טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentYaniv Yael
SubjectIdentification of the Mechanoelectric Feedback in the
Cardiac Muscle
DepartmentDepartment of Biomedical Engineering
Supervisor Professor Amir Landesberg
Full Thesis textFull thesis text - English Version


Abstract

Changes in the mechanical loadings conditions affect cardiac electrical activity. This phenomenon is denoted as the mechanoelectric feedback (MEF). Although the phenomenon was originally characterized about 30 years ago, the underlying cellular mechanisms remain elusive. There is a tight correlation between the severity of myocardial structural and functional inhomogeneities and the susceptibility to lethal arrhythmia. Mechanical inhomogeneities can elicit arrhythmias by triggering afterdepolarization or generating the spatial electrical disparity required for development of reentrant arrhythmias.

The prevailing hypothesis assumes that the MEF results from the existence of stretch activated channels (SACs). An alternative hypothesis postulates that mechanical perturbations affect calcium dissociation from troponin, and the ensuing changes in the free intercellular calcium ([Ca2+]i) alter the action potential duration (APD).

This study aims to characterize and test the two plausible hypotheses theoretically and experimentally.

The study tests these hypotheses by integrating a modified Luo-Rudy model of the sarcolemma with the regulation of cytosolic calcium and sarcomere dynamics. The SACs and the reverse excitation-contraction coupling (rECC) pathways yield opposing predictions. The rECC hypothesis suggests that lengthening affects the [Ca2+]i and always shortens the AP duration. The SAC hypothesis stipulates that lengthening has negligible effect on [Ca2+]i and prolongs the AP when the plateau of the AP is below the SAC reverse potential. The rECC hypothesis predictions are congruent with available data.

These stretch and calcium mediated hypotheses were investigated experimentally in isolated trabeculae from rat right ventricle (n=7) by separately controlling SL and [Ca2+]i. SL was controlled by a rapid servomotor. [Ca2+]i was clamped by utilizing tetanic contractions at different extracellular calcium concentrations ([Ca2+]0s). Tetanus was achieved by 8Hz stimulation in the presence of cyclopiazonic acid. APD was evaluated by voltage sensitive dye (Di-4-ANEPPS). SL was measured by laser diffraction and force by strain gauge. Sarcomere lengthening from 1.85 to 2.2μm, at constant [Ca2+]0 (3mM), decreased the APD90 from 90.7±4.1 to 62±1.5msec. However, an increase in [Ca2+]0 from 1.5 to 4.5mM, at the same SL (2µm), decreased the APD90 from 84.6±3.8 to 69.2±1.6msec. Interestingly, a consistent identical inverse relationship between APD90 and stress was obtained, and similar APD90 was observed at similar stress with different pairs of SL and [Ca2+]0. The APD90 decreased from 89.8±2.1 to 62±1.3msec as the stress increased from 7±0.8 to 103.8±2% of normalized force.  These conspicuous observations are readily explained by the rECC and negate the SAC hypothesis.