Sinus node-like pacemaker mechanisms regulate ectopic pacemaker activity in the adult rat atrioventricular ring

Logantha, Sunil Jit R. J.; Kharche, Sanjay; Zhang, Y.; Atkinson, Andrew; Hao, Guoliang; Boyett, Mark R.; Dobrzynski, Halina

doi:10.1038/s41598-019-48276-0

Cited by 10 publications

(6 citation statements)

References 58 publications

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“…Here, we show that the healthy, denervated ex vivo isolated rat and human RA both exhibit 2 distinct clusters of functional pacemaking activity specifically located near the SVC and IVC—denoted here as the sSAN and iSAN—which preferentially control high and low HRs, respectively ( Central Illustration ). Previous reports from various species ( 3 , 12 , 29 – 33 ) have also demonstrated that leading pacemaker sites can and generally do move toward an inferior location within the SAN with high vagal tone (in addition to activity from the atrioventricular node or atrioventricular ring) ( 34 ), but this inferior, or “backup,” pacemaker located near the IVC has not yet been fully characterized. With the application of state-of-the-art optical mapping and novel signal processing techniques on a beat-to-beat basis, we observed a clear phenomenon of 2 distinct RA pacemaking regions over the entire range of SAN-initiated physiological HRs in the healthy rat heart and over a normal range of physiological HRs in the healthy human heart.…”

Section: Discussionmentioning

confidence: 99%

Evidence of Superior and Inferior Sinoatrial Nodes in the Mammalian Heart

Brennan

Chen

Gams

et al. 2020

JACC: Clinical Electrophysiology

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OBJECTIVES This study sought to investigate the shift of leading pacemaker locations in healthy and failing mammalian hearts over the entire range of physiological heart rates (HRs), and to molecularly characterize spatial regions of spontaneous activity. BACKGROUND A normal heartbeat originates as an action potential in a group of pacemaker cells known as the sinoatrial node (SAN), located near the superior vena cava. HRs and the anatomical site of origin of pacemaker activity in the adult heart are known to dynamically change in response to various physiological inputs, yet the mechanism of this pacemaker shift is not well understood. METHODS Optical mapping was applied to ex vivo rat and human isolated right atrial tissues, and HRs were modulated with acetylcholine and isoproterenol. RNA sequencing was performed on tissue areas that elicited spontaneous activity, and comparisons were made to neighboring myocardial tissues. RESULTS Functional and molecular evidence identified and confirmed the presence of 2 competing right atrial pacemakers localized near the superior vena cava and the inferior vena cava—the superior SAN (sSAN) and inferior SAN (iSAN), respectively—which preferentially control the fast and slow HRs. Both of these regions were evident in non-failing rat and human hearts and maintained spontaneous activity in the rat heart when physically separated from one another. Molecular analysis of these 2 pacemaker regions revealed unique but similar transcriptional profiles, suggesting iSAN dominance when the sSAN is silent. CONCLUSIONS The presence of 2 spatially distinct dominant pacemakers, sSAN and iSAN, in the mammalian heart clarifies previous identification of migrating pacemakers and corresponding changes in P-wave morphology in mammalian species.

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Section: Discussionmentioning

confidence: 99%

Evidence of Superior and Inferior Sinoatrial Nodes in the Mammalian Heart

Brennan

Chen

Gams

et al. 2020

JACC: Clinical Electrophysiology

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“…V m was recorded at 10 kHz with the PowerLab data acquisition device controlled by LabChart (ADInstruments, Colorado Springs, CO, United States). From the V m recordings, characteristics of the SAN, atrial, and ventricular cell AP were calculated, using custom routines in Matlab following previously described algorithms ( Bucchi et al, 2007 ; Logantha et al, 2019 ). For the SAN, these included: (i) maximum diastolic potential (MDP), defined as the most negative V m reached during AP repolarisation; (ii) slope of DD, defined as the change in V m over the time between the point of MDP and the initiation of the AP, which was determined as the point at which the rate of change of V m was greater than 500 mV/s; (iii) maximum rate of change of V m during the upstroke (dV/dt max ); (iv) maximum V m during the AP; (v) AP amplitude, defined as the change in V m between the initiation and peak of the AP; and (vi) AP duration at 50% (APD 50 ) and 80% (APD 80 ) repolarisation, defined as the time between the initiation of the AP and the restoration of V m from peak to 50% or 80% of MDP.…”

Section: Methodsmentioning

confidence: 99%

Drivers of Sinoatrial Node Automaticity in Zebrafish: Comparison With Mechanisms of Mammalian Pacemaker Function

et al. 2022

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Cardiac excitation originates in the sinoatrial node (SAN), due to the automaticity of this distinct region of the heart. SAN automaticity is the result of a gradual depolarisation of the membrane potential in diastole, driven by a coupled system of transarcolemmal ion currents and intracellular Ca2+ cycling. The frequency of SAN excitation determines heart rate and is under the control of extra- and intracardiac (extrinsic and intrinsic) factors, including neural inputs and responses to tissue stretch. While the structure, function, and control of the SAN have been extensively studied in mammals, and some critical aspects have been shown to be similar in zebrafish, the specific drivers of zebrafish SAN automaticity and the response of its excitation to vagal nerve stimulation and mechanical preload remain incompletely understood. As the zebrafish represents an important alternative experimental model for the study of cardiac (patho-) physiology, we sought to determine its drivers of SAN automaticity and the response to nerve stimulation and baseline stretch. Using a pharmacological approach mirroring classic mammalian experiments, along with electrical stimulation of intact cardiac vagal nerves and the application of mechanical preload to the SAN, we demonstrate that the principal components of the coupled membrane- Ca2+ pacemaker system that drives automaticity in mammals are also active in the zebrafish, and that the effects of extra- and intracardiac control of heart rate seen in mammals are also present. Overall, these results, combined with previously published work, support the utility of the zebrafish as a novel experimental model for studies of SAN (patho-) physiological function.

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“…The decreased amplitude and increased PRi is consistent with the slowing of atrial conduction, likely due to the actions of acetylcholine on atrial M2 muscarinic receptors following increases in reflex parasympathetic activity (Hooper et al, 2019). Notched or negative P waves are likely ectopic atrial beats (Waldo et al, 1975), and this is consistent with heterogeneity of conduction throughout the rat atria and pacemaker activity near the rat pulmonary vein (Masani, 1986;Maupoil et al, 2007;Fan et al, 2019;Logantha et al, 2019). AITC inhalation caused an increase in negative P waves in SH rats but not WKY rats, despite the observation that AITC-evoked increases in PRi were similar between the strains and AITC-evoked increases in RRi and Pwidth were greater in the WKY rat (Figures 3, 4).…”

Section: Discussionmentioning

confidence: 58%

Irritant Inhalation Evokes P Wave Morphological Changes in Spontaneously Hypertensive Rats via Reflex Modulation of the Autonomic Nervous System

Hooper

Taylor‐Clark

2021

Front. Physiol.

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Irritant inhalation is associated with increased incidence of atrial fibrillation (AF) and stroke. Irritant inhalation acutely regulates cardiac function via autonomic reflexes. Increases in parasympathetic and sympathetic reflexes may increase atrial susceptibility to ectopic activity and the initiation of arrhythmia such as AF. Both age and hypertension are risk factors for AF. We have shown that irritant-evoked pulmonary–cardiac reflexes are remodeled in spontaneously hypertensive (SH) rats to include a sympathetic component in addition to the parasympathetic reflex observed in normotensive Wistar-Kyoto (WKY) rats. Here, we analyzed P wave morphology in 15-week old WKY and SH rats during inhalation of the transient receptor potential ankyrin 1 agonist allyl isothiocyanate (AITC). P Wave morphology was normal during vehicle inhalation but was variably modulated by AITC. AITC increased RR intervals (RRi), PR intervals, and the P Wave duration. In SH rats only, AITC inhalation increased the occurrence of negative P waves. The incidence of AITC-evoked negative P waves in SH rats was dependent on RRi, increasing during bradycardic and tachycardic cardiac cycles. Inhibition of both parasympathetic (using atropine) and sympathetic (using atenolol) components of the pulmonary–cardiac reflex decreased the incidence of negative P waves. Lastly, the probability of evoking a negative P Wave was increased by the occurrence of preceding negative P waves. We conclude that the remodeled irritant-evoked pulmonary–cardiac reflex in SH rats provides a substrate for altered P Wave morphologies. These are likely ectopic atrial beats that could provide a trigger for AF initiation in structurally remodeled atria.

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Sinus node-like pacemaker mechanisms regulate ectopic pacemaker activity in the adult rat atrioventricular ring

Cited by 10 publications

References 58 publications

Evidence of Superior and Inferior Sinoatrial Nodes in the Mammalian Heart

Evidence of Superior and Inferior Sinoatrial Nodes in the Mammalian Heart

Drivers of Sinoatrial Node Automaticity in Zebrafish: Comparison With Mechanisms of Mammalian Pacemaker Function

Irritant Inhalation Evokes P Wave Morphological Changes in Spontaneously Hypertensive Rats via Reflex Modulation of the Autonomic Nervous System

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