Clinical expression of plakophilin-2 mutations in familial arrhythmogenic right ventricular cardiomyopathy

Background - Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disorder characterized by loss of cardiomyocytes and their replacement by adipose and fibrous tissue. It is considered a disease of cell adhesion because mutations in desmosomal genes, desmoplakin and plakoglobin, have been implicated in the pathogenesis of ARVC. In a recent report, mutations in plakophilin-2, a gene highly expressed in cardiac desmosomes, have been shown to cause ARVC.Methods and Results - We investigated 100 white patients with ARVC for mutations in plakophilin-2. Nine different mutations were identified by direct sequencing in 11 cases. Five of these mutations are novel (A733fsX740, L586fsX658, V570fsX576, R413X, and P533fsX561) and predicted to cause a premature truncation of the plakophilin-2 protein. Family studies showed incomplete disease expression in mutation carriers and identified a number of individuals who would be misdiagnosed with the existing International Task Force and modified diagnostic criteria for ARVC.Conclusions - In this study, we provide new evidence that mutations in the desmosomal plakophilin-2 gene can cause ARVC. A systematic clinical evaluation of mutation carriers within families demonstrated variable phenotypic expression, even among individuals with the same mutation, and highlighted the need for a more accurate set of diagnostic criteria for ARVC

Geotechnical Field Reconnaissance: Gorkha (Nepal) Earthquake of April 25, 2015 and Related Shaking Sequence

The April 25, 2015 Gorkha (Nepal) Earthquake and its related aftershocks had a devastating impact on Nepal. The earthquake sequence resulted in nearly 9,000 deaths, tens of thousands of injuries, and has left hundreds of thousands of inhabitants homeless. With economic losses estimated at several billion US dollars, the financial impact to Nepal is severe and the rebuilding phase will likely span many years. The Geotechnical Extreme Events Reconnaissance (GEER) Association assembled a reconnaissance team under the leadership of D. Scott Kieffer, Binod Tiwari and Youssef M.A. Hashash to evaluate geotechnical impacts of the April 25, 2015 Gorkha Earthquake and its related aftershocks. The focus of the reconnaissance was on time-sensitive (perishable) data, and the GEER team included a large group of experts in the areas of Geology, Engineering Geology, Seismology, Tectonics, Geotechnical Engineering, Geotechnical Earthquake Engineering, and Civil and Environmental Engineering. The GEER team worked in close collaboration with local and international organizations to document earthquake damage and identify targets for detailed follow up investigations. The overall distribution of damage relative to the April 25, 2015 epicenter indicates significant ground motion directivity, with pronounced damage to the east and comparatively little damage to the west. In the Kathmandu Basin, characteristics of recorded strong ground motion data suggest that a combination of directivity and deep basin effects resulted in significant amplification at a period of approximately five seconds. Along the margins of Kathmandu Basin structural damage and ground failures are more pronounced than in the basin interior, indicating possible basin edge motion amplification. Although modern buildings constructed within the basin generally performed well, local occurrences of heavy damage and collapse of reinforced concrete structures were observed. Ground failures in the basin included cyclic failure of silty clay, lateral spreading and liquefaction. Significant landsliding was triggered over a broad area, with concentrated activity east of the April 25, 2015 epicenter and between Kathmandu and the Nepal-China border. The distribution of concentrated landsliding partially reflects directivity in the ground motion. Several landslides have dammed rivers and many of these features have already been breached. Hydropower is a primary source of electric power in Nepal, and several facilities were damaged due to earthquake-induced landsliding. Powerhouses and penstocks experienced significant damage, and an intake structure currently under construction experienced significant dynamic settlement during the earthquake. Damage to roadways, bridges and retaining structures was also primarily related to landsliding. The greater concentration of infrastructure damage along steep hillsides, ridges and mountain peaks offers a proxy for the occurrence of topographic amplification. The lack of available strong motion records has severely limited the GEER team’s ability to understand how strong motions were distributed and how they correlate to distributions of landsliding, ground failure and infrastructure damage. It is imperative that the engineering and scientific community continues to install strong motion stations so that such data is available for future earthquake events. Such information will benefit the people of Nepal through improved approaches to earthquake resilient design

Geotechnical Effects of the 2015 Magnitude 7.8 Gorkha, Nepal, Earthquake and Aftershocks

This article summarizes the geotechnical effects of the 25 April 2015 M 7.8 Gorkha, Nepal, earthquake and aftershocks, as documented by a reconnaissance team that undertook a broad engineering and scientific assessment of the damage and collected perishable data for future analysis. Brief descriptions are provided of ground shaking, surface fault rupture, landsliding, soil failure, and infrastructure performance. The goal of this reconnaissance effort, led by Geotechnical Extreme Events Reconnaissance, is to learn from earthquakes and mitigate hazards in future earthquakes

Asymptomatic papillary fibroelastoma of the Aortic valve in a young woman - a case report

Echocardiography represents an invaluable diagnostic tool for the detection of intracardiac masses while simultaneously provides information about their size, location, mobility and attachment site as well as the presence and extent of any consequent hemodynamic derangement

Diagnosis of arrhythmogenic cardiomyopathy: The Padua criteria.

The original designation of "Arrhythmogenic right ventricular (dysplasia/) cardiomyopathy"(ARVC) was used by the scientists who first discovered the disease, in the pre-genetic and pre-cardiac magnetic resonance era, to describe a new heart muscle disease predominantly affecting the right ventricle, whose cardinal clinical manifestation was the occurrence of malignant ventricular arrhythmias. Subsequently, autopsy investigations, genotype-phenotype correlations studies and the increasing use of contrast-enhancement cardiac magnetic resonance showed that the fibro-fatty replacement of the myocardium represents the distinctive phenotypic feature of the disease that affects the myocardium of both ventricles, with left ventricular involvement which may parallel or exceed the severity of right ventricular involvement. This has led to the new designation of "Arrhythmogenic Cardiomyopathy" (ACM), that represents the evolution of the original term of ARVC. The present International Expert Consensus document proposes an upgrade of the criteria for diagnosis of the entire spectrum of the phenotypic variants of ACM. The proposed "Padua criteria" derive from the diagnostic approach to ACM, which has been developed over 30 years by the multidisciplinary team of basic researchers and clinical cardiologists of the Medical School of the University of Padua. The Padua criteria are a working framework to improve the diagnosis of ACM by introducing new diagnostic criteria regarding tissue characterization findings by contrast-enhanced cardiac magnetic resonance, depolarization/repolarization ECG abnormalities and ventricular arrhythmia features for diagnosis of the left ventricular phenotype. The proposed diagnostic criteria need to be further validated by future clinical studies in large cohorts of patients

Desmoplakin maintains gap junctions by inhibiting Ras/MAPK and lysosomal degradation of connexin-43

Desmoplakin (DP) is an obligate component of desmosomes, intercellular adhesive junctions that maintain the integrity of the epidermis and myocardium. Mutations in DP can cause cardiac and cutaneous disease, including arrhythmogenic cardiomyopathy (ACM), an inherited disorder that frequently results in deadly arrhythmias. Conduction defects in ACM are linked to the remodeling and functional interference with Cx43-based gap junctions that electrically and chemically couple cells. How DP loss impairs gap junctions is poorly understood. We show that DP prevents lysosomal-mediated degradation of Cx43. DP loss triggered robust activation of ERK1/2-MAPK and increased phosphorylation of S279/282 of Cx43, which signals clathrin-mediated internalization and subsequent lysosomal degradation of Cx43. RNA sequencing revealed Ras-GTPases as candidates for the aberrant activation of ERK1/2 upon loss of DP. Using a novel Ras inhibitor, Ras/Rap1-specific peptidase (RRSP), or K-Ras knockdown, we demonstrate restoration of Cx43 in DP-deficient cardiomyocytes. Collectively, our results reveal a novel mechanism for the regulation of the Cx43 life cycle by DP in cardiocutaneous models

Prospective Evaluation of Clinico-Pathological Predictors of Postoperative Atrial Fibrillation

Background: Postoperative atrial fibrillation (POAF) occurs in 30% to 50% of patients undergoing cardiac surgery and is associated with increased morbidity and mortality. Prospective identification of structural/molecular changes in atrial myocardium that correlate with myocardial injury and precede and predict risk of POAF may identify new molecular pathways and targets for prevention of this common morbid complication. Methods: Right atrial appendage samples were prospectively collected during cardiac surgery from 239 patients enrolled in the OPERA trial (Omega-3 Fatty Acids for Prevention of Post-Operative Atrial Fibrillation), fixed in 10% buffered formalin, and embedded in paraffin for histology. We assessed general tissue morphology, cardiomyocyte diameters, myocytolysis (perinuclear myofibril loss), accumulation of perinuclear glycogen, interstitial fibrosis, and myocardial gap junction distribution. We also assayed NT-proBNP (N-terminal pro-B-type natriuretic peptide), hs-cTnT, CRP (C-reactive protein), and circulating oxidative stress biomarkers (F2-isoprostanes, F3-isoprostanes, isofurans) in plasma collected before, during, and 48 hours after surgery. POAF was defined as occurrence of postcardiac surgery atrial fibrillation or flutter of at least 30 seconds duration confirmed by rhythm strip or 12-lead ECG. The follow-up period for all arrhythmias was from surgery until hospital discharge or postoperative day 10. Results: Thirty-five percent of patients experienced POAF. Compared with the non-POAF group, they were slightly older and more likely to have chronic obstructive pulmonary disease or heart failure. They also had a higher European System for Cardiac Operative Risk Evaluation and more often underwent valve surgery. No differences in left atrial size were observed between patients with POAF and patients without POAF. The extent of atrial interstitial fibrosis, cardiomyocyte myocytolysis, cardiomyocyte diameter, glycogen score or Cx43 distribution at the time of surgery was not significantly associated with incidence of POAF. None of these histopathologic abnormalities were correlated with levels of NT-proBNP, hs-cTnT, CRP, or oxidative stress biomarkers. Conclusions: In sinus rhythm patients undergoing cardiac surgery, histopathologic changes in the right atrial appendage do not predict POAF. They also do not correlate with biomarkers of cardiac function, inflammation, and oxidative stress

Mutations with pathogenic potential in proteins located in or at the composite junctions of the intercalated disk connecting mammalian cardiomyocytes: a reference thesaurus for arrhythmogenic cardiomyopathies and for Naxos and Carvajal diseases

In the past decade, an avalanche of findings and reports has correlated arrhythmogenic ventricular cardiomyopathies (ARVC) and Naxos and Carvajal diseases with certain mutations in protein constituents of the special junctions connecting the polar regions (intercalated disks) of mature mammalian cardiomyocytes. These molecules, apparently together with some specific cytoskeletal proteins, are components of (or interact with) composite junctions. Composite junctions contain the amalgamated fusion products of the molecules that, in other cell types and tissues, occur in distinct separate junctions, i.e. desmosomes and adherens junctions. As the pertinent literature is still in an expanding phase and is obviously becoming important for various groups of researchers in basic cell and molecular biology, developmental biology, histology, physiology, cardiology, pathology and genetics, the relevant references so far recognized have been collected and are presented here in the following order: desmocollin-2 (Dsc2, DSC2), desmoglein-2 (Dsg2, DSG2), desmoplakin (DP, DSP), plakoglobin (PG, JUP), plakophilin-2 (Pkp2, PKP2) and some non-desmosomal proteins such as transmembrane protein 43 (TMEM43), ryanodine receptor 2 (RYR2), desmin, lamins A and C, striatin, titin and transforming growth factor-β3 (TGFβ3), followed by a collection of animal models and of reviews, commentaries, collections and comparative studies