Synergistic effects of inward rectifier (I K1) and pacemaker (I f) currents on the induction of bioengineered cardiac automaticity

Abstract

Synergistic Effects of I K1 and I f Currents. Introduction: Normal heart rhythms originate in the sinoatrial node. HCN-encoded funny current (I f) and the Kir2-encoded inward rectifier (I K1) counteract each other by respectively oscillating and stabilizing the negative resting membrane potential, and controlling action potential firing. Therefore, I K1 suppression and I f overexpression have been independently exploited to convert cardiomyocytes (CMs) into AP-firing bioartificial pacemakers. Although the 2 strategies have been largely assumed synergistic, their complementarity has not been investigated. Methods and Results: We explored the interrelationships of automaticity, I f and I K1 by transducing single left ventricular (LV) CMs isolated from guinea pig hearts with the recombinant adenoviruses Ad-CMV-GFP-IRES-HCN1- ÄÄÄ and/or Ad-CGI-Kir2.1 to mediate their current densities via a whole-cell patch clamp technique at 37°C. Results showed that Ad-CGI-HCN1-ÄÄÄ but not Ad-CGI-Kir2.1 transduction induced automaticity (181.1 ± 13.1 bpm). Interestingly, Ad-CGI-HCN1- ÄÄÄ/Ad-CGI-Kir2.1 cotransduction significantly promoted the induced firing frequency (320.0 ± 15.8 bpm; P < 0.05). Correlation analysis revealed that the firing frequency, phase-4 slope and APD 90 of AP-firing LV CMs were correlated with I f (R 2 > 0.7) only when -2 >I K1 >-4 pA/pF but not with I K1 over the entire I f ranges examined (0.02 < R 2 < 0.4). Unlike I f, I K1 displayed correlation with neither the phase-4 slope (R 2 = 0.02) nor phase-4 length (R 2 = 0.04) when -2 > I f > -4 pA/pF. As anticipated, however, APD 90 was correlated with I K1 (R 2 = 0.4). Conclusion: We conclude that an optimal level of I K1 maintains a voltage range for I f to operate most effectively during a dynamic cardiac cycle. (J Cardiovasc Electrophysiol, Vol. 20, pp. 1048-1054) © 2009 Wiley Periodicals, Inc.