Our work is focused on the intrinsic regulation of cardiac function and the effects of mechano-electric interactions on heart rhythm. We employ a multi-scale, multi-species approach (in whole animals to isolated tissue and cell preparations, including rabbit, mouse, and zebrafish), combining engineering-based experimental methods with computational modeling to gain insight into normal cardiovascular function and pathologies at various levels of functional and structural complexity. Our overall goals are to: (i) define organ-, tissue-, cell-, and subcellular-level mechanisms responsible for (patho-)physiological responses; (ii) discover their relevance for heart rhythm in health and disease; and (iii) use this knowledge to develop novel targeted anti-arrhythmic therapies.
Current projects in the lab are described below.
Mechanically-induced arrhythmias during acute regional ischemia
Funded by the Canadian Institutes of Health Research (CIHR)
Ischemia-induced ventricular arrhythmias are a major cause of sudden death. Arrhythmias have been linked to altered mechanics, however the underlying mechanisms are unknown. Our aim is to determine the mechanical contribution to ventricular arrhythmias during acute regional ischemia. Experiments are carried out in rabbit isolated whole hearts and single ventricular cells, with controlled alterations of mechanical activity, fluorescent measurement of voltage-calcium dynamics, and pharmacological interrogation of underlying mechanisms.
stress-induced arrhythmias with popdc mutation
Funded by the Heart and Stroke Foundation of Canada (HSFC)
The sinoatrial node is highly innervated by the intracardiac nervous system and neuronal modulation of its firing is essential for the maintenance of normal heart rhythm. The popeye domain-containing (popdc) gene family encodes cAMP-binding proteins expressed in the sinoatrial node and intracardiac neurons. Though it is known that popdc mutation results in age-dependent sinoatrial node dysfunction and stress-induced arrhythmias through autonomic stimulation, the specific role of the intracardiac nervous system in this process is unknown. Our aim is to determine the role of the intracardiac nervous system in stress-induced arrhythmias with popdc mutation. Experiments involve zebrafish expressing the popdc1(S191F) mutation (homologous to a popdc mutation found in humans), in which electrical, pharmacological, and cell-specific optogenetic stimulation of intracardiac nerves is performed, while measuring rhythm by ECG, voltage and calcium by optical mapping, and membrane potential by intracellular microelectrode recordings, followed by post hoc immuno-histochemical analysis of intracardiac nervous system and sinoatrial node structure.
INTRINSIC REGULATION OF sinoatrial node function
Funded by the Natural Sciences and Engineering Research Council of Canada (NSERC)