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HEART FAILURE

Altered myocardial Ca²⁺ cycling after left ventricular assist device support in the failing human heart

Khuram W. Chaudhary, PhD^*, Eric I. Rossman, PhD^*, Valentino Piacentino, III, PhD^*, Agnes Kenessey, PhD, Chris Weber, PhD, John P. Gaughan, PhD^*, Kaie Ojamaa, PhD, Irwin Klein, MD, Donald M. Bers, PhD, Steven R. Houser, PhD^* and Kenneth B. Margulies, MD^*,*

^* Cardiovascular Research Center, Temple University, Philadelphia, Pennsylvania, USA
North Shore-Long Island Jewish Research Institute, Manhasset, New York, USA
Department of Physiology, Loyola University Chicago, Chicago, Illinois, USA
Department of Endocrinology, North Shore Hospital Medical Center, Manhasset, New York, USA

Manuscript received January 23, 2003; revised manuscript received April 28, 2004, accepted May 11, 2004.

^* Reprint requests and correspondence: Dr. Kenneth B. Margulies, Associate Professor of Medicine and Physiology, Cardiovascular Research Center, Temple University School of Medicine, Room 805 MRB, 3420 North Broad Street, Philadelphia, Pennsylvania 19140 (Email: margul{at}temple.edu).

OBJECTIVES: The objective of the present study was to determine whether improved contractility after left ventricular assist device (LVAD) support reflects altered myocyte calcium cycling and changes in calcium-handling proteins.

BACKGROUND: Previous reports demonstrate that LVAD support induces sustained unloading of the heart with regression of pathologic hypertrophy and improvements in contractile performance.

METHODS: In the human myocardium of subjects with heart failure (HF), with non-failing hearts (NF), and with LVAD-supported failing hearts (HF-LVAD), intracellular calcium ([Ca²⁺]_i) transients were measured in isolated myocytes at 0.5 Hz, and frequency-dependent force generation was measured in multicellular preparations (trabeculae). Abundance of sarcoplasmic reticulum Ca²⁺ adenosine triphosphatase (SERCA), Na⁺/Ca²⁺ exchanger (NCX), and phospholamban was assessed by Western analysis.

RESULTS: Compared with NF myocytes, HF myocytes exhibited a slowed terminal decay of the Ca²⁺ transient (DT_terminal, 376 ± 18 ms vs. 270 ± 21 ms, HF vs. NF, p < 0.0008), and HF-LVAD myocytes exhibited a DT_terminal that was much shorter than that observed in HF myocytes (278 ± 10 ms, HF vs. HF-LVAD, p < 0.0001). Trabeculae from HF showed a negative force-frequency relationship, compared with a positive relationship in NF, whereas a neutral relationship was observed in HF-LVAD. Although decreased SERCA abundance in HF was not altered by LVAD support, improvements in [Ca²⁺]_i transients and frequency-dependent contractile function were associated with a significant decrease in NCX abundance and activity from HF to HF-LVAD.

CONCLUSIONS: Improvement in rate-dependent contractility in LVAD-supported failing human hearts is associated with a faster decay of the myocyte calcium transient. These improvements reflect decreases in NCX abundance and transport capacity without significant changes in SERCA after LVAD support. Our results suggest that reverse remodeling may involve selective, rather than global, normalization of the pathologic patterns associated with the failing heart.

Abbreviations and Acronyms   [Ca2+]i = intracellular calcium   HF = heart failure   HF-LVAD = failing hearts supported by a left ventricular assist device   INCX = Ni+-sensitive inward current   KHB = Krebs-Henseleit buffer   LV = left ventricle/ventricular   LVAD = left ventricular assist device   NCX = sodium-calcium exchanger   NF = non-failing   PLB = phospholamban   RV = right ventricle/ventricular   SERCA = sarcoplasmic reticulum calcium adenosine triphosphatase

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