Publications by authors named "Angeliki Asimaki"

65 Publications

Desmosomal COP9 regulates proteome degradation in arrhythmogenic right ventricular dysplasia/cardiomyopathy.

J Clin Invest 2021 Apr 15. Epub 2021 Apr 15.

Department of Medicine, University of California San Diego, La Jolla, United States of America.

Dysregulated protein degradative pathways are increasingly recognized as mediators of human disease. This mechanism may have particular relevance to desmosomal proteins that play critical structural roles in both tissue architecture and cell-cell communication as destabilization/breakdown of the desmosomal proteome is a hallmark of genetic-based desmosomal-targeted diseases, such as the cardiac disease, arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). However, no information exists on whether there are resident proteins that regulate desmosomal proteome homeostasis. Here we uncovered a cardiac COP9 desmosomal resident protein complex, composed of subunit 6 of the COP9 signalosome (CSN6), that enzymatically restricted neddylation and targeted desmosomal proteome degradation. CSN6 binding, localization, levels and function were impacted in hearts of classic mouse and human models of ARVD/C impacted by desmosomal loss and mutations, respectively. Loss of desmosomal proteome degradation control due to CSN6 loss and human desmosomal mutations destabilizing CSN6 were also sufficient to trigger ARVD/C in mice. We identified a desmosomal resident regulatory complex that restricted desmosomal proteome degradation and disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI137689DOI Listing
April 2021

Exercise triggers CAPN1-mediated AIF truncation, inducing myocyte cell death in arrhythmogenic cardiomyopathy.

Sci Transl Med 2021 Feb;13(581)

Division of Cardiology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.

Myocyte death occurs in many inherited and acquired cardiomyopathies, including arrhythmogenic cardiomyopathy (ACM), a genetic heart disease plagued by the prevalence of sudden cardiac death. Individuals with ACM and harboring pathogenic desmosomal variants, such as desmoglein-2 (), often show myocyte necrosis with progression to exercise-associated heart failure. Here, we showed that homozygous mutant mice (), a model of ACM, die prematurely during swimming and display myocardial dysfunction and necrosis. We detected calcium (Ca) overload in hearts, which induced calpain-1 (CAPN1) activation, association of CAPN1 with mitochondria, and CAPN1-induced cleavage of mitochondrial-bound apoptosis-inducing factor (AIF). Cleaved AIF translocated to the myocyte nucleus triggering large-scale DNA fragmentation and cell death, an effect potentiated by mitochondrial-driven AIF oxidation. Posttranslational oxidation of AIF cysteine residues was due, in part, to a depleted mitochondrial thioredoxin-2 redox system. Hearts from exercised mice were depleted of calpastatin (CAST), an endogenous CAPN1 inhibitor, and overexpressing CAST in myocytes protected against Ca overload-induced necrosis. When cardiomyocytes differentiated from embryonic stem cells (ES-CMs) were challenged with β-adrenergic stimulation, CAPN1 inhibition attenuated CAPN1-induced AIF truncation. In addition, pretreatment of ES-CMs with an AIF-mimetic peptide, mirroring the cyclophilin-A (PPIA) binding site of AIF, blocked PPIA-mediated AIF-nuclear translocation, and reduced both apoptosis and necrosis. Thus, preventing CAPN1-induced AIF-truncation or barring binding of AIF to the nuclear chaperone, PPIA, may avert myocyte death and, ultimately, disease progression to heart failure in ACM and likely other forms of cardiomyopathies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/scitranslmed.abf0891DOI Listing
February 2021

The Novel Desmin Variant p.Leu115Ile Is Associated With a Unique Form of Biventricular Arrhythmogenic Cardiomyopathy.

Can J Cardiol 2020 Dec 5. Epub 2020 Dec 5.

Institute of Cardiovascular Science, University College London, London, United Kingdom; Inherited Cardiovascular Disease Unit, St Bartholomew's Hospital, London, United Kingdom.

Background: Arrhythmogenic cardiomyopathy (AC) is a heritable myocardial disorder and a major cause of sudden cardiac death. It is typically caused by mutations in desmosomal genes. Desmin gene (DES) variants have been previously reported in AC but with insufficient evidence to support their pathogenicity.

Methods: We aimed to assess a large AC patient cohort for DES mutations and describe a unique phenotype associated with a recurring variant in three families. A cohort of 138 probands with a diagnosis of AC and no identifiable desmosomal gene mutations were prospectively screened by whole-exome sequencing.

Results: A single DES variant (p.Leu115Ile, c.343C>A) was identified in 3 index patients (2%). We assessed the clinical phenotypes within their families and confirmed cosegregation. One carrier required heart transplantation, 2 died suddenly, and 1 died of noncardiac causes. All cases had right- and left-ventricular (LV) involvement. LV late gadolinium enhancement was present in all, and circumferential subepicardial distribution was confirmed on histology. A significant burden of ventricular arrhythmias was noted. Desmin aggregates were not observed macroscopically, but analysis of the desmin filament formation in transfected cardiomyocytes derived from induced pluripotent stem cells, and SW13 cells revealed cytoplasmic aggregation of mutant desmin. Atomic force microscopy revealed that the mutant form accumulates into short protofilaments and small fibrous aggregates.

Conclusions: DES p.Leu115Ile leads to disruption of the desmin filament network and causes a malignant biventricular form of AC, characterized by LV dysfunction and a circumferential subepicardial distribution of myocardial fibrosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cjca.2020.11.017DOI Listing
December 2020

Brugada syndrome and arrhythmogenic cardiomyopathy: overlapping disorders of the connexome?

Europace 2020 Nov 17. Epub 2020 Nov 17.

Institute of Molecular and Clinical Sciences, St. George's University of London, Cranmer Terrace, London SW17 0RE, UK.

Arrhythmogenic cardiomyopathy (ACM) and Brugada syndrome (BrS) are inherited diseases characterized by an increased risk for arrhythmias and sudden cardiac death. Possible overlap between the two was suggested soon after the description of BrS. Since then, various studies focusing on different aspects have been published pointing to similar findings in the two diseases. More recent findings on the structure of the cardiac cell-cell junctions may unite the pathophysiology of both diseases and give further evidence to the theory that they may in part be variants of the same disease spectrum. In this review, we aim to summarize the studies indicating the pathophysiological, genetic, structural, and electrophysiological overlap between ACM and BrS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/europace/euaa277DOI Listing
November 2020

Arrhythmogenic cardiomyopathy: An in-depth look at molecular mechanisms and clinical correlates.

Authors:
Angeliki Asimaki

Trends Cardiovasc Med 2020 Aug 1. Epub 2020 Aug 1.

St. George's University of London, London, United Kingdom. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.tcm.2020.07.007DOI Listing
August 2020

Prospective Evaluation of Clinico-Pathological Predictors of Postoperative Atrial Fibrillation: An Ancillary Study From the OPERA Trial.

Circ Arrhythm Electrophysiol 2020 08 12;13(8):e008382. Epub 2020 Jul 12.

Brigham and Women's Hospital, Boston, MA (D.M.).

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. Graphic Abstract: A graphic abstract is available for this article.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCEP.120.008382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457312PMC
August 2020

Diagnosis of arrhythmogenic cardiomyopathy: The Padua criteria.

Int J Cardiol 2020 11 16;319:106-114. Epub 2020 Jun 16.

Department of Cardiac, Thoracic and Vascular Sciences and Public Health, University of Padova, Italy.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijcard.2020.06.005DOI Listing
November 2020

Morphometric characterization of collagen and fat in normal ventricular myocardium.

Cardiovasc Pathol 2020 Sep - Oct;48:107224. Epub 2020 May 1.

Cardiology Clinical Academic Group, Molecular and Clinical Sciences Institute, St George's, University of London, London, United Kingdom. Electronic address:

Objective: We used automated image analysis software to determine the proportion of collagen, fat, and myocytes across six histological regions of normal ventricular myocardium.

Methods: Twenty-nine non-cardiac death cases referred to our national cardiac pathology center were included in this study. Whole hearts were macroscopically and microscopically normal following expert histopathological evaluation. Tissue sections from the right ventricular outflow tract, right ventricle (RV), anterior interventricular septum (IVS), posterior IVS, anterior left ventricle (LV), and posterior LV were stained with Picrosirius red for collagen and scanned using a high-resolution slide scanner. Quantification of collagen, fat, and myocyte proportions was performed using Visiopharm software after automated exclusion of perivascular collagen.

Results: The majority of decedents were male (25/29; 86%) with a mean age at death of 32.1 ± 9.9 (range 18-54) and mean BMI 28.7 ± 7.3. We report predicted values (collagen %, fat %, myocytes %) for cardiac tissue composition within the RV, IVS, and LV (including epicardial and endocardial layers). The proportion of collagen and fat were higher in the RV compared with the LV (ratios 1.61 [1.45-1.78]; 2.63 [1.99-3.48], respectively) and RV compared with the IVS (ratios 1.77 [1.60-1.97]; 8.41[6.35-11.13], respectively). The ratio of epicardial versus endocardial fat was increased in both ventricles (RV: ratio 4.49 [3.67-5.49]; LV: ratio 3.46 [2.49-4.81]). In multivariable analysis, there was no significant association between collagen or fat proportion and sex (p=0.12; p=0.08, respectively), age at death (p=0.36; p=0.23, respectively), or BMI (p=0.45; p=0.43, respectively).

Conclusions: Our findings provide location and sex-specific proportions of myocardial histological tissue composition that may aid quantitative evaluation of pathology in future studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.carpath.2020.107224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346882PMC
September 2020

RNA sequencing-based transcriptome profiling of cardiac tissue implicates novel putative disease mechanisms in FLNC-associated arrhythmogenic cardiomyopathy.

Int J Cardiol 2020 03 6;302:124-130. Epub 2019 Dec 6.

Centre for Heart Muscle Disease, Institute of Cardiovascular Science, University College London, London, UK. Electronic address:

Arrhythmogenic cardiomyopathy (ACM) encompasses a group of inherited cardiomyopathies including arrhythmogenic right ventricular cardiomyopathy (ARVC) whose molecular disease mechanism is associated with dysregulation of the canonical WNT signalling pathway. Recent evidence indicates that ARVC and ACM caused by pathogenic variants in the FLNC gene encoding filamin C, a major cardiac structural protein, may have different molecular mechanisms of pathogenesis. We sought to identify dysregulated biological pathways in FLNC-associated ACM. RNA was extracted from seven paraffin-embedded left ventricular tissue samples from deceased ACM patients carrying FLNC variants and sequenced. Transcript levels of 623 genes were upregulated and 486 genes were reduced in ACM in comparison to control samples. The cell adhesion pathway and ILK signalling were among the prominent dysregulated pathways in ACM. Consistent with these findings, transcript levels of cell adhesion genes JAM2, NEO1, VCAM1 and PTPRC were upregulated in ACM samples. Moreover, several actin-associated genes, including FLNC, VCL, PARVB and MYL7, were suppressed, suggesting dysregulation of the actin cytoskeleton. Analysis of the transcriptome for dysregulated biological pathways predicted activation of inflammation and apoptosis and suppression of oxidative phosphorylation and MTORC1 signalling in ACM. Our data suggests dysregulated cell adhesion and ILK signalling as novel putative pathogenic mechanisms of ACM caused by FLNC variants which are distinct from the postulated disease mechanism of classic ARVC caused by desmosomal gene mutations. This knowledge could help in the design of future gene therapy strategies which would target specific components of these pathways and potentially lead to novel treatments for ACM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijcard.2019.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940594PMC
March 2020

Filamin C variants are associated with a distinctive clinical and immunohistochemical arrhythmogenic cardiomyopathy phenotype.

Int J Cardiol 2020 05 8;307:101-108. Epub 2019 Oct 8.

Centre for Heart Muscle Disease, Institute of Cardiovascular Science, University College London, London, UK.

Background: Pathogenic variants in the filamin C (FLNC) gene are associated with inherited cardiomyopathies including dilated cardiomyopathy with an arrhythmogenic phenotype. We evaluated FLNC variants in arrhythmogenic cardiomyopathy (ACM) and investigated the disease mechanism at a molecular level.

Methods: 120 gene-elusive ACM patients who fulfilled diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy (ARVC) were screened by whole exome sequencing. Fixed cardiac tissue from FLNC variant carriers who had died suddenly was investigated by histology and immunohistochemistry.

Results: Novel or rare FLNC variants, four null and five variants of unknown significance, were identified in nine ACM probands (7.5%). In FLNC null variant carriers (including family members, n = 16) Task Force diagnostic electrocardiogram repolarization/depolarization abnormalities were uncommon (19%), echocardiography was normal in 69%, while 56% had >500 ventricular ectopics/24 h or ventricular tachycardia on Holter and 67% had late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (CMRI). Ten gene positive individuals (63%) had abnormalities on ECG or CMRI that are not included in the current diagnostic criteria for ARVC. Immunohistochemistry showed altered key protein distribution, distinctive from that observed in ARVC, predominantly in the left ventricle.

Conclusions: ACM associated with FLNC variants presents with a distinctive phenotype characterized by Holter arrhythmia and LGE on CMRI with unremarkable ECG and echocardiographic findings. Clinical presentation in asymptomatic mutation carriers at risk of sudden death may include abnormalities which are currently non-diagnostic for ARVC. At the molecular level, the pathogenic mechanism related to FLNC appears different to classic forms of ARVC caused by desmosomal mutations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijcard.2019.09.048DOI Listing
May 2020

Therapeutic Modulation of the Immune Response in Arrhythmogenic Cardiomyopathy.

Circulation 2019 10 19;140(18):1491-1505. Epub 2019 Sep 19.

Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA (J.E.S.).

Background: Inflammation is a prominent feature of arrhythmogenic cardiomyopathy (ACM), but whether it contributes to the disease phenotype is not known.

Methods: To define the role of inflammation in the pathogenesis of ACM, we characterized nuclear factor-κB signaling in ACM models in vitro and in vivo and in cardiac myocytes from patient induced pluripotent stem cells.

Results: Activation of nuclear factor-κB signaling, indicated by increased expression and nuclear accumulation of phospho-RelA/p65, occurred in both an in vitro model of ACM (expression of in neonatal rat ventricular myocytes) and a robust murine model of ACM (homozygous knock-in of mutant desmoglein-2 []) that recapitulates the cardiac manifestations seen in patients with ACM. Bay 11-7082, a small-molecule inhibitor of nuclear factor-κB signaling, prevented the development of ACM disease features in vitro (abnormal redistribution of intercalated disk proteins, myocyte apoptosis, release of inflammatory cytokines) and in vivo (myocardial necrosis and fibrosis, left ventricular contractile dysfunction, electrocardiographic abnormalities). Hearts of mice expressed markedly increased levels of inflammatory cytokines and chemotactic molecules that were attenuated by Bay 11-7082. Salutary effects of Bay 11-7082 correlated with the extent to which production of selected cytokines had been blocked. Nuclear factor-κB signaling was also activated in cardiac myocytes derived from a patient with ACM. These cells produced and secreted abundant inflammatory cytokines under basal conditions, and this was also greatly reduced by Bay 11-7082.

Conclusions: Inflammatory signaling is activated in ACM and drives key features of the disease. Targeting inflammatory pathways may be an effective new mechanism-based therapy for ACM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCULATIONAHA.119.040676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817418PMC
October 2019

Definition and treatment of arrhythmogenic cardiomyopathy: an updated expert panel report.

Eur J Heart Fail 2019 08 18;21(8):955-964. Epub 2019 Jun 18.

Department of Clinical Genetics, Amsterdam Cardiovascular Sciences, University Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

It is 35 years since the first description of arrhythmogenic right ventricular cardiomyopathy (ARVC) and more than 20 years since the first reports establishing desmosomal gene mutations as a major cause of the disease. Early advances in the understanding of the clinical, pathological and genetic architecture of ARVC resulted in consensus diagnostic criteria, which proved to be sensitive but not entirely specific for the disease. In more recent years, clinical and genetic data from families and the recognition of a much broader spectrum of structural disorders affecting both ventricles and associated with a propensity to ventricular arrhythmia have raised many questions about pathogenesis, disease terminology and clinical management. In this paper, we present the conclusions of an expert round table that aimed to summarise the current state of the art in arrhythmogenic cardiomyopathies and to define future research priorities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ejhf.1534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685753PMC
August 2019

Distinct molecular signature of phospholamban p.Arg14del arrhythmogenic cardiomyopathy.

Cardiovasc Pathol 2019 May - Jun;40:2-6. Epub 2018 Dec 21.

University of Groningen, University Medical Center Groningen, Department of Pathology, Groningen, The Netherlands.

Phospholamban (PLN) p.Arg14del cardiomyopathy is characterized by a distinct arrhythmogenic biventricular phenotype that can be predominantly left ventricular, right ventricular, or both. Our aim was to further elucidate distinct features of this cardiomyopathy with respect to the distribution of desmosomal proteins observed by immunofluorescence (IF) in comparison to desmosomal arrhythmogenic cardiomyopathy and co-existent genetic variants. We studied eight explanted heart specimens from PLN p.Arg14del mutation carriers. Macro- and microscopic examination revealed biventricular presence of fibrofatty replacement and interstitial fibrosis. Five out of 8 (63%) patients met consensus criteria for both arrhythmogenic right ventricular cardiomyopathy (ARVC) and dilated cardiomyopathy (DCM). In four cases, targeted next-generation sequencing revealed one additional pathogenic variant and six variants of unknown significance. IF showed diminished junction plakoglobin signal intensity at the intercalated disks in 4 (67%) out of 6 cases fulfilling ARVC criteria but normal intensity in both cases fulfilling only DCM criteria. Notably, the four cases with diminished junction plakoglobin were also those where an additional gene variant was detected. IF for two proteins recently investigated in desmosomal arrhythmogenic cardiomyopathy (ACM), synapse-associated protein 97 and glycogen synthase kinase-3 beta, showed a distinct distributional pattern in comparison to desmosomal ACM. In 7 (88%) out of 8 cases we observed both a strong synapse-associated protein 97 signal at the sarcomeres and no glycogen synthase kinase-3 beta translocation to the intercalated discs. Phospholamban p.Arg14del cardiomyopathy is characterized by a distinct molecular signature compared to desmosomal ACM, specifically a different desmosomal protein distribution. This study substantiates the idea that additional genetic variants play a role in the phenotypical heterogeneity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.carpath.2018.12.006DOI Listing
July 2019

Sudden Death and Left Ventricular Involvement in Arrhythmogenic Cardiomyopathy.

Circulation 2019 04;139(15):1786-1797

Cardiology Clinical Academic Group, St George's University Hospitals' NHS Foundation Trust and Molecular and Clinical Sciences Institute, St George's University of London, United Kingdom (C.M., G.F., M.P., B.G., J.W., B.E., J.B., G.P.-W., E.P. C.P., A.M., A.A., M.T., S.S., E.R.B., M.N.S.).

Background: Arrhythmogenic cardiomyopathy (ACM) is an inherited heart muscle disorder characterized by myocardial fibrofatty replacement and an increased risk of sudden cardiac death (SCD). Originally described as a right ventricular disease, ACM is increasingly recognized as a biventricular entity. We evaluated pathological, genetic, and clinical associations in a large SCD cohort.

Methods: We investigated 5205 consecutive cases of SCD referred to a national cardiac pathology center between 1994 and 2018. Hearts and tissue blocks were examined by expert cardiac pathologists. After comprehensive histological evaluation, 202 cases (4%) were diagnosed with ACM. Of these, 15 (7%) were diagnosed antemortem with dilated cardiomyopathy (n=8) or ACM (n=7). Previous symptoms, medical history, circumstances of death, and participation in competitive sport were recorded. Postmortem genetic testing was undertaken in 24 of 202 (12%). Rare genetic variants were classified according to American College of Medical Genetics and Genomics criteria.

Results: Of 202 ACM decedents (35.4±13.2 years; 82% male), no previous cardiac symptoms were reported in 157 (78%). Forty-one decedents (41/202; 20%) had been participants in competitive sport. The adjusted odds of dying during physical exertion were higher in men than in women (odds ratio, 4.58; 95% CI, 1.54-13.68; P=0.006) and in competitive athletes in comparison with nonathletes (odds ratio, 16.62; 95% CI, 5.39-51.24; P<0.001). None of the decedents with an antemortem diagnosis of dilated cardiomyopathy fulfilled definite 2010 Task Force criteria. The macroscopic appearance of the heart was normal in 40 of 202 (20%) cases. There was left ventricular histopathologic involvement in 176 of 202 (87%). Isolated right ventricular disease was seen in 13%, isolated left ventricular disease in 17%, and biventricular involvement in 70%. Among whole hearts, the most common areas of fibrofatty infiltration were the left ventricular posterobasal (68%) and anterolateral walls (58%). Postmortem genetic testing yielded pathogenic variants in ACM-related genes in 6 of 24 (25%) decedents.

Conclusions: SCD attributable to ACM affects men predominantly, most commonly occurring during exertion in athletic individuals in the absence of previous reported cardiac symptoms. Left ventricular involvement is observed in the vast majority of SCD cases diagnosed with ACM at autopsy. Current Task Force criteria may fail to diagnose biventricular ACM before death.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCULATIONAHA.118.037230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467560PMC
April 2019

Homozygous Truncating Variant in PKP2 Causes Hypoplastic Left Heart Syndrome.

Circ Genom Precis Med 2018 12;11(12):e002397

Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands (J.M.A.V., M.v.d.B., S.K., I.M.B.H.v.d.L., M.A.v.S., M.W.W.).

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCGEN.118.002397DOI Listing
December 2018

Filamin C Truncation Mutations Are Associated With Arrhythmogenic Dilated Cardiomyopathy and Changes in the Cell-Cell Adhesion Structures.

JACC Clin Electrophysiol 2018 04 2;4(4):504-514. Epub 2018 Feb 2.

Cardiovascular Institute and Adult Medical Genetics Program, University of Colorado Denver, Aurora, Colorado. Electronic address:

Objectives: The purpose of this study was to assess the phenotype of Filamin C (FLNC) truncating variants in dilated cardiomyopathy (DCM) and understand the mechanism leading to an arrhythmogenic phenotype.

Background: Mutations in FLNC are known to lead to skeletal myopathies, which may have an associated cardiac component. Recently, the clinical spectrum of FLNC mutations has been recognized to include a cardiac-restricted presentation in the absence of skeletal muscle involvement.

Methods: A population of 319 U.S. and European DCM cardiomyopathy families was evaluated using whole-exome and targeted next-generation sequencing. FLNC truncation probands were identified and evaluated by clinical examination, histology, transmission electron microscopy, and immunohistochemistry.

Results: A total of 13 individuals in 7 families (2.2%) were found to harbor 6 different FLNC truncation variants (2 stopgain, 1 frameshift, and 3 splicing). Of the 13 FLNC truncation carriers, 11 (85%) had either ventricular arrhythmias or sudden cardiac death, and 5 (38%) presented with evidence of right ventricular dilation. Pathology analysis of 2 explanted hearts from affected FLNC truncation carriers showed interstitial fibrosis in the right ventricle and epicardial fibrofatty infiltration in the left ventricle. Ultrastructural findings included occasional disarray of Z-discs within the sarcomere. Immunohistochemistry showed normal plakoglobin signal at cell-cell junctions, but decreased signals for desmoplakin and synapse-associated protein 97 in the myocardium and buccal mucosa.

Conclusions: We found FLNC truncating variants, present in 2.2% of DCM families, to be associated with a cardiac-restricted arrhythmogenic DCM phenotype characterized by a high risk of life-threatening ventricular arrhythmias and a pathological cellular phenotype partially overlapping with arrhythmogenic right ventricular cardiomyopathy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jacep.2017.12.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6074050PMC
April 2018

MY APPROACH to the patient with arrhythmogenic right ventricular cardiomyopathy (ARVC).

Authors:
Angeliki Asimaki

Trends Cardiovasc Med 2017 05 2;27(4):293. Epub 2016 Nov 2.

Research Associate, Beth Israel Deaconess Medical Center, Faculty member (Instructor), Harvard Medical School, Boston, MA. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.tcm.2016.09.008DOI Listing
May 2017

Development of dilated cardiomyopathy and impaired calcium homeostasis with cardiac-specific deletion of ESRRβ.

Am J Physiol Heart Circ Physiol 2017 Apr 27;312(4):H662-H671. Epub 2017 Jan 27.

Cardiovascular Institute, Department of Medicine, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, Massachusetts.

Mechanisms underlying the development of idiopathic dilated cardiomyopathy (DCM) remain poorly understood. Using transcription factor expression profiling, we identified estrogen-related receptor-β (ESRRβ), a member of the nuclear receptor family of transcription factors, as highly expressed in murine hearts and other highly oxidative striated muscle beds. Mice bearing cardiac-specific deletion of ESRRβ (MHC-ERRB KO) develop DCM and sudden death at ~10 mo of age. Isolated adult cardiomyocytes from the MHC-ERRB KO mice showed an increase in calcium sensitivity and impaired cardiomyocyte contractility, which preceded echocardiographic cardiac remodeling and dysfunction by several months. Histological analyses of myocardial biopsies from patients with various cardiomyopathies revealed that ESRRβ protein is absent from the nucleus of cardiomyocytes from patients with DCM but not other forms of cardiomyopathy (ischemic, hypertrophic, and arrhythmogenic right ventricular cardiomyopathy). Taken together these observations suggest that ESRRβ is a critical component in the onset of DCM by affecting contractility and calcium balance. Estrogen-related receptor-β (ESRRβ) is highly expressed in the heart and cardiac-specific deletion results in the development of a dilated cardiomyopathy (DCM). ESRRβ is mislocalized in human myocardium samples with DCM, suggesting a possible role for ESRRβ in the pathogenesis of DCM in humans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/ajpheart.00446.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5407163PMC
April 2017

Central role for GSK3β in the pathogenesis of arrhythmogenic cardiomyopathy.

JCI Insight 2016 Apr;1(5)

Department of Medicine/Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Arrhythmogenic cardiomyopathy (ACM) is characterized by redistribution of junctional proteins, arrhythmias, and progressive myocardial injury. We previously reported that SB216763 (SB2), annotated as a GSK3β inhibitor, reverses disease phenotypes in a zebrafish model of ACM. Here, we show that SB2 prevents myocyte injury and cardiac dysfunction in vivo in two murine models of ACM at baseline and in response to exercise. SB2-treated mice with desmosome mutations showed improvements in ventricular ectopy and myocardial fibrosis/inflammation as compared with vehicle-treated (Veh-treated) mice. GSK3β inhibition improved left ventricle function and survival in sedentary and exercised mice compared with Veh-treated mice and normalized intercalated disc (ID) protein distribution in both mutant mice. GSK3β showed diffuse cytoplasmic localization in control myocytes but ID redistribution in ACM mice. Identical GSK3β redistribution is present in ACM patient myocardium but not in normal hearts or other cardiomyopathies. SB2 reduced total GSK3β protein levels but not phosphorylated Ser 9-GSK3β in ACM mice. Constitutively active GSK3β worsens ACM in mutant mice, while GSK3β shRNA silencing in ACM cardiomyocytes prevents abnormal ID protein distribution. These results highlight a central role for GSKβ in the complex phenotype of ACM and provide further evidence that pharmacologic GSKβ inhibition improves cardiomyopathies due to desmosome mutations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/jci.insight.85923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4861310PMC
April 2016

Cardiac sarcoidosis with severe involvement of the right ventricle: a case report.

Autops Case Rep 2015 Oct-Dec;5(4):53-63. Epub 2015 Dec 30.

Internal Medicine Department - Faculty of Medicine - Federal University of Minas Gerais, Belo Horizonte/MG - Brazil .

We present the case of a patient who underwent cardiac transplantation with the diagnosis of idiopathic dilated cardiomyopathy. Once the explanted heart was examined, a type of granulomatous myocarditis compatible with cardiac sarcoidosis was observed. However, there was severe involvement of the right ventricle, with markedly reduced width of the muscular layer and extensive fibrofatty replacement, findings similar to the ones encountered in cases of arrhythmogenic right ventricular cardiomyopathy (ARVC). Confocal immunofluorescence analysis revealed a reduced signal for plakoglobin and desmoplakin at the cardiac intercalated disks. The immunoreactive signal for desmin showed the typical sarcomeric distribution but not a concentrated signal at the intercalated disks, a pattern previously seen in an 11-year-old girl with Carvajal syndrome bearing a C-terminal truncating mutation in the desmoplakin gene. This case illustrates the difficult and challenging work involved in performing a differential diagnosis among idiopathic dilated cardiomyopathy, isolated cardiac sarcoidosis, and ARVC, all of which are clinical entities known to masquerade as one another.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4322/acr.2015.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4757920PMC
April 2016

Characterizing the Molecular Pathology of Arrhythmogenic Cardiomyopathy in Patient Buccal Mucosa Cells.

Circ Arrhythm Electrophysiol 2016 Feb;9(2):e003688

From the Department of Pathology, Beth Israel Deaconess Medical Center & Harvard Medical School, Boston, MA (A. Asimaki, A.G.K., J.E.S.); Nikos Protonotarios Medical Center, Naxos, Greece (A.P., A.T.); Department of Medicine/Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD (C.A.J., S.P.C., C.T., B.M., A.t.R., D.P.J., H.C.); and First Department of Cardiology, University of Athens Medical School, Athens, Greece (A. Anastasakis).

Background: Analysis of myocardium has revealed mechanistic insights into arrhythmogenic cardiomyopathy but cardiac samples are difficult to obtain from probands and especially from family members. To identify a potential surrogate tissue, we characterized buccal mucosa cells.

Methods And Results: Buccal cells from patients, mutation carriers, and controls were immunostained and analyzed in a blinded fashion. In additional studies, buccal cells were grown in vitro and incubated with SB216763. Immunoreactive signals for the desmosomal protein plakoglobin and the major cardiac gap junction protein Cx43 were markedly diminished in buccal mucosa cells from arrhythmogenic cardiomyopathy patients with known desmosomal mutations when compared with controls. Plakoglobin and Cx43 signals were also reduced in most family members who carried disease alleles but showed no evidence of heart disease. Signal for the desmosomal protein plakophilin-1 was reduced in buccal mucosa cells in patients with PKP2 mutations but not in those with mutations in other desmosomal genes. Signal for the desmosomal protein desmoplakin was reduced in buccal mucosa cells from patients with mutations in DSP, DSG2, or DSC2 but not in PKP2 or JUP. Abnormal protein distributions were reversed in cultured cells incubated with SB216763, a small molecule that rescues the disease phenotype in cardiac myocytes.

Conclusions: Buccal mucosa cells from arrhythmogenic cardiomyopathy patients exhibit changes in the distribution of cell junction proteins similar to those seen in the heart. These cells may prove useful in future studies of disease mechanisms and drug screens for effective therapies in arrhythmogenic cardiomyopathy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCEP.115.003688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4785796PMC
February 2016

Biallelic Truncating Mutations in ALPK3 Cause Severe Pediatric Cardiomyopathy.

J Am Coll Cardiol 2016 Feb;67(5):515-25

Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands.

Background: Cardiomyopathies are usually inherited and predominantly affect adults, but they can also present in childhood. Although our understanding of the molecular basis of pediatric cardiomyopathy has improved, the underlying mechanism remains elusive in a substantial proportion of cases.

Objectives: This study aimed to identify new genes involved in pediatric cardiomyopathy.

Methods: The authors performed homozygosity mapping and whole-exome sequencing in 2 consanguineous families with idiopathic pediatric cardiomyopathy. Sixty unrelated patients with pediatric cardiomyopathy were subsequently screened for mutations in a candidate gene. First-degree relatives were submitted to cardiac screening and cascade genetic testing. Myocardial samples from 2 patients were processed for histological and immunohistochemical studies.

Results: We identified 5 patients from 3 unrelated families with pediatric cardiomyopathy caused by homozygous truncating mutations in ALPK3, a gene encoding a nuclear kinase that plays an essential role in early differentiation of cardiomyocytes. All patients with biallelic mutations presented with severe hypertrophic and/or dilated cardiomyopathy in utero, at birth, or in early childhood. Three patients died from heart failure within the first week of life. Moreover, 2 of 10 (20%) heterozygous family members showed hypertrophic cardiomyopathy with an atypical distribution of hypertrophy. Deficiency of alpha-kinase 3 has previously been associated with features of both hypertrophic and dilated cardiomyopathy in mice. Consistent with studies in knockout mice, we provide microscopic evidence for intercalated disc remodeling.

Conclusions: Biallelic truncating mutations in the newly identified gene ALPK3 give rise to severe, early-onset cardiomyopathy in humans. Our findings highlight the importance of transcription factor pathways in the molecular mechanisms underlying human cardiomyopathies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jacc.2015.10.093DOI Listing
February 2016

Pathogenesis of Arrhythmogenic Cardiomyopathy.

Can J Cardiol 2015 Nov 24;31(11):1313-24. Epub 2015 Apr 24.

Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA. Electronic address:

Arrhythmogenic cardiomyopathy (ACM) is a primary myocardial disease. It is characterized by frequent ventricular arrhythmias and increased risk of sudden cardiac death typically arising as an early manifestation before the onset of significant myocardial remodelling. Myocardial degeneration, often confined to the right ventricular free wall, with replacement by fibrofatty scar tissue, develops in many patients. ACM is a familial disease but genetic penetrance can be low and disease expression is highly variable. Inflammation might promote disease progression. It also appears that exercise increases disease penetrance and accelerates its development. More than 60% of probands harbour mutations in genes that encode desmosomal proteins, which has raised the possibility that defective cell-cell adhesion might play a role in disease pathogenesis. Recent advances have implicated changes in the canonical wingless-type mouse mammary tumour virus integration site (Wnt)/β-catenin and Hippo signalling pathways and defects in forwarding trafficking of ion channels and other proteins to the intercalated disk in cardiac myocytes. In this review we summarize the current understanding of the pathogenesis of ACM and highlight future research directions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cjca.2015.04.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4619183PMC
November 2015

Arrhythmogenic Cardiomyopathy - New Insights into Disease Mechanisms and Drug Discovery.

Prog Pediatr Cardiol 2014 Dec;37(1-2):3-7

Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.

Arrhythmogenic cardiomyopathy (ACM) is a primary myocardial disorder characterized by the early appearance of ventricular arrhythmias often out of proportion to the degree of ventricular remodeling and dysfunction. ACM typically presents in adolescence or early adulthood. It accounts for 10% of sudden cardiac deaths in individuals under the age of 18 years. Although there has been significant progress in recognizing the genetic determinants of ACM, how specific gene mutations cause the disease remains poorly understood. Here, we review insights gained from studying the human disease as well as and experimental models. These observations have advanced our understanding of the molecular mechanisms underlying the pathogenesis of ACM and may lead to development of new mechanism-based therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ppedcard.2014.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4260412PMC
December 2014

Arrhythmogenic right ventricular cardiomyopathy mutations alter shear response without changes in cell-cell adhesion.

Cardiovasc Res 2014 Nov 24;104(2):280-9. Epub 2014 Sep 24.

Department of Biomedical Engineering, Columbia University, 351 Engineering Terrace, 500 W 120th Street, MC 8904, New York, NY 10027, USA

Aims: The majority of patients diagnosed with arrhythmogenic right ventricular cardiomyopathy (ARVC) have mutations in genes encoding desmosomal proteins, raising the possibility that abnormal intercellular adhesion plays an important role in disease pathogenesis. We characterize cell mechanical properties and molecular responses to oscillatory shear stress in cardiac myocytes expressing mutant forms of the desmosomal proteins, plakoglobin and plakophilin, which are linked to ARVC in patients.

Methods And Results: Cells expressing mutant plakoglobin or plakophilin showed no differences in cell-cell adhesion relative to controls, while knocking down these proteins weakened cell-cell adhesion. However, cells expressing mutant plakoglobin failed to increase the amount of immunoreactive signal for plakoglobin or N-cadherin at cell-cell junctions in response to shear stress, as seen in control cells. Cells expressing mutant plakophilin exhibited a similar attenuation in the shear-induced increase in junctional plakoglobin immunoreactive signal in response to shear stress, suggesting that the phenotype is independent of the type of mutant protein being expressed. Cells expressing mutant plakoglobin also showed greater myocyte apoptosis compared with controls. Apoptosis rates increased greatly in response to shear stress in cells expressing mutant plakoglobin, but not in controls. Abnormal responses to shear stress in cells expressing either mutant plakoglobin or plakophilin could be reversed by SB216763, a GSK3β inhibitor.

Conclusions: Desmosomal mutations linked to ARVC do not significantly affect cell mechanical properties, but cause myocytes to respond abnormally to mechanical stress through a mechanism involving GSK3β. These results may help explain why patients with ARVC experience disease exacerbations following strenuous exercise.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cvr/cvu212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4296114PMC
November 2014

Identification of a new modulator of the intercalated disc in a zebrafish model of arrhythmogenic cardiomyopathy.

Sci Transl Med 2014 Jun;6(240):240ra74

Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.

Arrhythmogenic cardiomyopathy (ACM) is characterized by frequent cardiac arrhythmias. To elucidate the underlying mechanisms and discover potential chemical modifiers, we created a zebrafish model of ACM with cardiac myocyte-specific expression of the human 2057del2 mutation in the gene encoding plakoglobin. A high-throughput screen identified SB216763 as a suppressor of the disease phenotype. Early SB216763 therapy prevented heart failure and reduced mortality in the fish model. Zebrafish ventricular myocytes that expressed 2057del2 plakoglobin exhibited 70 to 80% reductions in I(Na) and I(K1) current densities, which were normalized by SB216763. Neonatal rat ventricular myocytes that expressed 2057del2 plakoglobin recapitulated pathobiological features seen in patients with ACM, all of which were reversed or prevented by SB216763. The reverse remodeling observed with SB216763 involved marked subcellular redistribution of plakoglobin, connexin 43, and Nav1.5, but without changes in their total cellular content, implicating a defect in protein trafficking to intercalated discs. In further support of this mechanism, we observed SB216763-reversible, abnormal subcellular distribution of SAP97 (a protein known to mediate forward trafficking of Nav1.5 and Kir2.1) in rat cardiac myocytes expressing 2057del2 plakoglobin and in cardiac myocytes derived from induced pluripotent stem cells from two ACM probands with plakophilin-2 mutations. These observations pinpoint aberrant trafficking of intercalated disc proteins as a central mechanism in ACM myocyte injury and electrical abnormalities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/scitranslmed.3008008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4471875PMC
June 2014

Persistent lone atrial fibrillation: clinicopathologic study of 19 cases.

Heart Rhythm 2014 Jul 18;11(7):1250-8. Epub 2014 Feb 18.

Cardiothoracic Surgery Unit, Department of Cardiology, San Raffaele University Hospital, Milan, Italy.

Background: The extent to which atrial myocardium is remodeled in patients with persistent lone atrial fibrillation (LAF) is largely unknown.

Objective: The purpose of this study was to perform a clinicopathologic investigation in patients with persistent LAF.

Methods: We characterized structural and molecular remodeling in atrial biopsies from 19 patients (17 males, mean age 49 years) with persistent (>7 days; n = 8) or long-lasting persistent (>1 year; n = 11) LAF who underwent surgical ablation. Atrial tissue from 15 autopsy samples without clinicopathologic evidence of heart disease served as controls.

Results: Morphometric analysis showed cardiomyocyte hypertrophy and greater amounts of myolytic damage and interstitial fibrosis in persistent LAF patients compared to controls (P <.0001). Atrial tissue levels of heme oxygenase-1 and 3-nitrotyrosine were increased in persistent LAF patients (P <.001), consistent with oxidative stress. Levels of superoxide dismutase-2, interleukin-8, interleukin-10, tumor necrosis factor-α, and thiobarbituric acid reactive substance were greater in controls than in persistent LAF patients. Immunoreactive signal for connexin43 was reduced more frequently in persistent LAF patients than controls. There was no correlation between features of structural or molecular remodeling and clinical parameters, including persistent LAF duration.

Conclusion: In persistent LAF patients, the atria are modified by structural remodeling and molecular changes of oxidative stress. Tissue changes in persistent LAF appear to occur early after its onset and are qualitatively no different than those observed in patients with atrial fibrillation related to conventional risk factors. These findings suggest that different types of atrial fibrillation are associated with the same spectrum of tissue lesions. Early intervention to restore sinus rhythm in persistent LAF patients may prevent irreversible tissue change, especially interstitial fibrosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.hrthm.2014.02.008DOI Listing
July 2014