iPSCs

Pluripotent stem cells can be isolated from the blood of an individual patient and turned into beating heart muscle cells. These cardiomyocytes can then be studied and exposed to drugs to assess response to therapy. This may help us understand rare diseases (e.g. dilated cardiomyopathy with ataxia syndrome) and customize therapy for a particular patient.

Next-generation sequencing (NGS) has been applied to identify rejection in adult heart transplant patients (Snyder et al. PNAS USA 2011; 108(15):6229). Dying myocytes release nucleic acids into the circulation and levels of donor cell-free DNA in the recipient bloodstream appear to correlate with rejection of the transplanted organ.

We have modified this approach to develop a novel assay (Gordon et al. 2016 Frontiers Cardiovascular Medicine) that we are applying to non-invasively identify allograft rejection in paediatric and adult heart transplant patients. Work is ongoing to prospectively validate our assay and develop specificity for this assay to distinguish between non-immune (e.g. infectious) and immune-mediated injury.

We have also explored the utility of cell-free DNA for the diagnosis of congenital heart disease in pregnancy, the non-invasive diagnosis of cancer and differential methylation of cell-free DNA as a biomarker for aortopathy associated with a bicuspid aortic valve and as an alternative strategy to diagnose rejection after heart transplantation.

Transplant Microbiome

Colonizing bacteria form the microbiome which is now recognized as having an important role in host immunity and metabolism. Indeed, the metabolic capacity of the human body is a product of resident microbial communities integrated with human cells. These interactions may have important secondary effects since gut metabolites have been implicated in contributing to the development of diabetes and cardiovascular disease.

Another key process of the microbiome is the biotransformation of medications. Specific microbes have been shown to affect multiple drugs including chemotherapeutic agents and antibiotics. The drug-microbe-host interaction is complex; bacterial metabolism can alter the effects of medications (leading to drug inactivation, activation and toxicity), dietary nutrients can regulate microbial metabolism, metabolites of microbial origin may interfere with host drug metabolism and the expression and activity of the gut microbiome can be modulated by medications or their derivatives.

An important class of medications are the immunosuppressive drugs. The microorganisms responsible for their metabolism and the mechanisms and consequences of the metabolites on the host immune system and microbiome are largely unknown. Furthermore, the relationship between the microbiome and the immune system is recognized but the impact of immunosuppressive treatment on this relationship is uncharacterized.

The goal of this research project is to understand the relationship between immunosuppressive drugs, the gastrointestinal microbiome and the host immune system.

In collaboration with Dr. Simon Hirota we have developed a mouse model of chronic immunosuppression (Flannigan et al. Journal of Heart and Lung Transplantation 2018). We are also collecting samples from adult and paediatric heart transplant patients to characterize their microbiota.