Phenotypes Associated with This Genotype

Genotype
MGI:5688197

• Allelic Composition: Hcn1^tm2Kndl/Hcn1^tm2Kndl
• Genetic Background: involves: 129 * 129S/SvEv * C57BL/6J * C57BL/6N

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

cardiovascular system

decreased cardiac output ( J:219164 )

• reduction in cardiac output to 69% of wild-type

• however, stroke volume is normal

abnormal heartbeat ( J:219164 )

• mice exhibit congenital sinus node dysfunction characterized by bradycardia, sinus dysrhythmia, prolonged sinoatrial node recovery time, increased sinoatrial conduction time, and recurrent sinus pauses

• however, echocardiographic analysis indicates normal cardiac structure, diastolic function, and systolic function and cardiac morphology

increased heart rate variability ( J:219164 )

• mutants exhibit an increase in heart rate variability

• intact sinoatrial node preparations exhibit pronounced fluctuations of the beat-to-beat interval

sinus bradycardia ( J:219164 )

• in vivo telemetric long-term ECG in freely moving mutants and echocardiographic analysis indicates a sinus bradycardia characterized by lower mean heart rates by 16% compared to wild-type and more frequent episodes of low heart rate

• bradycardia is not due to an increase in resting phases because mutants exhibit the same activity and resting behavior as wild-type mice

• beta-adrenergic stimulation with isoproterenol results in the same relative increase in heart rate as in wild-type mice, however the maximum heart rate is lower in mutants

• intact sinoatrial node preparations show a reduced firing rate of spontaneous pacemaker potentials by 29% compared with wild-type

• isolated perfused hearts exhibit a reduction in beating rate by 20.2%

• isolated sinoatrial pacemaker cells show a shifted resting membrane potential to more hyperpolarized potentials, and a reduced firing rate (by 13%), indicating reduced beating frequency

abnormal RR interval ( J:219164 )

• dramatic fluctuations of the RR interval; fluctuations in RR interval are more pronounced during phases of slow heart rate

abnormal sinoatrial node conduction ( J:219164 )

• intracardiac electrophysiological analysis indicates increased sinus node recovery time, indicating a delayed impulse formation within the sinoatrial node

• atrial pacing (continuously for 10 seconds at 10 Hz) of isolated right atrial preparation containing the sinoatrial node indicates an increase in sinus node recovery time

• isolated central pacemaker cells, both spindle cells and elongated cells, show reduced amplitude of I(f) current in response to hyperpolarizing voltage steps and slowing of the activation kinetics of I(f) current

• however, atrioventricular conduction is normal

sinoatrial block ( J:219164 )

• premature atrial stimulation indicates a prolonged sinoatrial conduction time independent of changes in sinus cycle lengths, indicating impaired impulse propagation and sinoatrial exit block

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
sick sinus syndrome		DOID:13884	OMIM:163800 OMIM:608567	J:219164