Abstract
Mechanisms for human sinoatrial node (SAN) dysfunction are poorly understood and whether human SAN excitability requires voltage-gated sodium channels (Nav) remains controversial. Here, we report that neuronal (n)Nav blockade and selective nNav1.6 blockade during high-resolution optical mapping in explanted human hearts depress intranodal SAN conduction, which worsens during autonomic stimulation and overdrive suppression to conduction failure. Partial cardiac (c)Nav blockade further impairs automaticity and intranodal conduction, leading to beat-to-beat variability and reentry. Multiple nNav transcripts are higher in SAN vs atria; heterogeneous alterations of several isoforms, specifically nNav1.6, are associated with heart failure and chronic alcohol consumption. In silico simulations of Nav distributions suggest that INa is essential for SAN conduction, especially in fibrotic failing hearts. Our results reveal that not only cNav but nNav are also integral for preventing disease-induced failure in human SAN intranodal conduction. Disease-impaired nNav may underlie patient-specific SAN dysfunctions and should be considered to treat arrhythmias.
Highlights
Mechanisms for human sinoatrial node (SAN) dysfunction are poorly understood and whether human SAN excitability requires voltage-gated sodium channels (Nav) remains controversial
Normal cardiac rhythm is maintained by the human sinoatrial node (SAN) complex, which is compartmentalized into multiple intranodal pacemakers and conduction pathways within an intramural three-dimensional (3D) structure[1,2,3]
We investigated the contribution of Nav in protecting SAN conduction during metabolic challenge with adenosine bolus or overdrive suppression by fast atrial pacing, which are clinically employed tests to unmask SND25,26
Summary
Mechanisms for human sinoatrial node (SAN) dysfunction are poorly understood and whether human SAN excitability requires voltage-gated sodium channels (Nav) remains controversial. Disease-induced remodeling of many of the molecular components critical to SAN function including hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and G-protein-coupled inwardly rectifying potassium channels, adenosine receptors (A1R), and L-type calcium channels, as well as structural fibrotic remodeling can lead to SND3,10–13. Some patients with symptomatic SND are found to harbor loss-of-function mutations in the SCN5A gene, which encodes the α-subunit of the cardiac isoform Nav1.5 (ref.18), suggesting that functional voltage-gated Na+ current (INa) may be necessary for maintaining human SAN pacemaking and conduction. The primary goal of the current study is to determine the existence and specific role of nNav and cNav isoforms in human SAN pacemaking and intranodal conduction, and to reveal their disease-induced alterations in explanted human hearts. Our data suggest that by altering nNav in the SAN and/or atria, HF and chronic alcohol consumption could promote a patient-specific, mechanistic substrate for tachy-brady arrhythmias and SAN conduction blocks
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
