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BACKGROUND: Asymptomatic premature ventricular complex (PVC) in childhood often disappears over time. However, predictive factors for persistent PVC are unknown. We examined predictive factors for persistent PVCs on initial Holter electrocardiogram (ECG) in pediatric patients with asymptomatic PVC.Methods and Results: The initial Holter ECG findings of untreated PVC patients (n=216) between 2010 and 2021 were examined. Multivariable analysis was performed to clarify predictive factors for subsequent persistent PVC burden for each index (age, sex, PVC burden, PVC origin, minimum and maximum mean RR intervals [RRmin and RRmax, respectively]) of the 3 heartbeats of baseline sinus rhythm immediately before the PVC. The median age at initial Holter ECG was 11.6 years (range 5.8-18.8 years), the PVC burden was 5.22% (range 0.01-44.21%), RRmin was 660 ms, RRmax was 936 ms, RRrange (=RRmax-RRmin) was 273 ms, and 15 (7%) PVC runs were identified. The median follow-up period was 5.1 years (range 0.8-9.4 years), and the final Holter PVC burden was 3.99% (range 0-36.38%). In multivariate analysis, RRrange was the only independent risk factor for predicting a final Holter PVC burden >10%, with an area under the curve of 0.920 using an RRrange of 600 ms as the cut-off value. CONCLUSIONS: A wide RRrange at the initial Holter ECG may be a predictive indicator for persistent PVC in childhood.

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BACKGROUND: Autonomic nerve activity is important in the mechanisms of paroxysmal atrial fibrillation (PAF). OBJECTIVE: The purpose of this study was to test the hypothesis that a single burst of skin sympathetic nerve activity (SKNA) can toggle on and off PAF or premature atrial contraction (PAC) clusters. METHODS: Simultaneous recording of SKNA and electrocardiogram (neuECG) recording was performed over 7 days in patients with PAF. RESULTS: In study 1, 8 patients (7 men and 1 woman; age 62 ± 8 years) had 124 episodes of PAF. An SKNA burst toggled both on and off PAF in 8 episodes (6.5%) (type 1), toggled on but not off in 12 episodes (9.7%) (type 2), and toggled on a PAC cluster followed by PAF in 4 episodes (3.2%) (type 3). The duration of these PAF episodes was <10 minutes. The remaining 100 episodes (80.6%) were associated with active SKNA bursts throughout PAF (type 4) and lasted longer than type 1 (P = .0185) and type 2 (P = .0027) PAF. There were 47 PAC clusters. Among them, 24 (51.1%) were toggled on and off, and 23 (48.9%) were toggled on but not off by an SKNA burst. In study 2, 17 patients (9 men and 8 women; age 58 ± 12 years) had <10 minutes of PAF (4, 8, 0, and 31 of types 1, 2, 3, and 4, respectively). There were significant circadian variations of all types of PAF. CONCLUSION: A single SKNA burst can toggle short-duration PAF and PAC cluster episodes on and off. The absence of continued SKNA after the onset might have affected the maintenance of these arrhythmias.

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If the appropriate immobilization method and carrier support are not selected, partial decreases in the activity of enzymes may occur after immobilization. Herein, to overcome this challenge, an excitation mechanism that enables energy transfer was proposed. Modified upconverting nanoparticles (UCNPs) were constructed and the important role of near-infrared (NIR) excitation in enhancing the catalytic activity of the enzyme was demonstrated. For this purpose, UCNPs were first synthesized via the hydrothermal method, functionalized with isocyanate groups, and then, PEG-L-ASNase was immobilized via covalent binding. UCNPs with and without PEG-L-ASNase were extensively characterized by different methods. These supports had immobilization yield and activity efficiency of >96 % and 78 %, respectively. Moreover, immobilized enzymes exhibited improved pH, thermal, and storage stability. In addition, they retained >65 % of their initial activity even after 20 catalytic cycles. Biochemical and histological findings did not indicate a trend of toxicity in rats due to UCNPs. Most importantly, PEG-L-ASNase activity was triggered approximately 5- and 2-fold under in vitro and in vivo conditions, respectively. Overall, it is anticipated that this pioneering work will shed new light on the realistic and promising usage of NIR-excited UCNPs for the immobilization of enzymes in expensive and extensive applications.

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Cardiac arrhythmias pose a major threat to a patient's health, yet prove to be often difficult to predict, prevent and treat. A key mechanism in the occurrence of arrhythmias is disturbed Ca2+ homeostasis in cardiac muscle cells. As a Ca2+-activated non-selective cation channel, TRPM4 has been linked to Ca2+-induced arrhythmias, potentially contributing to translating an increase in intracellular Ca2+ concentration into membrane depolarisation and an increase in cellular excitability. Indeed, evidence from genetically modified mice, analysis of mutations in human patients and the identification of a TRPM4 blocking compound that can be applied in vivo further underscore this hypothesis. Here, we provide an overview of these data in the context of our current understanding of Ca2+-dependent arrhythmias.

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Most forms of sustained ventricular tachycardia (VT) are caused by re-entry, resulting from altered myocardial conduction and refractoriness secondary to underlying structural heart disease. In contrast, VT caused by triggered activity (TA) is unrelated to an abnormal structural substrate and is often caused by molecular defects affecting ion channel function or regulation of intracellular calcium cycling. This review summarizes the cellular and molecular bases underlying TA and exemplifies their clinical relevance with selective representative scenarios. The underlying basis of TA caused by delayed afterdepolarizations is related to sarcoplasmic reticulum calcium overload, calcium waves, and diastolic sarcoplasmic reticulum calcium leak. Clinical examples of TA caused by delayed afterdepolarizations include sustained right and left ventricular outflow tract tachycardia and catecholaminergic polymorphic VT. The other form of afterpotentials, early afterdepolarizations, are systolic events and inscribe early afterdepolarizations during phase 2 or phase 3 of the action potential. The fundamental defect is a decrease in repolarization reserve with associated increases in late plateau inward currents. Malignant ventricular arrhythmias in the long QT syndromes are initiated by early afterdepolarization-mediated TA. An understanding of the molecular and cellular bases of these arrhythmias has resulted in generally effective pharmacologic-based therapies, but these are nonspecific agents that have off-target effects. Therapeutic efficacy may need to be augmented with an implantable defibrillator. Next-generation therapies will include novel agents that rescue arrhythmogenic abnormalities in cellular signaling pathways and gene therapy approaches that transfer or edit pathogenic gene variants or silence mutant messenger ribonucleic acid.

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Background: Sustained forms of tachycardia especially from the left ventricular summit are rare. Adenosine sensitive outflow tachycardias, especially from the left ventricular summit, are rarer still. These arrhythmias may be exercise or stress induced as they are facilitated by catecholamines and characteristically terminate with adenosine, vagal manoeuvres, and beta-blockers. The surface 12-lead electrocardiogram can be used to localize the anatomic site of origin before catheter ablation; however, prediction of the precise origin may still be challenging due to the intimate and complex anatomy of the outflow tracts. Case summary: A 12-year-old female presented to an emergency room with frequent runs of wide complex tachycardia that terminated with adenosine but would spontaneously reinitiate. After three additional temporary terminations with adenosine and because of an inability to completely eliminate tachycardia, she was started on an esmolol infusion that resulted in an abrupt termination of tachycardia. At follow-up, she reported breakthrough episodes of tachycardia with exercise, especially associated with beta-blocker non-compliance. The rest of her cardiac testing was normal apart from an anomalous right coronary artery origin from the left coronary sinus. Given the increased frequency of symptomatic palpitations and medication non-compliance, she underwent an electrophysiology study. During the study, a ventricular tachycardia was successfully mapped to an epicardial focus at the left ventricle summit and was successfully ablated. Discussion: The response of this patient's ventricular tachycardia to adenosine suggests a triggered mechanism. To our knowledge, this is the first unambiguous example of left ventricular tachycardia due to cAMP-mediated triggered activity in this age group.

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BACKGROUND AND OBJECTIVE: Excessive prolongation of QT interval on ECGs in patients with congenital/acquired long QT syndrome and heart failure is a sign suggesting the development of early afterdepolarization (EAD), an abnormal repolarization in the action potential of ventricular cardiomyocytes. The development of EAD has been believed to be a trigger for fatal tachyarrhythmia, which can be a risk for sudden cardiac death. The role of EAD in triggering ventricular tachycardia (VT) remains unclear. The aim of this study was to elucidate the mechanism of EAD-induced triggered activity formation that leads to the VT such as Torsades de Pointes. METHODS: We investigated the relationship between EAD and tachyarrhythmia initiation by constructing homogeneous myocardial sheet models consisting of the mid-myocardial cell version of a human ventricular myocyte model and performing simulations of excitation propagation. RESULTS: A solitary island-like (clustering) occurrence of EADs in the homogeneous myocardial sheet could induce a focal excitation wave. However, reentrant excitation, an entity of tachyarrhythmia, was not able to be triggered regardless of the EAD cluster size when the focal excitation wave formed a repolarization potential difference boundary consisting of only a convex surface. The discontinuous distribution of multiple EAD clusters in the ventricular tissue formed a specific repolarization heterogeneity due to the repolarization potential difference, the shape of which depended on EAD cluster size and placed intervals. We found that the triggered activity was formed in such a manner that the repolarization potential difference boundary included a concave surface. CONCLUSIONS: The formation of triggered activity that led to tachyarrhythmia required not only the occurrence of EAD onset-mediated focal excitation wave but also a repolarization heterogeneity-based specific repolarization potential difference boundary shape formed within the tissue.

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Termination of focal atrial tachycardia with adenosine is considered a defining feature for triggered activity. Recent evidence, however, suggests that the perinodal adenosine-sensitive AT has reentry as the mechanism of tachycardia. In this report, we were able to confirm the mechanism of AT as reentry by observing the response to programmed electrical stimulation and demonstrating the fallacy of traditional teaching that the adenosine responsiveness of AT is a criterion for labeling the mechanism as triggered activity.

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We aimed to investigate the effect of apocynin (APO) on delayed afterdepolarizations (DADs) in rat atrial myocytes and the underlying mechanisms. Rat atrial myocytes were isolated by a Langendorff perfusion apparatus. DADs were induced by isoproterenol (ISO). Action potentials (APs) and ion currents were recorded by the whole-cell clamp technique. The fluorescent indicator fluo-4 was used to visualize intracellular Ca2+ transients, and western blotting was used to measure the expression of related proteins. The incidence of DADs in rat atrial myocytes increased significantly after ISO treatment, leading to an increased incidence of triggered activity (TA). The incidence of ISO-induced DADs and TA were reduced by 100.0 µM APO from 48.89% to 25.56% and 17.78% to 5.56%, respectively. In the range of 3.0 µM-300.0 µM, the effect of APO was concentration dependent, with a half maximal inhibitory concentration (IC50) of 120.1 µM and a Hill coefficient of 1.063. APO reversed the increase in transient inward current (Iti) and Na+/Ca2+-exchange current (INCX) densities induced by ISO in atrial myocytes. The frequency of spontaneous Ca2+ transients in atrial myocytes was reduced by 100.0 µM APO. Compared with ISO, APO downregulated the expression of NOX2 and increased the phosphorylation of PLNSer16 and the sarcoplasmic reticulum Ca2+-ATPase-2a (SERCA2a) level; however, it had little effect on ryanodine-receptor channel type-2 (RyR2). These findings showed that APO may block Iti and INCX and reduce intracellular Ca2+ levels in rat atrial myocytes, thus reducing the incidence of ISO-induced DADs and TA.

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BACKGROUND: The role of sympathetic nerve activity to maintain sinus rate acceleration remains unclear. OBJECTIVE: The purpose of this study was to test the hypothesis that sustained (>30 seconds) sinus rate acceleration can be associated with either a sympathetic driven or a sympathetic toggled mechanism. METHODS: We used a patch monitor to record skin sympathetic nerve activity (SKNA) and electrocardiogram over 24 hours. Study 1 included chronic orthostatic intolerance (OI) (n = 18), atrial fibrillation (n = 7), and asymptomatic normal control (n = 19) groups. Study 2 included 17 participants with chronic OI not treated with ivabradine, pyridostigmine, or ß-blockers. RESULTS: While a majority of sinus rate acceleration was driven by persistent SKNA in study 1, some episodes were toggled on and off by SKNA bursts without persistent SKNA elevation. The sympathetic toggled sinus rate acceleration episodes were found in 7 of 18 participants with chronic OI (39%), 2 of 7 participants with atrial fibrillation (29%), and 6 of 19 normal control participants (32%) (P = .847) and were faster and longer in the chronic OI group than in other groups. In study 2, there were a total of 11 episodes of sinus rate acceleration that persisted for >200 seconds. Among these episodes, 6 (35%) were toggled on and off by SKNA bursts. CONCLUSION: Sustained sinus rate acceleration (may be toggled on or off) is associated with SKNA bursts in participants with chronic OI, participants with atrial fibrillation, and normal controls. Patients with OI had more frequent and longer episodes than did other groups.

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AIMS: Cardiac arrhythmias are a major factor in the occurrence of morbidity and sudden death in patients with cardiovascular disease. Disturbances of Ca2+ homeostasis in the heart contribute to the initiation and maintenance of cardiac arrhythmias. Extrasystolic increases in intracellular Ca2+ lead to delayed afterdepolarizations and triggered activity, which can result in heart rhythm abnormalities. It is being suggested that the Ca2+-activated nonselective cation channel TRPM4 is involved in the aetiology of triggered activity, but the exact contribution and in vivo significance are still unclear. METHODS AND RESULTS: In vitro electrophysiological and calcium imaging technique as well as in vivo intracardiac and telemetric electrocardiogram measurements in physiological and pathophysiological conditions were performed. In two distinct Ca2+-dependent proarrhythmic models, freely moving Trpm4-/- mice displayed a reduced burden of cardiac arrhythmias. Looking further into the specific contribution of TRPM4 to the cellular mechanism of arrhythmias, TRPM4 was found to contribute to a long-lasting Ca2+ overload-induced background current, thereby regulating cell excitability in Ca2+ overload conditions. To expand these results, a compound screening revealed meclofenamate as a potent antagonist of TRPM4. In line with the findings from Trpm4-/- mice, 10 µM meclofenamate inhibited the Ca2+ overload-induced background current in ventricular cardiomyocytes and 15 mg/kg meclofenamate suppressed catecholaminergic polymorphic ventricular tachycardia-associated arrhythmias in a TRPM4-dependent manner. CONCLUSION: The presented data establish that TRPM4 represents a novel target in the prevention and treatment of Ca2+-dependent triggered arrhythmias.

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Bidirectional ventricular tachycardia (BVT) is a rare and unusual ventricular dysrhythmia that is characterized by a beat-to-beat alternation of the QRS axis. This can sometimes manifest as alternating left and right bundle branch blocks. To the best of our knowledge, there are two previous cases of BVT in the setting of type I myocardial infarction. Our case would be the third and showed a subtle change in the anterior-posterior axis that can be seen in lead V2. The coronary angiography of our patient demonstrated severe multivessel coronary artery disease with complete total occlusion of the proximal dominant right coronary artery, 100% in-stent restenosis of the ostial left circumflex, 40% stenosis of left main, and 90% stenosis of mid left anterior descending artery (LAD). The BVT resolved after two amiodarone boluses followed by a drip. We attempted to transition to oral mexiletine, however, the patient was unable to tolerate the medication due to intractable nausea and vomiting. The patient subsequently underwent high risk coronary artery bypass graft surgery with no further episodes of BVT following revascularization and was discharged after six weeks of hospitalization. Although rare, type I myocardial infarction is an important differential diagnosis of BVT.

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Dysfunctional sarcoplasmic reticulum Ca2+ handling is commonly observed in heart failure, and thought to contribute to arrhythmogenesis through several mechanisms. Some time ago we developed a cardiomyocyte-specific inducible SERCA2 knockout mouse, which is remarkable in the degree to which major adaptations to sarcolemmal Ca2+ entry and efflux overcome the deficit in SR reuptake to permit relatively normal contractile function. Conventionally, those adaptations would also be expected to dramatically increase arrhythmia susceptibility. However, that susceptibility has never been tested, and it is possible that the very rapid repolarization of the murine action potential (AP) allows for large changes in sarcolemmal Ca2+ transport without substantially disrupting electrophysiologic stability. We investigated this hypothesis through telemetric ECG recording in the SERCA2-KO mouse, and patch-clamp electrophysiology, Ca2+ imaging, and mathematical modeling of isolated SERCA2-KO myocytes. While the SERCA2-KO animals exhibit major (and unique) electrophysiologic adaptations at both the organ and cell levels, they remain resistant to arrhythmia. A marked increase in peak L-type calcium (I CaL) current and slowed I CaL decay elicited pronounced prolongation of initial repolarization, but faster late repolarization normalizes overall AP duration. Early afterdepolarizations were seldom observed in KO animals, and those that were observed exhibited a mechanism intermediate between murine and large mammal dynamical properties. As expected, spontaneous SR Ca2+ sparks and waves were virtually absent. Together these findings suggest that intact SR Ca2+ handling is an absolute requirement for triggered arrhythmia in the mouse, and that in its absence, dramatic changes to the major inward currents can be resisted by the substantial K+ current reserve, even at end-stage disease.

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BACKGROUND: Electrical remodelling as a result of the homeodomain transcription factor 2 (Pitx2)-dependent gene regulation induces atrial fibrillation (AF) with different mechanisms. The purpose of this study was to identify Pitx2-induced changes in ionic currents that cause action potential (AP) shortening and lead to triggered activity. METHODS: Populations of computational atrial AP models were developed based on AP recordings from sinus rhythm (SR) and AF patients. Models in the AF population were divided into triggered and untriggered AP groups to evaluate the relationship between each ion current regulated by Pitx2 and triggered APs. Untriggered AP models were then divided into shortened and unshortened AP groups to determine which Pitx2-dependent ion currents contribute to AP shortening. RESULTS: According to the physiological range of AP biomarkers measured experimentally, populations of 2,885 SR and 4,781 AF models out of the initial pool of 30,000 models were selected. Models in the AF population predicted AP shortening and triggered activity observed in experiments in Pitx2-induced remodelling conditions. The AF models included 925 triggered AP models, 1,412 shortened AP models and 2,444 unshortened AP models. Intersubject variability in IKs and ICaL primarily modulated variability in AP duration (APD) in all shortened and unshortened AP models, whereas intersubject variability in IK1 and SERCA mainly contributed to the variability in AP morphology in all triggered and untriggered AP models. The incidence of shortened AP was positively correlated with IKs and IK1 and was negatively correlated with INa , ICaL and SERCA, whereas the incidence of triggered AP was negatively correlated with IKs and IK1 and was positively correlated with INa , ICaL and SERCA. CONCLUSIONS: Electrical remodelling due to Pitx2 upregulation may increase the incidence of shortened AP, whereas electrical remodelling arising from Pitx2 downregulation may favor to the genesis of triggered AP.

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One of the less frequent underlying mechanisms of ventricular tachycardia (VT) is triggered activity. Triggered activity refers to an extrasystole due to a premature depolarization that occurs when the amplitude of an early or delayed afterdepolarization brings the cardiac membrane to its threshold potential. Hydrochlorothiazide and hydroxyzine can prolong repolarization and QT interval and are associated with early afterdepolarizations. Cyclic AMP-mediated, delayed afterdepolarizations can occur as a result of catecholaminergic surge. Delayed afterdepolarization is classically associated with outflow tract (OT) tachycardia, a type of VT that is uniquely defined by its termination with adenosine. We present a case of triggered OT tachycardia for which intravenous amiodarone through its antiadrenergic effect may have been effective. Infusions of magnesium and a cardioselective, ß-receptor antagonist that does not prolong repolarization may have been more appropriate given the concurrent, acquired prolonged QT syndrome. After initial stabilization, considering the underlying VT mechanism may prompt the clinician to select the most appropriate, further treatment.

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A lot of animal models are developed with aim to advance in atrial fibrillation (AF) understanding. The hybrid B6CBAF1 mice are used extensively as a background to create manifestation of various diseases, however, their atrial electrophysiology, autonomic sympathetic innervation of the heart and potential for AF investigation is poorly characterized. In the present study we used ECG and microelectrode recordings from multicellular atrial preparations to reveal attributes of atrial electrical activity in B6CBAF1. Also, experiments with a fluorescent false monoamine neurotransmitter and glyoxylic acid-based staining were carried out to characterize functionally and morphologically catecholaminergic innervation of the B6CBAF1 atria. Atrial myocardium of B6CBAF1 is highly prone to ectopic automaticity and exhibits abnormal spontaneous action potential accompanied by multiple postdepolarizations that result in proarrhythmic triggered activity unlike two parental C57Bl/6 and CBA strains. In vivo experiments revealed that B6CBAF1 hybrids are more susceptible to the norepinephrine induced AF. Also, sympathetic nerve terminals are partially dysfunctional in B6CBAF1 revealing lower ability to accumulate and release neurotransmitters unlike two parental strains. The analysis of the heart rate variability revealed suppressed sympathetic component of the autonomic heart control in B6CBAF1. The organization of sympathetic innervation is very similar morphologically in all three murine strains however the abundance of non-bifurcated catecholamine-positive fibers in B6CBAF1 was increased. These results suggest that B6CBAF1 mice exhibit enhanced intrinsic atrial proarrhythmicity, while the abnormalities of sympathetic neurotransmitter cycling probably underlie disturbed autonomic heart control.

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Determining optimal treatment strategies for complex arrhythmogenesis in AF is confounded by the lack of consensus regarding the mechanisms causing AF. Studies report different mechanisms for AF, ranging from hierarchical drivers to anarchical multiple activation wavelets. Differences in the assessment of AF mechanisms are likely due to AF being recorded across diverse models using different investigational tools, spatial scales and clinical populations. The authors review different AF mechanisms, including anatomical and functional re-entry, hierarchical drivers and anarchical multiple wavelets. They then describe different cardiac mapping techniques and analysis tools, including activation mapping, phase mapping and fibrosis identification. They explain and review different data challenges, including differences between recording devices in spatial and temporal resolutions, spatial coverage and recording surface, and report clinical outcomes using different data modalities. They suggest future research directions for investigating the mechanisms underlying human AF.

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We describe a case wherein the presence of premature ventricular contractions was related to an increased heart rate that occurred due to supra-ventricular tachycardia: atrial tachycardia or atrioventricular nodal reentry tachycardia.

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The electrophysiological properties of pulmonary vein (PV)-cardiomyocytes, and their responses to the sympathetic neurotransmitter, noradrenaline (NA), are thought to differ from those of the left atrium (LA) and contribute to atrial ectopy. The aim of this study was to examine rat PV cardiomyocyte electrophysiology and responses to NA in comparison with LA cells. LA and PV cardiomyocytes were isolated from adult male Wistar rat hearts, and membrane potentials and ion currents recorded at 36°C using whole-cell patch-clamp techniques. PV and LA cardiomyocytes did not differ in size. In control, there were no differences between the two cell-types in zero-current potential or action potential duration (APD) at 1 Hz, although the incidence of early afterdepolarizations (EADs) was greater in PV than LA cardiomyocytes. The L-type Ca2+ current (ICaL ) was ~×1.5 smaller (p = .0029, Student's t test) and the steady-state K+ current (IKss ) was ~×1.4 larger (p = .0028, Student's t test) in PV than in LA cardiomyocytes. PV cardiomyocyte inward-rectifier current (IK1 ) was slightly smaller than LA cardiomyocyte IK1 . In LA cardiomyocytes, NA significantly prolonged APD30 . In PV cells, APD30 responses to 1 µM NA were heterogeneous: while the mean percentage change in APD30 was not different from 0 (16.5 ± 9.7%, n cells/N animals = 12/10, p = .1177, one-sample t test), three cells showed shortening (-18.8 ± 6.0%) whereas nine showed prolongation (28.3 ± 10.1%, p = .008, Student's t test). NA had no effect on IK1 in either cell-type but inhibited PV IKss by 41.9 ± 4.1% (n/N = 23/11 p < .0001), similar to LA cells. NA increased ICaL in most PV cardiomyocytes (median × 2.2-increase, p < .0001, n/N = 32/14, Wilcoxon-signed-rank test), although in 7/32 PV cells ICaL was decreased following NA. PV cardiomyocytes differ from LA cells and respond heterogeneously to NA.

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