Our Research
Ted Rogers Centre for Heart Research: Cardiac Precision Medicine Program
The Cardiac Precision Medicine Program was built on the premise that understanding the genetic basis of heart failure will allow us to develop medicines that are targeted to the unique type of heart failure, making them safer and more effective. Learn more through the video below.
Canadian Heart Function Alliance (CHF Alliance)
The Canadian Heart Function Alliance (CHF Alliance) brings together an extensive network of researchers, clinicians, patients, caregivers, Indigenous elders, policy-makers and other partner organizations across the country to explore a breadth of approaches to extending the lifespan of Canadians who have heart failure.
SickKids Drs. Mital and Jeewa are leading the paediatric arm of the CHF Alliance, with a project entitled “Precision Medicine for Heart Failure in the Young” (PRIORITY). The PRIORITY study, which encompasses three research streams, will develop biological, technological and social solutions for early diagnosis, closer monitoring and personalized management of patients who experience childhood heart failure.
The research team will develop and validate an artificial intelligence-based model to diagnose diastolic heart failure, implement remote monitoring for childhood cardiomyopathy, and create an online peer support program to improve self-managed care among adolescents transitioning from paediatric into adult care.
PRecIsion Medicine in CardiomyopathY (PRIMaCY)
Hypertrophic cardiomyopathy is the leading cause of sudden cardiac death in adolescents and young adults. Despite the availability of implantable cardioverter-defibrillators (ICD) as a life-saving intervention, the lack of precision in predicting sudden death risk hampers timely ICDs in at-risk patients resulting in deaths that could have been prevented.
PRIMaCY has developed an eHealth clinical decision support tool that generates an individualized 5-year risk prediction for sudden death for each patient. The primary goal is to implement the PRIMaCY tool in hospital information systems for use by physicians as a point of care tool, to evaluate the effectiveness of the tool in adherence to clinical practice guidelines, and to evaluate how it influences patient/family counseling.
PeRsOnalized Genomics For CongEnital HEart Disease (PROCEED)
Congenital heart disease (CHD) is the leading cause of newborn deaths. Its genetic cause remains elusive in 80% cases. We will use whole genome sequencing to explore the human genome to find gene defects that cause CHD – tetralogy of Fallot (TOF) and transposition of the great arteries (TGA), and determine how these gene defects predict severity of heart disease and outcomes.
The ability to individualize risk prediction based on genotype will help personalize reproductive counselling and help personalize management of CHD families. Genetic based prediction of outcomes can inform timing and type of fetal and postnatal interventions.
Early Diagnosis of Patients at Risk for Heart Failure Using Genome-Based Diagnostics
We developed an automated pipeline to interrogate a patient’s whole genome sequencing (WGS) for disease-causing and disease-modifying variants in both coding- (exome) as well as non-coding- (regulome) regions. By combining genomic and myocardial expression data and high-throughput functional validation of variants in regulatory regions using human hiPSC-derived cardiomyocytes, we are developing a first-of-its-kind human cardiac atlas of functioning regulatory regions of the genome important in childhood heart disease. Compared to conventional genetic testing, genome sequencing of over 300 cardiomyopathy cases from our biobank enabled us to identify the genetic cause in twice as many families.
Early Biomarker-Based Diagnosis of Patients at Risk for Arrhythmogenic Cardiomyopathy
Arrhythmogenic ventricular cardiomyopathy (AVC) is a leading cause of HF and sudden cardiac death (SCD). We discovered a novel antibody, anti-desmoglein-2, in the blood stream that can diagnose 95% of patients with this condition before it manifests clinically. The findings are being externally validated. This will lead to the development of a new clinical blood test for AVC, which will enable early interventions to prevent sudden death and heart failure.
Precision Therapeutics for Cardiomyopathy
Myosin variants are the leading genetic cause of cardiomyopathies for which there are no effective therapies. Using iPSCs from patients with myosin variants in our biobank, we generated diseased and gene-corrected cardiomyocytes to model disease and test targeted therapies. We found that a myosin-targeted compound is effective at rescuing disease phenotype in childhood cardiomyopathy caused by these variants. Through ongoing discussion with industry partners, our findings will inform a first in pediatric trial of myosin-targeted drugs, and also identify genetic responders who are likely to benefit from these drugs. By choosing the right drug for the right patient, we will avoid futile therapies, reduce heart failure progression and ultimately the need for heart transplants.
National Biobank Sites and International Collaborations
Please also see Recent Highlights for more!
Elastin gene defects occur in Williams-Beuren syndrome (WBS) and non-syndromic supravalvar aortic stenosis (SVAS). These defects cause reduction of elastin in blood vessel walls making them stiff and narrow and affecting blood flow to major organs like the heart, brain and kidney. Treatment involves one or more surgery or catheter-based interventions to relieve these vascular stenoses. Our study found that infants and children with non-syndromic SVAS usually have earlier more severe disease and require more operations to relieve recurrent stenoses. Our findings highlight the importance of knowing the genetic basis of this disease which may help clinicians to not only choose the right interventions but also to counsel families regarding what to expect and how to plan for the future.
Cardiomyopathy, a genetic disease of the heart muscle, is the leading cause of heart failure and sudden cardiac death in children. It is inherited in families in at least a third of cases. Despite availability of genetic testing, the genetic cause of the majority of cardiomyopathies remains unknown since current tests only look for defects in a small number of known genes in the genome. In a first of its kind study posted on the MedRxiv preprint server, we used whole genome sequencing in cardiomyopathy families in our biobank and uncovered novel genes and non-coding variants in 20% of the cases that were previously deemed gene-elusive. These findings demonstrate the power of genome sequencing in unraveling the genetic basis of cardiomyopathy (and possibly other diseases), bringing clinicians and families one step closer to a future of personalized medicine.
