The heart muscle diseases hypertrophic (HCM) and dilated (DCM) cardiomyopathies are leading causes of sudden death and heart failure in young otherwise healthy individuals. We conducted genome-wide association studies (GWAS) and multi-trait analyses in HCM (1,733 cases), DCM (5,521 cases), and nine left ventricular (LV) traits in 19,260 UK Biobank participants with structurally normal hearts. We identified 16 loci associated with HCM, 13 with DCM, and 23 with LV traits. We show strong genetic correlations between LV traits and cardiomyopathies, with opposing effects in HCM and DCM. Two-sample Mendelian randomization supports a causal association linking increased contractility with HCM risk. A polygenic risk score (PRS) explains a significant portion of phenotypic variability in carriers of HCM-causing rare variants. Our findings thus provide evidence that PRS may account for variability in Mendelian diseases. More broadly, we provide insights into how genetic pathways may lead to distinct disorders through opposing genetic effects.

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is an inherited cardiomyopathy that can lead to sudden cardiac death and heart failure. Our understanding of its pathophysiology and clinical expressivity is continuously evolving. The diagnosis of ARVC/D remains particularly challenging due to the absence of specific unique diagnostic criteria, its variable expressivity, and incomplete penetrance. Advances in genetics have enlarged the clinical spectrum of the disease, highlighting possible phenotypes that overlap with arrhythmogenic dilated cardiomyopathy and channelopathies. The principal challenges for ARVC/D diagnosis include the following: earlier detection of the disease, particularly in cases of focal right ventricular involvement; differential diagnosis from other arrhythmogenic diseases affecting the right ventricle; and the development of new objective electrocardiographic and imaging criteria for diagnosis. This review provides an update on the diagnosis of ARVC/D, focusing on the contribution of emerging imaging techniques, such as echocardiogram/magnetic resonance imaging strain measurements or computed tomography scanning, new electrocardiographic parameters, and high-throughput sequencing.

Dilated cardiomyopathy (DCM) is defined by the presence of left ventricular or biventricular dilatation and systolic dysfunction in the absence of abnormal loading conditions or coronary artery disease sufficient to explain these changes. This is a heterogeneous disease frequently having a genetic background. Imaging is important for the diagnosis, the prognostic assessment and for guiding therapy. A multimodality imaging approach provides a comprehensive evaluation of all the issues related to this disease. The present document aims to provide recommendations for the use of multimodality imaging according to the clinical question. Selection of one or another imaging technique should be based on the clinical condition and context. Techniques are presented with the aim to underscore what is ‘clinically relevant’ and what are the tools that ‘can be used’. There remain some gaps in evidence on the impact of multimodality imaging on the management and the treatment of DCM patients where ongoing research is important.

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Sudden cardiac death (SCD) accounts for 10–20% of total mortality, i.e., one in five individuals will eventually die suddenly. Given the substantial genetic component of SCD in younger cases, postmortem genetic testing may be particularly useful in elucidating etiological factors in the cause of death in this subset. The identification of genes responsible for inherited cardiac diseases have led to the organization of cardiogenetic consultations in many countries worldwide. Expert recommendations are available, emphasizing the importance of genetic testing and appropriate information provision of affected individuals, as well as their relatives. However, the context of postmortem genetic testing raises some particular ethical, legal, and practical (including economic or financial) challenges. The Public and Professional Policy Committee of the European Society of Human Genetics (ESHG), together with international experts, developed recommendations on management of SCD after a workshop sponsored by the Brocher Foundation and ESHG in November 2016. These recommendations have been endorsed by the ESHG Board, the European Council of Legal Medicine, the European Society of Cardiology working group on myocardial and pericardial diseases, the ERN GUARD-HEART, and the Association for European Cardiovascular Pathology. They emphasize the importance of increasing the proportion of both medical and medicolegal autopsies and educating the professionals. Multidisciplinary collaboration is of utmost importance. Public funding should be allocated to reach these goals and allow public health evaluation.

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.

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Lamins are intermediate filament proteins able to polymerise and form an organised meshwork underlying the inner nuclear membrane in most differentiated somatic cells. Mutations in the LMNA gene, which encodes the two major lamin A and C isoforms, cause a diverse range of diseases, called laminopathies, including dilated cardiomyopathy, associated with a poor prognosis and high rate of sudden death due to conduction defect and early ventricular arrhythmia. Identification of mutations inLMNAgene in clinical practice is rapidly increasing, as well as comprehensive cardiac and genetic family screening. As a consequence, cardiologists are more and more frequently faced to difficult questions regarding optimal management of patients and relatives, especially timing for prophylactic cardioverter defibrillator. This review focuses on recent data useful for the clinician, as well as therapeutic perspectives both in human and animal models.