Inhibition of CaMKII Attenuates Progressing Disruption of Ca2+ Homeostasis Upon Left Ventricular Assist Device Implantation in Human Heart Failure

Abstract

In heart failure, left ventricular assist device (LVAD) implantation is performed to ensure sufficient cardiac output. Whereas some patients are subsequently weaned from LVAD support, other patients still need heart transplantation. To elucidate underlying mechanisms, we assessed the arrhythmogenic SR-Ca2+ leak at the time of LVAD implantation (HF-Im) and heart transplantation (HF-Tx) and evaluated the effects of CaMKII-inhibition. Human left-ventricular cardiomyocytes were isolated, paced at 1Hz for 10 beats to ensure SR-Ca2+ loading and scanned for diastolic Ca2+ sparks (confocal microscopy). In HF-Im, the high diastolic spark frequency (CaSpF) of 0.76 +/- 0.12x100m(-1)xs(-1) could be reduced to 0.48 +/- 0.10x100m(-1)xs(-1) by CaMKII inhibition (AIP, 1M). The amplitude of Ca2+ sparks, width, and length was not significantly altered. In sum, CaMKII inhibition yielded a clear tendency toward a reduction of the SR-Ca2+ leak (n cells/patients=76/6 vs. 108/6, P=0.08). In HF-Tx, we detected an even higher CaSpF of 1.00 +/- 0.10 100m(-1)xs(-1) and a higher SR-Ca2+ leak compared with HF-Im (increase by 81 +/- 33%, n cells/patients=156/7 vs. 130/7, P<0.05), which fits to the further decreased LV function. Here, CaMKII inhibition likewise reduced CaSpF (0.35 +/- 0.09 100m(-1)xs(-1,)P=0.06) and significantly reduced spark duration (n sparks/patients=58/3 vs. 159/3, P<0.05). Conclusively, the SR-Ca2+ leak was reduced by 69 +/- 12% in HF-Tx upon CaMKII inhibition (n cells/patients=53/3 vs. 91/3, P<0.05). These data show that the SR-Ca2+ leak correlates with the development of LV function after LVAD implantation and may represent an important pathomechanism. The fact that CaMKII inhibition reduces the SR-Ca2+ leak in HF-Tx suggests that CaMKII inhibition may be a promising option to beneficially influence clinical course after LVAD implantation.