Dataset Information

Genetic Complexity of Sinoatrial Node Dysfunction.

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.

SUBMITTER: Wallace MJ

PROVIDER: S-EPMC8047474 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Genetic Complexity of Sinoatrial Node Dysfunction.

Wallace Michael J MJ El Refaey Mona M Mesirca Pietro P Hund Thomas J TJ Mangoni Matteo E ME Mohler Peter J PJ

Frontiers in genetics 20210401

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 wi ...[more]

PMID: 33868385

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Project description:BackgroundThe ability to increase heart rate during exercise and other stressors is a key homeostatic feature of the sinoatrial node (SAN). When the physiological heart rate response is blunted, chronotropic incompetence limits exercise capacity, a common problem in patients with heart failure with preserved ejection fraction (HFpEF). Despite its clinical relevance, the mechanisms of chronotropic incompetence remain unknown.MethodsDahl salt-sensitive rats fed a high-salt diet and C57Bl6 mice fed a high-fat diet and an inhibitor of constitutive nitric oxide synthase (Nω-nitro-L-arginine methyl ester [L-NAME]; 2-hit) were used as models of HFpEF. Myocardial infarction was created to induce HF with reduced ejection fraction. Rats and mice fed with a normal diet or those that had a sham surgery served as respective controls. A comprehensive characterization of SAN function and chronotropic response was conducted by in vivo, ex vivo, and single-cell electrophysiologic studies. RNA sequencing of SAN was performed to identify transcriptomic changes. Computational modeling of biophysically-detailed human HFpEF SAN was created.ResultsRats with phenotypically-verified HFpEF exhibited limited chronotropic response associated with intrinsic SAN dysfunction, including impaired β-adrenergic responsiveness and an alternating leading pacemaker within the SAN. Prolonged SAN recovery time and reduced SAN sensitivity to isoproterenol were confirmed in the 2-hit mouse model. Adenosine challenge unmasked conduction blocks within the SAN, which were associated with structural remodeling. Chronotropic incompetence and SAN dysfunction were also found in rats with HF with reduced ejection fraction. Single-cell studies and transcriptomic profiling revealed HFpEF-related alterations in both the "membrane clock" (ion channels) and the "Ca2+ clock" (spontaneous Ca2+ release events). The physiologic impairments were reproduced in silico by empirically-constrained quantitative modeling of human SAN function.ConclusionsChronotropic incompetence and SAN dysfunction were seen in both models of HF. We identified that intrinsic abnormalities of SAN structure and function underlie the chronotropic response in HFpEF.

Dataset Information

Genetic Complexity of Sinoatrial Node Dysfunction.

Publications

Genetic Complexity of Sinoatrial Node Dysfunction.

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