Summary

Our work is focused on the intrinsic regulation of cardiac function and the effects of mechano-electric interactions on heart rhythm. We employ an integrative multi-scale, multi-species approach (from whole animals to isolated tissue and cell preparations from human, rabbit, rat, mouse, and zebrafish) that combines advanced experimental techniques (mechanical interventions, optical mapping, fluorescence microscopy, and optogenetics) with computational modeling to gain insight into normal and diseased cardiac function at various levels of functional and structural complexity. This builds on expertise in basic, translational, and clinical collaborative research, with the goal to: (i) define organ-, tissue-, cell-, and subcellular-level autoregulatory mechanisms responsible for (patho-)physiological responses; (ii) discover their relevance for heart rhythm in health and disease; and (iii) apply insights to develop novel targeted anti-arrhythmic therapies.

Current research projects in the lab are described below.

Atrial and Ventricular Mechano-arrhythmogenesis in CARDIAC Disease

Heart disease is a leading cause of death worldwide, in part due to an increased risk for atrial fibrillation and ventricular tachyarrhythmias. These lethal arrhythmias can be triggered by acute electrophysiological fluctuations driven by acute (patho-)physiological fluctuations in the heart’s mechanical load (‘mechano-arrhythmogenesis’). If these acute electrophysiological interact with persistent, structure-function alterations in cell-level (e.g., ion channel activity, cytoskeletal elements, or oxidative state) or tissue-level (e.g., cellular connectivity or fibrosis) factors, they can result in sustained arrhythmias. Yet, the underlying mechanisms of mechano-arrhythmogenesis are generally unknown. The goal of this project is to define the mechanisms and importance of atrial and ventricular mechano-arrhythmogenesis in various forms of heart disease. Experiments are carried out in rabbit isolated cells, tissue, and whole hearts - as well as human patient cells and tissue - with controlled alterations of mechanical load, functional fluorescence imaging, video-based mechanical measurements, microelectrode and patch-clamp recordings, immunofluorescent and molecular assessments, and targeted pharmacological interventions. Ultimately, this work which will provide crucial insight into the mechanisms and importance of mechano-arrhythmogenesis and identify potential novel anti-arrhythmic targets for its prevention.

 

The Importance of the Intracardiac Nervous System for Cardiac Function in Health, Disease, and Ageing

Innervated Heart.png

One of the principal drivers of the heart’s adaption to changes in physiological demand is the autonomic nervous system, which is composed of sympathetic and parasympathetic nerves that project from the central nervous system to a network of nerves in the heart, known as the intracardiac nervous system (IcNS). The IcNS has classically been considered simply a ‘relay station’ for signals coming from outside the heart, however there is growing evidence that it is composed of afferent, efferent, and local-circuit neurons, which are involved in the independent processing and local feedback of neuronal information within the heart. Yet, little is known about the overall function of the IcNS, as it is embedded within the tissue of the heart, so difficult to study with current technologies. The goal of this project is to develop a new innovative approach for the study of the IcNS, to determine whether it is important for local control the heart activity and may be involved in cardiac dysfunction in disease and with age. Experiments are carried out in whole zebrafish and isolated hearts - in which activity of the entire IcNS can be measured and manipulated - involving cell-specific three-dimensional imaging and optogenetic interrogation of IcNS interconnectivity, function, and cardiac effects during application of (patho-)physiological stressors. Ultimately, this work will provide direct evidence demonstrating whether the IcNS plays an important independent role in local control of heart function in health, disease, and with age, opening the door for the development of new ‘nerve-based’ treatments for cardiac dysfunction.

 

THE IMPORTANCE OF Mechano-electric COUPLING FOR Cardiac Autoregulation

The heart beats an incredible 3-4 billion times over a lifetime. To accomplish this amazing feat, millions of cells must work in a well-coordinated fashion, while rapidly adjusting their activity to changes in physiological demand. This coordination and adaptation is driven largely by regulation that occurs entirely within the heart, including responses to change in mechanical load, which allows for electro-mechanical adaptation on a beat-by-beat basis. This mechanically-driven responses occur through a variety of mechano-electric coupling mechanisms, including changes in the heart’s electrical activity, intracellular calcium handling, and intracardiac nervous system function. This cardiac autoregulation is both critical for physiological heart function and in disease can lead to pathophysiological effects. Yet the molecular mechanisms and mechanical determinants of observed responses remain ill-defined. This goal of this project is to determine factors underlying cardiac autoregulation and its importance in heath and disease. Experiments involve the full use of our integrative multi-scale, multi-species experimental-computational approach to interrogate underlying mechanisms. Ultimately, this work will improve our fundamental understanding of cardiac mechano-electric coupling and autoregulation in health and disease.

 

TREATING CARDIAC ARRHYTHMIAS WITH SUB-THRESHOLD OPTOGENETICS

Cardiac arrhythmias, including cell- and tissue-level disturbances in the generation or conduction of the heart’s electrical activity, impair it’s blood pumping ability. While various treatments for the prevention or termination of arrhythmias exist, they generally lack in effectiveness and are often associated with harmful side effects, so the development of new therapies is needed. The goal of this project is to explore the use of optogenetics - which entails the control of cellular activity with genetically-encoded light-activated ion channels and pumps - as a novel anti-arrhythmic tool. Experiments are carried out in isolated hearts and tissue from zebrafish and mouse expressing a suite of optogenetic transducers, with temporally- and spatially-controlled light stimulation and measurement of cell and whole heart electrical activity by high-speed, high-resolution intracellular microelectrode recordings and fluorescent imaging in various disease conditions. This is combined with computational modelling-based optimisation and clinical translation. Ultimately, this work will determine the potential for the use of optogenetics as a transformative anti-arrhythmic therapy.

 

techniques

Cell/Tissue Stretch · Optical Mapping · Optogenetics · Macro/Microscopic Fluorescence Imaging · Echocardiography · Immunofluorescence · Molecular Biology · Computational Modelling

FUNDING