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Synchronization of sinoatrial node pacemaker cell clocks and its autonomic modulation impart complexity to heart beating intervals.

ABSTRACT: BACKGROUND:A reduction of complexity of heart beating interval variability that is associated with an increased morbidity and mortality in cardiovascular disease states is thought to derive from the balance of sympathetic and parasympathetic neural impulses to the heart. However, rhythmic clocklike behavior intrinsic to pacemaker cells in the sinoatrial node (SAN) drives their beating, even in the absence of autonomic neural input. OBJECTIVE:To test how this rhythmic clocklike behavior intrinsic to pacemaker cells interacts with autonomic impulses to the heart beating interval variability in vivo. METHODS:We analyzed beating interval variability in time and frequency domains and by fractal and entropy analyses: (1) in vivo, when the brain input to the SAN is intact; (2) during autonomic denervation in vivo; (3) in isolated SAN tissue (ie, in which the autonomic neural input is completely absent); (4) in single pacemaker cells isolated from the SAN; and (5) after autonomic receptor stimulation of these cells. RESULTS:Spontaneous beating intervals of pacemaker cells residing in the isolated SAN tissue exhibit fractal-like behavior and have lower approximate entropy compared with those in the intact heart. Isolation of pacemaker cells from SAN tissue, however, leads to a loss in the beating interval order and fractal-like behavior. ?-Adrenergic receptor stimulation of isolated pacemaker cells increases intrinsic clock synchronization, decreases their action potential period, and increases system complexity. CONCLUSIONS:Both the average beating interval in vivo and beating interval complexity are conferred by the combined effects of clock periodicity intrinsic to pacemaker cells and their response to autonomic neural input.

SUBMITTER: Yaniv Y

PROVIDER: S-EPMC4065846 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Synchronization of sinoatrial node pacemaker cell clocks and its autonomic modulation impart complexity to heart beating intervals.

Yaniv Yael Y Ahmet Ismayil I Liu Jie J Lyashkov Alexey E AE Guiriba Toni-Rose TR Okamoto Yosuke Y Ziman Bruce D BD Lakatta Edward G EG

Heart rhythm 20140405 7

<h4>Background</h4>A reduction of complexity of heart beating interval variability that is associated with an increased morbidity and mortality in cardiovascular disease states is thought to derive from the balance of sympathetic and parasympathetic neural impulses to the heart. However, rhythmic clocklike behavior intrinsic to pacemaker cells in the sinoatrial node (SAN) drives their beating, even in the absence of autonomic neural input.<h4>Objective</h4>To test how this rhythmic clocklike beh ...[more]

PMID: 24713624

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Project description:BackgroundIncreasing evidence suggests that cardiac arrhythmias are frequent clinical features of coronavirus disease 2019 (COVID-19). Sinus node damage may lead to bradycardia. However, it is challenging to explore human sinoatrial node (SAN) pathophysiology due to difficulty in isolating and culturing human SAN cells. Embryonic stem cells (ESCs) can be a source to derive human SAN-like pacemaker cells for disease modeling.MethodsWe used both a hamster model and human ESC (hESC)-derived SAN-like pacemaker cells to explore the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on the pacemaker cells of the heart. In the hamster model, quantitative real-time polymerase chain reaction and immunostaining were used to detect viral RNA and protein, respectively. We then created a dual knock-in SHOX2:GFP;MYH6:mCherry hESC reporter line to establish a highly efficient strategy to derive functional human SAN-like pacemaker cells, which was further characterized by single-cell RNA sequencing. Following exposure to SARS-CoV-2, quantitative real-time polymerase chain reaction, immunostaining, and RNA sequencing were used to confirm infection and determine the host response of hESC-SAN-like pacemaker cells. Finally, a high content chemical screen was performed to identify drugs that can inhibit SARS-CoV-2 infection, and block SARS-CoV-2-induced ferroptosis.ResultsViral RNA and spike protein were detected in SAN cells in the hearts of infected hamsters. We established an efficient strategy to derive from hESCs functional human SAN-like pacemaker cells, which express pacemaker markers and display SAN-like action potentials. Furthermore, SARS-CoV-2 infection causes dysfunction of human SAN-like pacemaker cells and induces ferroptosis. Two drug candidates, deferoxamine and imatinib, were identified from the high content screen, able to block SARS-CoV-2 infection and infection-associated ferroptosis.ConclusionsUsing a hamster model, we showed that primary pacemaker cells in the heart can be infected by SARS-CoV-2. Infection of hESC-derived functional SAN-like pacemaker cells demonstrates ferroptosis as a potential mechanism for causing cardiac arrhythmias in patients with COVID-19. Finally, we identified candidate drugs that can protect the SAN cells from SARS-CoV-2 infection.

Dataset Information

Synchronization of sinoatrial node pacemaker cell clocks and its autonomic modulation impart complexity to heart beating intervals.

Publications

Synchronization of sinoatrial node pacemaker cell clocks and its autonomic modulation impart complexity to heart beating intervals.

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