Circulation, Vol 88, 2267-2276, Copyright © 1993 by American Heart Association
RH Schwinger, M Bohm, J Muller-Ehmsen, R Uhlmann, U Schmidt, A Stablein, P Uberfuhr, E Kreuzer, B Reichart and HJ Eissner
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 mumol/L) and BDF 9148 (0.1 mumol/L)
as well as the beta-adrenoceptor agonist isoprenaline (0.01 mumol/L and 0.1
mumol/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 myocardium, 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 mumol/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 of isoprenaline (0.1 mumol/L) and an elevation of the
extracellular Ca2+ concentration enhanced the decline in force of
contraction in the presence of higher stimulation frequencies. CONCLUSIONS.
It is concluded that functionally important changes occur in the
intracellular Ca2+ handling, leading to the negative force-frequency
relationship in terminally failing human myocardium. Interestingly, the
negative force-frequency relationship can be restored by agents producing
positive inotropic effects by elevation of the intracellular Na+
concentration. These findings suggest that hitherto unknown changes in the
intracellular ionic homeostasis occur in the failing human heart. Even
though increasing [Ca2+]i in failing heart cells may be detrimental,
increasing [Na+bdi may be beneficial through a mechanism independent of an
increase in [Ca2+]i.
ARTICLES
Effect of inotropic stimulation on the negative force-frequency relationship in the failing human heart
Klinik III fur Innere Medizin, Universitat zu Koln, Germany.
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