Genetic Approaches for the Treatment of Bradycardias

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Since the identification of the hyperpolarisation-activated cyclic nucleotide channel 4 (HNC4), a major constituent of the pacemaker current (If) in the sinoatrial node, as a modulator of heart rate,1 several genetic causes of sinus bradycardia by means of mutations in ion channel encoding genes have been described. They may result in isolated sick sinus sydrome or other arrhythmia and cardiomyopathy syndromes.2,3

Gene ‘therapy’ strategies using gene transfer vectors have, therefore, been attractive as an alternative method for treating bradycardia syndromes, and non-viral methods, including the revolution of CRISPR gene editing technology, are also becoming available.

Genetics may be of service in treating bradycardias in other ways too. Very recently, one heterozygous mutation, KCNJ3 c.247A>C, p.N83H, was identified as a novel cause of hereditary bradyarrhythmias.4 KCNJ3 encodes the inwardly rectifying potassium channel Kir3.1, which combines with Kir3.4 (encoded by KCNJ5) to form the acetylcholine-activated potassium channel (IKAChchannel) with specific expression in the atrium. Studies on patients with sporadic AF also identified another five rare mutations in KCNJ3 and KCNJ5, suggesting the relevance of both genes to these arrhythmias.4

More importantly, in this study, NIP-151, a benzopyran derivative and selective IKACh channel blocker, effectively inhibited the mutant IKACh channel and up-regulated heart rate in a zebrafish model. Thus, pharmacological blockade of IKACh channels appears as a promising, safe therapy for increasing heart rate or preventing AF in patients with sick sinus syndrome and gain-of-function mutations in the IKACh channel.

I believe that a new era is beginning for the treatment of conduction disorders in humans. Perhaps the possibility of treating sick sinus syndrome and AV block without any invasive pacing procedure is not very far away. The cardiology community is eagerly awaiting clinical implementation of this possibility.

Demosthenes G Katritsis
Editor-in-Chief, Arrhythmia and Electrophysiology Review
Hygeia Hospital, Athens, Greece


  1. Milanesi R, Baruscotti M, Gnecchi-Ruscone T, et al. Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel. N Engl J Med 2006;354:151–7.
    Crossref | PubMed
  2. Milano A, Vermeer AM, Lodder EM, et al. HCN4 mutations in multiple families with bradycardia and left ventricular noncompaction cardiomyopathy. J Am Coll Cardiol 2014;64:745–56.
    Crossref | PubMed
  3. Schweizer PA, Schröter J, Greiner S, et al. The symptom complex of familial sinus node dysfunction and myocardial noncompaction is associated with mutations in the HCN4 channel. J Am Coll Cardiol 2014;64:757–67.
    Crossref | PubMed
  4. Yamada N, Asano Y, Fujita M, et al. Mutant KCNJ3 and KCNJ5 potassium channels as novel molecular targets in bradyarrhythmias and atrial fibrillation. Circulation 2019.
    Crossref | PubMed