Genetic Complexity of Sinoatrial Node Dysfunction

doi:10.3389/fgene.2021.654925

Review

. 2021 Apr 1:12:654925.

doi: 10.3389/fgene.2021.654925. eCollection 2021.

Genetic Complexity of Sinoatrial Node Dysfunction

Michael J Wallace^{1

2

3}, Mona El Refaey^{1

2

3}, Pietro Mesirca^{4

5}, Thomas J Hund^{1

2

6}, Matteo E Mangoni^{4

5}, Peter J Mohler^{1

2

3

7}

Affiliations

¹ Frick Center for Heart Failure and Arrhythmia Research, The Ohio State University Wexner Medical Center, Columbus, OH, United States.
² Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, United States.
³ Department of Physiology and Cell Biology, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, United States.
⁴ CNRS, INSERM, Institut de Génomique Fonctionnelle, Université de Montpellier, Montpellier, France.
⁵ Laboratory of Excellence ICST, Montpellier, France.
⁶ Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, OH, United States.
⁷ Division of Cardiovascular Medicine, Department of Internal Medicine, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, United States.

PMID: 33868385
PMCID: PMC8047474
DOI: 10.3389/fgene.2021.654925

Review

Genetic Complexity of Sinoatrial Node Dysfunction

Michael J Wallace et al. Front Genet. 2021.

. 2021 Apr 1:12:654925.

doi: 10.3389/fgene.2021.654925. eCollection 2021.

Authors

Michael J Wallace^{1

2

3}, Mona El Refaey^{1

2

3}, Pietro Mesirca^{4

5}, Thomas J Hund^{1

2

6}, Matteo E Mangoni^{4

5}, Peter J Mohler^{1

2

3

7}

Affiliations

¹ Frick Center for Heart Failure and Arrhythmia Research, The Ohio State University Wexner Medical Center, Columbus, OH, United States.
² Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, United States.
³ Department of Physiology and Cell Biology, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, United States.
⁴ CNRS, INSERM, Institut de Génomique Fonctionnelle, Université de Montpellier, Montpellier, France.
⁵ Laboratory of Excellence ICST, Montpellier, France.
⁶ Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, OH, United States.
⁷ Division of Cardiovascular Medicine, Department of Internal Medicine, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, United States.

PMID: 33868385
PMCID: PMC8047474
DOI: 10.3389/fgene.2021.654925

Abstract

The pacemaker cells of the cardiac sinoatrial node (SAN) are essential for normal cardiac automaticity. Dysfunction in cardiac pacemaking results in human sinoatrial node dysfunction (SND). SND more generally occurs in the elderly population and is associated with impaired pacemaker function causing abnormal heart rhythm. Individuals with SND have a variety of symptoms including sinus bradycardia, sinus arrest, SAN block, bradycardia/tachycardia syndrome, and syncope. Importantly, individuals with SND report chronotropic incompetence in response to stress and/or exercise. SND may be genetic or secondary to systemic or cardiovascular conditions. Current management of patients with SND is limited to the relief of arrhythmia symptoms and pacemaker implantation if indicated. Lack of effective therapeutic measures that target the underlying causes of SND renders management of these patients challenging due to its progressive nature and has highlighted a critical need to improve our understanding of its underlying mechanistic basis of SND. This review focuses on current information on the genetics underlying SND, followed by future implications of this knowledge in the management of individuals with SND.

Keywords: GIRK4; HCN4; Nav1.5; atrial fibrillation; calsequestrin-2; genetics; sick sinus syndrome; sinoatrial node dysfunction.

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Conflict of interest statement

The reviewer HZ declared a past co-authorship with the authors PM and MM to the handling editor. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

**FIGURE 1**
Schematic of proteins implicated in sinoatrial node dysfunction. Shown is a partial sinoatrial (SA) pacemaker cell. Proteins are labeled in black text, while various cellular locations are labeled in red text. Abbreviations include calsequestrin-2 (Casq2), ryanodine receptor 2 (RyR2), G protein-activated inward rectifier potassium channel 1/4 (GIRK1/4), guanine nucleotide-binding protein subunit beta-2/5 (Gnb2/5), G protein-coupled receptor (GPCR), sodium/calcium exchanger 1 (NCX1), voltage-gated sodium channel alpha subunit 5 (Na_v 1.5), hyperpolarization activated cyclic nucleotide gated potassium channel 4 (HCN4), ankyrin-B (AnkB), short-stature homeobox 2 (Shox2), transient receptor potential cation channel subfamily C member 3 (TRPC3), stromal interaction molecule 1 (STIM1), calcium-release-activated calcium channel protein 1 (Orai1), potassium two pore domain channel subfamily K member 2 (TREK-1), and transient receptor potential melastatin 4 (TRPM4).

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References

1. Abe K., Machida T., Sumitomo N., Yamamoto H., Ohkubo K., Watanabe I., et al. (2014). Sodium channelopathy underlying familial sick sinus syndrome with early onset and predominantly male characteristics. Circ. Arrhythm. Electrophysiol. 7 511–517. 10.1161/circep.113.001340 - DOI - PubMed
1. Accili E. A., Proenza C., Baruscotti M., DiFrancesco D. (2002). From funny current to HCN channels: 20 years of excitation. News Physiol. Sci. 17 32–37. 10.1152/physiologyonline.2002.17.1.32 - DOI - PubMed
1. Akoum N., McGann C., Vergara G., Badger T., Ranjan R., Mahnkopf C., et al. (2012). Atrial fibrosis quantified using late gadolinium enhancement MRI is associated with sinus node dysfunction requiring pacemaker implant. J. Cardiovasc. Electrophysiol. 23 44–50. 10.1111/j.1540-8167.2011.02140.x - DOI - PMC - PubMed
1. Alboni P., Ratto B., Cappato R., Rossi P., Gatto E., Antonioli G. E. (1991). Clinical effects of oral theophylline in sick sinus syndrome. Am. Heart J. 122 1361–1367. 10.1016/0002-8703(91)90578-6 - DOI - PubMed
1. Alig J., Marger L., Mesirca P., Ehmke H., Mangoni M. E., Isbrandt D. (2009). Control of heart rate by cAMP sensitivity of HCN channels. Proc. Natl. Acad. Sci. U.S.A. 106 12189–12194. 10.1073/pnas.0810332106 - DOI - PMC - PubMed

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[1] Abe K., Machida T., Sumitomo N., Yamamoto H., Ohkubo K., Watanabe I., et al. (2014). Sodium channelopathy underlying familial sick sinus syndrome with early onset and predominantly male characteristics. Circ. Arrhythm. Electrophysiol. 7 511–517. 10.1161/circep.113.001340 - DOI - PubMed

[2] Abe K., Machida T., Sumitomo N., Yamamoto H., Ohkubo K., Watanabe I., et al. (2014). Sodium channelopathy underlying familial sick sinus syndrome with early onset and predominantly male characteristics. Circ. Arrhythm. Electrophysiol. 7 511–517. 10.1161/circep.113.001340 - DOI - PubMed

[3] Accili E. A., Proenza C., Baruscotti M., DiFrancesco D. (2002). From funny current to HCN channels: 20 years of excitation. News Physiol. Sci. 17 32–37. 10.1152/physiologyonline.2002.17.1.32 - DOI - PubMed

[4] Accili E. A., Proenza C., Baruscotti M., DiFrancesco D. (2002). From funny current to HCN channels: 20 years of excitation. News Physiol. Sci. 17 32–37. 10.1152/physiologyonline.2002.17.1.32 - DOI - PubMed

[5] Akoum N., McGann C., Vergara G., Badger T., Ranjan R., Mahnkopf C., et al. (2012). Atrial fibrosis quantified using late gadolinium enhancement MRI is associated with sinus node dysfunction requiring pacemaker implant. J. Cardiovasc. Electrophysiol. 23 44–50. 10.1111/j.1540-8167.2011.02140.x - DOI - PMC - PubMed

[6] Akoum N., McGann C., Vergara G., Badger T., Ranjan R., Mahnkopf C., et al. (2012). Atrial fibrosis quantified using late gadolinium enhancement MRI is associated with sinus node dysfunction requiring pacemaker implant. J. Cardiovasc. Electrophysiol. 23 44–50. 10.1111/j.1540-8167.2011.02140.x - DOI - PMC - PubMed

[7] Alboni P., Ratto B., Cappato R., Rossi P., Gatto E., Antonioli G. E. (1991). Clinical effects of oral theophylline in sick sinus syndrome. Am. Heart J. 122 1361–1367. 10.1016/0002-8703(91)90578-6 - DOI - PubMed

[8] Alboni P., Ratto B., Cappato R., Rossi P., Gatto E., Antonioli G. E. (1991). Clinical effects of oral theophylline in sick sinus syndrome. Am. Heart J. 122 1361–1367. 10.1016/0002-8703(91)90578-6 - DOI - PubMed

[9] Alig J., Marger L., Mesirca P., Ehmke H., Mangoni M. E., Isbrandt D. (2009). Control of heart rate by cAMP sensitivity of HCN channels. Proc. Natl. Acad. Sci. U.S.A. 106 12189–12194. 10.1073/pnas.0810332106 - DOI - PMC - PubMed

[10] Alig J., Marger L., Mesirca P., Ehmke H., Mangoni M. E., Isbrandt D. (2009). Control of heart rate by cAMP sensitivity of HCN channels. Proc. Natl. Acad. Sci. U.S.A. 106 12189–12194. 10.1073/pnas.0810332106 - DOI - PMC - PubMed

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Genetic Complexity of Sinoatrial Node Dysfunction

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Genetic Complexity of Sinoatrial Node Dysfunction

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