Pacemaker current (I(f)) in the human sinoatrial node.
OBJECTIVE
Animal studies revealed that the hyperpolarization-activated pacemaker current, I(f), contributes to action potential (AP) generation in sinoatrial node (SAN) and significantly determines heart rate. I(f) is becoming a novel therapy target to modulate heart rate. Yet, no studies have demonstrated that I(f) is functionally present and contributes to pacemaking in human SAN. We aimed to study I(f) properties in human SAN.


RESULTS
In a patient undergoing SAN excision, we identified SAN using epicardial activation mapping. From here, we isolated myocytes and recorded APs and I(f) 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 I(f). 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 approximately 350 ms (-130 mV) to approximately 1 s (-100 mV), deactivation time constant 156 +/- 45 ms (-40 mV). The role of I(f) in pacemaker activity was demonstrated by slowing of pacemaker cell diastolic depolarization and beating rate by Cs(+).


CONCLUSIONS
I(f) is functionally expressed in human SAN and probably contributes to pacemaking in human SAN.
Verkerk
Arie O
AO
Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Wilders
Ronald
R
van Borren
Marcel M G J
MM
Peters
Ron J G
RJ
Broekhuis
Eli
E
Lam
Kayan
K
Coronel
Ruben
R
de Bakker
Jacques M T
JM
Tan
Hanno L
HL
D000200:Action Potentials / Q000502:physiology*; D005260:Female; D005500:Follow-Up Studies; D006329:Heart Conduction System / Q000166:cytology / Q000502:physiology; D006801:Humans; D007473:Ion Channels / Q000502:physiology*; D008875:Middle Aged; D012849:Sinoatrial Node / Q000166:cytology / Q000502:physiology* / Q000601:surgery; D013614:Tachycardia, Paroxysmal / Q000503:physiopathology