M.Sc Thesis

M.Sc StudentShemer Isaac
SubjectEffect of Non Excitatory Electric Signals on Cardiac
DepartmentDepartment of Medicine
Supervisor PROFESSOR EMERITUS Yoram Palti


Myocardial contractility can be altered using voltage clamp techniques by modulating the duration of transmembrane depolarization in isolated muscle strips. Whether extracellular electrical currents could have similar effects is unknown. In the present study, extracellular square current waves were applied to isometrically contracting rabbit papillary muscles or human trabeculae during the absolute refractory period. Stimuli were defined as non-excitatory contractility modulation signals (NECM) since they did not initiate new contractions or action potentials.

NECM signals modulated action potential duration (shortened or lengthened) and contractility (depressed or enhanced, respectively). Modulations depended on signal amplitude, duration and delay from pacing stimulus. The mechanisms underlying the inotropic effects of NECM signals are different from post-extrasystolic potentiation: (1)NECM can reduce the contractility; (2)NECM exhibit a dose dependent correlation with signal amplitude; (3)direct measurement of transmembrane potentials shows that NECM does not initiate additional action potential. NECM effect is not mediated by norepinephrine release from excited nerve terminals: (1)NECM effects were preserved in the presence of beta-receptor blockade; (2)reversing NECM polarity reverse the inotropic effects; (3)response to the NECM stimuli delivered on every other beat yielded an alternating inotropic response, with strong contractions observed on the beats not receiving the signal.

The NECM effect, as a novel tool for modulating contractility in intact myocardium, has been validated in this study of ex-vivo rabbit myocardium as well as failing human myocardium. The mechanism involves modulation of the action potential duration with associated changes in trans-sarcolemmal calcium fluxes followed by modulation of the SR calcium content.