Journal
CIRCULATION
Volume 139, Issue 18, Pages 2157-2169Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCULATIONAHA.118.036761
Keywords
atrial fibrillation; bradyarrhythmia; genetic research; inward rectifier potassium channel; molecular targeted therapy
Funding
- Ministry of Health, Labor, and Welfare-Japan [201442084A]
- Japan Agency for Medical Research and Development (AMED) [16ek0109069h003, 18ek0109184h0003, 18kk0205001s0603, 18ek0109348s041, 18lk1403025h0001, 18ek0109283h0002, 18bm0804008h0002]
- Ministry of Education, Culture, Sports, Science, and Technology-Japan [15H04820, 15H02370]
- Japan Society for the Promotion of Science [15K09139, 15K09111, 18K19547]
- Core Research for Evolutional Science and Technology (CREST) from the Japan Science and Technology Agency
- Japan Heart Foundation
- Japan Cardiovascular Research Foundation
- Japan Intractable Diseases Research Foundation
- Takeda Science Foundation
- Inoue Foundation for Science
- Mochida Memorial Foundation
- Japan Foundation of Applied Enzymology
- Japan Vascular Disease Research Foundation
- Osaka Medical Research Foundation for Intractable Diseases
- Osaka University Interdisciplinary Program for Biomedical Sciences (IPBS)
- National BioResource Project
- Grants-in-Aid for Scientific Research [15H04820, 15H02370, 15K09111, 15K09139, 18K19547] Funding Source: KAKEN
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BACKGROUND: Bradyarrhythmia is a common clinical manifestation. Although the majority of cases are acquired, genetic analysis of families with bradyarrhythmia has identified a growing number of causative gene mutations. Because the only ultimate treatment for symptomatic bradyarrhythmia has been invasive surgical implantation of a pacemaker, the discovery of novel therapeutic molecular targets is necessary to improve prognosis and quality of life. METHODS: We investigated a family containing 7 individuals with autosomal dominant bradyarrhythmias of sinus node dysfunction, atrial fibrillation with slow ventricular response, and atrioventricular block. To identify the causative mutation, we conducted the family-based whole exome sequencing and genome-wide linkage analysis. We characterized the mutation-related mechanisms based on the pathophysiology in vitro. After generating a transgenic animal model to confirm the human phenotypes of bradyarrhythmia, we also evaluated the efficacy of a newly identified molecular-targeted compound to upregulate heart rate in bradyarrhythmias by using the animal model. RESULTS: We identified one heterozygous mutation, KCNJ3 c. 247A> C, p. N83H, as a novel cause of hereditary bradyarrhythmias in this family. KCNJ3 encodes the inwardly rectifying potassium channel Kir3.1, which combines with Kir3.4 (encoded by KCNJ5) to form the acetylcholine-activated potassium channel (I KACh channel) with specific expression in the atrium. An additional study using a genome cohort of 2185 patients with sporadic atrial fibrillation revealed another 5 rare mutations in KCNJ3 and KCNJ5, suggesting the relevance of both genes to these arrhythmias. Cellular electrophysiological studies revealed that the KCNJ3 p. N83H mutation caused a gain of I KACh channel function by increasing the basal current, even in the absence of m 2 muscarinic receptor stimulation. We generated transgenic zebrafish expressing mutant human KCNJ3 in the atrium specifically. It is interesting to note that the selective I KACh channel blocker NIP-151 repressed the increased current and improved bradyarrhythmia phenotypes in the mutant zebrafish. CONCLUSIONS: The I KACh channel is associated with the pathophysiology of bradyarrhythmia and atrial fibrillation, and the mutant I KACh channel (KCNJ3 p. N83H) can be effectively inhibited by NIP-151, a selective I KACh channel blocker. Thus, the I KACh channel might be considered to be a suitable pharmacological target for patients who have bradyarrhythmia with a gainof- function mutation in the I KACh channel.
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