South Asian Arrhythmogenic Cardiomyopathy Registry

Brief Title

South Asian Arrhythmogenic Cardiomyopathy Registry

Official Title

South Asian Arrhythmogenic Cardiomyopathy Registry

Brief Summary

      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.
    

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 [Patient Registry]


Primary Outcome

Completion of Data collection and phenotypic evaluation


Condition

Arrhythmogenic Right Ventricular Cardiomyopathy

Intervention

ECG

Study Arms / Comparison Groups

 Diagnosed ACM patients
Description:  

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Diagnostic Test

Estimated Enrollment

100

Start Date

April 10, 2021

Completion Date

May 1, 2022

Primary Completion Date

May 1, 2022

Eligibility Criteria

        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.
      

Gender

All

Ages

N/A - N/A

Accepts Healthy Volunteers

No

Contacts

, , 

Location Countries

India

Location Countries

India

Administrative Informations


NCT ID

NCT04895540

Organization ID

SKIMSCL-2021-001


Responsible Party

Principal Investigator

Study Sponsor

Sheri Kashmir Institute of Medical Sciences

Collaborators

 Indian Heart Rhythm Society

Study Sponsor

, , 


Verification Date

May 2021