Nissim Darvish

Electric currents applied during the refractory period can modulate cardiac contractility in vitro and in vivo.

Daniel Burkhoff MD PhD , Itzik Shemer , Bella Felzen , Juichiro Shimizu , Yuval Mika , Marc Dickstein , David Prutchi , Nissim Darvish 3 and Shlomo A. Ben-Haim 2,5 Divisions of Circulatory Physiology and Cardiology, Cardiac Physiology Laboratory, Department of Medicine, Columbia University, N.Y., Impulse Dynamics, Tirat HaCarmel 39120, Israel, Department of Physiology and Biophysics, The Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, P.O.B. 9649, Haifa 31096, Israel, Department of Anesthesiology, Columbia University, N.Y., Harvard-Thorndike Arrhythmia Institute, Beth-Israel Hospital, 330 Brookline Ave, Boston, Massachusetts 02215, USA

Cardiac contractility modulation with the impulse dynamics signal: studies in dogs with chronic heart failure.

The intravenous use of positive inotropic agents, such as sympathomimetics and phosphodiesterase inhibitors, in heart failure is limited by pro-arrhythmic and positive chronotropic effects. Chronic use of these agents, while eliciting an improvement in the quality of life of patients with advanced heart failure, has been abandoned because of marked increase in mortality when compared to placebo. Nevertheless, patients with advanced heart failure can benefit from long-term positive inotropic support if the therapy can be delivered ‘on demand’ and in a manner that is both safe and effective. In this review, we will examine the use of a novel, non-stimulatory electrical signal that can acutely modulate left ventricular (LV) contractility in dogs with chronic heart failure in such a way as to elicit a positive inotropic support. Cardiac contractility modulation (CCM) with the Impulse Dynamic™ signal was examined in dogs with chronic heart failure produced by intracoronary microembolizations. Delivery of the CCM signal from a lead placed in the great coronary vein for periods up to 10 minutes resulted in significant improvements in cardiac output, LV peak+dP/dt, LV fractional area of shortening and LV ejection fraction measured angiographically. Discontinuation of the signal resulted in a return of all functional parameters to baseline values. In cardiomyocytes isolated from dogs with chronic heart failure, application of the CCM signal resulted in improved shortening, rate of change of shortening and rate of change of relengthening suggesting that CCM application is associated with intrinsic improvement of cardiomyocyte function. The improvement in isolated cardiomyocyte function after application of the CCM signal was accompanied by an increase in the peak and integral of the Ca2+ transient suggesting modulation of calcium cycling by CCM application. In a limited number of normal dogs, intermittent chronic delivery of the CCM signal for up to 7 days showed chronic maintenance of LV functional improvement. In conclusion, pre-clinical results to date with the Impulse Dynamics CCM signal indicate that this non-pharmacologic therapeutic modality can provide short-term positive inotropic support to the failing heart and as such, may be a useful adjunct in the treatment of advanced heart failure. Additional, long-term studies in dogs with heart failure are needed to establish the safety and efficacy of this therapeutic modality for the chronic treatment of this disease syndrome.

Electrical modulation of cardiac contractility: Clinical aspects in congestive heart failure

Heart failure is a highly prevalent disease in western society. Drug therapies aimed at increasing myocardial contractility have been associated with decreased survival. Several short and mid term clinical studies have suggested adjuvant or alternative therapies to congestive heart failure using modified pacing techniques that were aimed to increase contractility (e.g. Paired pacing) or restore synchrony of contraction (biventricular pacing). While delivery of paired pacing was abandoned during the early 70s, biventricular pacing has recently emerged as an adjuvant treatment to limited group of congestive heart failure patients with aberrant left ventricular conduction. In this brief review, we describe our initial safety and efficacy experience in patients with heart failure using a novel non-stimulatory electrical approach to the delivery of positive inotropic therapy to the failing myocardium. The study suggests that unlike modified pacing techniques, delivery of the signal to the left ventricle during the refractory period resulted in a rapid increase in myocardial contractility and improved hemodynamic performance. The near instantaneous contractility improvement achieved by this type of stimulus was shown to be safe and effective independently of the primary cause of heart failure or the function of the conduction system. Unlike pharmacologic treatments, which have a relatively constant effect, use of electrical stimuli may prove useful as a new therapeutic modality in the treatment of heart failure with which contractility can be improved when and as needed.

Global Improvement in Left Ventricular Performance Observed with Cardiac Contractility Modulation is the Result of Changes in Regional Contractility

Cardiac Contractility Modulation (CCM) is a novel therapeutic strategy for increasing myocardial systolic performance. CCM involves nonexcitatory electrical stimulation that can be delivered via standard LV pacing lead approaches (i.e. temporary epicardial electrodes placed during surgery or specialized coronary venous leads presently under development). Unlike other heart failure therapies, CCM is targeted to a very speci®c region of the myocardium, thus avoiding extracardiac side effects and untoward effects related to nonspeci®c cardiac activation. The purpose of this paper is to review experiments performed for the most part in normal, acute experimental preparations, that assess the spatial extent of the CCM effect. These experiments support the hypothesis that the global effects on cardiac systolic function observed during CCM are the direct result of changes in regional contractility close to the CCM site. The implications of this observation, including the possibility of taking advantage of potential regional differences in susceptibility to CCM effect or optimizing therapy by multisite CCM stimulation will also be discussed.