Basic Res Cardio191: SuppI. 2, 17- 22 9 Steinkopff Verlag 1996 G. Hasenfuss H. Reinecke R. Studer B. Pieske M. Meyer H. Drexler H. Just Calcium cycling proteins and force- frequency relationship in heart failure Abstract Myocardial function, intra- cellular calcium and levels of calcium cycling proteins were analyzed in fail- ing and nonfailing human myocar- dium. Myocardial function was evaluated by the isometric force-fre- quency relation, and intracellular calcium was studied by aequorin light emission. When stimulation fre- quency was increased above 30 rain -1, there was a continuous increase in isometric tension development in the nonfailing myocardium. In contrast, in failing myocardium, frequency potentiation of contractile force was Supported by DFG grant HA 1233/3-2 G. Hasenfuss(N~) UniversitfitFreiburg MedizinischeKlinikII1 Hugstetter Strage 55 79106 Freiburg FRG blunted or inverse. As a conse- quence, at higher rates of stimula- tion, twitch tension was reduced significantly in failing compared to nonfailing human myocardium. Aequorin measurements indicated that the contractile deficit in the fail- ing myocardium at higher rates of stimulation is associated with decreased free intracellular calcium concentration. Western blot analysis indicated that in the failing myo- cardium protein levels of SR-Ca 2+- ATPase are significantly reduced and protein levels of Na+-Ca2+- exchanger are significantlyincreased. Levels of phospholamban are slightly reduced in the failing myocardium, and ryanodine receptor and calsequestrin protein levels are unchanged. There was a close posi- tive correlation between the protein levels of SR-Ca2+-ATPase and fre- quency potentiation of contractile force. From these data, we conclude that in failing compared to nonfailing human myocardium 1) force-fre- quency relation is blunted or inverse. 2) Frequency-dependence of contrac- tile force is closely correlated with frequency-dependence of intracellu- lar calcium cycling. 3) Protein levels of SR-Ca2+-ATPase may determine frequency-dependence of sarcoplas- mic reticulum calcium release. 4) Cal- cium elimination by an increased number of Na+-Ca2+-exchanger molecules may be a compensatory mechanism to prevent diastolic cal- cium accumulation in failing myocar- dium with a reduced number of SR calcium pumps. Key words Excitation-contraction coupling - heart failure - force-fre- quency relation - calcium cycling Introduction Bowditch was the first to show that force of contraction increases with increasing rate of stimulation in the frog heart (5). This frequency potentiation of contractile force has also been observed in other animal species and was considered to represent an important mechanism for regu- lation of myocardial performance. Frequency-dependent alterations of hemodynamic parameters indicative for increased myocardial contractile performance has also been observed in patients without heart failure under- going cardiac catheterization (8, 11). Furthermore, a posi- tive force-frequency relationship has been demonstrated in isolated muscle strips from nonfailing human hearts (7, 23). However, the situation was shown to be different in failing human myocardium in which frequency potentia- tion of contractile force was found to be blunted (7, 9, 23). Moreover, in many failing hearts force-frequency relation was shown to be inverse (23). Clinical studies demon- strated that the experimental finding of an altered force-