iPSC derived smooth muscle cells labeled with SM22 alpha

iPSC derived smooth muscle cells labeled with smooth muscle actin and elastin
Proliferation marker ki67 expression in cardiomycocytes
Cardiac troponin T expression in cardiomyocytes
Von Willebrand factor expression in fetal heart

Our research

Genomic basis of congenital heart disease

Congenital heart disease (CHD) is a complex group of birth defects affecting approximately 1 percent of live-born infants, and is a leading cause of neonatal mortality. The genetic basis is known in less than 20 per cent cases. We are using next-generation sequencing to identify the genomic basis of CHD.

Currently, we are studying the whole genomes of patients with tetralogy of Fallot, transposition of the great arteries and other CHDs.

Genomic basis of cardiomyopathy

Cardiomyopathies are diseases of the heart muscle that cause the ventricles to be weak and enlarged, or thick and stiff resulting in heart failure. There are five major types: dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), arrhythmogenic cardiomyopathy (AC), left ventricular non-compaction (LVNC), and restrictive cardiomyopathy (RCM). The genetic basis is known in less than 50 per cent cases. We are using next-generation sequencing to identify the genetic causes of cardiomyopathies, to determine how mutation type and number influence outcomes, and to study patient iPSC-derived cardiac lineages to model disease and test drugs.

Genetic modifiers of outcomes

Improved surgical methods have improved survival in CHD. However, the repaired hearts can fail over time.

Through the Ted Rogers Centre for Heart Research, Cardiac Precision Medicine Program, we are employing a systems biology approach to decipher the molecular signature of myocardial and vascular adaptation in CHD and cardiomyopathies using whole exome or whole genome sequencing. The goal is to identify genomic markers of heart failure, gene and protein expression profiling of myocardium and patient iPSC-derived lineages to eventually find new drug targets within the dysregulated molecular pathways.

Pharmacogenetics and personalized medicine: making drugs safer

How we respond to drugs depends on our genes. Our lab has led a first in pediatrics pharmacogenetics clinical trial in solid organ transplants and used machine learning to identify clinical and genetic factors that would lead to better individualized drug dosing in pediatric cancer and solid organ transplants. We are currently expanding use of pharmacogenetic approaches in heart failure through our Cardiac Precision Medicine program.

Improving cardiac outcomes in childhood cancer survivors

Childhood cancer survivors are at risk for late complications often related to cancer therapy. Cardiac disease is the third leading cause of premature death in childhood cancer survivors (after cancer recurrence and second malignancies), with a 7-fold increased risk of premature cardiac death as compared to the general population. Through a collaborative team of oncologists and cardiologists, we are studying novel approaches to the prediction, diagnosis and treatment of cardiac late effects in survivors of childhood cancer, with special emphasis on identifying genomic predictors and early biomarkers of cardiac toxicity that can be used to employ cardioprotective strategies in at-risk children. A large cohort of ~1100 paediatric cancer acute and long-term survivors have been recruited for genomics and study of biomarkers.

Disease modelling using induced pluripotent stem cells

The Nobel prize-winning technology that allows reprogramming of somatic cells into an embryonic state has revolutionized the approach to the study of human disease. We have established one of the largest banks of skin fibroblasts from children with heart disease and are using cardiac lineages derived from patient iPSCs to model heart disease in a dish and test new drugs. It is hoped that this approach will expedite the search for new therapies.

Cardiomyopathies are the leading cause of heart failure and sudden cardiac death in children. With the help of stem cell experts, we reprogram samples from patients with cardiomyopathies into iPSCs, differentiate them into cardiomyocytes, and study their phenotype in vitro.

  1. Patients with elastin insufficiency as seen in Williams Beuren syndrome (WBS) are born with cardiovascular defects caused by narrowing of blood vessels due to proliferation of the smooth muscle cells lining the blood vessels. Surgery can relieve the obstruction but it often recurs and there are no drugs to treat this condition. We modelled WBS using patient derived iPS-smooth muscle cells and showed partial rescue of the cellular abnormalities seen in this disease (Kinnear C, et al. Arterioscler Thromb Vasc Biol. 2020; Kinnear C, Chang WY, Khattak S et al., Stem Cells Transl Med. 2013).
  2. Hypoplastic left heart syndromeis a severe cardiac malformation characterized by a poorly developed left ventricle. We found that these hypoplastic left ventricles have an aging phenotype early on in fetal life and that this phenotype can be reproduced in a dish using stem cell derived cardiomyocytes, smooth muscle and endothelial cells (Gaber N, Gagliardi M, Patel P et al., Am J Pathol. 2013). This cellular model allowed us to study signaling defects in fetal stage cells and may have implications in the study of environmental and teratogenic factors on cardiac development.

Ted Rogers Centre for Heart Research

The vision of Ted Rogers Centre for Heart Research (TRCHR) is to transform and dramatically improve the future of heart health for children, adults and families across Canada and around the world. In the the centre aims to reduce hospitalization by 50 per cent and implement devices in patient homes to enable remote monitoring for cardiac function.

Our research team focuses on studying the genetics of heart diseases and we are constantly working on studies that aim to decode genetic foundation for cardiac diseases and to discover methods for implementing patient specific drugs to treat heart diseases. Currently our research team is also conducting myocardial tissue studies to decode the genetic foundations of cardiac disease on genomic, transcriptional, and translational levels. In these tissues proteomic studies are being done in parallel with RNA-sequencing to unravel biomarkers that play important roles in causing heart diseases and use that knowledge to aid us in searching for therapeutic targets.