BackgroundPatients with dilated cardiomyopathy (DCM) may present with ventricular arrhythmias early in the disease course, unrelated to the severity of left ventricular dysfunction. These patients may be classified as having an arrhythmogenic DCM (AR‐DCM). We investigated the phenotype and natural history of patients with AR‐DCM.Methods and ResultsTwo hundred eighty‐five patients with a recent diagnosis of DCM (median duration of the disease 1 month, range 0 to 7 months) and who had Holter monitoring at baseline were comprehensively evaluated and followed for 107 months (range 29 to 170 months). AR‐DCM was defined by the presence of ≥1 of the following: unexplained syncope, rapid nonsustained ventricular tachycardia (≥5 beats, ≥150 bpm), ≥1000 premature ventricular contractions/24 hours, and ≥50 ventricular couplets/24 hours, in the absence of overt heart failure. The primary end points were sudden cardiac death (SCD), sustained ventricular tachycardia (SVT), or ventricular fibrillation (VF). The secondary end points were death from congestive heart failure or heart transplantation. Of the 285 patients, 109 (38.2%) met criteria for AR‐DCM phenotype. AR‐DCM subjects had a higher incidence of SCD/SVT/VF compared with non–AR‐DCM patients (30.3% vs 17.6%, P=0.022), with no difference in the secondary end points. A family history of SCD/SVT/VF and the AR‐DCM phenotype were statistically significant and cumulative predictors of SCD/SVT/VF.ConclusionsOne‐third of DCM patients may have an arrhythmogenic phenotype associated with increased risk of arrhythmias during follow‐up. A family history of ventricular arrhythmias in DCM predicts a poor prognosis and increased risk of SCD.
BackgroundThe titin gene (TTN) encodes the largest human protein, which plays a central role in sarcomere organization and passive myocyte stiffness. TTN truncating mutations cause dilated cardiomyopathy (DCM); however, the role of TTN missense variants in DCM has been difficult to elucidate because of the presence of background TTN variation.Methods and ResultsA cohort of 147 DCM index subjects underwent DNA sequencing for 313 TTN exons covering the N2B and N2BA cardiac isoforms of TTN. Of the 348 missense variants, we identified 44 “severe” rare variants by using a bioinformatic filtering process in 37 probands. Of these, 5 probands were double heterozygotes (additional variant in another DCM gene) and 7 were compound heterozygotes (2 TTN “severe” variants). Segregation analysis allowed the classification of the “severe” variants into 5 “likely” (cosegregating), 5 “unlikely” (noncosegregating), and 34 “possibly” (where family structure precluded segregation analysis) disease‐causing variants. Patients with DCM carrying “likely” or “possibly” pathogenic TTN “severe” variants did not show a different outcome compared with “unlikely” and noncarriers of a “severe” TTN variant. However, the “likely” and “possibly” disease‐causing variants were overrepresented in the C‐zone of the A‐band region of the sarcomere.Conclusions TTN missense variants are common and present a challenge for bioinformatic classification, especially when informative families are not available. Although DCM patients carrying bioinformatically “severe” TTN variants do not appear to have a worse clinical course than noncarriers, the nonrandom distribution of “likely” and “possibly” disease‐causing variants suggests a potential biological role for some TTN missense variants.
Dilated cardiomyopathy is a disease of the myocardium characterized by left ventricular dilatation and/or dysfunction, affecting both adult and pediatric populations. Almost half of cases are genetically determined with an autosomal pattern of inheritance. Up to 40 genes have been identified affecting proteins of a wide variety of cellular structures such as the sarcomere, the nuclear envelope, the cytoskeleton, the sarcolemma and the intercellular junction. Novel gene mutations have been recently identified thanks to advances in next-generation sequencing technologies. Genetic screening is an essential tool for early diagnosis, risk assessment, prognostic stratification and, possibly, adoption of primary preventive measures in affected patients and their asymptomatic relatives. The purpose of this article is to review the genetic basis of DCM, the known genotype-phenotype correlations, the role of current genetic sequencing techniques in the discovery of novel pathogenic gene mutations and new therapeutic perspectives.
Background In dilated cardiomyopathy (DCM), the clinical and prognostic implications of rare variants in sarcomeric genes remain poorly understood. To address this question, we analyzed the outcome of rare sarcomeric gene variants in patients enrolled in our Familial Cardiomyopathy Registry. Methods DCM families harboring rare sarcomeric variants in MYH6, MYH7, MYBPC3, TNNT2 and TTN were identified. Genotype-phenotype association analysis was performed, and long-term survival-free from death or heart transplant was compared between carriers and non-carriers. Results We found 24 rare variants (3 in MYH6, 3 in MYH7, 3 in MYBPC3, 2 in TNNT2 and 13 in TTN) affecting 52 subjects in 25 families. The phenotypes of variant carriers were severe (3 sudden deaths, 6 heart failure deaths, 8 heart transplants, 2 ventricular fibrillations). There was no difference in the overall long-term survival between carriers and the 33 non-carriers (p=0.322). However after 50 years of age, the combined endpoint of death or transplant was decreased in carriers as compared to non-carriers (p=0.026). Conclusions Patients with DCM carrying rare variants in sarcomeric genes manifest a poorer prognosis as compared to non-carriers after the age of 50 years. These data further support the role genetic testing in DCM for risk stratification.
Background Genotype-phenotype correlations are poorly characterized in arrhythmogenic right ventricular cardiomyopathy (ARVC). We investigated whether carriers of rare variants in desmosomal genes (DC) and titin gene (TTN) display different phenotypes and clinical outcomes, when compared to non-carriers (NT-ND). Methods and Results Thirty-nine ARVC families (173 subjects, 67 affected) with extensive follow up (mean 9 years), prospectively enrolled in the International Familial Cardiomyopathy Registry since 1991, were screened for rare variants in TTN and desmosomal genes (DSP, PKP2, DSG2, DSC2). Multiple clinical and outcome variables were compared between 3 genetic groups (TTN, DC, NT-ND) to define genotype-phenotype associations. Of the 39 ARVC families, 13% (5/39) carried TTN rare variants (11 affected subjects), 13% (5/39) DC (8 affected), while 74% (29/39) were NT-ND (48 affected). Compared to NT-ND, DC had a higher prevalence of inverted T waves in V2-3 (75% vs. 31%, p=0.004), while TTN had more supraventricular arrhythmias (46% vs. 13%, p=0.013) and conduction disease (64% vs. 6% p<0.001). Compared to the NT-ND group, the DC group experienced a worse prognosis (67% vs. 11%, p=0.03) and exhibited a lower survival free from death or heart transplant (59% vs. 95% at 30 years, and 31% vs. 89% at 50 years, HR 9.66, p=0.006), while the TTN group showed an intermediate survival curve (HR 4.26, p=0.037). Conclusions TTN carriers display distinct phenotypic characteristics including a greater risk for supraventricular arrhythmias and conduction disease. Conversely, DC are characterized by negative T waves in anterior leads, severe prognosis, high mortality and morbidity.
BackgroundArrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) carries a risk of sudden death. We aimed to assess whether vectorcardiographic (VCG) parameters directed toward the right heart and a measured angle of the S-wave would help differentiate ARVD/C with otherwise normal electrocardiograms from controls.MethodsTask Force 2010 definite ARVD/C criteria were met for all patients. Those who did not fulfill Task Force depolarization or repolarization criteria (−ECG) were compared with age and gender-matched control subjects. Electrocardiogram measures of a 3-dimentional spatial QRS-T angle, a right-precordial-directed orthogonal QRS-T (RPD) angle, a root mean square of the right sided depolarizing forces (RtRMS-QRS), QRS duration (QRSd) and the corrected QT interval (QTc), and a measured angle including the upslope and downslope of the S-wave (S-wave angle) were assessed.ResultsDefinite ARVD/C was present in 155 patients by 2010 Task Force criteria (41.7 ± 17.6 years, 65.2% male). -ECG ARVD/C patients (66 patients) were compared to 66 control patients (41.7 ± 17.6 years, 65.2% male). All parameters tested except the QRSd and QTc significantly differentiated -ECG ARVD/C from control patients (p < 0.004 to p < 0.001). The RPD angle and RtRMS-QRS best differentiated the groups. Combined, the 2 novel criteria gave 81.8% sensitivity, 90.9% specificity and odds ratio of 45.0 (95% confidence interval 15.8 to 128.2).ConclusionARVD/C disease process may lead to development of subtle ECG abnormalities that can be distinguishable using right-sided VCG or measured angle markers better than the spatial QRS-T angle, the QRSd or QTc, in the absence of Taskforce ECG criteria.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.