Aims Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a life-threatening entity with a highly heterogeneous genetic background. Cardiac magnetic resonance (CMR) imaging can identify fibrofatty scar by late gadolinium enhancement (LGE). Our aim is to investigate genotype–phenotype correlation in ARVC/D mutation carriers, focusing on CMR-LGE and myocardial fibrosis patterns. Methods and results A cohort of 44 genotyped patients, 33 with definite and 11 with borderline ARVC/D diagnosis, was characterized using CMR and divided into groups according to their genetic condition (desmosomal, non-desmosomal mutation, or negative). We collected information on cardiac volumes and function, as well as LGE pattern and extension. In addition, available ventricular myocardium samples from patients with pathogenic gene mutations were histopathologically analysed. Half of the patients were women, with a mean age of 41.6 ± 17.5 years. Next-generation sequencing identified a potential pathogenic mutation in 71.4% of the probands. The phenotype varied according to genetic status, with non-desmosomal male patients showing lower left ventricular (LV) systolic function. LV fibrosis was similar between groups, but distribution in non-desmosomal patients was frequently located at the posterolateral LV wall; a characteristic LV subepicardial circumferential LGE pattern was significantly associated with ARVC/D caused by desmin mutation. Histological analysis showed increased fibrillar connective tissue and intercellular space in all the samples. Conclusion Desmosomal and non-desmosomal mutation carriers showed different morphofunctional features but similar LV LGE presence. DES mutation carriers can be identified by a specific and extensive LV subepicardial circumferential LGE pattern. Further studies should investigate the specificity of LGE in ARVC/D.
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.
Background: Arrhythmogenic cardiomyopathy (AC) is a life-threatening disease which predispose to malignant arrhythmias and sudden cardiac death (SCD) in the early stages of the disease. Risk stratification relies on the electrical, genetic, and imaging data. Our study aimed to investigate how myocardial deformation parameters may identify the subjects at risk of known predictors of major ventricular arrhythmias.Methods: A cohort of 45 subjects with definite or borderline diagnosis of AC was characterized using the advanced transthoracic echocardiography (TTE) and cardiac magnetic resonance (CMR) and divided into the groups according to the potential arrhythmic risk markers, such as non-sustained ventricular tachycardia (NSVT), late gadolinium enhancement (LGE), and genetic status. Layer-specific global longitudinal strain (GLS) by TTE 2D speckle tracking was compared in patients with and without these arrhythmic risk markers.Results: In this study, 23 (51.1%) patients were men with mean age of 43 ± 16 years. Next-generation sequencing identified a potential pathogenic mutation in 39 (86.7%) patients. Thirty-nine patients presented LGE (73.3%), mostly located at the subepicardial-to-mesocardial layers. A layer-specific-GLS analysis showed worse GLS values at the epicardial and mesocardial layers in the subjects with NSVT and LGE. The epicardial GLS values of −15.4 and −16.1% were the best cut-off values for identifying the individuals with NSVT and LGE, respectively, regardless of left ventricular ejection fraction (LVEF).Conclusions: The layer-specific GLS assessment identified the subjects with high-risk arrhythmic features in AC, such as NSVT and LGE. An epicardial GLS may emerge as a potential instrument for detecting the subjects at risk of SCD in AC.
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