Diminished posttetanic potentiation in failing human myocardium

In heart failure a decreased function of SERCA2 has been demonstrated. The present study aimed at investigating the relation between sarcoplasmic reticulum-Ca²⁺-load (SR-Ca²⁺-load) and the activity of the SERCA2. SR-Ca²⁺ load was evaluated by measuring posttetanic potentiation (PTP) in human nonfailing (NF, n=10) and endstage failing myocardium (DCM, n=11). In addition, the effect of cyclopiazonic acid (CPA), a specific inhibitor of SERCA2, on PTP was studied in both NF and DCM. In crude membrane preparations from the same hearts the maximal SERCA2 activity was determined and correlated with the PTP. In failing myocardium the PTP was significantly reduced compared to nonfailing myocardium (13.7±0.75 mN/mm² vs. 17.1±1.55 mN/mm², p<0.05, ±SEM). When PTP was studied in the presence of increased extracellular Ca²⁺-concentrations, the difference between NF and DCM was further pronounced. CPA decreased PTP in both nonfailing and failing human tissue. The maximal SERCA2 activity was significantly reduced in failing myocardium (NF 267±18.5 nmol ATP/mg protein · min⁻¹ vs. DCM 191±13.4 nmol ATP/mg protein · min⁻¹, p<0.05, ± SEM). Correlation of the PTP and maximal SERCA2 activity revealed a close correlation between both parameters in NF and DCM. In summary, the presented results suggest that reduced SERCA2 activity in DCM influences posttetanic force potentiation probably through a reduced SR-Ca²⁺-load. Received: 30 July 1999 Returned for 1. revision: 9 September 1999 1. Revision received: 24 November 1999 Returned for 2. revision: 26 January 2000 2. Revision received: 26 April 2000 Accepted: 9 May 2000