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CLINICAL STUDY: LEFT VENTRICULAR ASSIST DEVICE

Left ventricular assist device implantation augments nitric oxide dependent control of mitochondrial respiration in failing human hearts

Seema Mital, MD^*, Kit E. Loke, PhD, Linda J. Addonizio, MD^*, Mehmet C. Oz, MD^* and Thomas H. Hintze, PhD

^* Department of Pediatrics, Divisions of Pediatric Cardiology and Cardiothoracic Surgery, Columbia University College of Physicians and Surgeons, New York, New York, USA
Department of Physiology, New York Medical College, Valhalla, New York, USA

Manuscript received January 13, 2000; revised manuscript received May 4, 2000, accepted July 10, 2000.

Reprint requests and correspondence: Dr. Thomas H. Hintze, Department of Physiology, Basic Science Bldg, Rm 636, New York Medical College, Valhalla, New York 10595
thomas_hintze{at}nymc.edu

OBJECTIVES

The objective of the study was to evaluate nitric oxide (NO) mediated regulation of mitochondrial respiration after implantation of a mechanical assist device in end-stage heart failure.

BACKGROUND

Ventricular unloading using a left ventricular assist device (LVAD) can improve mitochondrial function in end-stage heart failure. Nitric oxide modulates the activity of the mitochondrial electron transport chain to regulate myocardial oxygen consumption (MVO₂).

METHODS

Myocardial oxygen consumption was measured polarographically using a Clark-type oxygen electrode in isolated left ventricular myocardium from 26 explanted failing human hearts obtained at the time of heart transplantation.

RESULTS

The rate of decrease in oxygen concentration was expressed as a percentage of baseline. Results of the highest dose of drug are shown. Decrease in MVO₂ was greater in LVAD hearts (n = 8) compared with heart failure controls (n = 18) in response to the following drugs: bradykinin (–34 ± 3% vs. –24 ± 5%), enalaprilat (–37 ± 5% vs. –23 ± 5%) and amlodipine (–43 ± 13% vs. –16 ± 5%; p < 0.05 from controls). The decrease in MVO₂ in LVAD hearts was not significantly different from controls in response to diltiazem (–22 ± 5% in both groups) and exogenous NO donor, nitroglycerin (–33 ± 7% vs. –30 ± 3%). N^w-nitro-L-arginine methyl ester, inhibitor of NO synthase, attenuated the response to bradykinin, enalaprilat and amlodipine. Reductions in MVO₂ in response to diltiazem and nitroglycerin were not altered by inhibiting NO.

CONCLUSIONS

Chronic LVAD support potentiates endogenous NO-mediated regulation of mitochondrial respiration. Use of medical or surgical interventions that augment NO bioavailability may promote myocardial recovery in end-stage heart failure.

Abbreviations and Acronyms   ACE = angiotensin-converting enzyme   L-NAME = Nw-nitro-L-arginine methyl ester   LVAD = left ventricular assist device   MVO2 = myocardial oxygen consumption   NO = nitric oxide

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