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PRECLINICAL STUDY

Therapy With Cardiac Contractility Modulation Electrical Signals Improves Left Ventricular Function and Remodeling in Dogs With Chronic Heart Failure

Makoto Imai, MD^_*, Sharad Rastogi, MD^_*, Ramesh C. Gupta, PhD^_*, Sudhish Mishra, PhD^_*, Victor G. Sharov, MD, PhD^_*, William C. Stanley, PhD, Yuval Mika, PhD, Benny Rousso, PhD, Daniel Burkhoff, MD, PhD, FACC, Shlomo Ben-Haim, MD, PhD and Hani N. Sabbah, PhD, FACC^_*,_*

^_* Division of Cardiovascular Medicine, Henry Ford Heart and Vascular Institute, Detroit, Michigan
Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio
Impulse Dynamics USA, Inc., Orangeburg, New York

Manuscript received August 1, 2006; accepted October 1, 2006.

^_* Reprint requests and correspondence: Dr. Hani N. Sabbah, Cardiovascular Research, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, Michigan 48202. (Email: HSABBAH1{at}hfhs.org).

Objectives: This study examined the effects of long-term delivery of cardiac contractility modulation (CCM) electric signals on left ventricular (LV) function and global, cellular, and molecular remodeling in dogs with chronic heart failure (HF).

Background: Acute studies in dogs with experimentally induced HF showed that CCM signals applied to the failing myocardium during the absolute refractory period improved LV function without increasing myocardial oxygen consumption.

Methods: In one study, dogs with intracoronary microembolization-induced HF were randomized to 3 months of active CCM monotherapy or to a sham-operated control group. In another study, 19 HF dogs were randomized to 3 months chronic monotherapy with extended release metoprolol succinate (MET-ER), MET-ER with CCM, or no therapy at all (control group).

Results: In CCM-only treated dogs, LV ejection fraction (EF) increased (27 ± 1% vs. 33 ± 1%, p < 0.0001) compared with a decrease in sham-operated control animals (27 ± 1% vs. 23 ± 1%, p < 0.001). The increase in EF seen with CCM-treated dogs was accompanied by reduced LV volumes, improved myocardial structure, reversal of the maladaptive fetal gene program, and an improvement in sarcoplasmic reticulum calcium cycling proteins. Dogs treated with a combination of MET-ER and CCM showed a greater increase in LV EF and a greater reversal of LV global, structural, and biochemical remodeling compared with dogs treated with MET-ER alone.

Conclusions: In dogs with HF, long-term CCM therapy improves LV systolic function. The improvements are additive to those seen with beta-blockers. These findings are further strengthened by the concomitant benefits of CCM therapy on LV global, cellular, and biochemical remodeling.

Abbreviations and Acronyms   ANP = atrial natriuretic peptide   AR = adrenergic receptor   BNP = brain natriuretic peptide   CCM = cardiac contractility modulation   CD = capillary density   CSQ = calsequestrin   EDV = left ventricular end-diastolic volume   EF = ejection fraction   ESV = end-systolic volume   GAPDH = glyceraldehyde-3-phosphate dehydrogenase   HF = heart failure   LV = left ventricular   MCSA = myocyte cross-sectional area   MET-ER = metoprolol succinate-extended release   MHC = -myosin heavy chain   MVO2 = myocardial oxygen consumption   ODD = oxygen diffusion distance   PLB = phospholamban   P-PLB = phosphorylated phospholamban   RyR = ryanodine receptor   SERCA-2a = sarcoplasmic reticulum calcium ATPase   SR = sarcoplasmic reticulum   VFIF = volume fraction of interstitial fibrosis   VFRF = volume fraction of replacement fibrosis

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