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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

View larger version (27K): [in a new window]   Figure 1 Effects of left ventricular assist device (LVAD) support on [Ca2+]i transients in cardiac myocytes from failing hearts with and without previous LVAD support. Data were collected during field stimulation at 0.5 Hz, and [Ca2+]i was measured by Fluo-3 fluorescence. (A) Raw fluorescence intensity traces from representative myocytes. (B) Schematic illustrating curve-fitting technique for initial and delayed portions of the [Ca2+]i transient decay. (C) Average initial and delayed time constants for the [Ca2+]i transients in each of the three experimental groups (NF = non-failing; HF = failing; HF-LVAD = LVAD support). Data are expressed as mean ± SEM. *p < 0.0001 HF-only versus HF-LVAD; p < 0.001.

View larger version (37K): [in a new window]   Figure 2 Western blot demonstrating protein abundance for sarcoplasmic reticulum calcium adenosine triphosphatase (SERCA2), sodium-calcium exchanger (NCX), and phospholamban (PLB). NF = non-failing; HF = failing; LVAD = left ventricular assist device support.

View larger version (17K): [in a new window]   Figure 3 Assessment of forward-mode sodium-calcium exchanger transport capacity in isolated cardiac myocytes from failing hearts with and without previous left ventricular assist device (LVAD) support. (A) Schematic illustration of the voltage-ramp (67 mV/s) protocol employed to increase cytosolic-free calcium (see "Methods"). (B) The Ni+-sensitive inward current (INCX) is plotted as a function of [Ca2+]i after membrane repolarization. (C) Average data are depicted from failing myocytes with and without previous LVAD support (n = 31, n = 10). HF= failing; HF-LVAD = LVAD support. Data are expressed as mean ± SEM.

View larger version (23K): [in a new window]   Figure 4 Force generation by isolated right ventricular trabeculae from non-failing, failing, and left ventricular assist device (LVAD)-supported hearts. (A) Representative force transients at low stimulation frequency (0.5 Hz) showing higher developed force in failing and LVAD-supported trabeculae than in non-failing muscles. *p < 0.05 NF versus HF and HF-LVAD. (B) Representative force transients at high stimulation frequencies (2.5 Hz) showing higher developed force in non-failing and LVAD-supported trabeculae compared with unsupported failing trabeculae. p < 0.05 NF versus HF. (C) Averaged data (± SEM) in which developed force is plotted as a function of stimulation frequency in each of the three groups. A clearly positive force-frequency relationship is seen in non-failing myocardium, a clearly negative force-frequency relationship is seen in unsupported failing myocardium, and a flat force-frequency relationship is seen after LVAD support.