Elsevier

Heart Rhythm

Volume 14, Issue 5, May 2017, Pages 717-724
Heart Rhythm

Sick sinus syndrome with HCN4 mutations shows early onset and frequent association with atrial fibrillation and left ventricular noncompaction

https://doi.org/10.1016/j.hrthm.2017.01.020Get rights and content

Background

Familial sick sinus syndrome (SSS) is often attributable to mutations in genes encoding the cardiac Na channel SCN5A and pacemaker channel HCN4. We previously found that SSS with SCN5A mutations shows early onset of manifestations and male predominance. Despite recent reports on the complications of atrial fibrillation (AF) and left ventricular noncompaction (LVNC) in patients with SSS caused by HCN4 mutations, their overall clinical spectrum remains unknown.

Objective

The purpose of this study was to investigate the clinical and demographic features of SSS patients carrying HCN4 mutations.

Methods

We genetically screened 38 unrelated SSS families and functionally analyzed the mutant SCN5A and HCN4 channels by patch clamping. We also evaluated the clinical features of familial SSS by a meta-analysis of 48 SSS probands with mutations in HCN4 (n = 16) and SCN5A (n = 32), including previously reported cases, and 538 sporadic SSS cases.

Results

We identified two HCN4 and three SCN5A loss-of-function mutations in our familial SSS cohort. Meta-analysis of HCN4 mutation carriers showed a significantly younger age at diagnosis (39.1 ± 21.7 years) than in sporadic SSS (74.3 ± 0.4 years; P <.001), but a significantly older age than in SCN5A mutation carriers (20.0 ± 17.6 years; P = .003). Moreover, HCN4 mutation carriers were more frequently associated with AF (43.8%) and LVNC (50%) and with older age at pacemaker implantation (43.5 ± 22.1 years) than were SCN5A mutation carriers (17.8 ± 16.5 years; P <.001).

Conclusion

SSS with HCN4 mutations may form a distinct SSS subgroup characterized by early clinical manifestation after adolescence and frequent association with AF and LVNC.

Introduction

Sick sinus syndrome (SSS) is a clinically common and heterogeneous arrhythmia comprising sinus bradycardia, sinus arrest, and bradycardia–tachycardia syndrome. SSS is often associated with primary structural heart disorders, and its occurrence increases with age.1 SSS can also occur in a familial form as a genetic disorder.2 The most prevalent genes responsible for familial SSS are those encoding the cardiac sodium channel α subunit (SCN5A) and hyperpolarization-activated cyclic nucleotide-gated channel (HCN4).3, 4 Mutations in SCN5A result in conduction delay or exit block without disturbing impulse generation in the sinoatrial node (SAN). However, HCN4 mutations reduce the pacemaker current and suppress diastolic depolarization and automaticity in the SAN.4 We previously showed a male predominance and early onset of manifestations in familial SSS caused by SCN5A mutations.5 However, the clinical features of SSS caused by HCN4 mutations have not been statistically evaluated, mainly because of the scarcity of individuals with this condition.

Mutations in HCN4 are thought to predominantly underlie pure SAN disorders because HCN4 expression is mostly limited to the cardiac conduction system, especially the SAN area.6 However, several recent genetic studies have revealed associations between HCN4 mutations and atrial fibrillation (AF) and left ventricular noncompaction (LVNC) of SSS.7, 8, 9 These studies suggest that HCN4 mutations constitute a subgroup of familial SSS associated with AF and LVNC, although their detailed clinical and demographic properties remain to be determined.

In this study, we investigated the clinical spectrum of familial SSS probands carrying HCN4 mutations, those with SCN5A mutations, and those with sporadic SSS, consisting of our cohort and those from previous publications. We found that the familial SSS subgroup with HCN4 mutations had an intermediate age of onset between the subgroup with SCN5A mutations and sporadic SSS cases. Permanent pacemaker (PPM) implantation was usually required after adolescence in the HCN4 subgroup, whereas it was frequently required during the first decade of life in the SCN5A subgroup. Complications of AF and LVNC were also observed more frequently in the HCN4 subgroup than in the SCN5A subgroup. Finally, HCN4 mutations appeared to confer more complex cardiac disorders comprising electrical and structural abnormalities, which were distinct from those with SCN5A mutations.

Section snippets

Genetic analysis

Thirty-eight unrelated familial SSS probands and their family members who participated in the study provided written informed consent in accordance with the Declaration of Helsinki and local ethics committees. Genetic screening was performed on genomic DNA extracted from peripheral blood cells using standard methods.5 All probands underwent genetic testing for mutations in 3 major bradyarrhythmia genes (SCN5A, LMNA, HCN4) by polymerase chain reaction and direct sequencing (see Online

Results

Candidate gene screening for mutations in SCN5A, LMNA, and HCN4 identified two HCN4 mutations for families 1 and 2, and three SCN5A mutations for families 3, 4, and 5. No mutation was detected in LMNA. The profiles of identified HCN4 and SCN5A mutations are given in Online Supplemental Table S3. None of these mutations are registered in the human genetic variations databases, including dbSNP, 1000 Genomes, ESP6500, ExAC, or the ethnic-specific Japanese database HGVD, and these variations

Discussion

In this study, we identified two HCN4 and three SCN5A mutations in a familial SSS cohort by candidate gene approaches. Epidemiologic meta-analysis based on our cohort, and 8 publications showed that a moderately older phenotype manifested in SSS and that a higher prevalence of AF and LVNC was associated with familial SSS caused by HCN4 mutations than in familial SSS caused by SCN5A mutations. The other clinical characteristics of SSS resulting from SCN5A mutations, male predominance and higher

Conclusion

HCN4 mutations form a clinically distinct familial SSS subset. This subset is distinguishable from familial SSS with SCN5A mutations with a postadolescent diagnosis and frequent association with AF and LVNC without sex differences.

Acknowledgments

We thank attending physicians for data collections and for referral of bradyarrhythmia patients. We also thank Chisa Hayashida, Saori Nakano, Atsuko Iida, and Hiromi Noda for technical assistance.

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    This work was supported by Grants-in-Aid for Scientific Research 26860572 to Dr. Ishikawa, JP15K09680 to Dr. Horigome, and 5H04823 and 15K15311 to Dr. Makita from the Ministry of Education, Culture, Sports, Science and Technology, Japan; Research Grant for the Cardiovascular Diseases (H26-002, H26-084, H27-019 and H27-032) from the Japanese Ministry of Health, Labour and Welfare, Japan; research grant from Japan Agency for Medical Research and Development; AMED (15km0305015h0101) to Dr. Makita; research grant from Suzuken Memorial Foundation to Dr. Makita; and research grant from Takeda Science Foundation to Dr. Ishikawa.

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