Pacemaker current (If) in the human sinoatrial node

Animal studies revealed that the hyperpolarization-activated pacemaker current, If, contributes to action potential (AP) generation in sinoatrial node (SAN) and significantly determines heart rate. If is becoming a novel therapy target to modulate heart rate. Yet, no studies have demonstrated that If is functionally present and contributes to pacemaking in human SAN. We aimed to study If properties in human SAN. In a patient undergoing SAN excision, we identified SAN using epicardial activation mapping. From here, we isolated myocytes and recorded APs and If using patch-clamp techniques. Pacemaker cells generated spontaneous APs (cycle length 828 ± 15 ms) following slow diastolic depolarization, maximal diastolic potential − 61.7 ± 4.3 mV, and maximal AP upstroke velocity 4.6 ± 1.2 V/s. They exhibited an hyperpolarization-activated inward current, blocked by external Cs+ (2 mmol/L), characterizing it as If. Fully-activated conductance was 75.2 ± 3.8 pS/pF, reversal potential − 22.1 ± 2.4 mV, and half-maximal activation voltage and slope factor of steady-state activation − 96.9 ± 2.7 and − 8.8 ± 0.5 mV. Activation time constant ranged from ∼350 ms (−130 mV) to ∼1 s (−100 mV), deactivation time constant 156 ± 45 ms (−40 mV). The role of If in pacemaker activity was demonstrated by slowing of pacemaker cell diastolic depolarization and beating rate by Cs+. If is functionally expressed in human SAN and probably contributes to pacemaking in human SAN.