title: Cardiac contractility modulation by non-excitatory currents: studies in isolated cardiac muscle.
abstract: 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.
authors.affiliation: Institute of Cardiology, University Hospital Zurich, Ramistr. 100, Zurich 8091, Switzerland.
authors.forename: Corinna B
authors.initials: CB
authors.lastname: Brunckhorst
authors.forename: Isaac
authors.initials: I
authors.lastname: Shemer
authors.forename: Yuval
authors.initials: Y
authors.lastname: Mika
authors.forename: Shlomo A
authors.initials: SA
authors.lastname: Ben-Haim
authors.forename: Daniel
authors.initials: D
authors.lastname: Burkhoff
mesh_terms: 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