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Left ventricular assist device support normalizes left and right ventricular beta-adrenergic pathway properties

Stefan Klotz, MD^*, Alessandro Barbone, MD, Steven Reiken, PhD^*,||, Jeffrey W. Holmes, PhD, Yoshifumi Naka, MD, PhD, Mehmet C. Oz, MD, Andrew R. Marks, MD^*,,|| and Daniel Burkhoff, MD, PhD^*,*

^* Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York
Department of Surgery, College of Physicians and Surgeons, Columbia University, New York, New York
Department of Biomedical Engineering, College of Physicians and Surgeons, Columbia University, New York, New York
Department of Pharmacology, College of Physicians and Surgeons, Columbia University, New York, New York
^|| Center for Molecular Cardiology, College of Physicians and Surgeons, Columbia University, New York, New York

View larger version (16K): [in a new window]   Figure 1 V30, the ex vivo volume providing a ventricular pressure of 30 mm Hg, is an index of ventricular size. Left ventricular (LV) V30 was decreased after left ventricular assist device (LVAD) support, but right ventricular (RV) V30 did not change significantly. Ruled bars = nonfailing hearts; black bars = medical support; open bars = LVAD support. All data are mean ± SD. *p < 0.05 vs. LVAD support and nonfailing hearts.

View larger version (40K): [in a new window]   Figure 2 Representative force tracing from right ventricular (RV) and left ventricular (LV) endocardial trabeculae showing the responses to isoproterenol (1 µg/ml). Whereas responses were blunted in RV and LV muscle of medically managed transplanted hearts, left ventricular assist device (LVAD) support markedly improved responses in both ventricles similar to nonfailing hearts. Arrows = time when perfusion was switched to solution containing isoproterenol. Scale bar = 30 s.

View larger version (25K): [in a new window]   Figure 3 Change of developed (filled lines) and diastolic (dashed lines) isometric force of left ventricle (LV) (A) and right ventricle (RV) (B) endocardial trabeculae from baseline to peak response to isoproterenol perfusion (1 µg/ml). Left ventricular assist device (LVAD) support resulted in significantly increased developed isometric force generation in both the LV and RV muscle. (C) Change in isometric developed force generation after isoproterenol perfusion. Ruled bars = nonfailing hearts; black bars = medical support; open bars = LVAD support. All data are mean ± SEM. *p < 0.01, p < 0.05 vs. medical support.

View larger version (20K): [in a new window]   Figure 4 Representative Scatchard blots of [3H]DHA binding in left ventricular (LV) (A) and right ventricular (RV) (B) samples are shown of nonfailing (triangles), medical (squares), and left ventricular assist device (LVAD)-supported hearts (circles). (C) Density of beta-adrenergic receptors in LV and RV myocardial samples of nonfailing (ruled bars), medical (black bars), and LVAD-supported hearts (open bars). Data reported are the means ± SD of maximal binding (Bmax) values determined from Scatchard transformation of saturated binding data. *p < 0.01 vs. nonfailing and LVAD-supported hearts.

View larger version (27K): [in a new window]   Figure 5 (A) Ryanodine receptor 2 (RyR2) immunoblots (lower panel) and back phosphorylation gels. For the latter, the darker bands correspond to higher amounts of 32P transferred to RyR2 by protein kinase A (PKA), which is indicative of reduced RyR2 PKA phosphorylation in vivo. Note double band present in right ventricle (RV) RyR2 immunoblot. There is no special significance to the double bands in the RyR2 samples from the RV—moreover, given that the samples from nonfailing, medically, and left ventricular assist device (LVAD)-supported hearts are all equivalent (equal densities of the top and bottom bands) indicates that these samples are comparable and that measurements of the PKA phosphorylation levels are not affected by the presence of the two bands. Moreover, this does not represent nonspecific degradation as that would result in a smear. (B) RyR2 phosphorylation was markedly increased in failing myocardium, but was normalized by LVAD support in both ventricles. *p < 0.01 vs. nonfailing and LVAD-supported hearts. LV = left ventricle; HF = heart failure; PKI = protein kinase A inhibitor.