Synergistic Effects of Inward Rectifier (I K1 ) and Pacemaker (I f ) Currents on the Induction of Bioengineered Cardiac Automaticity

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‐ C MV‐ G FP‐ I RES‐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.