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CLINICAL RESEARCH: HEART FAILURE

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

Manuscript received July 13, 2004; accepted November 16, 2004.

^* Reprint requests and correspondence: Dr. Daniel Burkhoff, Columbia University, Department of Medicine, Division of Cardiology, 177 Fort Washington Avenue, MHB5-435, New York, New York 10032 (Email: db59{at}columbia.edu).

OBJECTIVES: We hypothesized that some aspects of left ventricular assist device (LVAD) reverse remodeling could be independent of hemodynamic factors and would primarily depend upon normalization of neurohormonal milieu.

BACKGROUND: The relative contributions of LVAD-induced hemodynamic unloading (provided to the left ventricle [LV]) and normalized neurohormonal milieu (provided to LV and right ventricle [RV]) to reverse remodeling are not understood.

METHODS: Structural and functional characteristics were measured from hearts of 65 medically managed transplant patients (MED), 30 patients supported with an LVAD, and 5 nonfailing donor hearts not suitable for transplantation.

RESULTS: Compared with MED patients, diastolic pulmonary pressures trended lower (p < 0.01) and cardiac output higher (p < 0.001) in LVAD patients; V₃₀ (ex vivo ventricular volume yielding 30 mm Hg, an index of ventricular size) in LVAD patients was decreased in the LV (p < 0.05) but did not change significantly in RV. The LVAD support improved force generation in response to beta-adrenergic stimulation in isolated LV (increase in developed force from 6.3 ± 0.6 to 18.5 ± 4.4 mN/m², p < 0.01) and RV (increase in developed force, from 10.9 ± 2.0 to 20.5 ± 3.1 mN/m², p < 0.05) trabeculae. The LVAD patients had higher myocardial beta-adrenergic receptor density in LV (p < 0.01) and RV (p < 0.01). Protein kinase A (PKA) hyperphosphorylation of the ryanodine receptor 2 (RyR2)/calcium release channel was significantly reduced by LVAD in both RV and LV (p < 0.01).

CONCLUSIONS: Improved beta-adrenergic responsiveness, normalization of the RyR2 PKA phosphorylation, and increased beta-adrenergic receptor density in LV and RV after LVAD support suggest a primary role of neurohormonal environment in determining reverse remodeling of the beta-adrenergic pathway.

Abbreviations and Acronyms   LV = left ventricle/ventricular   LVAD = left ventricular assist device   PKA = protein kinase A   RV = right ventricle/ventricular   RyR = ryanodine receptor   SERCA2a = sarcoplasmic reticulum Ca2+-ATPase, isoform 2a

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