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. 2020 Mar 5;9(3):e17241.
doi: 10.2196/17241.

Thanatogenomic Investigation of the Hydroxymethylome and Mitochondrial Genome of Cadaveric Cardiomyocytes: Proposal for a Proof-of-Concept Study

Nerissa Naidoo  1 , Gurjyot Bajwa  2 , Ruthwik Duvuru  1 , Yajnavalka Banerjee  1   3
Affiliations

Thanatogenomic Investigation of the Hydroxymethylome and Mitochondrial Genome of Cadaveric Cardiomyocytes: Proposal for a Proof-of-Concept Study

Nerissa Naidoo et al. JMIR Res Protoc. .

Abstract

Background: Cardiovascular disease (CVD) remains the leading cause of death in the United Arab Emirates (UAE). One of the common CVDs is hypertrophic cardiomyopathy (HCM). Recent studies conducted in heart cells of mice have shown that this condition involves a chemical modification called hydroxymethylation of the DNA of heart cells.

Objective: Objectives of the proposed research are to profile the distribution of 5-hydroxymethylation in the cardiomyocyte (CMC) genome of cadaveric cardiac tissue and cardiac biopsy specimens; to compare the hydroxymethylome of cadaveric CMCs with that of cardiac biopsy specimens from HCM patients and/or cardiac transplant patients (control) undergoing cardiac catheterization; to histologically appraise sarcomere distribution and mitochondrial morphology of CMCs in the presence of HCM; to correlate the mitochondrial genome with the HCM phenotype; and to integrate anatomy with biochemistry and genetics into the instructional design of HCM in the core medical curriculum at Mohammed Bin Rashid University of Medicine and Health Sciences (MBRU).

Methods: Normal and hypertrophic heart specimens will be obtained from 8 whole-body cadavers (2/8, 25% control and 6/8, 75% HCM). Myocardial biopsy specimens will be obtained from cardiothoracic and transplant units at the Cleveland Clinic in Abu Dhabi, UAE. As this is a proof-of-concept study, we plan to recruit 5 patients with HCM, where HCM has been diagnosed according to the guidelines of the 2014 European Society of Cardiology Guidelines. Patients with valvular heart disease, history of myocarditis, regular alcohol consumption, or cardiotoxic chemotherapy will be excluded. The control biopsy specimens will be obtained from patients who had received heart transplants. Three investigational approaches will then be employed: (1) gross anatomical evaluation, (2) histological analysis, and (3) profiling and analysis of the hydroxymethylome. These investigations will be pursued with minor modifications, if required, to the standard protocols and in accordance with institutional policy. The objective associated with the education of health professionals will be addressed through a strategy based on Graham's knowledge translation model.

Results: This study is at the protocol-development stage. The validated questionnaires have been identified in relation to the objectives. The MBRU and the Cleveland Clinic Abu Dhabi Institutional Review Board (IRB) are reviewing this study. Further clarification and information can be obtained from the MBRU IRB. There is funding in place for this study (MBRU-CM-RG2019-08). Currently, we are in the process of standardizing the protocols with respect to the various molecular techniques to be employed during the course of the study. The total duration of the proposed research is 24 months, with a provision for 6 months of a no-cost extension.

Conclusions: The spectrum of CVDs has recently received significant focus from the public health sector in the UAE. HCM is a common familial heart disease, contributing to the sudden increase in the mortality rate of young Emiratis in the UAE. Incorporating artificial intelligence into the identification of epigenetic risk factors associated with HCM will promote accurate diagnosis and lead to the development of improved management plans, hence, positive patient outcomes. Furthermore, integration of these findings into the instructional design of undergraduate, postgraduate, and continuous professional development medical curricula will further contribute to the body of knowledge regarding HCM.

International registered report identifier (irrid): PRR1-10.2196/17241.

Keywords: epigenomics; hypertrophic cardiomyopathy; mitochondrial genome; undergraduate medical education.

PubMed Disclaimer

Conflict of interest statement

Conflicts of Interest: None declared.

Figures

Figure 1
Figure 1
Top 25 causes of death in the Arab population in 1990 and 2010 (mean rank). A comparative analysis is provided. Solid blue lines indicate the elevation in rank for a condition or factor responsible for causing death in the Arab population from 1990 to 2010. Green dotted lines indicate a fall in rank of a condition or factor responsible causing death in the Arab population from 1990 to 2010. Red solid lines indicate the elevation or fall in rank of the factors contributing to cardiometabolic syndrome (CMS) in causing death from 1990 to 2010 (note: all the factors contributing to CMS are elevated in rank when compared between 1990 and 2010). Redrawn with modifications from Mokdad et al, 2014. COPD: chronic obstructive pulmonary disease; CV: cardiovascular.
Figure 2
Figure 2
Death rates (ie, number of deaths per 100,000 people) from vascular diseases in selected countries in Africa and the Middle East compared to western countries. Drawn from data presented by the World Health Organization. UAE: United Arab Emirates.
Figure 3
Figure 3
Summary of the proposed study; important steps are indicated (note: the results from this study will be used for competency-based medical education at different levels of training). 5mC: 5-methylation of cytosine; CCAD: Cleveland Clinic Abu Dhabi; HCM: hypertrophic cardiomyopathy; LVAD: left ventricular assist device; SOAP: short oligonucleotide alignment program.
Figure 4
Figure 4
Sequence of primers that will be used to amplify cardiomyocyte (CMC) mitochondrial DNA fragment 1 (9289 bp in length) and fragment 2 (7626 bp in length). 18srRNA: 18S ribosomal RNA; MT-ND1: mitochondrial NADH-ubiquinone oxidoreductase chain 1.
Figure 5
Figure 5
Graham's knowledge translation process (Straus et al, 2011). The central idea of this process is to create knowledge through diverse knowledge tools, which may be in the form of research, that could create new knowledge.
Figure 6
Figure 6
The framework for knowledge translation to be implemented in this study, elaborated using a vignette of autosomal dominant familial hypercholesterolemia. A. Description of the blended lesson plan: Gagne's events of instruction and Peyton's approach. B. The sequential steps of the lesson plan and skills gained. ExPASy: Expert Protein-Analysis System of the Swiss Institute of Bioinformatics; GOF: gain of function; NCBI: National Center for Biotechnology Information; PCSK9: proprotein convertase subtilisin/kexin type 9; PI: isoelectric point; MW: molecular weight.
Figure 7
Figure 7
Framework for outcomes-based continuing professional development (CPD) to be used in the proposed research.
Figure 8
Figure 8
Timeline and key milestones for the study; the sites where the research will be conducted are also indicated. BGI: Beijing Genomics Institute; IFAA: International Federation of Associations of Anatomists; MBRU: Mohammed Bin Rashid University of Medicine and Health Sciences; UAE: United Arab Emirates.
See this image and copyright information in PMC

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