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Familial Sinus Bradycardia Associated with a Mutation in the Cardiac Pacemaker Channel

2006; Massachusetts Medical Society; Volume: 354; Issue: 2 Linguagem: Inglês

10.1056/nejmoa052475

1533-4406

Raffaella Milanesi, Mirko Baruscotti, Tomaso Gnecchi‐Ruscone, Dario DiFrancesco,

Cardiac Arrhythmias and Treatments

We found that sinus bradycardia in members of a large family was associated with a mutation in the gene coding for the pacemaker HCN4 ion channel. Pacemaker channels of the sinoatrial node generate spontaneous activity and mediate cyclic AMP (cAMP)-dependent autonomic modulation of the heart rate. The mutation associated with bradycardia is located near the cAMP-binding site; functional analysis found that mutant channels respond normally to cAMP but are activated at more negative voltages than are wild-type channels. These changes, which mimic those of mild vagal stimulation, slow the heart rate by decreasing the inward diastolic current. Thus, diminished function of pacemaker channels is linked to familial bradycardia.