Differential regulation of Ca2+-dependent ATPase-activity in left ventricular myocardium during mechanical circulatory support

Abstract

Background: Myocardial recovery is observed in some end-stage heart failure patients after mechanical circulatory support. The sarcoplasmic reticulum Ca2+-adenosine triphosphatase (Ca2+-ATPase) activity is down-regulated in failing myocardium and contributes to heart failure-associated contraction/relaxation abnormalities. Regulation of Ca2+-ATPase after mechanical support was shown to be heterogenous. Thus, we analyzed Ca2+-ATPase activity and protein expression in the paired myocardial samples of 21 patients supported by ventricular assist devices to identify factors that influence restoration of the Ca2+-transient after ventricular assist device support. Methods: We measured Ca2+-ATPase activity using a reduced nicotinamide-adenine dinucleotide-coupled reaction, determined sarcoplasmic reticulum Ca2+-dependent ATPase protein using Western blotting, and determined 4-hydroxyproline using amino-acid analysis. Results: The mean Ca2+-ATPase activity decreased at assist-device implantation and slightly increased at transplantation, but remained significantly lower than in non-failing donor hearts. However, individual responses were heterogeneous. Patients with older age, increased left ventricular diameter, and increased 4-hydroxyproline content showed down-regulation of Ca2+-ATPase activity, whereas we found up-regulation in patients with low values for these parameters after assist-device support. Conclusions: Sarcoplasmic reticulum Ca2+-ATPase activity, which influences the myocardial Ca2+-transient, generally is not restored to normal values in assist-device-supported hearts, but depends on a combined score of the left ventricular end-diastolic diameter, degree of ventricular fibrosis, and age of the patient at the time of assist-device implantation.