Desmosomal protein degradation as an underlying cause of arrhythmogenic cardiomyopathy.

Arrhythmogenic cardiomyopathy (ACM) is an inherited progressive cardiac disease. Many patients with ACM harbor mutations in desmosomal genes, predominantly in plakophilin-2 (). Although the genetic basis of ACM is well characterized, the underlying disease-driving mechanisms remain unresolved.

PITX2 induction leads to impaired cardiomyocyte function in arrhythmogenic cardiomyopathy.

Arrhythmogenic cardiomyopathy (ACM) is an inherited progressive disease characterized by electrophysiological and structural remodeling of the ventricles. However, the disease-causing molecular pathways, as a consequence of desmosomal mutations, are poorly understood. Here, we identified a novel missense mutation within desmoplakin in a patient clinically diagnosed with ACM.

No major role for rare plectin variants in arrhythmogenic right ventricular cardiomyopathy.

Aims: Likely pathogenic/pathogenic variants in genes encoding desmosomal proteins play an important role in the pathophysiology of arrhythmogenic right ventricular cardiomyopathy (ARVC). However, for a substantial proportion of ARVC patients, the genetic substrate remains unknown. We hypothesized that plectin, a cytolinker protein encoded by the PLEC gene, could play a role in ARVC because it has been proposed to link the desmosomal protein desmoplakin to the cytoskeleton and therefore has a potential function in the desmosomal structure.

Cardiac phenotype and long-term prognosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia patients with late presentation.

Background: The clinical profile of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) patients with late presentation is unknown.

Objective: The purpose of this study was to characterize the genotype, cardiac phenotype, and long-term outcomes of ARVC/D patients with late presentation (age ≥50 years at diagnosis).

Methods: Five hundred two patients with an ARVC/D diagnosis from Johns Hopkins and Utrecht Registries were studied and long-term clinical outcomes ascertained.

Risk Stratification in Arrhythmic Right Ventricular Cardiomyopathy Without Implantable Cardioverter-Defibrillators.

Objectives: The primary objective of this study is risk stratification of patients with arrhythmic right ventricular cardiomyopathy (ARVC).

Background: There is a need to identify those who need an automatic implantable defibrillator (ICD) to prevent sudden death.

Methods: This is an analysis of 88 patients with ARVC from three centers who were not treated with an ICD.

Pregnancy course and outcomes in women with arrhythmogenic right ventricular cardiomyopathy.

Objectives: To characterise pregnancy course and outcomes in women with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C).

Methods: From a combined Johns Hopkins/Dutch ARVD/C registry, we identified 26 women affected with ARVD/C (by 2010 Task Force Criteria) during 39 singleton pregnancies >13 weeks (1-4 per woman). Cardiac symptoms, treatment and episodes of sustained ventricular arrhythmias (VAs) and heart failure (HF) ≥ Class C were characterised.

Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy in the Pediatric Population: Clinical Characterization and Comparison With Adult-Onset Disease.

Objectives: The aims of this study were to determine the clinical characteristics and outcomes of pediatric-onset arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) and to compare these with those of adult-onset ARVD/C.

Background: Improved early detection and increased awareness of ARVD/C have led to a growing group of pediatric patients seeking management recommendations. Prior studies have mainly included adults with ARVD/C; however, clinical features and outcomes may differ in pediatric subjects.

Prolonged Electromechanical Interval Unmasks Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy in the Subclinical Stage.

Introduction: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is characterized by high incidence of ventricular arrhythmias. Overt ARVD/C is preceded by a subclinical stage with lack of detectable ECG and structural abnormalities. Activation delay is present before structural abnormalities and is a hallmark of arrhythmogenesis.

Approach to family screening in arrhythmogenic right ventricular dysplasia/cardiomyopathy.

Aims: A combination of variable expression, age-related penetrance, and unpredictable arrhythmic events complicates management of relatives of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) patients. We aimed to (i) determine predictors of ARVD/C diagnosis and (ii) optimize arrhythmic risk stratification among first-degree relatives of ARVD/C patients.

Methods And Results: Detailed phenotypic and outcome data of 274 first-degree relatives (46% male; 36.

Left Ventricular Involvement in Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Assessed by Echocardiography Predicts Adverse Clinical Outcome.

Background: Among studies describing the phenotype of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), significant discrepancy exists regarding the extent and impact of left ventricular (LV) involvement. The capability of conventional and new quantitative echocardiographic techniques to accurately detect LV involvement in ARVD/C remains unknown. The aim of this study was to test the hypothesis that accurate detection of LV involvement on echocardiography identifies patients at additional risk for cardiac events during follow-up.

Clinical Presentation, Long-Term Follow-Up, and Outcomes of 1001 Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Patients and Family Members.

Background: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a progressive cardiomyopathy. We aimed to define long-term outcome in a transatlantic cohort of 1001 individuals.

Methods And Results: Clinical and genetic characteristics and follow-up data of ARVD/C index-patients (n=439, fulfilling of 2010 criteria in all) and family members (n=562) were assessed.

Impact of genotype on clinical course in arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated mutation carriers.

Aims: We sought to determine the influence of genotype on clinical course and arrhythmic outcome among arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C)-associated mutation carriers.

Methods And Results: Pathogenic mutations in desmosomal and non-desmosomal genes were identified in 577 patients (241 families) from USA and Dutch ARVD/C cohorts. Patients with sudden cardiac death (SCD)/ventricular fibrillation (VF) at presentation (n = 36) were younger (median 23 vs.

Functional assessment of potential splice site variants in arrhythmogenic right ventricular dysplasia/cardiomyopathy.

Background: Interpretation of genetic screening results in arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) often is difficult. Pathogenicity of variants with uncertain clinical significance may be predicted by software algorithms. However, functional assessment can unambiguously demonstrate the effect of such variants.

Outcome in phospholamban R14del carriers: results of a large multicentre cohort study.

Background: The pathogenic phospholamban R14del mutation causes dilated and arrhythmogenic right ventricular cardiomyopathies and is associated with an increased risk of malignant ventricular arrhythmias and end-stage heart failure. We performed a multicentre study to evaluate mortality, cardiac disease outcome, and risk factors for malignant ventricular arrhythmias in a cohort of phospholamban R14del mutation carriers.

Methods And Results: Using the family tree mortality ratio method in a cohort of 403 phospholamban R14del mutation carriers, we found a standardized mortality ratio of 1.

Mutation-positive arrhythmogenic right ventricular dysplasia/cardiomyopathy: the triangle of dysplasia displaced.

Introduction: The traditional description of the Triangle of Dysplasia in Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) predates genetic testing and excludes biventricular phenotypes.

Methods And Results: We analyzed Cardiac Magnetic Resonance (CMR) studies of 74 mutation-positive ARVD/C patients for regional abnormalities on a 5-segment RV and 17-segment LV model. The location of electroanatomic endo- and epicardial scar and site of successful VT ablation was recorded in 11 ARVD/C subjects.

Arrhythmogenic right ventricular dysplasia/cardiomyopathy according to revised 2010 task force criteria with inclusion of non-desmosomal phospholamban mutation carriers.

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is frequently associated with desmosomal mutations. However, nondesmosomal mutations may be involved. The aim of this study was to assess the contribution of a phospholamban (PLN) gene mutation to ARVD/C diagnosis according to the revised 2010 task force criteria (TFC).

Malignant arrhythmogenic right ventricular dysplasia/cardiomyopathy with a normal 12-lead electrocardiogram: a rare but underrecognized clinical entity.

Background: In Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C), a normal electrocardiogram (ECG) is considered reassuring. However, some patients with ARVD/C experiencing ventricular arrhythmias have a normal ECG.

Objectives: To estimate how often patients with ARVD/C experiencing ventricular arrhythmias have a normal ECG during sinus rhythm, and to provide a clinical profile of these patients.

Left-dominant arrhythmogenic cardiomyopathy in a large family: associated desmosomal or nondesmosomal genotype?

Background: Arrhythmogenic cardiomyopathy (AC) is considered a predominantly right ventricular (RV) desmosomal disease. However, left-dominant forms due to desmosomal gene mutations, including PKP2 variant c.419C>T, have been described.

Remodeling of the cardiac sodium channel, connexin43, and plakoglobin at the intercalated disk in patients with arrhythmogenic cardiomyopathy.

Background: Arrhythmogenic cardiomyopathy (AC) is closely associated with desmosomal mutations in a majority of patients. Arrhythmogenesis in patients with AC is likely related to remodeling of cardiac gap junctions and increased levels of fibrosis. Recently, using experimental models, we also identified sodium channel dysfunction secondary to desmosomal dysfunction.

End stage of arrhythmogenic cardiomyopathy with severe involvement of the interventricular septum.

Detailed histopathologic, immunohistochemical, and ultrastructural analysis of the heart of a 56-year-old woman with end-stage arrhythmogenic cardiomyopathy with a pathogenic plakophilin-2 mutation is described. The explanted heart revealed severe fibrofatty replacement of nearly the entire right ventricular free wall. The left ventricle was severely affected, and, most remarkable, there was massive involvement of the interventricular septum.

Impact of new electrocardiographic criteria in arrhythmogenic cardiomyopathy.

Arrhythmogenic cardiomyopathy (AC) has originally been described as a disorder characterized by fibrofatty replacement of the myocardium, primarily of the right ventricle (RV), and ventricular tachyarrhythmias, sudden death, and at a late stage progressive heart failure. Arrhythmogenic right ventricular dysplasia or cardiomyopathy (ARVD/C) was the previous name of the disease. However, similar histopathologic changes are also found in the left ventricle (LV).

Cellular mechanisms of the anticancer effects of the lichen compound usnic acid.

The lichen compound usnic acid is used for its antimicrobial activities in cosmetic products and is also a component of slimming agents. Its effect against cancer cells was first noted over 30 years ago. In this study possible mechanisms of this effect were investigated using two human cell lines, the breast cancer cell line T-47D and the pancreatic cancer cell line Capan-2.