Multifactorial Immune Cell Based Development of Non-Ischemic Cardiomyopathy
Slava Epelman, MD, PhD (Collaborators: Tania Watts, PhD, and Boris Hinz, PhD)
Hypertension (HTN) – the leading cause of heart failure (HF) with preserved ejection fraction (HFpEF) –can cause cardiac hypertrophy, tissue fibrosis, diastolic dysfunction, and ultimately chamber dilation and non-ischemic cardiomyopathy [NICM]. Yet not all patients with HTN develop HFpEF or NICM. Another mechanism underlying NICM is viral infection, with viral genomes detected in ~67% of affected hearts. We believe that such cardiac stresses alter the between protective and pathogenic immune cells, which in turn determines disease outcomes. We hypothesize that the combination of viral infection and HTN predisposes the heart to specific, amplified, immune cell-driven HF – which we will test with genetic fate mapping tools in mouse models.
Development of a novel device for treatment of failing Fontan circulation
Osami Honjo, MD (Collaborators: Lucy Roche, MD; Cristina Amon, ScD, P.Eng; Thomas Forbes, MD)
Fontan failure is a growing cause of morbidity and mortality in patients with complex congenital heart disease. Using computational fluid dynamics (CFD), we will develop a system of mechanical support to optimize the physiology and hemodynamics of failing juvenile and adult Fontan patients. Previous CFD models of Fontan circulation focused on optimizing initial surgical success but not late outcomes of heart failure. With the world’s largest Fontan population, SickKids and UHN are ideally placed to meet this challenge. With expertise in cardiovascular medicine and mechanical and biomedical engineering, our team seeks to improve both survival and transplant outcomes with an innovative new device.
Functional analysis of novel regulators of cardiac function using the zebrafish model
(Anthony Gramolini, PhD (Co-principal applicant: Ian Scott, PhD)
While therapies aimed at treating heart failure (HF) exist, they are not fully effective. To discover novel therapeutic targets, we have completed several large-scale studies that identified ~100 proteins enriched in human cardiac myocytes, conserved through evolution, and differentially expressed in transcriptomes and proteomes of multiple models of mouse and human HF. This project will use the zebrafish model to investigate the cardiac function of these unstudied-yet-cardiac-relevant proteins. By combining expertise in cardiac proteomics and informatics, physiology and HF (Gramolini lab, U of T) with generation and analysis of cardiac development and disease in zebrafish (Scott lab, SickKids), we will identify novel proteins involved in cardiac function and create models for in vivo therapeutic analysis.