The intracellular Ca(2+)-homeostasis influences the frequency-dependent force-generation in man

The present study investigates the effect of stimulation frequency and external Ca(2+)-concentration on intracellular systolic and diastolic Ca2+ as well as on the force-frequency relationship (FFR, 0.5 to 3.0 Hz, 1.0 mmol/l extracellular Ca2+) in human myocardium using fura-2 AM loaded electrically stimulated right atrial muscle strips (coronary bypass surgery, n = 15, age: 60.0 +/- 1.9 years). The FFR was positive (3.0 vs. 0.5 Hz: 184 +/- 43% of basal value) and linked to an increase in peak systolic (R340/380sys, 119 +/- 7%) as well as diastolic Ca2+ (R340/380ED, delta fura-2 ratio +0.20 +/- 0.02). After elevating the extracellular Ca2+ concentration from 1.0 to 2.4 mmol/l, force of contraction (FOC) increased from 0.5 up to 1.0 Hz (128 +/- 8%) and declined after further augmentation of stimulation frequency (3.0 Hz: 87 +/- 15%). However, this decrease in FOC was accompanied by an increase in diastolic Ca2+ (delta fura-2 ratio +0.45 +/- 0.08), while systolic Ca2+ declined at high stimulation frequencies. In conclusion, the frequency-dependent force generation is accompanied by an increase in both systolic and diastolic Ca2+ levels. Thus, especially at high stimulation frequencies the Ca(2+)-lowering mechanisms may become crucial and may be responsible for the blunted force-frequency relationship in failing human myocardium.