Pacemaker channel dysfunction in a patient with sinus node disease
Eric Schulze-Bahr, … , Olaf Pongs, Dirk Isbrandt
Eric Schulze-Bahr, … , Olaf Pongs, Dirk Isbrandt
Published May 15, 2003
Citation Information: J Clin Invest. 2003;111(10):1537-1545. https://doi.org/10.1172/JCI16387.
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Article Cardiology

Pacemaker channel dysfunction in a patient with sinus node disease

Abstract

The cardiac pacemaker current If is a major determinant of diastolic depolarization in sinus nodal cells and has a key role in heartbeat generation. Therefore, we hypothesized that some forms of “idiopathic” sinus node dysfunction (SND) are related to inherited dysfunctions of cardiac pacemaker ion channels. In a candidate gene approach, a heterozygous 1-bp deletion (1631delC) in exon 5 of the human HCN4 gene was detected in a patient with idiopathic SND. The mutant HCN4 protein (HCN4-573X) had a truncated C-terminus and lacked the cyclic nucleotide–binding domain. COS-7 cells transiently transfected with HCN4-573X cDNA indicated normal intracellular trafficking and membrane integration of HCN4-573X subunits. Patch-clamp experiments showed that HCN4-573X channels mediated If-like currents that were insensitive to increased cellular cAMP levels. Coexpression experiments showed a dominant-negative effect of HCN4-573X subunits on wild-type subunits. These data indicate that the cardiac If channels are functionally expressed but with altered biophysical properties. Taken together, the clinical, genetic, and in vitro data provide a likely explanation for the patient’s sinus bradycardia and the chronotropic incompetence.

Authors

Eric Schulze-Bahr, Axel Neu, Patrick Friederich, U. Benjamin Kaupp, Günter Breithardt, Olaf Pongs, Dirk Isbrandt

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Figure 1

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(a) Baseline electrocardiogram of the index patient showing marked sinus...
(a) Baseline electrocardiogram of the index patient showing marked sinus bradycardia (41 bpm). (b) ECG recorded during an episode of intermittent atrial fibrillation. (c) P-wave histograms obtained from pacemaker interrogation after implantation. At day 68, 98% of the atrial rates were below a threshold level of 60 bpm. (d) Heart rates (at sinus rhythm) of the index patient during bicycle exercise, before pacemaker implantation. The vertical dotted line and gray area indicate the predicted mean maximal work performance ± SD (with respect to the patient’s age [65–70 years] and gender) (25). The dotted horizontal line indicates the predicted heart rate value during maximal work load for women 66 years of age (25).