Cholinergic regulation of cardiac pacemaker activity by l-type cav1.3 channels

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
L Talssi ◽  
I Bidaud ◽  
P Mesirca ◽  
M Mangoni
Keyword(s):  
Heart Rate ◽  
Action Potentials ◽  
Ex Vivo ◽  
Sinus Node ◽  
Cardiac Pacemaker ◽  
Intracellular Concentration ◽  
Pacemaker Activity ◽  
Funding Source ◽  
Cholinergic Regulation ◽  
Frequency Of Action Potentials

Abstract Introduction The cholinergic regulation of heart rate (HR) is mediated by acetylcholine (ACh)-dependent activation of M2-receptors (M2R). Activated M2R promote release of the βγ-subunit of G-proteins to directly gate GIRK1/4 channels (underlying the cardiac IKACh current), while αi-subunits inhibit adenylate cyclase (AC) activity. AC inhibition reduces the intracellular concentration of cAMP, decreasing the activity of ion channels involved in pacemaking, including “funny” f-(HCN4) and L-type Cav1.3 calcium channels. Purpose To determine the importance of L-type Cav1.3 channels in the cholinergic regulation of heart rate. Methods We recorded the frequency and the position of the pacemaker leading site in ex vivo sinus nodes and the HR of isolated Langendorff perfused hearts of mice in control or during ACh perfusion. We used control wild type (WT) mice, and five genetically modified mouse models: Cav1.3 knockout (KO, ablated Cav1.3-mediated L-type current), GIRK4KO (ablated IKACh current), HCN4-CNBD (selective deletion of cAMP-dependent regulation of HCN4), GIRK4KO/HCN4-CNBD and GIRK4KO/Cav1.3KO. Results Data from optical mapping experiments showed that, under basal conditions, perfusion of 3 μM ACh significantly reduced the frequency of action potentials in WT (44%), HCN4-CNBD (38%), Cav1.3KO (65%) and GIRK4KO (8%) isolated mouse sinus node tissues. ACh application did not significantly affect the frequency of action potentials recorded in tissue from GIRK4KO/HCN4-CNBD and GIRK4KO/Cav1.3KO animals. Furthermore, in all the sinus node tissues tested, regardless of the genotypes, ACh shifted the pacemaker leading site from its normal position by at least 0.7 mm. Upon stimulation of the β-adrenergic pathway by Isoproterenol, to reproduce conditions of accentuated antagonism, 3μM ACh reduced HR in isolated hearts from WT (43.8%), HCN4-CNBD (38.7%), Cav1.3KO (25,4%), GIRK4KO (16.9%) and GIRK4KO/HCN4-CNBD (16.4%) mice. No significant HR reduction was recorded in hearts from GIRK4KO/Cav1.3KO animals. Conclusion Our data indicate that L-type Cav1.3 channels are involved in cholinergic regulation of heart rate in mice. In addition, when the intracellular concentration of cAMP is elevated (i.e. under conditions of accentuated antagonism), the cholinergic regulation of sinus node pacemaking is predominantly ensured by Cav1.3 and KACh channels. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): “Fondation pour la recherche medicale” FRM

scholarly journals Cholinergic regulation of cardiac pacemaker activity by L-type Cav1.3 channels

EP Europace ◽  
2021 ◽  
Vol 23 (Supplement_3) ◽  
Author(s):  
L Talssi ◽  
I Bidaud ◽  
ME Mangoni ◽  
P Mesirca
Keyword(s):  
Heart Rate ◽  
Action Potentials ◽  
Receptor Agonist ◽  
Sinus Node ◽  
Cardiac Pacemaker ◽  
Intracellular Concentration ◽  
Pacemaker Activity ◽  
Cholinergic Regulation ◽  
Frequency Of Action Potentials

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Fondation Recherche Médicale Introduction The cholinergic regulation of heart rate (HR) is mediated by acetylcholine (ACh)-dependent activation of M2-receptors (M2R). Activated M2R promote release of the βγ-subunit of G-proteins to directly gate GIRK1/4 channels (underlying the cardiac IKACh current), while αi-subunits inhibit adenylate cyclase (AC) activity. AC inhibition reduces the intracellular concentration of cAMP, decreasing the activity of ion channels involved in pacemaking, including "funny" f-(HCN4) and L-type Cav1.3 calcium channels. Purpose To determine the role of L-type Cav1.3 channels in cholinergic regulation of heart rate. Methods We recorded the frequency of activation and position of pacemaker leading site in ex vivo sinus nodes and the HR of isolated Langendorff perfused hearts of mice at baseline or during ACh perfusion.  We used control wild type (WT) mice, and five genetically modified mouse models: Cav1.3 knockout (KO, ablated Cav1.3-mediated L-type current), GIRK4KO (ablated IKACh current), HCN4-CNBD (selective deletion of cAMP-dependent regulation of HCN4), GIRK4KO/HCN4-CNBD and GIRK4KO/Cav1.3KO. We performed in vivo telemetric recordings of heart rate (HR) in WT and GIRK4KO/Cav1.3KO animals. Results Data from optical mapping experiments showed that, under basal conditions, perfusion of 3 μM ACh significantly reduced the frequency of action potentials in WT (44%), HCN4-CNBD (38%), Cav1.3KO (65%) and GIRK4KO (8%) isolated mouse sinus node tissues. ACh application did not significantly affect the frequency of action potentials recorded in tissue from GIRK4KO/HCN4-CNBD and GIRK4KO/Cav1.3KO animals. Furthermore, in all sinus nodes tested, regardless of genotype, ACh shifted the pacemaker leading site from its normal position by at least 0.7 mm. Upon stimulation of the β-adrenergic pathway by Isoproterenol, to reproduce conditions of accentuated antagonism, 3µM ACh reduced HR in isolated hearts from WT (43.8%), HCN4-CNBD (38.7%), Cav1.3KO (25,4%), GIRK4KO (16.9%) and GIRK4KO/HCN4-CNBD (16.4%) mice. No significant HR reduction was recorded in hearts from GIRK4KO/Cav1.3KO animals. In vivo data indicate that HR reduction induced by combined injection of Hexamethonium ( a Nicotinic acetylcholine receptor blocker) with Carbamoylcholine (CCH, M2 receptor agonist) or with 2-Chloro-N6-Cyclopentyladenosine (CCPA, A1 receptor agonist) is higher in WT than in GIRK4KO/Cav1.3KO animals (68% vs 48% CCH, and 79% vs 62% CCPA, respectively). Conclusion Our data indicate that L-type Cav1.3 channels are involved in cholinergic regulation of heart rate in mice. In addition, when the intracellular concentration of cAMP is elevated (i.e. under conditions of accentuated antagonism), cholinergic regulation of sinus node pacemaking is reliant on Cav1.3 and KACh channels.

ANP has no postsynaptic effect on autonomic regulation of cardiac pacemaker rate in the rat

1993 ◽  
Vol 265 (6) ◽  
pp. H1983-H1987 ◽  
Author(s):  
D. J. Atchison ◽  
P. S. Pennefather ◽  
U. Ackermann
Keyword(s):  
Salt Solution ◽  
Action Potentials ◽  
Sinoatrial Node ◽  
Cardiac Pacemaker ◽  
Pacemaker Activity ◽  
Physiological Salt Solution ◽  
Sprague Dawley ◽  
Pacemaker Cells ◽  
Frequency Of Action Potentials ◽  
The Right

We studied whether atrial natriuretic peptide (ANP) influences sinoatrial node pacemaker activity or whether it modifies the response to activation of postsynaptic autonomic receptors. Male Sprague-Dawley rats were anesthetized with pentobarbital sodium (45 mg/kg). Their hearts were removed quickly and placed in physiological salt solution. The atria were isolated; the right intra-atrial chamber was exposed to allow intracellular recording from sinoatrial node pacemaker cells. The tissue was placed in a temperature-regulated recording chamber and superfused with warmed oxygenated physiological salt solution. With use of standard microelectrode recording techniques, action potentials were recorded from spontaneously depolarizing cells in the presence of muscarine (62.5–500 nM) or norepinephrine (0.1 and 1.0 microM). Muscarine reduced the frequency of action potentials dose dependently, whereas norepinephrine increased their frequency. The addition of ANP (0.1–100 nM) to the superfusion had no effect on the frequency of action potentials during the superfusion of physiological salt solution or in the presence of either muscarine or norepinephrine. We conclude that ANP does not act on cardiac pacemaker cells to modulate the effect of neurotransmitters.

The increase of extracellular Ca2+ from physiological concentrations to hypercalcemia impairs sino-atrial automaticity

EP Europace ◽  
2021 ◽  
Vol 23 (Supplement_3) ◽  
Author(s):  
AG Torrente ◽  
L Fossier ◽  
M Baudot ◽  
E Torre ◽  
I Bidaud ◽  
...  
Keyword(s):  
Action Potentials ◽  
Ex Vivo ◽  
Pacemaker Activity ◽  
Funding Source ◽  
Cell Contractility ◽  
Funding Sources ◽  
Spontaneous Action ◽  
Spontaneous Action Potentials ◽  
Ca2 Channels ◽  
Funding Acknowledgements

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): ESC FRM Lefoulon Delalande Aims To investigate whether extracellular hypercalcemia alters the conduction through L-type Ca2+ channels (LTCCs), impairing the pacemaker activity of the heart. Introduction In the sino-atrial node (SAN), membrane currents and the dynamics of intracellular Ca2+ ([Ca2+]i) generate the pacemaker activity of the heart. SAN dysfunctions (SNDs) harm heart automaticity and have been associated with abnormal dynamics of [Ca2+]i. The LTCCs, Cav1.2 and Cav1.3 carry the main Ca2+ influx of SAN cells, which is necessary to sustain [Ca2+]i dynamics. Modified extracellular Ca2+ ([Ca2+]o) could alter Ca2+ influx through these channels. For example, cancer and hyperparathyroidism can raise [Ca2+]o, causing an extracellular hypercalcemia that could alter [Ca2+]i dynamics and impair SAN activity and heart automaticity. Methods and results To test this hypothesis, we measured contractions, [Ca2+]i release and L-type Ca2+ current (ICa,L) in spontaneous cells of the murine SAN. Then, we recorded rate and propagation of the spontaneous action potentials (APs) generated by the SAN tissue ex-vivo. In spontaneously beating SAN cells, we observed that the modification of [Ca2+]o affected [Ca2+]i and cell contractility through changes of ICa,L. In particular, the increase of [Ca2+]o dysregulated pacemaker activity, likely through excessive Ca2+ influx mediated by Cav1.2. [Ca2+]o increase to hypercalcemia induced arrhythmia also in the intact SAN tissues, activating ectopic leading regions of pacemaking and impairing conduction towards the atria. Conclusions Hypercalcemia causes excessive Cav1.2-mediated Ca2+ influx, which alters [Ca2+]I leading to pacemaker impairment. Modulation of LTCC may reduce pacemaker dysfunctions, preventing SND progression.

scholarly journals The Chronotropic Function of Propofol and the Underlying Mechanism in Rabbits

2021 ◽  
Vol 2021 ◽  
pp. 1-6
Author(s):  
Wenjie Cheng ◽  
Xiaohua Sun ◽  
Yanfang Liu ◽  
Shiqi Han ◽  
Wanlu Ren
Keyword(s):  
Heart Rate ◽  
Action Potentials ◽  
Sinus Node ◽  
Underlying Mechanism ◽  
Dependent Manner ◽  
Pacemaker Cells ◽  
Concentration Dependent Manner ◽  
Sinoatrial Nodes ◽  
Chronotropic Action ◽  
Dose Dependent

The report of bradycardia caused by propofol is increasing. In the experiment, we investigated the chronotropic function of propofol and the underlying mechanism. Rabbits of both sexes were randomly divided into 4 groups: propofol 5 mg/kg group, 10 mg/kg group, 15 mg/kg group, and sham group. Heart rate and frequency of vagal efferent discharge were recorded before the injection and 0, 0.5, 1, 2, and 10 min after the injection through intravenous mode. Then, their hearts were removed, and sinoatrial nodes were dissected. The action potentials of the sinus node pacemaker cells were recorded by the intracellular glass microelectrode technique, and the sinoatrial (SA) node was exposed to propofol 1, 3, 5, and 10 µM respectively. The action potentials were recorded after the sinoatrial nodes were exposed to each concentration of propofol for 15 min. Our results show that the heart rate significantly decreased, and the vagal efferent discharge was significantly increased at 0, 0.5, 1, and 2 min after the injection, respectively. Besides, as the dose increases, the magnitude of change shows a dose-dependent manner. Propofol exerts a negative chronotropic action on sinoatrial node pacemaker cells. The drug significantly decreased APA, VDD, RPF, and prolonged APD90 in a concentration-dependent manner. These effects may be the main mechanism of propofol-induced bradycardia in clinical study.

scholarly journals Conserved Role of the Large Conductance Calcium-Activated Potassium Channel, KCa1.1, in Sinus Node Function and Arrhythmia Risk

2020 ◽  
Author(s):  
Santiago Pineda ◽  
Vesna Nikolova-Krstevski ◽  
Christiana Leimena ◽  
Andrew J. Atkinson ◽  
Ann-Kristin Altekoester ◽  
...  
Keyword(s):  
Action Potentials ◽  
Ex Vivo ◽  
Sinus Bradycardia ◽  
Sinus Node ◽  
Immunogold Electron Microscopy ◽  
Loss Of Function ◽  
Α Subunit ◽  
Cardiac Functions ◽  
Electrophysiological Characterization

ABSTRACTBackgroundKCNMA1 encodes the α-subunit of the large-conductance Ca2+-activated K+ channel, KCa1.1, and lies within a linkage interval for atrial fibrillation (AF). Insights into the cardiac functions of KCa1.1 are limited and KCNMA1 has not been investigated as an AF candidate gene.Methods and ResultsKCNMA1 sequencing in 118 patients with familial AF identified a novel complex variant in one kindred. To evaluate potential disease mechanisms, we first evaluated the distribution of KCa1.1 in normal hearts using immunostaining and immunogold electron microscopy. KCa1.1 was seen throughout the atria and ventricles in humans and mice, with strong expression in the sinus node. In an ex vivo murine sinoatrial node preparation, addition of the KCa1.1 antagonist, paxilline, blunted the increase in beating rate induced by adrenergic receptor stimulation. Knockdown of the KCa1.1 ortholog, kcnma1b, in zebrafish embryos resulted in sinus bradycardia with dilatation and reduced contraction of the atrium and ventricle. Genetic inactivation of the Drosophila KCa1.1 ortholog, slo, systemically or in adult stages, also slowed the heartbeat and produced cardiac arrhythmias.Electrophysiological characterization of slo-deficient flies revealed bursts of action potentials, reflecting increased events of fibrillatory arrhythmias. Flies with cardiac-specific overexpression of the human KCNMA1 mutant also showed increased heart period and bursts of action potentials, similar to the KCa1.1 loss-of-function models.ConclusionsOur data point to a highly conserved role of KCa1.1 in sinus node function in humans, mice, zebrafish and fly and suggest that KCa1.1 loss of function may predispose to AF.

scholarly journals Conserved Role of the Large Conductance Calcium-Activated Potassium Channel, K Ca 1.1, in Sinus Node Function and Arrhythmia Risk

2021 ◽  
Vol 14 (2) ◽  
Author(s):  
Santiago Pineda ◽  
Vesna Nikolova-Krstevski ◽  
Christiana Leimena ◽  
Andrew J. Atkinson ◽  
Ann-Kristin Altekoester ◽  
...  
Keyword(s):  
Action Potentials ◽  
Ex Vivo ◽  
Sinus Bradycardia ◽  
Sinus Node ◽  
Immunogold Electron Microscopy ◽  
Loss Of Function ◽  
Α Subunit ◽  
Electrophysiological Characterization ◽  
And Function

Background: KCNMA1 encodes the α-subunit of the large-conductance Ca 2+ -activated K + channel, K Ca 1.1, and lies within a linkage interval for atrial fibrillation (AF). Insights into the cardiac functions of K Ca 1.1 are limited, and KCNMA1 has not been investigated as an AF candidate gene. Methods: The KCNMA1 gene was sequenced in 118 patients with familial AF. The role of K Ca 1.1 in normal cardiac structure and function was evaluated in humans, mice, zebrafish, and fly. A novel KCNMA1 variant was functionally characterized. Results: A complex KCNMA1 variant was identified in 1 kindred with AF. To evaluate potential disease mechanisms, we first evaluated the distribution of K Ca 1.1 in normal hearts using immunostaining and immunogold electron microscopy. K Ca 1.1 was seen throughout the atria and ventricles in humans and mice, with strong expression in the sinus node. In an ex vivo murine sinoatrial node preparation, addition of the K Ca 1.1 antagonist, paxilline, blunted the increase in beating rate induced by adrenergic receptor stimulation. Knockdown of the K Ca 1.1 ortholog, kcnma1b , in zebrafish embryos resulted in sinus bradycardia with dilatation and reduced contraction of the atrium and ventricle. Genetic inactivation of the Drosophila K Ca 1.1 ortholog, slo , systemically or in adult stages, also slowed the heartbeat and produced fibrillatory cardiac contractions. Electrophysiological characterization of slo -deficient flies revealed bursts of action potentials, reflecting increased events of fibrillatory arrhythmias. Flies with cardiac-specific overexpression of the human KCNMA1 mutant also showed increased heart period and bursts of action potentials, similar to the K Ca 1.1 loss-of-function models. Conclusions: Our data point to a highly conserved role of K Ca 1.1 in sinus node function in humans, mice, zebrafish, and fly and suggest that K Ca 1.1 loss of function may predispose to AF.

Primary negativity does not predict dominant pacemaker location: implications for sinoatrial conduction

1995 ◽  
Vol 269 (3) ◽  
pp. H877-H887 ◽  
Author(s):  
B. I. Bromberg ◽  
D. E. Hand ◽  
R. B. Schuessler ◽  
J. P. Boineau
Keyword(s):  
Right Atrium ◽  
Action Potentials ◽  
Normal Sinus Rhythm ◽  
Sinus Node ◽  
Pacemaker Activity ◽  
Crista Terminalis ◽  
Normal Sinus ◽  
Pace Maker ◽  
Pentobarbital Sodium Anesthesia ◽  
The Right

Activation sequence maps derived during normal sinus rhythm from extracellular potentials in the canine right atrium exhibit widely separated sites of origin. The objectives of this study were to characterize the distribution of pacemakers within the right atrium and to determine the relationship of pacemaker action potentials to sites of earliest surface activation as well as to local extracellular electrograms. The right atria of six adult mongrel dogs were rapidly excised under deep pentobarbital sodium anesthesia and perfused with 95% O2-5% CO2 Krebs-Henseleit solution. Action potentials from the epicardial surface were recorded throughout the region bounded by the crista terminalis laterally and the atrial septum medially. Simultaneously, unipolar extracellular electrograms were recorded from 250 endocardial sites. The earliest pacemakers preceded the earliest electrogram by 63 +/- 34 ms; the latest pacemakers followed the earliest electrogram by 71 +/- 40 ms. Primary negativity in the extracellular electro gram did not predict the site of the earliest or dominant pace maker and in some cases was associated with the latest pace makers. We conclude that primary negativity and/or the sites of earliest activation reflect the point at which the impulse engages atrial myocardium, not the site of earliest pacemaker activity. As such, early extracellular activation appears to represent sites of exit from a relatively insulated sinus node.

scholarly journals The G-protein–gated K+ channel, IKACh, is required for regulation of pacemaker activity and recovery of resting heart rate after sympathetic stimulation

2013 ◽  
Vol 142 (2) ◽  
pp. 113-126 ◽  
Author(s):  
Pietro Mesirca ◽  
Laurine Marger ◽  
Futoshi Toyoda ◽  
Riccardo Rizzetto ◽  
Matthieu Audoubert ◽  
...  
Keyword(s):  
Heart Rate ◽  
G Protein ◽  
Pacemaker Activity ◽  
Sympathetic Stimulation ◽  
Resting Heart Rate ◽  
Adrenergic Stimulation ◽  
Rate Regulation ◽  
Heart Rate Regulation ◽  
Cholinergic Regulation ◽  
Stimulation Of

Parasympathetic regulation of sinoatrial node (SAN) pacemaker activity modulates multiple ion channels to temper heart rate. The functional role of the G-protein–activated K+ current (IKACh) in the control of SAN pacemaking and heart rate is not completely understood. We have investigated the functional consequences of loss of IKACh in cholinergic regulation of pacemaker activity of SAN cells and in heart rate control under physiological situations mimicking the fight or flight response. We used knockout mice with loss of function of the Girk4 (Kir3.4) gene (Girk4−/− mice), which codes for an integral subunit of the cardiac IKACh channel. SAN pacemaker cells from Girk4−/− mice completely lacked IKACh. Loss of IKACh strongly reduced cholinergic regulation of pacemaker activity of SAN cells and isolated intact hearts. Telemetric recordings of electrocardiograms of freely moving mice showed that heart rate measured over a 24-h recording period was moderately increased (10%) in Girk4−/− animals. Although the relative extent of heart rate regulation of Girk4−/− mice was similar to that of wild-type animals, recovery of resting heart rate after stress, physical exercise, or pharmacological β-adrenergic stimulation of SAN pacemaking was significantly delayed in Girk4−/− animals. We conclude that IKACh plays a critical role in the kinetics of heart rate recovery to resting levels after sympathetic stimulation or after direct β-adrenergic stimulation of pacemaker activity. Our study thus uncovers a novel role for IKACh in SAN physiology and heart rate regulation.

scholarly journals Identification of Key Small Non‐Coding MicroRNAs Controlling Pacemaker Mechanisms in the Human Sinus Node

2020 ◽  
Vol 9 (20) ◽  
Author(s):  
Maria Petkova ◽  
Andrew J. Atkinson ◽  
Joseph Yanni ◽  
Luke Stuart ◽  
Abimbola J. Aminu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ex Vivo ◽  
Sinus Node ◽  
Luciferase Reporter ◽  
Pacemaker Activity ◽  
Luciferase Reporter Gene ◽  
Atrial Muscle ◽  
Expression Of Genes ◽  
Gene Assay ◽  
Inhibit Gene Expression

Background The sinus node (SN) is the primary pacemaker of the heart. SN myocytes possess distinctive action potential morphology with spontaneous diastolic depolarization because of a unique expression of ion channels and Ca 2+ ‐handling proteins. MicroRNAs (miRs) inhibit gene expression. The role of miRs in controlling the expression of genes responsible for human SN pacemaking and conduction has not been explored. The aim of this study was to determine miR expression profile of the human SN as compared with that of non‐pacemaker atrial muscle. Methods and Results SN and atrial muscle biopsies were obtained from donor or post‐mortem hearts (n=10), histology/immunolabeling were used to characterize the tissues, TaqMan Human MicroRNA Arrays were used to measure 754 miRs, Ingenuity Pathway Analysis was used to identify miRs controlling SN pacemaker gene expression. Eighteen miRs were significantly more and 48 significantly less abundant in the SN than atrial muscle. The most interesting miR was miR‐486‐3p predicted to inhibit expression of pacemaking channels: HCN1 (hyperpolarization‐activated cyclic nucleotide‐gated 1), HCN4, voltage‐gated calcium channel (Ca v )1.3, and Ca v 3.1. A luciferase reporter gene assay confirmed that miR‐486‐3p can control HCN4 expression via its 3′ untranslated region. In ex vivo SN preparations, transfection with miR‐486‐3p reduced the beating rate by ≈35±5% ( P <0.05) and HCN4 expression ( P <0.05). Conclusions The human SN possesses a unique pattern of expression of miRs predicted to target functionally important genes. miR‐486‐3p has an important role in SN pacemaker activity by targeting HCN4, making it a potential target for therapeutic treatment of SN disease such as sinus tachycardia.

Ivabradine in children with postural orthostatic tachycardia syndrome: a retrospective study

2020 ◽  
Vol 30 (7) ◽  
pp. 975-979 ◽  
Author(s):  
Arooge Towheed ◽  
Zeid Nesheiwat ◽  
Muhammad A Mangi ◽  
Beverly Karabin ◽  
Blair P Grubb
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Sinus Node ◽  
Vital Signs ◽  
Pacemaker Activity ◽  
P Value ◽  
Postural Orthostatic Tachycardia Syndrome ◽  
Patient Reported ◽  
Before And After ◽  
Visual Disturbances

AbstractBackground:Ivabradine is a unique medication that reduces the intrinsic heart rate by specifically blocking the inward funny current that controls the pacemaker activity of the sinus node. We conducted a retrospective cohort study to assess the efficacy of ivabradine in children suffering from postural orthostatic tachycardia syndrome.Methods:A chart review was conducted of patients less than 18 years of age who were diagnosed with postural orthostatic tachycardia syndrome who had received ivabradine as treatment from January 2015 to February 2019 at our institution. Twenty-seven patients (25 females, 92.5%) were identified for the study. The outcomes which were assessed included a change in the severity and frequency of symptoms, heart rate, and blood pressure before and after starting ivabradine.Results:There was an improvement in the symptoms of 18 (67%) out of 27 patients. The most notable symptom affected was syncope/presyncope with a reduction in 90%, followed by lightheadedness (85%) and fatigue (81%). The vital signs of the patients showed an overall significant lowering of the heart rate during sitting (89.7 ± 17.9 versus 73.2 ± 12.1; p-value <0.05) and standing (100.5 ± 18.1 versus 80.9 ± 10.1; p-value <0.05) without a significant change in the blood pressure. Two patients had visual disturbances (luminous phenomena). Severe bradycardia and excessive flushing were seen in two patients, respectively. Another one patient reported joint pain and fatigue.Conclusion:This study indicates that 67% of children treated with ivabradine report an improvement in symptoms.

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