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A: atrial tachycardia/fibrillation (AT/F) induced with burst pacing (Burst) of the MRA in a 1-mo-old wild-type (WT) mouse. B: AT/F induced with burst pacing of the MRA in a 1-mo-old RGS2 / mouse. Note the different tachycardia rates between the His bundle region electrogram (HBE) and the HRA electrogram as well as the irregularly irregular ventricular response seen on limb lead I (LL1) and RV electrogram.
Source publication
Atrial fibrillation (AF) is the most common arrhythmia seen in general practice. Muscarinic ACh receptors (M2R, M3R) are involved in vagally induced AF. M2R and M3R activate the heterotrimeric G proteins, G(i) and G(q), respectively, by promoting GTP binding, and these in turn activate distinct K(+) channels. Signaling is terminated by GTP hydrolys...
Contexts in source publication
Context 1
... tachyarrhythmia induction. Atrial burst pacing (Fig. 3) and PES (Fig. 4) (18) induced atrial tachyarrhythmias that demonstrated properties of AF; however, validating AF would require high-density mapping and recording from the LA, Fig. 2. Atrial effective refractory period (AERP) was measured using programmed electrical stimulation (PES) with a 100-ms drive train (AERP100) in 1-mo-old male ...
Context 2
... expected, 1-mo-old WT mice were mostly insensitive to single stimulus-induced AT/F (4%, 1/25) compared with burst pacing (40%, 10/25, P 0.05) (Fig. 3, top). Carbachol in- creased the susceptibility to both single extrastimulus (33%, 4/12) and burst pacing (58%, 7/12). Muscarinic receptor acti- vation also prolonged the duration of AT/F episodes with only 2 of 12 untreated mice having sustained AT/F, whereas 5 of the 12 had sustained AT/F after carbachol ...
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Citations
... In the same way that increased parasympathetic tone promotes AF, K ir 3.4 autoantibodies in mice reduced atrial refractoriness, thus giving way to reentry wavelets and AF. [28][29][30][31]41,42 The pathogenesis of AF is complex and essentially requires 2 critical components: a trigger that initiates the event and a substrate that maintains the arrhythmia. 33 Consistent with this notion, we detected K ir 3.4 autoantibodies in patients with no structural heart disease before AF manifests clinically. ...
... Although widely used and accepted, the mouse model is imperfect for the study of AF due to the insufficient critical mass of the structurally normal murine heart that prevents sustained reentry circuits. 29,30,52 For this reason, atrial pacing protocols have been introduced to use AF inducibility as a surrogate for human AF vulnerability. Likewise, we documented no spontaneous AF in K ir 3.4-immunized mice, but pacing-induced AF upon electrophysiological study. ...
Background:
Atrial fibrillation (AF) is by far the most common cardiac arrhythmia. In about 3% of individuals, AF develops as a primary disorder without any identifiable trigger (idiopathic or historically termed lone AF). In line with the emerging field of autoantibody-related cardiac arrhythmias, the objective of this study was to explore whether autoantibodies targeting cardiac ion channels can underlie unexplained AF.
Methods:
Peptide microarray was used to screen patient samples for autoantibodies. We compared patients with unexplained AF (n=37 pre-existent AF; n=14 incident AF on follow-up) to age- and sex-matched controls (n=37). Electrophysiological properties of the identified autoantibody were then tested in vitro with the patch clamp technique and in vivo with an experimental mouse model of immunization.
Results:
A common autoantibody response against Kir3.4 protein was detected in patients with AF and even before the development of clinically apparent AF. Kir3.4 protein forms a heterotetramer that underlies the cardiac acetylcholine-activated inwardly rectifying K+ current, IKACh. Functional studies on human induced pluripotent stem cell-derived atrial cardiomyocytes showed that anti-Kir3.4 IgG purified from patients with AF shortened action potentials and enhanced the constitutive form of IKACh, both key mediators of AF. To establish a causal relationship, we developed a mouse model of Kir3.4 autoimmunity. Electrophysiological study in Kir3.4-immunized mice showed that Kir3.4 autoantibodies significantly reduced atrial effective refractory period and predisposed animals to a 2.8-fold increased susceptibility to AF.
Conclusions:
To our knowledge, this is the first report of an autoimmune pathogenesis of AF with direct evidence of Kir3.4 autoantibody-mediated AF.
... Acetylcholine released by vagal nerve endings has been shown to stimulate G i -coupled M2 muscarinergic receptors that activate G-protein-gated K+ channels, thereby reducing atrial action potential duration and increasing susceptibility to early after-depolarisations as well as reentrant mechanisms [34]. However, while arrhythmogenic effects have been largely attributed to G i -mediated signaling downstream of M2 muscarinic receptors, G q -coupled M3 muscarinic receptors are also expressed in the atria and appear to mediate arrhythmogenic effects of vagal activation to some extent [35,36]. These arrhythmogenic M3 effects seem to involve DADs generated by abnormal Ca 2+ events. ...
Background:
Atrial fibrillation (AF) is promoted by various stimuli like angiotensin II, endothelin-1, epinephrine/norepinephrine, vagal activation, or mechanical stress, all of which activate receptors coupled to G-proteins of the Gαq/Gα11-family (Gq). Besides pro-fibrotic and pro-inflammatory effects, Gq-mediated signaling induces inositol trisphosphate receptor (IP3R)-mediated intracellular Ca2+ mobilization related to delayed after-depolarisations and AF. However, direct evidence of arrhythmogenic Gq-mediated signaling is absent.
Methods and results:
To define the role of Gq in AF, transgenic mice with tamoxifen-inducible, cardiomyocyte-specific Gαq/Gα11-deficiency (Gq-KO) were created and exposed to intracardiac electrophysiological studies. Baseline electrophysiological properties, including heart rate, sinus node recovery time, and atrial as well as AV nodal effective refractory periods, were comparable in Gq-KO and control mice. However, inducibility and mean duration of AF episodes were significantly reduced in Gq-KO mice-both before and after vagal stimulation. To explore underlying mechanisms, left atrial cardiomyocytes were isolated from Gq-KO and control mice and electrically stimulated to study Ca2+-mobilization during excitation-contraction coupling using confocal microscopy. Spontaneous arrhythmogenic Ca2+ waves and sarcoplasmic reticulum content-corrected Ca2+ sparks were less frequent in Gq-KO mice. Interestingly, nuclear but not cytosolic Ca2+ transient amplitudes were significantly decreased in Gq-KO mice.
Conclusion:
Gq-signaling promotes arrhythmogenic atrial Ca2+-release and AF in mice. Targeting this pathway, ideally using Gq-selective, biased receptor ligands, may be a promising approach for the treatment and prevention of AF. Importantly, the atrial-specific expression of the Gq-effector IP3R confers atrial selectivity mitigating the risk of life-threatening ventricular pro-arrhythmic effects.
... Atrial fibrillation [68] . ...
Similia Similibus Curantur is also called the law of similars. That is, when a drug produces pathological/pathogenic symptoms in healthy individual means, the same drug can relieve similar kinds of symptoms in individuals with the disease. The biological, pharmacological and toxicological action of capsaicin alkaloids is a perfect example to explain the Similia Similibus Curantur principle. Most of the drugs in homoeopathic materia medica contain toxicological, pharmacological, drug-proving, and traditional use-related symptoms and indications. Abnormal sensations and symptoms of the disease are caused by the involvement of a specific receptor or molecular pathway and gene functions. These receptors or molecules may be stimulated or suppressed by environmental, natural or artificial agents. In such conditions, the administration of specific homoeopathic medicine having a similar kind of affinity towards the particular receptors or molecules involved in the disease process leads to modulation of such receptor or molecular pathways (e.g., desensitization, sensitization, inhibition). These kinds of actions cause the betterment of symptoms or curative effects. So “Similia similibus curanter” can be understood as a similar receptor or molecular pathway involved in both drug molecules biological/ pharmacological and toxicological action and disease pathogenesis". The selection of medicine is by comparing the similarity between the receptor or molecular pathway in disease pathogenesis and drug pathogenesis. To avoid unwanted aggravations or side effects while using mother tinctures or solutions, administer them less than their physiological dose. The theory of the pharmacological basis of Similia Similia Curantur creates a rational method to apply this Similia Principle. Based on this theory, there is a possibility of discovering Novel drugs in the future that acts and gives a cure in similia similibus curantur way.
... Atrial tachycardia and atrial fibrillation [68] . ...
Similia Similibus Curantur is also called the law of similars. That is, when a drug produces pathological/pathogenic symptoms in healthy individual means, the same drug can relieve similar kinds of symptoms in individuals with the disease. The biological, pharmacological and toxicological action of capsaicin alkaloids is a perfect example to explain the Similia Similibus Curantur principle. Most of the drugs in homoeopathic materia medica contain toxicological, pharmacological, drug-proving, and traditional use-related symptoms and indications. Abnormal sensations and symptoms of the disease are caused by the involvement of a specific receptor or molecular pathway and gene functions. These receptors or molecules may be stimulated or suppressed by environmental, natural or artificial agents. In such conditions, the administration of specific homoeopathic medicine having a similar kind of affinity towards the particular receptors or molecules involved in the disease process leads to modulation of such receptor or molecular pathways (e.g., desensitization, sensitization, inhibition). These kinds of actions cause the betterment of symptoms or curative effects. So “Similia similibus curantur” can be understood as a similar receptor or molecular pathway involved in both drug molecules biological/ pharmacological and toxicological action and disease pathogenesis". The selection of medicine is by comparing the similarity between the receptor or molecular pathway in disease pathogenesis and drug pathogenesis. To avoid unwanted aggravations or side effects while using mother tinctures or solutions, administer them less than their physiological dose. The theory of the pharmacological basis of Similia Similia Curantur creates a rational method to apply this Similia Principle. Based on this theory, there is a possibility of discovering Novel drugs in the future that acts and gives a cure in similia similibus curantur way.
... Besides having mildly elevated or reduced resting blood pressure, mice lacking RGS2 or RGS5 alone do not show any baseline cardiac phenotype except when subjected to experimental stressors including pressure overload and cardiac pacing [12,26,32,33]. Previous studies have also reported that the absence of RGS2 or 5 increases the incidence of atrial tachyarrhythmia induced with muscarinic receptor stimulation [34,35], and ventricular tachyarrhythmia in response to programmed electrical stimulation of isolated hearts [9,10]. Our findings now show that the dual absence of RGS2 and 5 causes unprovoked left ventricular dilatation without cardiomyocyte hypertrophy and independently of the associated baseline blood pressure elevation. ...
... Other lines of evidence also indicate that the inhibitory G i/o class G protein is regulated by many RGS proteins from other subfamilies beside R4/B RGS proteins in the heart [46,47]. However, evidence to date indicate that the regulation of G i/o by RGS2 and 5, individually, is critical to maintaining normal cardiac structure and function, since mice lacking RGS2 or 5 have been shown to be more sensitive to ISO-induced cardiac dysfunction and atrial fibrillation induced by cardiac pacing [6,7,9,10,35]. Despite these studies demonstrating the key roles of RGS2 and 5 in the myocardium, the fundamental questions that remain unexplored are how multiple RGS proteins coordinate their activity and, whether there is a functional redundancy in vivo in the fine-tuning of G protein signaling involved in the maintenance of normal physiology. ...
... Despite these studies demonstrating the key roles of RGS2 and 5 in the myocardium, the fundamental questions that remain unexplored are how multiple RGS proteins coordinate their activity and, whether there is a functional redundancy in vivo in the fine-tuning of G protein signaling involved in the maintenance of normal physiology. Addressing these questions has been necessitated partly by previous studies showing that mice singly lacking RGS2 or 5 develop mild hypertension without any cardiac phenotype unless subjected to some experimental perturbation such as cardiac pacing or pressure-overload by transverse aortic constriction [12,22,35]. Because RGS2 and 5 both potently regulate G q/11 and G i/o , the dual absence of such key regulatory proteins was expected to be developmentally detrimental. ...
Aims
Cardiac contractility, essential to maintaining proper cardiac output and circulation, is regulated by G protein-coupled receptor (GPCR) signaling. Previously, the absence of regulator of G protein signaling (RGS) 2 and 5, separately, was shown to cause G protein dysregulation, contributing to modest blood pressure elevation and exaggerated cardiac hypertrophic response to pressure-overload. Whether RGS2 and 5 redundantly control G protein signaling to maintain cardiovascular homeostasis is unknown. Here we examined how the dual absence of RGS2 and 5 (Rgs2/5 dbKO) affects blood pressure and cardiac structure and function.
Methods and results
We found that Rgs2/5 dbKO mice showed left ventricular dilatation at baseline by echocardiography. Cardiac contractile response to dobutamine stress test was sex-dependently reduced in male Rgs2/5 dbKO relative to WT mice. When subjected to surgery-induced stress, male Rgs2/5 dbKO mice had 75% mortality within 72–96 h after surgery, accompanied by elevated baseline blood pressure and decreased cardiac contractile function. At the cellular level, cardiomyocytes (CM) from Rgs2/5 dbKO mice showed augmented Ca²⁺ transients and increased incidence of arrhythmia without augmented contractile response to electrical field stimulation (EFS) and activation of β-adrenergic receptors (βAR) with isoproterenol. Dual loss of Rgs2 and 5 suppressed forskolin-induced cAMP production, which was restored by Gi/o inactivation with pertussis toxin that also reduced arrhythmogenesis during EFS or βAR stimulation. Cardiomyocyte NCX and PMCA mRNA expression was unaffected in Rgs2/5 dbKO male mice. However, there was an exaggerated elevation of EFS-induced cytoplasmic Ca²⁺ in the presence of SERCA blockade with thapsigargin.
Conclusions
We conclude that RGS2 and 5 promote normal ventricular rhythm by coordinating their regulatory activity towards Gi/o signaling and facilitating cardiomyocyte calcium handling.
... 2) Anesthetize the mouse. We commonly use a single intraperitoneal injection of Avertin (2,2,2-tribromoethanol; 250 mg/kg; for preparation, use, and scientific justification see Supplemental Material), but other injectable (e.g., pentobarbital, ketamine/xylazine) (15,23) or inhalational (e.g., isoflurane) (15) anesthetics have been reported. 3) Optional: the operative field (approximately from neck to midsternal region) can be shaved using hair clippers, or hair removal cream can be applied. ...
Cardiac arrhythmias are associated with cardiovascular morbidity and mortality. Cardiac electrophysiology studies (EPS) use intracardiac catheter recording and stimulation for profound evaluation of the heart's electrical properties. The main clinical application is investigation and treatment of rhythm disorders. These techniques have been translated to the murine setting to open opportunities for detailed evaluation of the impact of different characteristics (including genetics) and interventions on cardiac electrophysiology and -pathology. Currently, a detailed description of the technique of murine transjugular EPS (which is the standard route of catheter introduction) is lacking. This article provides detailed information on EPS in mice via the transjugular route. This includes catheter placement, stimulation protocols, intracardiac tracing interpretation, artefact reduction and surface ECG recording. In addition, reference values as obtained in C57BL/6N mice are presented for common electrophysiological parameters. This detailed methodological description aims to increase accessibility and standardisation of EPS in mice. Ultimately, also human research and patient care may benefit from translation of the knowledge obtained in preclinical models using this technique.
... Among several subtypes, RGS2 and RGS5 are predominantly expressed in the cardiovascular system and are known as negative regulators of the GPCR signaling pathway [31]. Several in vivo studies have demonstrated the association of RGS2 inhibition with atrial tachycardia, hypertension, and cardiac hypertrophy [32][33][34]. RGS2 deficiency is reported to prolong vasoconstrictor signaling via AT1R and P2Y and increase internal calcium release via ryanodine receptors [35,36]. Similarly, loss of RGS5 has been reported to be associated with tachyarrhythmia and cardiac hypertrophy in mice [37,38]. ...
Ritodrine, a β2-adrenergic receptor agonist, is among most commonly prescribed tocolytic agents. This study aimed to evaluate the associations of single nucleotide polymorphisms in GNAS, RGS2, and RGS5 with the risk of ritodrine-induced adverse events (AEs) and develop a risk scoring system to identify high-risk patients. This is the prospective cohort study conducted at the Ewha Woman’s University Mokdong Hospital between January 2010 and October 2016. Pregnant women were included if they were treated with ritodrine for preterm labor with regular uterine contractions (at least 3 every 10 min) and cervical dilation. A total of 6, 3, and 5 single nucleotide polymorphisms (SNPs) of GNAS, RGS2, and RGS5 genes were genotyped and compared in patients with and without ritodrine-induced AEs. A total of 163 patients were included in this study. After adjusting confounders, GNAS rs3730168 (per-allele odds ratio (OR): 2.1; 95% confidence interval (95% CI): 1.0–4.3) and RGS2 rs1152746 (per-allele OR: 2.6, 95% CI: 1.1–6.5) were significantly associated with ritodrine-induced AEs. According to the constructed risk scoring models, patients with 0, 1, 2, 3, 4, and 5 points showed 0%, 13%, 19%, 31%, 46%, and 100% risks of AEs. This study suggested that GNAS and RGS2 polymorphisms could affect the risk of AEs in patients treated with ritodrine.
... Example materia medica pura and encyclopedia of pure materia medica, Herrings guiding symptoms of our material medica contains provings of nitric acid in mother solution, 2X, to 12X potencies (Table 3). Homoeopathic drug proving record shows the oral administration of an aqueous solution of nitric acid and its low concentration (low potency) for several days in provers leads appearance of symptoms like inflammation of gums, glossitis, aphthous ulcer, gastritis etc, among the drug provers [69,76] . In the homoeopathic system of medicine, potentised or diluted form of nitric acid is used to treat the conditions like gingivitis, aphthous ulcers, gastritis, and stomach ulcers. ...
... Table 3: Comparing biological activity of the active ingredients of Homoeopathic medicines, their respective receptor interaction or molecular pathway and involvement of such receptor interaction or similar kind of molecular pathway in disease condition, symptoms of Homoeopathic medicines derived from drug proving and potencies of commonly used in homoeopathic practice especially in the earliest period of homoeopathic history. [69,76] Nitric oxide is generated in tissues from arginine by nitric oxide synthase (NOS) [45] . NO works as a physiological messenger through the production of cGMP by activating guanylate cyclase [35,45] . ...
... Ulcer on tongue. Ulcerated and blistered lips [69,76] . ...
The Homoeopathic system follows the principle of similia similibus curantur. The concept of potentisation, molecular action of Homoeopathic drug substances, can be explained through an in-vitro study by using Staphylococcus aureus culture. Microbial culture prepared with nutrient agar medium, Hear the bacteria itself considered a whole organism. Nitric acid 1X, 2X, 3X, 4X, 5X, 6X, and 30C as taken as study sample, erythromycin 1X, 2X, 3X, 4X, 5X, 6X, and 30C used as a comparison, water plus ethanol solution used as a negative control. Nitric acid shows inhibitory effects on culture growth up to 3X. Erythromycin up to 5X. Negative control and other dilutions produce no inhibitory effects. There is no growth-stimulating effects or any other effects seen on the culture. A drug in its high concentration produces a group of symptoms during drug proving through its molecular or receptor interactions. Such drugs in their low concentrations follow the same molecular pathway or receptor pathway. We can understand the concepts much better with the action of capsaicin alkaloid on TRPV1 receptor, indications of capsicum annum homoeopathic drug from its drug proving records, Along with that, examples of homoeopathic medicine's active compounds and their molecular or receptor interactions compared with the involvement of such receptors in the disease process. Administration of specific homoeopathic medicine having an affinity towards the particular receptors or molecules involved in the disease process leads to modulation of such receptor or molecular pathway it offers the betterment of symptoms or curative effects.
... Intracardiac studies were performed as we have previously described. 10,20 Arrhythmia induction used both programmed electrical stimulation and burst pacing (2-ms pulses at 50 Hz, 400-ms burst duration) to determine susceptibility to AF (rapid atrial activity lasting >1 second) as well as atrial effective refractory period, ventricular effective refractory period, atrioventricular node effective refractory period, and Wenckebach cycle length. Additional information is available in Data S1. ...
Background
Ibrutinib and acalabrutinib are Bruton tyrosine kinase inhibitors used in the treatment of B‐cell lymphoproliferative disorders. Ibrutinib is associated with new‐onset atrial fibrillation. Cases of sinus bradycardia and sinus arrest have also been reported following ibrutinib treatment. Conversely, acalabrutinib is less arrhythmogenic. The basis for these different effects is unclear.
Methods and Results
The effects of ibrutinib and acalabrutinib on atrial electrophysiology were investigated in anesthetized mice using intracardiac electrophysiology, in isolated atrial preparations using high‐resolution optical mapping, and in isolated atrial and sinoatrial node (SAN) myocytes using patch‐clamping. Acute delivery of acalabrutinib did not affect atrial fibrillation susceptibility or other measures of atrial electrophysiology in mice in vivo. Optical mapping demonstrates that ibrutinib dose‐dependently impaired atrial and SAN conduction and slowed beating rate. Acalabrutinib had no effect on atrial and SAN conduction or beating rate. In isolated atrial myocytes, ibrutinib reduced action potential upstroke velocity and Na ⁺ current. In contrast, acalabrutinib had no effects on atrial myocyte upstroke velocity or Na ⁺ current. Both drugs increased action potential duration, but these effects were smaller for acalabrutinib compared with ibrutinib and occurred by different mechanisms. In SAN myocytes, ibrutinib impaired spontaneous action potential firing by inhibiting the delayed rectifier K ⁺ current, while acalabrutinib had no effects on SAN myocyte action potential firing.
Conclusions
Ibrutinib and acalabrutinib have distinct effects on atrial electrophysiology and ion channel function that provide insight into the basis for increased atrial fibrillation susceptibility and SAN dysfunction with ibrutinib, but not with acalabrutinib.
... Mice electrophysiological studies were performed as previously described [23][24][25]. Briefly, all mice were anaesthetized with an intraperitoneal injection of 1% pentobarbital sodium, and surface limb lead ECGs were recorded on each limb. ...
... The electrode was inserted through the esophagus near the left atrium (LA), and ECGs were recorded using PowerLab and LabChart 7 software. Both programmed electrical stimulation (PES) and burst pacing (2 ms at 50 Hz) were used to determine their susceptibility to pacing-induced AF [23,24]. AF in ibrutinib-treated mice was identified through differentiation from the normal sinus rhythm if the ECGs showed a lack of regular P waves. ...
Atrial fibrillation (AF) occurs in up to 11% of cancer patients treated with ibrutinib. The pathophysiology of ibrutinib promoted AF is complicated, as there are multiple interactions involved; the detailed molecular mechanisms underlying this are still unclear. Here, we aimed to determine the electrophysiological and molecular mechanisms of burst-pacing-induced AF in ibrutinib-treated mice. The results indicated differentially expressed proteins in ibrutinib-treated mice, identified through proteomic analysis, were found to play a role in oxidative stress-related pathways. Finally, treatment with an inhibitor of NADPH oxidase (NOX) prevented and reversed AF development in ibrutinib-treated mice. It was showed that the related protein expression of reactive oxygen species (ROS) in the ibrutinib group was significantly increased, including NOX2, NOX4, p22-phox, XO and TGF-β protein expression. It was interesting that ibrutinib group also significantly increased the expression of ox-CaMKII, p-CaMKII (Thr-286) and p-RyR2 (Ser2814), causing enhanced abnormal sarcoplasmic reticulum (SR) Ca2+ release and mitochondrial structures, as well as atrial fibrosis and atrial hypertrophy in ibrutinib-treated mice, and apocynin reduced the expression of these proteins. Ibrutinib-treated mice were also more likely to develop AF, and AF occurred over longer periods. In conclusion, our study has established a pathophysiological role for ROS signaling in atrial cardiomyocytes, and it may be that ox-CaMKII and p-CaMKII (Thr-286) are activated by ROS to increase AF susceptibility following ibrutinib treatment. We have also identified the inhibition of NOX as a potential novel AF therapy approach.
