Research ArticleHeart Disease

Redundant and diverse intranodal pacemakers and conduction pathways protect the human sinoatrial node from failure

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Science Translational Medicine  26 Jul 2017:
Vol. 9, Issue 400, eaam5607
DOI: 10.1126/scitranslmed.aam5607

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Keeping the beat

The human heart beats more than 100,000 times per day. Arrhythmia, or irregular heartbeat, can occur due to heart disease, changes in diet or hormones, electrolyte imbalances, or for other reasons—but these inconsistencies only infrequently lead to total loss of heart function. Li et al. uncovered how the heart is hardwired to maintain consistency. Optical and molecular mapping of human hearts ex vivo coupled with electrocardiograms and histology revealed that the sinoatrial node is home to multiple pacemakers, specialized cardiomyocytes that generate electrical heartbeat-inducing impulses. This means that multiple conduction pathways can deliver the electrical impulses required for rhythm control, so total cardiac arrest occurs only when all pacemakers and conduction pathways fail. Understanding inherent cardiac robustness may help develop treatments for arrhythmias.

Abstract

The human sinoatrial node (SAN) efficiently maintains heart rhythm even under adverse conditions. However, the specific mechanisms involved in the human SAN’s ability to prevent rhythm failure, also referred to as its robustness, are unknown. Challenges exist because the three-dimensional (3D) intramural structure of the human SAN differs from well-studied animal models, and clinical electrode recordings are limited to only surface atrial activation. Hence, to innovate the translational study of human SAN structural and functional robustness, we integrated intramural optical mapping, 3D histology reconstruction, and molecular mapping of the ex vivo human heart. When challenged with adenosine or atrial pacing, redundant intranodal pacemakers within the human SAN maintained automaticity and delivered electrical impulses to the atria through sinoatrial conduction pathways (SACPs), thereby ensuring a fail-safe mechanism for robust maintenance of sinus rhythm. During adenosine perturbation, the primary central SAN pacemaker was suppressed, whereas previously inactive superior or inferior intranodal pacemakers took over automaticity maintenance. Sinus rhythm was also rescued by activation of another SACP when the preferential SACP was suppressed, suggesting two independent fail-safe mechanisms for automaticity and conduction. The fail-safe mechanism in response to adenosine challenge is orchestrated by heterogeneous differences in adenosine A1 receptors and downstream GIRK4 channel protein expressions across the SAN complex. Only failure of all pacemakers and/or SACPs resulted in SAN arrest or conduction block. Our results unmasked reserve mechanisms that protect the human SAN pacemaker and conduction complex from rhythm failure, which may contribute to treatment of SAN arrhythmias.

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