Hyperpolarization-Activated Inward Current in Ventricular Myocytes From Normal and Failing Human Hearts

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Abstract
Background—The hyperpolarization-activated inward current (If) was found to be overexpressed in hypertrophied rat ventricular myocytes, indicating that If might favor arrhythmias in hypertrophied or failing ventricular myocardium. In the present study, we evaluated whether If 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 If in isolated ventricular myocytes from 34 failing (dilated [DCM] or ischemic [ICM] cardiomyopathy) and 13 donor hearts (NF). If was observed in all myocytes showing typical current properties, ie, time and voltage dependence, block by [Cs+]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-maximal 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 If (6 and 12 myopathic, 3 and 3 NF, respectively) but reversibly antagonized β-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 If could be found, although there was a trend toward increased If. Together with an elevated plasma norepinephrine concentration and a previously reported reduction in IK1 in human heart failure, If might favor diastolic depolarization in individual myopathic cells.