the TTN gene (TTNtv) are the commonest cause of heritable dilated cardiomyopathy. This study aimed to study the phenotypes and outcomes of TTNtv carriers. Methods: Five hundred thirty-seven individuals (61% men; 317 probands) with TTNtv were recruited in 14 centers (372 [69%] with baseline left ventricular systolic dysfunction [LVSD]). Baseline and longitudinal clinical data were obtained. The primary end point was a composite of malignant ventricular arrhythmia and end-stage heart failure. The secondary end point was left ventricular reverse remodeling (left ventricular ejection fraction increase by ≥10% or normalization to ≥50%). Results: Median follow-up was 49 (18–105) months. Men developed LVSD more frequently and earlier than women (45±14 versus 49±16 years, respectively; P =0.04). By final evaluation, 31%, 45%, and 56% had atrial fibrillation, frequent ventricular ectopy, and nonsustained ventricular tachycardia, respectively. Seventy-six (14.2%) individuals reached the primary end point (52 [68%] end-stage heart failure events, 24 [32%] malignant ventricular arrhythmia events). Malignant ventricular arrhythmia end points most commonly occurred in patients with severe LVSD. Male sex (hazard ratio, 1.89 [95%CI, 1.04–3.44]; P =0.04) and left ventricular ejection fraction (per 10% decrement from left ventricular ejection fraction, 50%; hazard ratio, 1.63 [95%CI, 1.30–2.04]; P <0.001) were independent predictors of the primary end point. Two hundred seven of300 (69%) patients with LVSD had evidence of left ventricular reverse remodeling. In a subgroup of 29 of74 (39%) patients with initial left ventricular reverse remodeling, there was a subsequent left ventricular ejection fraction decrement. TTNtv location was not associated with statistically significant differences in baseline clinical characteristics, left ventricular reverse remodeling, or outcomes on multivariable analysis ( P =0.07). Conclusions: TTNtv is characterized by frequent arrhythmia, but malignant ventricular arrhythmias are most commonly associated with severe LVSD. Male sex and LVSD are independent predictors of outcomes. Mutation location does not impact clinical phenotype or outcomes.