In failing human hearts (FHH) (NYHA IV) the cardiac output is inadequate to meet the metabolic needs of the peripheral systems. By means of thermo-mechanical analysis we have shown that epicardial strips from FHH (37 °C) have a depressed tension independent heat (TIH) and tension independent heat rate (dTIH/dt) liberation that correlates with depression in peak isometric force and the rate of relaxation. Furthermore, in response to a change in frequency of stimulation, FHH shows a severe blunting of the force-frequency relationship resulting in a decrease in myocardial reserve and in the frequency at which optimum force is obtained. We used ventricular ANF as an index of the severity of myocardial disease and demonstrated an inverse relationship between ANF mRNA and the sarcoplasmic reticulum (SR) calcium cycling proteins (SERCA 2, Phospholamban, Ryanodine Receptor) while these latter proteins all had a positive correlation with each other. At the same time there was an increase in sarcolemmal sodium calcium exchange protein. The decrease in SR pump proteins correlates with the decrease in myocardial reserve and optimum frequency of contraction. The latter mechanical changes are explainable in terms of a frequency dependent decrease in calcium concentration (aequorin light) in FHH. (Jpn Heart J 2000; 41:103-116)