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CLINICAL RESEARCH: VENTRICULAR ASSIST DEVICES

Ventricular Assist Device Therapy Normalizes Inducible Nitric Oxide Synthase Expression and Reduces Cardiomyocyte Apoptosis in the Failing Human Heart

Richard D. Patten, MD^_*,,_*, David DeNofrio, MD, FACC, Mohamad El-Zaru, MD, FACC, Rahul Kakkar, MD^_*, Jessica Saunders, MD, Flore Celestin^_*, Kenneth Warner, MD, Hassan Rastegar, MD, Kamal R. Khabbaz, MD, James E. Udelson, MD, FACC, Marvin A. Konstam, MD, FACC and Richard H. Karas, MD, PhD, FACC^_*,

^_* Molecular Cardiology Research Institute, Tufts-New England Medical Center, Boston, Massachusetts
Division of Cardiology, Tufts-New England Medical Center, Boston, Massachusetts
Division of Cardiothoracic Surgery, Tufts-New England Medical Center, Boston, Massachusetts.

Manuscript received March 12, 2004; revised manuscript received May 17, 2004, accepted May 18, 2004.

^_* Reprint requests and correspondence: Dr. Richard D. Patten, Molecular Cardiology Research Institute, New England Medical Center, Box #80, 750 Washington Street, Boston, Massachusetts 02111. (Email: rpatten{at}tufts-nemc.org).

OBJECTIVES: We examined the effect of mechanical unloading with ventricular assist device (VAD) therapy on myocardial inducible nitric oxide synthase (iNOS) expression and cardiomyocyte apoptosis in patients with end-stage heart failure (HF).

BACKGROUND: Despite advances in medical therapy, HF continues to be a progressive and ultimately fatal disorder. High levels of iNOS expression are present in the myocardium of failing hearts, suggesting a potential role for iNOS in HF progression.

METHODS: Inducible NOS protein expression was analyzed by Western blotting and cardiomyocyte apoptosis by terminal deoxynucleotidyltransferase dUTP nick end-labeling (TUNEL) in myocardial samples from failing hearts. Included in these analyses were tissues from 9 patients at the time of transplantation (HF-transplant group), 10 patients at the time of VAD insertion (pre-VAD group), and 11 patients undergoing transplant after VAD support (post-VAD group). Seven control samples were obtained at autopsy.

RESULTS: Low or undetectable levels of iNOS were present in controls (0.005 ± 0.002). The HF-transplant and pre-VAD myocardial specimens exhibited a marked increase in iNOS expression (1.48 ± 0.34 and 1.29 ± 0.26, respectively; p < 0.01 for both vs. controls). The increase in iNOS expression was reversed in the post-VAD group (0.36 ± 0.16; p < 0.01 vs. HF-transplant and pre-VAD groups). The rate of TUNEL-positive cardiomyocytes was high in the pre-VAD group and significantly lower in the post-VAD group (0.64 ± 0.15% in pre-VAD group and 0.16 ± 0.07% in post-VAD group; p < 0.01). The iNOS levels correlated significantly with cardiomyocyte apoptosis (r = 0.66, p < 0.01).

CONCLUSIONS: Therapy with VAD normalizes iNOS expression in association with diminished cardiomyocyte apoptosis in the failing heart. Further work is required to define whether a causal relationship exists between iNOS and cardiomyocyte apoptosis.

Abbreviations and Acronyms   GAPDH = glyceraldehyde-3-phosphate dehydrogenase   HF = heart failure   iNOS = inducible nitric oxide synthase   LV = left ventricular   NO = nitric oxide   PBS = phosphate-buffered saline   RV = right ventricular   TNF-alpha = tumor necrosis factor-alpha   TUNEL = terminal deoxynucleotidyltransferase dUTP nick-end labeling   VAD = ventricular assist device

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