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Background: Truncating variants in desmoplakin ( DSP tv) are an important cause of arrhythmogenic cardiomyopathy; however the genetic architecture and genotype-specific risk factors are incompletely understood. We evaluated phenotype, risk factors for ventricular arrhythmias, and underlying genetics of DSP tv cardiomyopathy., Methods: Individuals with DSP tv and any cardiac phenotype, and their gene-positive family members were included from multiple international centers. Clinical data and family history information were collected. Event-free survival from ventricular arrhythmia was assessed. Variant location was compared between cases and controls, and literature review of reported DSP tv performed., Results: There were 98 probands and 72 family members (mean age at diagnosis 43±8 years, 59% women) with a DSP tv, of which 146 were considered clinically affected. Ventricular arrhythmia (sudden cardiac arrest, sustained ventricular tachycardia, appropriate implantable cardioverter defibrillator therapy) occurred in 56 (33%) individuals. DSP tv location and proband status were independent risk factors for ventricular arrhythmia. Further, gene region was important with variants in cases (cohort n=98; Clinvar n=167) more likely to occur in the regions resulting in nonsense mediated decay of both major DSP isoforms, compared with n=124 genome aggregation database control variants (148 [83.6%] versus 29 [16.4%]; P <0.0001)., Conclusions: In the largest series of individuals with DSP tv, we demonstrate that variant location is a novel risk factor for ventricular arrhythmia, can inform variant interpretation, and provide critical insights to allow for precision-based clinical management.

The etiology of dilated cardiomyopathy (DCM) can be grouped as either genetic or nongenetic. More than 50 pathogenic genes have been described, with sarcomeric and lamin A/C mutations being the most common. Mutation carriers for genetic DCM are often asymptomatic until cardiac disease manifests with heart failure, arrhythmias, or sudden cardiac death. Preventive strategies are promising but can only be applied and tested adequately if genetic DCM can be diagnosed at an early stage. Early diagnosis of mutation carriers that may develop overt DCM requires advanced imaging techniques that can detect subtle structural and functional abnormalities. Advanced echocardiographic techniques such as tissue Doppler imaging and speckle tracking strain analysis permit early detection of functional abnormalities, whereas cardiovascular magnetic resonance techniques provide information on tissue characterization and myocardial energetics that may be altered at an early stage. Furthermore, nuclear imaging techniques provide information on cellular function (metabolism, perfusion). Once the diagnosis of overt DCM has been established, various imaging parameters such as echocardiography-based myocardial mechanics and cardiovascular magnetic resonance-based tissue characterization have shown incremental benefit to left ventricular ejection fraction in risk stratification. Further research is required to understand how imaging techniques may help to choose management strategies that could delay progression when instituted early in the course of the disease. The present article reviews the role of imaging in the risk stratification of genetic DCM in general, with specific emphasis on DCM associated with neuromuscular disorders., (© 2018 American Heart Association, Inc.)

Background: Interpretation of missense variants can be especially difficult when the variant is also found in control populations. This is what we encountered for the LMNA c.992G>A (p.(Arg331Gln)) variant. Therefore, to evaluate the effect of this variant, we combined an evaluation of clinical data with functional experiments and morphological studies., Methods and Results: Clinical data of 23 probands and 35 family members carrying this variant were retrospectively collected. A time-to-event analysis was performed to compare the course of the disease with carriers of other LMNA mutations. Myocardial biopsies were studied with electron microscopy and by measuring force development of the sarcomeres. Morphology of the nuclear envelope was assessed with immunofluorescence on cultured fibroblasts. The phenotype in probands and family members was characterized by atrioventricular conduction disturbances (61% and 44%, respectively), supraventricular arrhythmias (69% and 52%, respectively), and dilated cardiomyopathy (74% and 14%, respectively). LMNA p.(Arg331Gln) carriers had a significantly better outcome regarding the composite end point (malignant ventricular arrhythmias, end-stage heart failure, or death) compared with carriers of other pathogenic LMNA mutations. A shared haplotype of 1 Mb around LMNA suggested a common founder. The combined logarithm of the odds score was 3.46. Force development in membrane-permeabilized cardiomyocytes was reduced because of decreased myofibril density. Structural nuclear LMNA -associated envelope abnormalities, that is, blebs, were confirmed by electron microscopy and immunofluorescence microscopy., Conclusions: Clinical, morphological, functional, haplotype, and segregation data all indicate that LMNA p.(Arg331Gln) is a pathogenic founder mutation with a phenotype reminiscent of other LMNA mutations but with a more benign course., (© 2017 American Heart Association, Inc.)

Background: Current methods for predicting adverse events in patients with hypertrophic cardiomyopathy are still limited. Left ventricular global longitudinal strain (GLS) and left atrial volume index (LAVI) have been recently proposed as novel prognostic factors in several cardiovascular diseases. The objective of this study was to evaluate the prognostic value of GLS and LAVI in patients with hypertrophic cardiomyopathy., Methods and Results: Two-dimensional echocardiography was performed in 427 patients with hypertrophic cardiomyopathy (66% men, age 52±15 years), and LAVI and GLS were assessed. During follow-up, the primary end point of all-cause mortality, heart transplantation, sudden cardiac death, and appropriate implantable cardioverter defibrillator therapy was noted. A total of 103 patients reached the primary end point during a follow-up of 6.7 (interquartile range, 3.3-10.0) years. Multivariable Cox regression analysis revealed GLS and LAVI to be independently associated with the primary end point (hazard ratio GLS, 1.10 [1.03-1.19], P =0.007; hazard ratio LAVI, 4.27 [2.35-7.74], P <0.001) after correcting for other clinical variables. When applying the pre-specified cut-off values of 34 mL/m 2 for LAVI and -15% for GLS, Kaplan-Meier survival curves showed significant better survival for patients with LAVI <34 mL/m 2 ( P <0.001) and GLS <-15% ( P <0.001) as compared with their counterparts. The likelihood ratio test showed a significant incremental prognostic value of LAVI and GLS ( P <0.001) as compared with a model with clinical and standard echocardiographic risk factors. The C-statistic for this model increased from 0.68 to 0.73 when adding GLS and LAVI., Conclusions: GLS and LAVI are independently associated with adverse outcome in patients with hypertrophic cardiomyopathy and may help to optimize risk stratification in these patients., (© 2017 American Heart Association, Inc.)