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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.

View larger version (22K): [in a new window]   Figure 1 (A) Bar graph demonstrating mean inducible nitric oxide synthase (iNOS) levels in myocardial samples from all patients in this study, including control hearts without heart disease, patients with heart failure (HF) at the time of transplantation (HF-transplant), at the time of ventricular assist device (VAD) insertion (pre-VAD), and after VAD support (post-VAD). Levels of iNOS were quantified by Western blotting, correcting for the control protein, glyceraldehyde-3-phosphate dehydrogenase (GAPDH). *p < 0.01 vs. control; p < 0.05 vs. HF-transplant and pre-VAD groups. (B) Representative iNOS Western blot from three patients with matched pre- and post-VAD myocardial samples. All three samples demonstrate a notable decrease in iNOS within the myocardium after VAD support. The corresponding Western blot for the control protein, GAPDH, performed on the same membrane, is shown in the lower panel. The positive control (Con) was cell lysate from cultured cardiomyocytes stimulated with lipopolysaccharide. (C) Line graphs representing the change in iNOS protein levels from myocardial samples obtained from the same patient before and after VAD therapy (n = 7). Six of seven patients demonstrated a marked decrease in iNOS.

View larger version (74K): [in a new window]   Figure 2 Representative inducible nitric oxide synthase (iNOS) immunohistochemical stains. (Left) Negative control (non-immune, rabbit immunoglobulin G in place of primary antibody). (Middle) Pre-VAD sample demonstrating positively stained cardiomyocytes with iNOS localized within the cytoplasm. (Right) Post-VAD myocardial sample obtained from the same patient shown in Figure 1B. Inducible NOS immunostaining is barely detectable in this sample. VAD = ventricular assist device.

View larger version (11K): [in a new window]   Figure 3 Line graph demonstrating the level of normalized inducible nitric oxide synthase (iNOS) protein abundance versus duration of ventricular assist device (VAD) support. A time-dependent decrease in iNOS abundance is apparent during VAD support. p = 0.09 for non-linear regression.

View larger version (18K): [in a new window]   Figure 4 Regression plot of percent terminal deoxynucleotidyltransferase dUTP nick-end labeling (TUNEL)-positive cardiomyocytes (CMs) versus normalized inducible nitric oxide synthase (iNOS) levels (iNOS/GAPDH) in which a significant correlation was present (r = 0.66, p < 0.01).