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-Ca(2+) 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 1 Hz for 10 beats to ensure SR-Ca(2+) loading and scanned for diastolic Ca(2+) sparks (confocal microscopy). In HF-Im, the high diastolic spark frequency (CaSpF) of 0.76 ± 0.12 × 100 μm(-1) × s(-1) could be reduced to 0.48 ± 0.10 × 100 μm(-1) × s(-1) by CaMKII inhibition (AIP, 1 μM). The amplitude of Ca(2+) sparks, width, and length was not significantly altered. In sum, CaMKII inhibition yielded a clear tendency toward a reduction of the SR-Ca(2+) leak (n cells/patients = 76/6 vs. 108/6, P = 0.08). In HF-Tx, we detected an even higher CaSpF of 1.00 ± 0.10 100 μm(-1) × s(-1) and a higher SR-Ca(2+) 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 ± 0.09 100 μm(-1) × s(-1,) P = 0.06) and significantly reduced spark duration (n sparks/patients = 58/3 vs. 159/3, P < 0.05). Conclusively, the SR-Ca(2+) 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-Ca(2+) 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-Ca(2+) leak in HF-Tx suggests that CaMKII inhibition may be a promising option to beneficially influence clinical course after LVAD implantation.

Rapid Electrical Stimulation Increased Cardiac Apoptosis Through Disturbance of Calcium Homeostasis and Mitochondrial Dysfunction in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

“…Upregulated CaMKII phosphorylation can also increase CaMKII-dependent phosphorylation of RyR2 and cause a diastolic SR Ca 2+ leak and further increase cytoplasmic calcium, thus creating a vicious cycle [35]. Breaking this cycle by inhibition of CaMKII has been reported to benefit heart failure animals and patients [36,37]. Consistently, KN93, a CaMKII inhibitor, used in our study significantly attenuated adverse effects caused by RES, including calcium transients and L-type calcium currents.…”

“…CaMKII has been reported to be activated in heart failure animal models [31] and patients [32] and is strongly associated with mitochondrial stress [33]. Activation of CaMKII has also been demonstrated to be a common intermediate of variable death stimuli [36,37], we prescribed 1 μM KN93 based on published studies [38,39] on S-24 h group cells during RES. As shown in Fig.…”

The reduced myofilament responsiveness to calcium contributes to the negative force-frequency relationship in rat cardiomyocytes: role of reactive oxygen species and p-38 map kinase

“…Moreover, we have demonstrated that during the increase in stimulation frequency, there occurs an activation of a pathway that involves ROS production, CaMKII oxidation, and p-38K phosphorylation, culminating in a decrease in myofilament responsiveness to Ca 2+ and a negative inotropic effect. The potential association of these findings to the typical negative or flat FFR observed in the human failing heart where ROS production and CaMKII and p-38K activity have been shown to be increased [2,5,7,21,25,34,39] represents an interesting idea that deserves future investigation.…”

Structural and functional cardiac profile after prolonged duration of mechanical unloading: potential implications for myocardial recovery

“…Increased cytoplasmic CaMKII phosphorylation has been linked to dilated cardiomyopathy (40) and increased CaMKII levels during unloading have been previously reported in a rat model of heterotopic transplant (32). CamKII inhibition has been recently shown to improve ionotropy in cardiomyocytes from patients with HF at the time of LVAD implantation (15). HDAC inhibitors have been proposed as a potential therapeutic strategy for HF by limiting MEF2 activity; antihypertrophic effects (20) as well as antifibrotic effects (22) of HDAC inhibitors have been described in animal models, but use in humans is in its infancy.…”