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(Circulation. 1997;95:568-571.)
© 1997 American Heart Association, Inc.

Articles

Characterization of the Hyperpolarization-Activated Current, I_f, in Ventricular Myocytes From Human Failing Heart

Elisabetta Cerbai, PhD; Roberto Pino, PhD; Francesco Porciatti, PhD; Guido Sani, MD; Michele Toscano, MD; Massimo Maccherini, MD; Gabriele Giunti, MD; Alessandro Mugelli, MD

the Department of Pharmacology, University of Firenze (E.C., R.P., F.P., A.M.); Cardiosurgery, University of Cagliari (G.S.); and Institute of Thoracic and Cardiovascular Surgery, University of Siena (M.T., M.M., G.G.), Italy.

Correspondence to Alessandro Mugelli, MD, Department of Preclinical and Clinical Pharmacology, University of Firenze, Viale G.B. Morgagni 65, 50134 Firenze, Italy. E-mail mugelli@stat.ds.unifi.it.

	Abstract

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Background Disease-associated electrophysiological alterations may contribute to the increased predisposition to arrhythmias of the hypertrophied or failing myocardium. An I_f-like current is expressed in rat left ventricular myocytes (LVMs), its amplitude being linearly related to the severity of cardiac hypertrophy. Here, we report the occurrence and electrophysiological properties of I_f in human LVMs.

Methods and Results LVMs were isolated from hearts of three male patients undergoing cardiac transplantation for terminal heart failure due to ischemic dilated cardiomyopathy. The patch-clamp technique was used to record I_f, ie, a barium-insensitive, cesium-sensitive, time-dependent increasing inward current elicited on hyperpolarization. Membrane capacitance was 244±27 pF (n=25). I_f occurred in all cells tested; its density measured at -120 mV was 2.1±0.3 pA/pF. Activation curves of I_f (n=24) were fitted by a Boltzmann function; the threshold was -55 mV; midpoint, -70.9±2.1 mV; slope, -5.4±0.3 mV; and maximal specific conductance, 19.6±2.5 pS/pF. I_f blockade by extracellular cesium was voltage dependent. Reducing extracellular potassium concentration from 25 to 5.4 mmol/L caused a shift of the reversal potential from -12.7±0.5 to -24.8±2.1 mV and a 64% decrease of current conductance.

Conclusions I_f is present in human LVMs. Its electrophysiological characteristics resemble those previously described in hypertrophied rat LVMs and suggest that I_f could be an arrhythmogenic mechanism in patients with severe heart failure.

Key Words: arrhythmia • electrophysiology • myocytes • heart failure • hypertrophy

	Introduction

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Mortality in heart failure patients is high. About half of the deaths are sudden and unexpected.¹ Apart from the high incidence of sudden death, patients with heart failure often experience ventricular arrhythmias.^{2 3} Occurrence of ventricular arrhythmias and incidence of sudden death are likely to be related. Many changes, eg, fibrosis, loss of viable myocytes, and dispersion of refractoriness, that occur in the hypertrophied heart are likely to predispose to arrhythmias.⁴ Recent studies have documented that the electrophysiological properties of cardiac cells are altered in disease. Action potentials of ventricular myocytes isolated from patients with congestive cardiomyopathy are prolonged.⁵ The underlying ionic mechanism appears to be a decrease in I_to.⁶ Prolongation of action potential duration and reduction of I_to have been reported in hypertrophied myocytes isolated from the hearts of SHRs.⁷ The similarities of the alterations found led us to consider the SHR a useful and predictive model for cardiac hypertrophy due to pressure overload and for its transition to failure.⁸ In >90% of myocytes isolated from the left ventricle of old SHRs (ie, hearts with severe hypertrophy), we previously demonstrated the presence of a time-dependent inward current, activated by hyperpolarization and having the properties of the I_f.⁹ I_f is a cesium-sensitive, barium-insensitive inward current generally thought to be present only in primary or secondary pacemakers, in which it might contribute to diastolic depolarization.¹⁰ More recently, we found that I_f density in ventricular myocytes can be linearly related to the severity of cardiac hypertrophy.¹¹ In SHRs with signs of heart failure, the amplitude of I_f was even larger.¹² Furthermore, I_f amplitude was increased by ß-adrenergic stimulation by shifting of its activation curve toward less negative potentials.¹¹ Because our previous results were suggestive of a contribution of I_f to the increased propensity for ventricular arrhythmias of the hypertrophied and failing (rat) heart, we assessed the presence of I_f in human ventricular myocytes. Here, we report that a current with the electrophysiological properties of I_f is consistently present in human ventricular myocytes isolated from three patients with postischemic dilated cardiomyopathy undergoing heart transplantation.

	Methods

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Preparation of Single Ventricular Myocytes
The hearts were obtained from three male patients undergoing cardiac transplantation for terminal heart failure due to ischemic cardiomyopathy; informed consent was obtained before heart transplantation. The patients chosen for this study were homogeneous for age (61 to 62 years) and dimension of the left ventricle (left ventricular diastolic diameter, 69 to 73 mm). All patients received digoxin and diuretics and were taking vasodilator therapy; therapy was discontinued 6 hours before the intervention. After explantation, a portion of the left ventricle was cut and transported to the laboratory in cold (4°C) cardioplegic solution. The procedure for cell isolation was similar to that described by Veldkamp et al.¹³ A portion of the free wall with a visible coronary artery was chosen and perfused through this arterial branch with LCS for 20 minutes and then with LCS containing 0.15 mg/mL collagenase B and 0.1 mg/mL collagenase P (both Boehringer Mannheim) for 25 minutes. The tissue that appeared clearly digested was cut into small pieces that were stirred in a bottle containing Kraftbruhe solution.^{13 14} The temperature of all perfusing solutions was 35°C. Cells were collected and allowed to sediment, the pellet was then resuspended in LCS, and Ca²⁺ concentration was gradually increased up to 0.5 mmol/L. The yield of viable cells was 5% to 8%.

Solutions and Reagents
The composition of the solutions (in mmol/L) was as follows: cardioplegic solution: NaCl 82, KCl 20, CaSO₄ 0.5, MgSO₄ 7.5, NaHCO₃ 23, glucose 25, and mannitol 55; LCS: NaCl 140, KCl 5.4, MgCl₂ 0.5, KH₂PO₄ 1.2, glucose 5.5, and HEPES 5, pH 6.9 with NaOH; and control Tyrode's solution: NaCl 137, KCl 5.4, CaCl₂ 1.5, MgCl₂ 1.2, HEPES 5, and glucose 10, pH 7.35 with NaOH. To study I_f, the control solution was modified to reduce the interference of other currents^{9 11} by addition of (in mmol/L) BaCl₂ 2, MnCl₂ 2, CdCl₂ 0.2, and 4-aminopyridine 0.5; [K⁺]_o was increased to 25 mmol/L (unless indicated). Pipette solution contained (in mmol/L): potassium aspartate 130, MgCl₂ 2, Na₂-ATP 5, CaCl₂ 5, EGTA 11, and HEPES 10; pH 7.2 with KOH. The liquid junction potential between the electrode tip and the extracellular solution was not corrected.^{9 11}

Recording Techniques
Cells were transferred to a recording chamber mounted on the stage of an inverted microscope (Nikon Diaphot) and superfused by gravity with a six-line microperfusor system placed near the cell at a flow rate of 1 mL/min (temperature, 36°C). The experimental setup used for patch-clamp recording in the whole-cell configuration was similar to that described previously.^{9 11} C_m was measured by ±10-mV voltage steps applied from a holding potential of -70 mV and calculated as described previously^{9 11} ; no capacitance correction was used. The cutoff frequency was 10 kHz. I_f was elicited by hyperpolarizing steps applied at low frequency (maximum rate, 0.1 Hz); because of its slow activation kinetics, I_f was sampled at 0.5 to 1 kHz.

Data Analysis
The amplitude of I_f was measured as the difference between the instantaneous current at the beginning of the hyperpolarizing step and the steady-state current recorded at the end of the step and normalized to C_m. From the I-V relations, specific conductance of I_f was determined for each cell according to the equation g=I/(V_m-V_rev), where g is the conductance calculated at membrane potential V_m, I the current amplitude, and V_rev is calculated from the analysis of tail currents. g_max was obtained by fitting values with the Boltzmann function: g=g_max/{1+exp[(V_H-V_m)/k]}, where k is the slope factor describing the steepness of the activation curve. V_rev was derived from tail-current analysis by fitting a linear relationship to the fully activated I-V relation of I_f performed at 5.4 or 25 mmol/L [K⁺]_o.^{9 11} All data are presented as mean±SEM.

	Results

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Twenty-five cells isolated from three patients undergoing heart transplantation for terminal heart failure due to postischemic dilated cardiomyopathy were studied. Membrane capacitance, an index of cell dimensions, was 244±27 pF. As detailed in "Methods," voltage-clamp experiments were performed with a modified Tyrode's solution to amplify I_f and to reduce overlapping inward and outward currents. We considered I_f to be present when a hyperpolarizing step to -120 mV from the holding potential (-40 mV) elicited a time-dependent increasing inward current that was blocked by addition of 4 mmol/L CsCl. I_f occurred in all cells tested (n=25); the density of the current measured at -120 mV was 2.1±0.3 pA/pF. Fig 1a shows representative traces of I_f recorded during hyperpolarizing steps to increasing negative potentials (-50 to -110 mV). The duration of the step was decreased (from 3200 to 2000 ms) as the activation of the current became progressively faster.

View larger version (21K): [in this window] [in a new window]   Figure 1. Voltage dependence of If in human ventricular myocytes. a, Representative current recordings elicited by hyperpolarizing voltage pulses between -50 and -110 mV in steps of 10 mV, according to the protocol drawn at the bottom (Cm=278 pF). b, Plot of mean specific conductance (gf) vs step potential (n=24). Curve was fitted to data points by a Boltzmann distribution. c, Plot of time-constant reciprocals (obtained by fitting exponential curves to If activation in 24 cells) vs membrane potential. Line is theoretical curve obtained by fitting mean data points with the function 1/=exp(-2.9-0.04xVm)+exp(3.6+0.11xVm).

Mean current specific conductance normalized to C_m was plotted as a function of the hyperpolarizing step potential (Fig 1b). The experimental points were fitted by a Boltzmann function; the average activation curve (represented by the line of Fig 1b), obtained from 24 individual curves, showed a threshold at approximately -55 mV, V_H at -70.9±2.1 mV, slope of -5.4±0.3 mV, and g_max of 19.6±2.5 pS/pF. Time-constant reciprocals obtained by single exponential fitting of individual current traces were reported as a function of the step voltage (Fig 1c): it clearly appears that the rate of current onset increases at larger hyperpolarizations. The line represents the theoretical curve obtained by fitting experimental data points with a function describing a first-order Hodgkin-Huxley kinetics.¹⁵

Effect of Extracellular Cesium and Potassium
The effect of cesium, which is a widely used tool to block I_f,⁹ was evaluated over a large range of potentials (-70 to +10 mV) by measurement of the amplitude of tail currents after a hyperpolarizing step to -120 mV, which fully activates I_f. The results of such an experiment are shown in Fig 2. Current traces recorded in the absence and presence of 4 mmol/L CsCl are shown (a). Addition of cesium resulted in an almost complete block of the inward current elicited by the step at -120 mV and markedly reduced tail inward currents at -50 mV but did not modify outward currents at +10 mV. In Fig 2b, tail-current amplitude normalized to C_m was plotted against the step voltage; in controls, fitting of data points gave a linear relationship similar to that previously reported in rat ventricular myocytes,^{9 11} with a slope conductance of 21.9±2.9 pS/pF and extrapolated V_rev of -13.1±1.2 mV (n=18). In the presence of cesium, the negative region of the fully activated I-V relationship was characterized by a progressive reduction of the current, showing a clear-cut voltage-dependent blockade. V_rev in the presence of cesium was -11.9±2.7 mV (n=4), a figure not different from that measured in control conditions.

View larger version (19K): [in this window] [in a new window]   Figure 2. Effect of cesium and [K+]o on If. a, Current traces recorded in the absence () and presence () of 4 mmol/L CsCl during hyperpolarization to -120 mV and after return to -50 or +10 mV. b, Plot of tail current amplitude, normalized to Cm (332 pF), vs voltage. c, Representative currents recorded in same cell (Cm=116 pF) superfused with 25 () or 5.4 () mmol/L [K+]o during hyperpolarization to -120 mV and after return to -20 mV. Note that small tail current is inward at 25 mmol/L [K+]o and outward at 5.4 mmol/L [K+]o. d, Plot of tail current amplitude, normalized to Cm, vs tail step potential (n=3). Lines are results of best linear fitting to experimental data.

The measurement of tail-current amplitude was used to evaluate V_rev of I_f at different [K⁺]_o. Tail currents, after a hyperpolarizing step to -120 mV, which maximally activates I_f, were elicited by steps in the range of -70 to +10 mV. Current tracings in Fig 2c were obtained in the same cell superfused with Tyrode's solution containing either 25 or 5.4 mmol/L [K⁺]_o. The most evident effect caused by the reduction in [K⁺]_o was a marked decrease in I_f amplitude. Fig 2d shows a fully activated I-V relationship obtained from three cells exposed to different [K⁺]_o; tail-current amplitude was normalized to C_m. With 25 mmol/L [K⁺]_o, the best fit through data points gave a linear relationship, with a slope of 37.7±9.3 pS/pF, which intersected the x axis (V_rev) at -12.7±0.5 mV (n=3). With 5.4 mmol/L [K⁺]_o, V_rev was shifted to more negative potentials (-24.8±2.1 mV) and the slope was reduced by 64% (13.4±5.4 pS/pF, n=3), in agreement with our previous results in hypertrophied rat myocytes.^{9 11}

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
In the present study, we demonstrate the presence of I_f in human ventricular myocytes and describe its electrophysiological properties. The presence of this current in human ventricular myocytes has been reported only in abstract form.¹⁶ We previously demonstrated that a current having the properties of I_f is present in hypertrophied rat ventricular myocytes and that its amplitude is related to the degree of hypertrophy, its density being larger as the severity of myocardial hypertrophy increases^{9 11} ; other factors, such as cell dimensions or age, are likely to be involved.¹¹ For these reasons, we wanted to assess the presence and properties of I_f in human ventricular myocytes isolated from patients as homogeneous as possible. Each of the three patients had heart failure due to ischemic cardiomyopathy, similar age, and comparable dilatation of the left ventricle. Myocytes isolated from the hearts of these patients had similar capacitances and consistently showed the occurrence of I_f. The electrophysiological characteristics of I_f turned out to be very similar to those previously described for I_f recorded in hypertrophied rat ventricular myocytes: the threshold of activation was at about -55 mV and the midpoint around -70 mV, voltages that most likely approximate the diastolic potential of these cells. The current was fully activated at -120 mV; its density was 2.1±0.3 pA/pF; and it was barium insensitive and blocked by extracellular cesium. Its reversal potential was consistent with selectivity for Na⁺ and K⁺: P_Na/P_K calculated from V_rev values is 0.42±0.03 (n=18) and 0.36±0.03 (n=3) at 25 and 5.4 mmol/L [K⁺]_o, respectively. Thus, the current has the properties (ie, voltage dependence, cesium sensitivity, permeability ratio) of I_f recorded in primary and secondary pacemaker cells.¹⁰ Obviously, further studies are necessary to better understand the factors controlling its development or its functional role in human myocytes. Results obtained in myocytes from undiseased donor hearts¹⁶ suggest that its amplitude at -120 mV is much smaller, as was also found in normal rat myocytes.^{9 11} If the current density is modulated by disease in humans as in rats,¹¹ it is possible to speculate that its relevance may increase in the failing heart. As we have previously hypothesized for the hypertrophied rat heart, it can be speculated that I_f might represent an important arrhythmogenic mechanism in patients with severe heart failure. Both automaticity and delayed afterdepolarizations are observed in ventricular trabeculae of failing human myocardium exposed to an altered extracellular environment mimicking that present in patients with heart failure.¹⁷ These alterations cannot explain the rapid ventricular tachycardias occurring in heart failure; however, they may induce extrasystoles, which can serve as a trigger in hearts in which the substrate for reentry is clearly present. It is not unreasonable to imagine that I_f could interact with other inward currents, such as the transient inward current underlying delayed afterdepolarizations, eventually bringing to threshold some subthreshold delayed afterdepolarizations and thus favoring the appearance of arrhythmias in the failing heart.

	Selected Abbreviations and Acronyms

 

Cm = membrane capacitance gmax = maximal specific conductance I-V = current-voltage If = pacemaker current (hyperpolarization-activated current) Ito = transient outward current [K+]o = extracellular potassium concentration LCS = low-calcium solution SHR = spontaneously hypertensive rat VH = voltage of half-maximal activation of If Vrev = reversal potential of If

	Acknowledgments

 
This work was supported by a grant from Telethon (project No. 709).

Received October 15, 1996; revision received November 27, 1996; accepted December 2, 1996.

	References

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