South Asian Arrhythmogenic Cardiomyopathy Registry

Arrhythmogenic Cardiomyopathy (ACM) is increasingly identified as an important cause of cardiac morbidity and mortality, especially of SCD, in a younger population.

Although there are no epidemiological data available, the investigators' experience is that in the North Indian region, ACM is rare outside our regions. ACM is also an understudied cardiac disorder in the South-Asian region.

An ethnic nonmigratory population inhabits the two regions, and consanguineous marriages are common. Based on these observations, the investigators firmly believe that there may be a founder gene in our populations responsible for the increased incidence of ACM.

Our project includes a thorough phenotypic analysis ((ECG, Holter, and echocardiography) in the ACM patients and their first-degree relatives; cardiac MRI and high resolution endocardial bipolar and unipolar voltage mapping (using HD grid catheter) in the patients.

The patient provided blood for the extraction of DNA will first undergo target panel sequencing for 20 known classic right-dominant ACM and left-dominant ACM. If this is negative for known pathogenic and likely pathogenic variants but identified novel variants of uncertain significance (VUS), then co-segregation analysis in family members will be performed. This technique can provide helpful information to reclassify VUSs. If both these are negative, then whole-exome 'trio' analysis will be performed, whch includes the proband and two family members, to triangulate from all 20,000 genes to a list of candidates for further interrogation.

The investigators wish to provide comprehensive answers to the research question by combining the genetic analysis with phenotypic evaluation.

Study Overview

• Status: Active, not recruiting
• Conditions: Ventricular Tachycardia; Sudden Cardiac Death; Arrhythmogenic Right Ventricular Cardiomyopathy; Arrhythmogenic Right Ventricular Dysplasia; Arrhythmogenic Ventricular Cardiomyopathy; Arrhythmogenic Cardiomyopathy
• Intervention / Treatment: Diagnostic test: ECG; Diagnostic test: Echocardiography; Diagnostic test: Cardiac MRI; Diagnostic test: Ambulatory ECG recording; Diagnostic test: Cardiac EP study; Genetic: All study subjects will undergo sample collection for genetic testing.

Detailed Description

Arrhythmogenic Cardiomyopathy (ACM) is an inherited cardiomyopathy characterized by structural and functional abnormalities in the right ventricle (and left ventricle, in 50%) resulting in ventricular arrhythmias.1 It is an important cause of sudden cardiac death (SCD) in young adults, accounting for 11% of all cases.2 The hallmark lesion of ACM is replacement of the ventricular myocardium by fibrofatty tissue. 3ARVC is most often familial, with autosomal dominant inheritance, autosomal recessive inheritance being uncommon. However, in relatively isolated populations, autosomal recessive forms are recognized and often have more severe phenotype. In fact, the first two genes discovered for ARVC were Naxos and Carvajal syndromes, in isolated populations of Naxos Island and Equadorian populations respectively.

The genes involved in the pathogenesis of ACM are most often desmosomal genes like plakoglobin (JUP), desmoplakin (DSP), plakophilin-2 (PKP2), desmoglein-2 (DSG2), desmocollin-2 (DSC2). PKP2 mutations are the most common. However, there are disease-causing genes that cause "classic" right ventricular ACM that do not encode for desmosomal proteins.4 The term "ALVC" has been proposed to recognize ACM of LV origin as distinct from right ventricular ACM in which there is predominantly LV arrhythmia and structural abnormalities.4 The most common clinical presentation consists of ventricular arrhythmias and related symptoms/events, which include palpitations, syncopal episodes (mostly occurring during physical exercise), and cardiac arrest. The diagnosis of biventricular or predominant left AC may be missed at the onset of symptoms in some patients who present years later with heart failure, with or without ventricular arrhythmias, and are incorrectly diagnosed as having idiopathic dilated cardiomyopathy.5 The diagnosis of ACM is based on the 2010 Task Force Criteria (TFC), which include repolarization abnormalities, depolarization abnormalities, arrhythmias, tissue characterization, structural abnormalities, and family history. However, there is no agreed gold-standard, and limitations of the Task Force Criteria are: a) the sentinel event can be SCD, with very subtle morphological abnormalities, which may not be identified at post-mortem examination b) Electrical abnormalities can precede the structural abnormalities, which can be easily missed. This has a huge impact on family members, as they do not undergo appropriate clinical or genetic testing - missing an opportunity to intervene and save lives c) Disease expression in the pediatric population is uncommon d) the long list of criteria and modalities in the TFC make diagnosing ACM complex and time-consuming. Identifying novel gene mutations in ACM may help in further understanding the pathogenesis of the disease and may help in finding a new pharmacological target for such patients.

i. Design of the study Prospective, cohort study

ii. Inclusion and exclusion criteria

Inclusion criteria:

Patients diagnosed with ACM according to 2010 Task Force Criteria Parents of ACM patients Siblings of ACM patients Relatives of ACM patients who have suffered an SCD

Exclusion criteria:

ACM patients or their relatives refuse to give consent for participation in the study. Study subjects who refuse to provide consent for a specific test or investigation will not be excluded.

iii. Endpoints:

1. Patients: Completion of the following data collection of all the patients:

   ECG, Holter, Echocardiography, cardiac MRI, Endocardial voltage mapping, genetic analysis along with blood and buccal samples for genetic analysis

2. Parents/siblings: Completion of the following data of all the parents, siblings: ECG, Echocardiography along with blood and buccal samples for genetic analysis
3. SCD affected relatives of ACM patients: Completion of the following data of the affected relatives: ECG, Holter, Echocardiography, cardiac MRI along with blood and buccal samples for genetic analysis.

• Study Type: Observational
• Enrollment (Actual): 100

Contacts and Locations

Study Locations

• India
  • Jammu And Kashmir
    • Srinagar, Jammu And Kashmir, India, 190011
      • Sher-I-Kashmir Institute of Medical Sciences
  • Karnataka
    • Bangalore, Karnataka, India, 560029
      • Sri Jayadeva Institute of Cardiovascular Sciences and Research
• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: ADULT; OLDER_ADULT; CHILD
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Study population will consist of ACM patients and their first degree relatives and other relatives who have suffered an SCD

Description

Inclusion Criteria:

• Patients diagnosed with ACM according to 2010 Task Force CriteriaParents of ACM patients
• Siblings of ACM patients
• Relatives of ACM patients who have suffered an SCD

Exclusion Criteria:

• ACM patients or their relatives who refuse to give consent for participation in the study.
• Study subjects who refuse to provide consent for a specific test or investigation will not be excluded.

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Diagnosed ACM patients	Diagnostic test: ECG; All study subjects will undergo ECG recording.; Diagnostic test: Echocardiography; All study subjects will undergo transthoracic echocardiography; Diagnostic test: Cardiac MRI; All ACM patients and SCD survivors will undergo cardiac MRI testing.; Diagnostic test: Ambulatory ECG recording; All ACM patients and SCD survivors will undergo 24-hour ambulatory ECG recording; Diagnostic test: Cardiac EP study; ACM patients and SCD survivors will undergo diagnostic cardiac Electrophysiology testing.; Genetic: All study subjects will undergo sample collection for genetic testing.; Blood samples and buccal swab will be collected from study subjects for genetic testing.
First degree relatives of ACM patients	Diagnostic test: ECG; All study subjects will undergo ECG recording.; Diagnostic test: Echocardiography; All study subjects will undergo transthoracic echocardiography; Genetic: All study subjects will undergo sample collection for genetic testing.; Blood samples and buccal swab will be collected from study subjects for genetic testing.
Relatives of ACM patients who have suffered an SCD	Diagnostic test: ECG; All study subjects will undergo ECG recording.; Diagnostic test: Echocardiography; All study subjects will undergo transthoracic echocardiography; Genetic: All study subjects will undergo sample collection for genetic testing.; Blood samples and buccal swab will be collected from study subjects for genetic testing.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Completion of Data collection and phenotypic evaluation	May 2021-April 2022
Completion of genetic analysis	May 2021-April 2022
Phenotypic and genotpic assessment	May 2022-June 2022

Collaborators and Investigators

• Sponsor: Sheri Kashmir Institute of Medical Sciences
• Collaborators: University of Pennsylvania; Indian Heart Rhythm Society; Sri Jayadeva Institute of Cardiovascular Sciences and Research

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 10, 2021
• Primary Completion (ANTICIPATED): May 1, 2022
• Study Completion (ANTICIPATED): May 1, 2022

Study Registration Dates

• First Submitted: May 17, 2021
• First Submitted That Met QC Criteria: May 17, 2021
• First Posted (ACTUAL): May 20, 2021

Study Record Updates

• Last Update Posted (ACTUAL): June 2, 2021
• Last Update Submitted That Met QC Criteria: May 29, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Congenital Abnormalities; Death, Sudden; Arrhythmias, Cardiac; Cardiac Conduction System Disease; Heart Defects, Congenital; Cardiovascular Abnormalities; Heart Arrest; Death; Tachycardia; Tachycardia, Ventricular; Cardiomyopathies; Death, Sudden, Cardiac; Arrhythmogenic Right Ventricular Dysplasia
• Other Study ID Numbers: SKIMSCL-2021-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No