Sick sinus syndrome in HCN1-deficient mice.
BACKGROUND
Sinus node dysfunction (SND) is a major clinically relevant disease that is associated with sudden cardiac death and requires surgical implantation of electric pacemaker devices. Frequently, SND occurs in heart failure and hypertension, conditions that lead to electric instability of the heart. Although the pathologies of acquired SND have been studied extensively, little is known about the molecular and cellular mechanisms that cause congenital SND.


RESULTS
Here, we show that the HCN1 protein is highly expressed in the sinoatrial node and is colocalized with HCN4, the main sinoatrial pacemaker channel isoform. To characterize the cardiac phenotype of HCN1-deficient mice, a detailed functional characterization of pacemaker mechanisms in single isolated sinoatrial node cells, explanted beating sinoatrial node preparation, telemetric in vivo electrocardiography, echocardiography, and in vivo electrophysiology was performed. On the basis of these experiments we demonstrate that mice lacking the pacemaker channel HCN1 display congenital SND characterized by bradycardia, sinus dysrhythmia, prolonged sinoatrial node recovery time, increased sinoatrial conduction time, and recurrent sinus pauses. As a consequence of SND, HCN1-deficient mice display a severely reduced cardiac output.


CONCLUSIONS
We propose that HCN1 stabilizes the leading pacemaker region within the sinoatrial node and hence is crucial for stable heart rate and regular beat-to-beat variation. Furthermore, we suggest that HCN1-deficient mice may be a valuable genetic disease model for human SND.
Center for Integrated Protein Science CIPS-M and Zentrum für Pharmaforschung, Department Pharmazie (S.F., S.C.K., S.I.H.H., E.B., F.A., R.B., V.H., C.P., M.B., C.A.W.-S.) and Medizinische Klinik und Poliklinik I, Klinikum Großhadern (C.K., P.L., T.Z.), Ludwig Maximilians University, Munich, Germany; DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (C.K., P.L., T.Z., M.B., C.A.W.-S.); Max-Planck-Institut für Psychiatrie München, Germany (C.T.W.); and School of Physics & Astronomy, University of Manchester, UK (H.Z.).
Stefanie
S
Fenske
Stefanie C
SC
Krause
Sami I H
SI
Hassan
Elvir
E
Becirovic
Franziska
F
Auer
Rebekka
R
Bernard
Christian
C
Kupatt
Philipp
P
Lange
Tilman
T
Ziegler
Carsten T
CT
Wotjak
Henggui
H
Zhang
Verena
V
Hammelmann
Christos
C
Paparizos
Martin
M
Biel
Christian A
CA
Wahl-Schott
D000818:Animals; D002302:Cardiac Output / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D006339:Heart Rate / Q000502:physiology; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015221:Potassium Channels / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D012804:Sick Sinus Syndrome / Q000503:physiopathology*; D012849:Sinoatrial Node / Q000378:metabolism / Q000503:physiopathology
C578666:Hcn1 protein, mouse; C578706:Hcn4 protein, mouse; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D015221:Potassium Channels
arrhythmias, cardiac; ion channels; sinoatrial node