Cardiac Arrhythmia Mechanisms-Excitation-Contraction coupling

Description of projects available to graduate students:
The strengths of this laboratory is the its multidisciplinary nature which combines studies of cardiac electrophysiology in a wide range of preparations and techniques to investigate arrhythmia mechanisms in several pathologies. We investigate the mechanisms underlying arrhythmias in the Long QT syndrome, heart failure, ischemic heart disease and sex differences in the susceptibility to polymorphoic tachyarrhythmias. To investigate these electrical dysfunctions we have developed optical mapping techniques to simultaneously map action potentials and Ca2+ transients at high spatial and temporal resolution. We developed the earliest instruments and remain at the forefront of the technology by applying the latest scientific CMOS cameras with data streaming to hard disk.
More recently we have been developing a 'confocal macroscope' to image different layers of cardiac tissue as a function of depth to map mechano-electrical properties of Purkinje fibers and their coupling to ventricular muscles located in a deeper layer. These studies provide the first images of the conduction system, its coupling to the working myocardium and its role in initiating and maintaining arrhythmias.
We have investigated sex differences in the susceptibility of women to have Torsade de Pointes in the long QT syndrome and showed that estrogen regulates L-type Calcium channels and sodium-calcium exchanger by a classical genomic mechanism. The regulation of cardiac ion channels by sex steroids is being actively investigated in animal models and human cardiac tissues.
We use cardiac myocytes derived from human inducible pluripotent stem (iPS) cells : a) to study mechanisms of pacemaking, b) sex-differences in action potential properties and susceptibility to arrhythmias in LQTS, c) familial atrial fibrillation, and d) long QT patients.

We are currently developing new probes to map extracellular K+ accumulation in T-tubules and interstitial spaces and probes to measure intracellular Na+. The physiological and pathological significance of ionic imbalances are investigated in intact Langendorff perfused hearts and isolated myocytes.
The PI has pioneered the development of voltage-sensitive dyes and imaging techniques to simultaneously measure electrical events from multiple sites on heart or other electrically excitable biological preparations. Genetically encoded Ca2+ and Voltage-sensitive probes are are being developed to track electrophysiological changes during chronic infarcts and heart failure.

Techniques graduate student will learn:
Optical mapping
Spectroscopy
Stop-flow technique
Patch clamping
Reconstitution of ion channels in planar bilayers
Western and Northern blots
Immunohistochemistry
Confocal imaging
Muscle contractility