Arrhythmogenic ventricular cardiomyopathies (AVCs) are clinically and genetically heterogeneous heart muscle disorders characterized by frequent, often life-threatening arrhythmias that typically precede structural remodeling of the heart muscle or clinical evidence of heart failure. In the majority of subjects having these inherited, family transmitted diseases the underlying cause is not known. AVCs include arrhythmogenic RV cardiomyopathy (ARVC), the more recently described arrhythmogenic LV cardiomyopathy (ALVC), and a group of dilated cardiomyopathies in which arrhythmias are prominent (aDCM). While these heart abnormalities may appear unrelated when compared by traditional clinical and pathological criteria, recent evidence indicates they share common genetic causes and result from disruption of the same """"""""final common pathways"""""""". Mutations in genes encoding desmosomal proteins or desmosome-interacting proteins appear to play a major role in causing ARVC and ALVC. Recent evidence suggests some common genetic causes between ALVC and aDCM (and therefore ARVC), as well as mechanistic links between mutations in genes encoding Z-disk proteins and desmosomal disruption in aDCM. Recently, Saffitz and colleagues have correlated cell biologic myocardial biomarkers with genetic and clinical/histopathologic findings of ARVC and ALVC and suggests these findings, as well as abnormalities in cardiac inflammatory mediators, are diagnostic of AVCs. In addition, we have shown that Wnt signaling pathways are impaired by changing ?-catenin stoichiometry, impairing forward trafficking of critical proteins to the intercalated disk by mechanisms involving SAP97 and ROCK/ microtubular transport, and activates apoptotic pathways, mechanisms linking cell injury and arrhythmias in AVCs. AVCs result from a consistent failure of critical proteins (Cx43, Nav1.5, Kir2.1) to localize to intercalated disks due to defects in forward trafficking. Despite this progress in understanding the origin and progression of classical ARVC, however, many questions remain unresolved. First, disease-causing genes are identified in only ~30-50 % of patients. Second, multiple mutations (compound and digenic heterozygosity) are emerging as frequent associations, adding more complexity to understanding the genetic basis of ARVC. Third, inter- and intra-familial variability is not explained by current knowledge, suggesting more complexity, potentially involving currently unknown epigenetic and environmental factors. Fourth, the proportion of ALVC due to desmosomal defects is unknown but its clinical identification is increasing. Fifth, much more work needs to be done to characterize aDCM in view of genetic and """"""""final common pathway"""""""" links to ALVC. In this proposal we will combine well-established, consistent and precise diagnostic approach developed in our previous ARVC Registry grant (published as the """"""""Modified Task Force Criteria"""""""") with a comprehensive primary genotyping approach and search for genetic modifiers using next generation high-throughput genetic discovery technologies and biomarker analysis to identify the genetic basis of all forms of AVCs (ARVC, ALVC, and aDCM), to establish detailed mechanistic and diagnostic understanding, and correlate these findings with clinical phenotypes to improve risk-stratification and better predict adverse events. We will test the general hypothesis that mutations in genes encoding """"""""final common pathway"""""""" proteins of the desmosome/cell-cell junction pathway (or its binding partners), leads to destabilization of desmosomes and disruption of the intercalated disk and inflammation, and impairs Wnt signaling pathways by changing the stoichiometry of ?-catenin. This impairs forward trafficking of critical proteins to the intercalated disk by mechanisms involving SAP97 and ROCK/ microtubular transport. It also activates apoptotic pathways, thus providing a mechanism linking cell injury and arrhythmias in AVCs.
The Specific Aims are: 1) To identify new genes causing ARVC, ALVC, and aDCM;2A) To evaluate genotype-phenotype associations in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC);2B) To evaluate patients with suspected arrhythmogenic left ventricular cardiomyopathy (ALVC) and arrhythmogenic dilated cardiomyopathy (aDCM) and to evaluate genotype-phenotype associations in patients with ALVC and aDCM;and 3) To discover new biomarkers in AVCs and critically assess their value in improving the sensitivity and accuracy of diagnosis and predicting arrhythmias or other manifestations of disease.

Public Health Relevance

This application proposes to study the genetic and mechanistic basis of the life-threatening heart muscle disorders called arrhythmogenic cardiomyopathies (AVCs), diseases associated with sudden death and heart failure. To date, limited information exists regarding the genes responsible for these disorders and even less is known about the prediction of risks associated with having these disorders. In this proposal, we will determine the causative genes, modifying influences that determine age of onset and severity of disease, early diagnostic testing approaches in order to prevent sudden events, and mechanisms responsible for disease in order to lay the groundwork for targeted treatments in the future.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Boineau, Robin
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Cincinnati Children's Hospital Medical Center
United States
Zip Code
Mestroni, Luisa; Sbaizero, Orfeo (2018) Arrhythmogenic Cardiomyopathy: Mechanotransduction Going Wrong. Circulation 137:1611-1613
McNally, Elizabeth M; Mestroni, Luisa (2017) Dilated Cardiomyopathy: Genetic Determinants and Mechanisms. Circ Res 121:731-748
Dal Ferro, Matteo; Stolfo, Davide; Altinier, Alessandro et al. (2017) Association between mutation status and left ventricular reverse remodelling in dilated cardiomyopathy. Heart 103:1704-1710
Calkins, Hugh; Corrado, Domenico; Marcus, Frank (2017) Risk Stratification in Arrhythmogenic Right Ventricular Cardiomyopathy. Circulation 136:2068-2082
Te Riele, Anneline S J M; Agullo-Pascual, Esperanza; James, Cynthia A et al. (2017) Multilevel analyses of SCN5A mutations in arrhythmogenic right ventricular dysplasia/cardiomyopathy suggest non-canonical mechanisms for disease pathogenesis. Cardiovasc Res 113:102-111
Peña, Brisa; Bosi, Susanna; Aguado, Brian A et al. (2017) Injectable Carbon Nanotube-Functionalized Reverse Thermal Gel Promotes Cardiomyocytes Survival and Maturation. ACS Appl Mater Interfaces 9:31645-31656
Chen, Suet Nee; Taylor, Matthew; Mestroni, Luisa (2017) Unraveling Missing Genes and Missing Inheritance in Arrhythmogenic Cardiomyopathy. Circ Arrhythm Electrophysiol 10:
Choudhary, Naila; Tompkins, Christine; Polonsky, Bronislava et al. (2016) Clinical Presentation and Outcomes by Sex in Arrhythmogenic Right Ventricular Cardiomyopathy: Findings from the North American ARVC Registry. J Cardiovasc Electrophysiol 27:555-62
Asimaki, Angeliki; Protonotarios, Alexandros; James, Cynthia A et al. (2016) Characterizing the Molecular Pathology of Arrhythmogenic Cardiomyopathy in Patient Buccal Mucosa Cells. Circ Arrhythm Electrophysiol 9:e003688
Corrado, Domenico; Wichter, Thomas; Link, Mark S et al. (2016) Response to Letter Regarding Article, ""Treatment of Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia: An International Task Force Consensus Statement"". Circulation 133:e437-8

Showing the most recent 10 out of 46 publications