Arrhythmic Genotypes in Familial Dilated Cardiomyopathy: Implications for Genetic Testing and Clinical Management

Peters, S.; Kumar, Saurabh; Elliott, Perry; Kalman, Jonathan M.; Fatkin, Diane

doi:10.1016/j.hlc.2018.09.010

Cited by 62 publications

(51 citation statements)

References 69 publications

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“…It should be noted that ALVC with LV segmental dysfunction can be confused with dilated cardiomyopathy or ischemic cardiomyopathy (chronic myocardial infarction). The prevalence of frequent ventricular arrhythmias reported in the literature was 30-42% [32][33][34] . Some special gene mutations in dilated cardiomyopathy such as DSP, LMNA, SCN5A, and FLNC have an arrhythmia rate of more than 30% 35 .…”

Section: Discussionmentioning

confidence: 99%

Arrhythmogenic Left Ventricular Cardiomyopathy: A Clinical and CMR Study

et al. 2020

Sci Rep

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The clinical features, CMR characteristics and outcomes of arrhythmogenic left ventricular cardiomyopathy (ALVC), which is a very rare nonischemic cardiomyopathy, are currently not well studied. The purpose of the study is to investigate the clinical and cardiovascular magnetic resonance (CMR) imaging characteristics of arrhythmogenic left ventricular cardiomyopathy (ALVC). Fiftythree consecutive patients with ALVC were divided into two groups: ALVC patients without right ventricular (RV) involvement (n = 36, group 1) and those with RV involvement (n = 17, group 2). Clinical symptoms, cardiac electrophysiological findings, and CMR parameters (morphology, ventricular function, and myocardial fibrosis and fatty infiltration) were evaluated in both groups. The two groups showed no significant difference in age, gender, or presenting symptoms (P > 0.05). Right bundle branch block ventricular arrhythmia was less common in patients without RV involvement (50.0% vs.64.7%, P = 0.031). There were no significant differences in left ventricular function between the two groups, however right ventricular ejection fraction was significantly lower in group 2 (40.1 ± 4.0% vs. 48.7 ± 3.9%, P < 0.001). Inverse correlations of left ventricular ejection fraction with fat volume (r = −0.883, p = 0.001), late gadolinium enhancement (LGE) volume (r = −0.892, 0.013), ratio of fat/ LGE (r = −0.848, p < 0.001), indexed left ventricular end diastolic volume (r = −0.877, p < 0.001) and indexed left ventricular end systolic volume (r = −0.943, p < 0.001) were all significant. ALVC is a rare disease with fibro-fatty replacement predominantly in the left ventricle, impaired left ventricular systolic function, and ventricular arrhythmias originating from the left ventricle. ALVC with right ventricular involvement may have a worse prognosis. Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare cardiomyopathy with a prevalence of 1/1000 to 1/5000 1. It has been described as an inherited cardiomyopathy characterized by progressive fibro-fatty or fatty replacement of the right ventricular (RV) myocardium resulting in abnormalities of RV morphology and function 2-5. Left ventricular function is often preserved at early stages of ARVC and even with end-stage disease, left ventricular morphology and function are much less affected than the right ventricle 4,6. However, cases of isolated

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Section: Discussionmentioning

confidence: 99%

Arrhythmogenic Left Ventricular Cardiomyopathy: A Clinical and CMR Study

et al. 2020

Sci Rep

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“…RNA-binding motif protein 20 is a splicing factor involved in regulating constitutive and alternative splicing of a number of key cardiac genes (sarcomeric, calcium regulation and ion regulation genes) [113,114]. Pathogenic RBM20 variants resulting in loss-of-function lead to missplicing of sarcomeric and calcium-handling genes, implicated in DCM (TTN missplicing considered to be the major contributing mechanism), and are associated with an aggressive early-onset phenotype with an increased predilection to cardiac transplantation, severe arrhythmia and SCD [114][115][116]. Brauch et al identified distinct heterozygous missense mutations in exon 9 of RBM20 in 2 large families with DCM [117].…”

Section: Rna-binding Motif Protein 20 (Rbm20) (Encoded By Rbm20)mentioning

confidence: 99%

State of the Art Review on Genetics and Precision Medicine in Arrhythmogenic Cardiomyopathy

Patel

Asatryan

Siripanthong

et al. 2020

IJMS

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Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiomyopathy characterised by ventricular arrhythmia and an increased risk of sudden cardiac death (SCD). Numerous genetic determinants and phenotypic manifestations have been discovered in ACM, posing a significant clinical challenge. Further to this, wider evaluation of family members has revealed incomplete penetrance and variable expressivity in ACM, suggesting a complex genotype-phenotype relationship. This review details the genetic basis of ACM with specific genotype-phenotype associations, providing the reader with a nuanced perspective of this condition; whilst also proposing a future roadmap to delivering precision medicine-based management in ACM.

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“…Left-dominant arrhythmogenic cardiomyopathy (LD-ACM) primarily involving the left ventricle and biventricular forms have also been described [ 74 , 75 ]. Furthermore, a growing body of data has shown genetic and clinical overlaps between LD-ACM and a subset of dilated cardiomyopathy (DCM) (so called arrhythmogenic-DCM, a-DCM) which presents with increased arrhythmogenic risk exceeding the degree of the morphological anomalies and systolic dysfunction [ 74 , 76 , 77 , 78 ]. On the basis of these observations, an expert panel of the Heart Rhythm Society (HRS) has proposed to include a-DCM, ARVC and LD-ACM in a common nosological entity whose hallmark is the electrical instability [ 11 ].…”

Section: Genetics Clinical and Histological Hallmarksmentioning

confidence: 99%

Established and Emerging Mechanisms in the Pathogenesis of Arrhythmogenic Cardiomyopathy: A Multifaceted Disease

Gao

Puthenvedu

Lombardi

et al. 2020

IJMS

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Arrhythmogenic cardiomyopathy (ACM) is a heritable myocardial disease that manifests with cardiac arrhythmias, syncope, sudden cardiac death, and heart failure in the advanced stages. The pathological hallmark of ACM is a gradual replacement of the myocardium by fibroadiposis, which typically starts from the epicardium. Molecular genetic studies have identified causal mutations predominantly in genes encoding for desmosomal proteins; however, non-desmosomal causal mutations have also been described, including genes coding for nuclear proteins, cytoskeleton componentsand proteins involved in excitation-contraction coupling. Despite the poor prognosis, currently available treatments can only partially control symptoms and to date there is no effective therapy for ACM. Inhibition of the canonical Wnt/β-catenin pathway and activation of the Hippo and the TGF-β pathways have been implicated in the pathogenesis of ACM. Yet, our understanding of the molecular mechanisms involved in the development of the disease and the cell source of fibroadiposis remains incomplete. Elucidation of the pathogenesis of the disease could facilitate targeted approaches for treatment. In this manuscript we will provide a comprehensive review of the proposed molecular and cellular mechanisms of the pathogenesis of ACM, including the emerging evidence on abnormal calcium homeostasis and inflammatory/autoimmune response. Moreover, we will propose novel hypothesis about the role of epicardial cells and paracrine factors in the development of the phenotype. Finally, we will discuss potential innovative therapeutic approaches based on the growing knowledge in the field.

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Arrhythmic Genotypes in Familial Dilated Cardiomyopathy: Implications for Genetic Testing and Clinical Management

Cited by 62 publications

References 69 publications

Arrhythmogenic Left Ventricular Cardiomyopathy: A Clinical and CMR Study

Arrhythmogenic Left Ventricular Cardiomyopathy: A Clinical and CMR Study

State of the Art Review on Genetics and Precision Medicine in Arrhythmogenic Cardiomyopathy

Established and Emerging Mechanisms in the Pathogenesis of Arrhythmogenic Cardiomyopathy: A Multifaceted Disease

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