“Engineering solutions to tackle heart disease mechanisms”

The rhythm and the strength of heart beats are controlled by three dynamic systems: the electrical system, the Ca²⁺ signaling system, and the contractile system.  Heart diseases such as cardiac arrhythmias and heart failure arise from molecular defects in these systems.  In the classic paradigm, the electrical excitation controls the Ca²⁺ signaling which, in turn, controls the muscle contraction.  Most previous work focused on each dynamic system in isolation.  However, recent research advancements reveal that defects in the Ca²⁺ signaling system and the contractile system can feedback to cause electric arrhythmias.  Such feedback mechanisms underlie various heart diseases including Hypertension -induced Hypertrophy and Heart Failure (HHHF) and Familial Hypertrophic Cardiomyopathy (FHC), both can cause arrhythmias and Sudden Cardiac Death.  I will report the innovative techniques we have developed recently to tackle heart disease mechanisms.

INNOVATION #1:  AP-clamp Sequential Dissection to fingerprint the ionic currents in cardiac cells.

The cardiac action potential (AP) is shaped by myriad ionic currents.  We have developed an innovative AP-clamp Sequential Dissection technique (nick named ‘onion-peeling’) to enable recording of multiple ionic currents in the single cell.  This new technique presents a significant step beyond the traditional way of recording only one current in any one cell.  The ability to measure multiple currents in a single cell has revealed two hitherto unknown characteristics of the ionic currents in cardiac cells: coordination of currents within a cell and large variation of currents between cells.  Hence, the AP-clamp Sequential Dissection technique provides a powerful tool for characterizing the individual cell electrophysiology.

INNOVATION #2:  AP-clamp with Ca²⁺ cycling.

We developed this technique to study the feedback from Ca²⁺ signaling to electrical system. We found that spontaneous Ca²⁺ oscillations mediate the induction of arrhythmogenic APs.

INNOVATION #3:  3D elastic gel matrix to control mechanical stress in the single cell.

We developed a novel 3-dimensional (3D) elastic gel matrix that deforms when the embedded single cardiac muscle cell undergoes shortening and broadening during excitation-contraction and thus exerts mechanical stress on the cell.  The gel matrix allows normal aqueous superfusion and confocal imaging of a single cell, and thus enables studying the feedback from mechanical system to Ca²⁺ signaling system.  We found that when myocytes contract under mechanical stress, the Ca²⁺ transient was increased to enhance contraction during systole, but can cause arrhythmogenic Ca²⁺ activities during diastole.

When: Thursday Sept. 27, 2012  4:10 PM

Where: 1005 GBSF