Effect of Inotropic Stimulation on the Negative Force-Frequency Relationship in the

Background. In severe human heart failure, an increase in frequency of stimulation is accompanied by a reduced force of contraction in vivo and in vitro. The present study was aimed to investigate whether inotropic stimulation influences the inverse force-frequency relationship in failing human myocardium. Methods and Results. The effects of the cAMP-independent positive inotropic agents ouabain (0.01,imol/L) and BDF 9148 (0.1,umol/L) as well as the 3-adrenoceptor agonist isoprenaline (0.01,umol/L and 0.1,umol/L) on the force-frequency relationship in electrically driven papillary muscle strips from nonfailing (brain death, n=5) and terminally failing (NYHA class IV, heart transplants, dilated cardiomyopathy, n=22) human myocardium were studied. For comparison, we examined the effect of elevation of the extracellular Ca2 ' concentration (3.2 mmol/L and 6.2 mmol/L). In nonfailing myocar-dium, force of contraction, peak rate of tension rise, and peak rate of tension decay increased, whereas time to peak tension and time to half relaxation decreased following an increase of stimulation frequency. In NYHA class IV, force of contraction gradually declined followed by changes of other parameters of isometric contraction. Moderate stimulation of contractility by isoprenaline (0.01,umol/L) partly reversed the negative force-frequency relationship in NYHA class IV and preserved the positive force-frequency relationship in nonfailing myocardium. The addition of ouabain and BDF 9148 together restored completely the force-frequency relationship in NYHA class IV. In contrast, high concentrations o