Hyperpolarization-activated inward current in ventricular myocytes from normal and failing human hearts

Background-The hyperpolarization-activated inward current (I-f) was found to be overexpressed in hypertrophied rat ventricular myocytes, indicating that I-f might favor arrhythmias in hypertrophied or failing ventricular myocardium. In the present study, we evaluated whether I-f is expressed in human ventricular myocardium, if it may be increased in human heart failure, and if its autonomic modulation may be altered. Methods and Results-The whole-cell patch-clamp technique was used to record I-f in isolated ventricular myocytes from 34 failing (dilated [DCM] or ischemic [ICM] cardiomyopathy) and 13 donor hearts (NF). I-f was observed in all myocytes showing typical current properties, ie, time and voltage dependence, blocs by [Csi](o), permeability for K+ and Na+, and current increase with raising [K+](o). There was a trend toward larger current densities in myopathic (at -130 mV in [K+](o) 25 mmol/L; DCM: -1.37+/-0.12 pA/pF, n=50; ICM: -1.39+/-0.24 pA/pF, n=30) than in nonfailing cells (-1.18+/-0.21 pA/pF, n=24), although this difference did not reach statistical significance (P=.23). Boltzmann distributions yielded an activation threshold of -80 mV and half-maxinal activation at -110.96+/-0.06 mV in myopathic and normal myocytes. Isoproterenol (10(-5) mol/L) shifted the current activation by 10 mV (31 myopathic, 5 NF). Carbachol and adenosine had no direct effect on I-f (6 and 12 myopathic, 3 and 3 NF, respectively) but reversibly antagonized beta-adrenergic stimulation (5 and 7 myopathic, 2 and 2 NF, respectively). Autonomic modulation was similar in failing and nonfailing cells. Conclusions-In end-stage heart failure, no significant change of I-f could be found, although there was a trend toward increased I-f. Together with an elevated plasma norepinephrine concentration and a previously reported reduction in I-K1 in human heart failure, I-f might favor diastolic depolarization in individual myopathic cells.