Cardiac contractility modulation by non-excitatory currents: studies in isolated cardiac muscle.
BACKGROUND
Myocardial contractility can be altered using voltage clamp techniques by modulating amplitude and duration of the action potential resulting in enhanced calcium entry in the cell of isolated muscle strips (Non-Excitatory Currents; NEC). Extracellular electrical stimuli delivered during the absolute refractory period (Cardiac Contractility Modulation; CCM) have recently been shown to produce inotropic effects in-vivo.


OBJECTIVE
Understanding the cellular mechanism, underlying the CCM effect, is essential for evaluating its clinical potential. We tested the hypothesis that NEC and CCM modulate contractility via similar cellular mechanisms.


METHODS
Square wave electric currents were applied in the organ bath to isometrically contracting rabbit RV papillary muscle and human failing trabecular muscle during the absolute refractory period (ARP).


RESULTS
These currents, which did not initiate new action potentials or contractions, modulated action potential duration (shortened or lengthened) and contractility (enhanced or depressed) in a manner that depended upon their amplitude, duration and delay from the pacing stimulus. The contractility modulation effect in the rabbit RV papillary muscle was markedly blunted after exposure to ryanodine, indicating that the sarcoplasmic reticulum plays an important role in the contractility modulation.


CONCLUSIONS
Like voltage clamping, extracellular currents applied during the ARP can similarly modulate action potential duration in-vitro and modulate myocardial contractility by similar intracellular mechanisms. This concept provides the potential of a therapeutic strategy in patients with heart failure to enhance contractility.
Brunckhorst
Corinna B
CB
Institute of Cardiology, University Hospital Zurich, Ramistr. 100, Zurich 8091, Switzerland.
Shemer
Isaac
I
Mika
Yuval
Y
Ben-Haim
Shlomo A
SA
Burkhoff
Daniel
D
D000818:Animals; D004558:Electric Stimulation; D006801:Humans; D066298:In Vitro Techniques; D008564:Membrane Potentials; D009200:Myocardial Contraction / Q000502:physiology*; D010210:Papillary Muscles / Q000502:physiology*; D018408:Patch-Clamp Techniques; D011817:Rabbits; D012519:Sarcoplasmic Reticulum / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D016276:Ventricular Function