title: Inhibition of CaMKII Attenuates Progressing Disruption of Ca(2+) 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.
authors.affiliation: Department for Cardiology and Pulmonology, Georg-August University, Göttingen, Germany.|German Center for Cardiovascular Research (DZHK), Göttingen, Germany.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Fischer
authors.affiliation: Department for Cardiology and Pulmonology, Georg-August University, Göttingen, Germany.
authors.forename: Astrid
authors.initials: A
authors.lastname: Kleinwächter
authors.affiliation: Department for Cardiology and Pulmonology, Georg-August University, Göttingen, Germany.|German Center for Cardiovascular Research (DZHK), Göttingen, Germany.
authors.forename: Jonas
authors.initials: J
authors.lastname: Herting
authors.affiliation: Department for Cardiology and Pulmonology, Georg-August University, Göttingen, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Eiringhaus
authors.affiliation: Department for Cardiology and Pulmonology, Georg-August University, Göttingen, Germany.|German Center for Cardiovascular Research (DZHK), Göttingen, Germany.
authors.forename: Nico
authors.initials: N
authors.lastname: Hartmann
authors.affiliation: Department for Heart and Transplantation Surgery, Heart Center, Bad Oeynhausen, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Renner
authors.affiliation: Department for Heart and Transplantation Surgery, Heart Center, Bad Oeynhausen, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Gummert
authors.affiliation: Department for Thoracic and Heart Surgery, Medical University of Hannover, Hannover, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Haverich
authors.affiliation: Department for Thoracic and Heart Surgery, Medical University of Hannover, Hannover, Germany.
authors.forename: Jan D
authors.initials: JD
authors.lastname: Schmitto
authors.affiliation: Department for Cardiology and Pulmonology, Georg-August University, Göttingen, Germany.|German Center for Cardiovascular Research (DZHK), Göttingen, Germany.|Department for Internal Medicine III, Cardiology, Angiology, and Intensive Care Medicine, University Medical Center, Kiel, Germany.
authors.forename: Samuel
authors.initials: S
authors.lastname: Sossalla
mesh_terms: D000328:Adult; D002118:Calcium / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D006333:Heart Failure / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D016027:Heart Transplantation; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology / Q000601:surgery; D006353:Heart-Assist Devices; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*
chemical_list: C503464:CaMKII inhibitor AIP; D010455:Peptides; D047428:Protein Kinase Inhibitors; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium
keywords: Ca2+ homeostasis; CaMKII; Cardiac surgery; Heart failure; Left ventricular assist device