Summary

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.png

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)

Innervated Heart.png

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)

SAN Stretch.png

The sinoatrial node is highly regulated to ensure proper function and enable adaptation to changes in physiological demand. Much of this regulation is intrinsic to the heart, triggered by changes in mechanical load, which allows electro-mechanical adaptation on a beat-by-beat basis. This occurs through a variety of mechanisms, including changes in the heart’s electrical activity, intracellular calcium handling, and intracardiac nervous system function, and in some settings may contribute to sinoatrial node dysfunction. Yet the molecular mechanisms and mechanical determinants of observed responses remain unknown. Our aim is to determine factors underlying intrinsic regulation of sinoatrial node function and its importance in heath and disease. Experiments are performed using the isolated sinoatrial node from zebrafish, rabbit, and mouse, with application of controlled stretch, measurement of beating rate and force, fluorescent voltage and calcium measurements, and microelectrode measurement of membrane potential, during cell-specific optogenetic and pharmacological interrogation of underlying mechanisms.

 

sustainability of Mechanical pacing

Mechanical Pacing.png

Mechanical stimulation by external percussion, high-intensity focused-ultrasound, or implanted microparticles can cause excitation, however is unsustainable. Yet, the cause for the loss of capture during mechanical pacing is unknown. Our aim is to determine the causes for the loss of mechanical pacing capture. Experiments are carried out in rabbit isolated whole hearts and single ventricular cells with repetitive mechanical stimulation, voltage optical mapping, measurement of tissue and cell stiffness, and pharmacological interrogation of underlying mechanisms.

 

zebrafish as a model for cardiac research

ZF Heart Activation.png

The zebrafish is an increasingly popular model for the study of cardiac electrophysiology due to its functional similarities to mammals, potential for genetic manipulation, and the ability for in vivo observation. We have been using the zebrafish to study intrinsic regulation (via stretch and intracardiac nervous system control) of the sinoatrial node. Yet, mechanisms underlying sinoatrial node automaticity in zebrafish are poorly defined. Our aim is to determine the components of the ‘membrane-/calcium-clock’ system found in mammals that contribute to pacemaking in the zebrafish, to better define its utility as an experimental model for studies of SAN function. Experiments use isolated zebrafish hearts, tissue, and cells, in which ECG, microelectrode, and fluorescent measurements of electrical activity (using both functional dyes and genetically-expressed optogenetic probes) are performed, during targeted pharmacological interventions.

 

techniques

Cell/Tissue Stretch · Optical Mapping · Optogenetics · Microscopic Fluorescence Imaging
Echocardiography · Immuno-histochemistry · Molecular Biology · Computational Modelling


FUNDING

Funding.png