RESUMEN
Atrial fibrillation (AF) is the most common arrhythmia, and atrial fibrosis is a pathological hallmark of structural remodeling in AF. Prostaglandin I2 (PGI2) can prevent the process of fibrosis in various tissues via cell surface Prostaglandin I2 receptor (IP). However, the role of PGI2 in AF and atrial fibrosis remains unclear. The present study aimed to clarify the role of PGI2 in angiotensin II (Ang II)-induced AF and the underlying molecular mechanism. PGI2 content was decreased in both plasma and atrial tissue from patients with AF and mice treated with Ang II. Treatment with the PGI2 analog, iloprost, reduced Ang II-induced AF and atrial fibrosis. Iloprost prevented Ang II-induced atrial fibroblast collagen synthesis and differentiation. RNA-sequencing analysis revealed that iloprost significantly attenuated transcriptome changes in Ang II-treated atrial fibroblasts, especially mitogen-activated protein kinase (MAPK)-regulated genes. We demonstrated that iloprost elevated cAMP levels and then activated protein kinase A, resulting in a suppression of extracellular signal-regulated kinase1/2 and P38 activation, and ultimately inhibiting MAPK-dependent interleukin-6 transcription. In contrast, cardiac fibroblast-specific IP-knockdown mice had increased Ang II-induced AF inducibility and aggravated atrial fibrosis. Together, our study suggests that PGI2/IP system protects against atrial fibrosis and that PGI2 is a therapeutic target for treating AF.The prospectively registered trial was approved by the Chinese Clinical Trial Registry. The trial registration number is ChiCTR2200056733. Data of registration was 2022/02/12.
Asunto(s)
Angiotensina II , Fibrilación Atrial , Remodelación Atrial , Epoprostenol , Ratones Endogámicos C57BL , Transducción de Señal , Animales , Fibrilación Atrial/metabolismo , Fibrilación Atrial/patología , Fibrilación Atrial/inducido químicamente , Fibrilación Atrial/prevención & control , Ratones , Humanos , Masculino , Transducción de Señal/efectos de los fármacos , Remodelación Atrial/efectos de los fármacos , Epoprostenol/metabolismo , Fibrosis , Fibroblastos/metabolismo , Fibroblastos/efectos de los fármacos , Fibroblastos/patología , Atrios Cardíacos/metabolismo , Atrios Cardíacos/patología , Atrios Cardíacos/efectos de los fármacos , Iloprost/farmacología , Receptores de Epoprostenol/metabolismo , Receptores de Epoprostenol/genética , FemeninoRESUMEN
The loss of semaphorin 3A (Sema3A), which is related to endothelial-to-mesenchymal transition (EndMT) in atrial fibrosis, is implicated in the pathogenesis of atrial fibrillation (AF). To explore the mechanisms by which EndMT affects atrial fibrosis and assess the potential of a Sema3A activator (naringin) to prevent atrial fibrosis by targeting transforming growth factor-beta (TGF-ß)-induced EndMT, we used human atria, isolated human atrial endocardial endothelial cells (AEECs), and used transgenic mice expressing TGF-ß specifically in cardiac tissues (TGF-ß transgenic mice). We evaluated an EndMT marker (Twist), a proliferation marker (proliferating cell nuclear antigen; PCNA), and an endothelial cell (EC) marker (CD31) through triple immunohistochemistry and confirmed that both EndMT and EC proliferation contribute to atrial endocardial fibrosis during AF in TGF-ß transgenic mice and AF patient tissue sections. Additionally, we investigated the impact of naringin on EndMT and EC proliferation in AEECs and atrial fibroblasts. Naringin exhibited an antiproliferative effect, to which AEECs were more responsive. Subsequently, we downregulated Sema3A in AEECs using small interfering RNA to clarify a correlation between the reduction in Sema3A and the elevation of EndMT markers. Naringin treatment induced the expression of Sema3A and a concurrent decrease in EndMT markers. Furthermore, naringin administration ameliorated AF and endocardial fibrosis in TGF-ß transgenic mice by stimulating Sema3A expression, inhibiting EndMT markers, reducing atrial fibrosis, and lowering AF vulnerability. This suggests therapeutic potential for naringin in AF treatment.
Asunto(s)
Fibrilación Atrial , Proliferación Celular , Células Endoteliales , Transición Epitelial-Mesenquimal , Flavanonas , Atrios Cardíacos , Semaforina-3A , Factor de Crecimiento Transformador beta , Animales , Humanos , Masculino , Ratones , Fibrilación Atrial/metabolismo , Fibrilación Atrial/patología , Fibrilación Atrial/genética , Fibrilación Atrial/tratamiento farmacológico , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Células Endoteliales/patología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/patología , Fibrosis , Flavanonas/farmacología , Atrios Cardíacos/metabolismo , Atrios Cardíacos/efectos de los fármacos , Atrios Cardíacos/patología , Ratones Transgénicos , Semaforina-3A/metabolismo , Semaforina-3A/genética , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
ABSTRACT: Type 2 diabetes mellitus increases the risk of cardiovascular diseases. Therefore, elucidation of the cardiovascular effects of antidiabetics is crucial. Incretin-based therapies are increasingly used for type 2 diabetes mellitus treatment as monotherapy and in combination. We aimed to study the effects of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sitagliptin on beating rates in isolated atria from diabetic rats. The chronotropic responses to GLP-1 RAs and sitagliptin as monotherapy and in combinations with metformin, pioglitazone, and glimepiride in isolated atria from control and diabetic rats were determined. GLP-1 (7-36), GLP-1 (9-36), and exendin-4 (1-39) produced increases in beating rates in both control and diabetic rat atria. However, sitagliptin increased the beating frequency only in the diabetic group. Exendin (9-39), nitro- l -arginine methyl ester hydrochloride, and indomethacin blocked responses to GLP-1 RAs but not the response to sitagliptin. Glibenclamide, 4-aminopyridine, apamin, charybdotoxin, superoxide dismutase, and catalase incubations did not change responses to GLP-1 RAs and sitagliptin. GLP-1 RAs increase beating rates in isolated rat atrium through GLP-1 receptor, nitric oxide, and cyclooxygenase pathways but not potassium channels and reactive oxygen radicals.
Asunto(s)
Diabetes Mellitus Experimental , Receptor del Péptido 1 Similar al Glucagón , Atrios Cardíacos , Frecuencia Cardíaca , Hipoglucemiantes , Fosfato de Sitagliptina , Animales , Fosfato de Sitagliptina/farmacología , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Masculino , Atrios Cardíacos/efectos de los fármacos , Atrios Cardíacos/fisiopatología , Atrios Cardíacos/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/fisiopatología , Frecuencia Cardíaca/efectos de los fármacos , Hipoglucemiantes/farmacología , Ratas , Ratas Wistar , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/fisiopatología , Diabetes Mellitus Tipo 2/metabolismo , Exenatida/farmacología , Incretinas/farmacología , Péptido 1 Similar al Glucagón/agonistas , Péptido 1 Similar al Glucagón/metabolismo , Pirazinas/farmacología , Agonistas Receptor de Péptidos Similares al GlucagónRESUMEN
ABSTRACT: Previous studies have found that anxiety disorders may increase the incidence of atrial fibrillation (AF). More and more studies have shown that α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are involved in the occurrence and development of cardiovascular diseases. However, the role of AMPARs in AF associated with anxiety disorder remains unclear. The aim of this study was to investigate the effect of AMPARs on AF susceptibility in rats with anxiety disorder and its possible mechanism. The anxiety disorder rat model was established by unpredictable empty bottle stimulation and was treated with AMPARs agonist and antagonist. Our results showed that AMPARs antagonist treatment significantly reduced sympathetic activity, improved heart rate variability, shortened action potential duration, prolonged effective refractory period, reduced AF induction rate, and improved cardiac electrical remodeling and the expression of inflammatory factors. In addition, inhibition of AMPARs reduced the phosphorylation of IκBα and p65. Our experimental results suggest that inhibition of AMPARs can reduce autonomic remodeling, improve atrial electrical remodeling, and suppress myocardial inflammation, which provides a potential therapeutic strategy for the treatment of AF associated with anxiety disorder.
Asunto(s)
Trastornos de Ansiedad , Fibrilación Atrial , Modelos Animales de Enfermedad , Atrios Cardíacos , Ratas Sprague-Dawley , Receptores AMPA , Animales , Fibrilación Atrial/fisiopatología , Fibrilación Atrial/tratamiento farmacológico , Fibrilación Atrial/metabolismo , Masculino , Trastornos de Ansiedad/tratamiento farmacológico , Trastornos de Ansiedad/metabolismo , Trastornos de Ansiedad/fisiopatología , Atrios Cardíacos/efectos de los fármacos , Atrios Cardíacos/fisiopatología , Atrios Cardíacos/metabolismo , Atrios Cardíacos/patología , Receptores AMPA/metabolismo , Remodelación Atrial/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Mediadores de Inflamación/metabolismo , Potenciales de Acción/efectos de los fármacos , Fosforilación , Transducción de Señal , Sistema Nervioso Simpático/fisiopatología , Sistema Nervioso Simpático/efectos de los fármacos , Sistema Nervioso Simpático/metabolismo , Factor de Transcripción ReIA/metabolismo , Ratas , Antiinflamatorios/farmacología , Periodo Refractario Electrofisiológico/efectos de los fármacos , Inhibidor NF-kappaB alfa/metabolismoRESUMEN
Oxysterol, 25-hydroxycholesterol (25HC), is a potent regulator of immune reactions, its synthesis greatly increases by macrophages during inflammation. We hypothesize that 25HC can have cardioprotective effects by limiting consequences of excessive ß-adrenoceptor (ßAR) stimulation, particularly reactive oxygen species (ROS) production, in mouse atria. Isoproterenol, a ßAR agonist, increased extra- and intracellular levels of ROS. This enhancement of ROS production was suppressed by NADPH oxidase antagonists as well as 25HC. Inhibition of ß3ARs, Gi protein and protein kinase Cε prevented the effect of 25HC on isoproterenol-dependent ROS synthesis. Furthermore, 25HC suppressed isoproterenol-induced lipid peroxidation and mitochondrial ROS generation as well as ROS-dependent component of positive inotropic response to isoproterenol. Additionally, 25HC decreased mitochondrial ROS production and lipid peroxidation induced by antimycin A, a mitochondrial poison. Thus, 25HC exerts antioxidant properties alleviating mitochondrial dysfunction-induced and ßAR-dependent cardiac oxidative damage. In the latter case, 25HC can act via signaling mechanism engaging ß3ARs, Gi protein and protein kinase Cε.
Asunto(s)
Antioxidantes , Atrios Cardíacos , Hidroxicolesteroles , Especies Reactivas de Oxígeno , Transducción de Señal , Animales , Hidroxicolesteroles/farmacología , Hidroxicolesteroles/metabolismo , Ratones , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Atrios Cardíacos/metabolismo , Atrios Cardíacos/efectos de los fármacos , Antioxidantes/farmacología , Antioxidantes/metabolismo , Masculino , Peroxidación de Lípido/efectos de los fármacos , Isoproterenol/farmacología , Ratones Endogámicos C57BLRESUMEN
The current study aimed to investigate the anti-atrial fibrillatory (AF) effects of a combination of valsartan and a calcium channel blocker (cilnidipine or amlodipine) in Dahl salt-sensitive (Dahl S) rats. Seven-week-old male Dahl S rats were fed an 8% salt diet. Six weeks later, valsartan (60 mg/kg, Val group), cilnidipine + valsartan (10 + 60 mg/kg, CV group), amlodipine + valsartan (3 + 60 mg/kg, AV group), or vehicle was orally administered daily for 5 weeks. Echocardiography and atrial electrophysiological evaluations were performed on the last day of treatment. Blood pressure in each drug treatment group was lower than in the Vehicle group. The duration of AF induced by atrial burst stimulation was shorter in the Val group (3.2 ± 1.6 s) than in the Vehicle group (11.2 ± 6.0 s), which was further shortened in the CV and AV groups (1.1 ± 0.3 and 1.3 ± 0.3 s, respectively). Left ventricular ejection fraction and left ventricular fractional shortening were greater in the CV and AV groups than those in the Vehicle group. Urinary albumin excretion in the CV group was the lowest among the drug-treated groups. The results collectively suggest that the combination of a calcium channel blocker with valsartan could be useful in terms of its anti-AF action as well as for improving cardiac and renal functions.
Asunto(s)
Presión Sanguínea , Bloqueadores de los Canales de Calcio , Dihidropiridinas , Ratas Endogámicas Dahl , Valsartán , Animales , Valsartán/farmacología , Dihidropiridinas/farmacología , Masculino , Bloqueadores de los Canales de Calcio/farmacología , Presión Sanguínea/efectos de los fármacos , Fibrilación Atrial/tratamiento farmacológico , Quimioterapia Combinada , Riñón/efectos de los fármacos , Ratas , Amlodipino/farmacología , Función Ventricular Izquierda/efectos de los fármacos , Atrios Cardíacos/efectos de los fármacosRESUMEN
We studied the effect of Refralon on the electrophysiological properties of the supraventricular myocardium against the background of adrenergic (epinephrine) influence in the zone of the pulmonary veins, the area where 50-90% of atrial arrhythmias is triggered. The experiments were carried out on isolated tissue preparations of Wistar rats. The multichannel microelectrode array technique was used to record action potentials simultaneously in the atrium and in the ostium and distal parts of the pulmonary veins. Epinephrine application (12-50 nM) led to depolarization of the resting potential and the conduction block in the distal part of the pulmonary veins. Refralon (30 µg/kg) restored the resting potential in the distal part of the pulmonary veins. Against the background of epinephrine, Refralon did not significantly change the duration of the action potential at 90% repolarization in comparison with control. At the same time, the comparison drug E-4031 against the background of epinephrine significantly increased the duration of action potential in the atrium and in the ostium of the pulmonary veins, and sotalol increased it only in the ostium. Neither E-4031, nor sotalol restored conduction in their distal part. Refralon has a biphasic effect under conditions of adrenergic stimulation: the fast component is responsible for stabilizing the resting potential in the pulmonary vein and reduces the dispersion of action potential duration in the atrium and pulmonary vein and is also quickly washed away, and the slow component is responsible for the increase of the action potential duration and is slowly washed away.
Asunto(s)
Potenciales de Acción , Antiarrítmicos , Epinefrina , Atrios Cardíacos , Venas Pulmonares , Ratas Wistar , Animales , Ratas , Epinefrina/farmacología , Potenciales de Acción/efectos de los fármacos , Antiarrítmicos/farmacología , Venas Pulmonares/efectos de los fármacos , Masculino , Atrios Cardíacos/efectos de los fármacos , Atrios Cardíacos/fisiopatología , Arritmias Cardíacas/fisiopatología , Arritmias Cardíacas/tratamiento farmacológicoRESUMEN
A number of pharmacological drugs have side effects that contribute to the occurrence of atrial fibrillation, the most common type of cardiac rhythm disorders. The clinical use of antihistamines is widespread; however, information regarding their anti- and/or proarrhythmic effects is contradictory. In this work, we studied the effects and mechanisms of the potential proarrhythmic action of the first-generation antihistamine chloropyramine (Suprastin) in the atrial myocardium and pulmonary vein (PV) myocardial tissue. In PV, chloropyramine caused depolarization of the resting potential and led to reduction of excitation wave conduction. These effects are likely due to suppression of the inward rectifier potassium current (IK1). In presence of epinephrine, chloropyramine induced spontaneous automaticity in the PV and could not be suppressed by atrial pacing. Chloropyramine change functional characteristics of PV and contribute to occurrence of atrial fibrillation. It should be noted that chloropyramine does not provoke atrial tachyarrhythmias, but create conditions for their occurrence during physical exercise and sympathetic stimulation.
Asunto(s)
Fibrilación Atrial , Venas Pulmonares , Venas Pulmonares/efectos de los fármacos , Venas Pulmonares/fisiopatología , Animales , Fibrilación Atrial/fisiopatología , Fibrilación Atrial/tratamiento farmacológico , Fibrilación Atrial/inducido químicamente , Atrios Cardíacos/efectos de los fármacos , Atrios Cardíacos/fisiopatología , Clorfeniramina/farmacología , Epinefrina/farmacología , Antagonistas de los Receptores Histamínicos H1/farmacología , Miocardio/metabolismo , Miocardio/patología , Masculino , Potenciales de Acción/efectos de los fármacos , Sistema de Conducción Cardíaco/efectos de los fármacos , Sistema de Conducción Cardíaco/fisiopatologíaRESUMEN
BACKGROUND: More than 50% of patients with atrial fibrillation (AF) suffer from sleep disordered breathing (SDB). Obstructive respiratory events contribute to a transient, vagally mediated atrial arrhythmogenic substrate, which is resistant to most available antiarrhythmic drugs. OBJECTIVE: The purpose of this study was to investigate the effect of pharmacologic inhibition of the G-protein-gated acetylcholine-regulated potassium current (IK,ACh) with and without acute autonomic nervous system activation by nicotine in a pig model for obstructive respiratory events. METHODS: In 21 pigs, SDB was simulated by applying an intermittent negative upper airway pressure (INAP). AF inducibility and atrial effective refractory periods (aERPs) were determined before and during INAP by an S1S2 atrial pacing-protocol. Pigs were randomized into 3 groups-group 1: vehicle (n = 4); group 2: XAF-1407 (IK,ACh inhibitor) (n = 7); and group 3: nicotine followed by XAF-1407 (n = 10). RESULTS: In group 1, INAP shortened aERP (ΔaERP -42.6 ms; P = .004) and transiently increased AF inducibility from 0% to 31%. In group 2, XAF-1407 prolonged aERP by 25.2 ms (P = .005) during normal breathing and prevented INAP-induced aERP shortening (ΔaERP -3.6 ms; P = .3) and AF inducibility. In group 3, INAP transiently shortened aERP during nicotine perfusion (ΔaERP -33.6 ms; P = .004) and increased AF inducibility up to 61%, which both were prevented by XAF-1407. CONCLUSION: Simulated obstructive respiratory events transiently shorten aERP and increase AF inducibility, which can be prevented by the IK,ACh-inhibitor XAF-1407. XAF-1407 also prevents these arrhythmogenic changes induced by obstructive respiratory events during nicotine perfusion. Whether IK,ACh channels represent a target for SDB-related AF in humans warrants further study.
Asunto(s)
Fibrilación Atrial , Modelos Animales de Enfermedad , Animales , Porcinos , Fibrilación Atrial/fisiopatología , Fibrilación Atrial/etiología , Fibrilación Atrial/prevención & control , Atrios Cardíacos/fisiopatología , Atrios Cardíacos/efectos de los fármacos , Atrios Cardíacos/metabolismo , Acetilcolina/farmacología , Nicotina/farmacología , Síndromes de la Apnea del Sueño/fisiopatología , Síndromes de la Apnea del Sueño/complicacionesRESUMEN
We propose a new mouse (C57Bl6/J) model combining several features of heart failure with preserved ejection fraction encountered in older women, including hypertension from Angiotensin II infusion (AngII), menopause, and advanced age. To mimic menopause, we delayed ovariectomy (Ovx) at 12 months of age. We also studied the effects of AngII infusion for 28 days in younger animals and the impact of losing gonadal steroids earlier in life. We observed that AngII effects on heart morphology were different in younger and adult mice (3- and 12-month-old; 20 and 19% increase in heart weight. P < 0.01 for both) than in older animals (24-month-old; 6%; not significant). Ovariectomy at 12 months restored the hypertrophic response to AngII in elderly females (23%, p = 0.0001). We performed a bulk RNA sequencing study of the left ventricle (LV) and left atrial gene expression in elderly animals, controls, and Ovx. AngII modulated (|Log2 fold change| ≥ 1) the LV expression of 170 genes in control females and 179 in Ovx ones, 64 being shared. In the left atrium, AngII modulated 235 genes in control females and 453 in Ovx, 140 shared. We observed many upregulated genes associated with the extracellular matrix regulation in both heart chambers. Many of these upregulated genes were shared between the ventricle and the atrium as well as in control and Ovx animals, namely for the most expressed Ankrd1, Nppb, Col3a1, Col1a1, Ctgf Col8a1, and Cilp. Several circadian clock LV genes were modulated differently by AngII between control and Ovx females (Clock, Arntl, Per2, Cry2, and Ciart). In conclusion, sex hormones, even in elderly female mice, modulate the heart's hypertrophic response to AngII. Our study identifies potential new markers of hypertensive disease in aging female mice and possible disturbances of their cardiac circadian clock.
Asunto(s)
Angiotensina II , Modelos Animales de Enfermedad , Hipertensión , Ratones Endogámicos C57BL , Ovariectomía , Animales , Femenino , Angiotensina II/farmacología , Ratones , Hipertensión/fisiopatología , Envejecimiento/fisiología , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/patología , Ventrículos Cardíacos/fisiopatología , Menopausia , Humanos , Factor de Crecimiento del Tejido Conjuntivo/genética , Factor de Crecimiento del Tejido Conjuntivo/metabolismo , Atrios Cardíacos/fisiopatología , Atrios Cardíacos/efectos de los fármacos , Atrios Cardíacos/patología , Colágeno Tipo IIIRESUMEN
Mollusks, including snails, possess two chambered hearts. The heart and cardiomyocytes of snails have many similarities with those of mammals. Also, the biophysics and pharmacology of Ca, K, and Na ion channels resemble. Similar to mammals, in mollusks, the ventricular cardiomyocytes and K channels are often studied, which are selectively sensitive to antagonists such as 4-AP, E-4031, and TEA. Since the physiological properties of the ventricular cardiac cells of snails are well characterized, the enzymatically dissociated atrial cardiomyocytes of Cornu aspersum (Müller, 1774) were studied using the whole-cell patch-clamp technique for detailed comparisons with mice, Mus musculus. The incubation of tissues in a solution simultaneously containing two enzymes, collagenase and papain, enabled the isolation of single cells. Recordings in the atrial cardiomyocytes of snails revealed outward K+ currents closely resembling those of the ventricle. The latter was consistent, whether the voltage ramp or steps and long or short pulses were used. Interestingly, under identical conditions, the current waveforms of atrial cardiomyocytes in snails were similar to those of mice left ventricles, albeit the kinetics and the absence of inward rectifier K channel (IK1) activation. Therefore, the heart of mollusks could be used as a simple and accessible experimental model, particularly for pharmacology and toxicology studies.
Asunto(s)
Atrios Cardíacos , Ventrículos Cardíacos , Miocitos Cardíacos , Animales , Atrios Cardíacos/efectos de los fármacos , Atrios Cardíacos/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/metabolismo , Ventrículos Cardíacos/citología , Ratones , Técnicas de Placa-Clamp , Canales de Potasio/metabolismo , CaracolesRESUMEN
Atrial fibrillation (AF), the most common cardiac arrhythmia, is an important contributor to mortality and morbidity. Ubquitin-specific protease 7 (USP7), one of the most abundant ubiquitin-specific proteases (USP), participated in many cellular events, such as cell proliferation, apoptosis, and tumourigenesis. However, its role in AF remains unknown. Here, the mice were treated with Ang II infusion to induce the AF model. Echocardiography was used to measure the atrial diameter. Electrical stimulation was programmed to measure the induction and duration of AF. The changes in atrial remodeling were measured using routine histologic analysis. Here, a significant increase in USP7 expression was observed in Ang II-stimulated atrial cardiomyocytes and atrial tissues, as well as in atrial tissues from patients with AF. The administration of p22077, the inhibitor of USP7, attenuated Ang II-induced inducibility and duration of AF, atrial dilatation, connexin dysfunction, atrial fibrosis, atrial inflammation, and atrial oxidase stress, and then inhibited the progression of AF. Mechanistically, the administration of p22077 alleviated Ang II-induced activation of TGF-ß/Smad2, NF-κB/NLRP3, NADPH oxidases (NOX2 and NOX4) signals, the up-regulation of CX43, ox-CaMKII, CaMKII, Kir2.1, and down-regulation of SERCA2a. Together, this study, for the first time, suggests that USP7 is a critical driver of AF and revealing USP7 may present a new target for atrial fibrillation therapeutic strategies.
Asunto(s)
Angiotensina II , Fibrilación Atrial , Peptidasa Específica de Ubiquitina 7 , Animales , Fibrilación Atrial/metabolismo , Fibrilación Atrial/inducido químicamente , Fibrilación Atrial/tratamiento farmacológico , Fibrilación Atrial/prevención & control , Peptidasa Específica de Ubiquitina 7/metabolismo , Ratones , Masculino , Ratones Endogámicos C57BL , Atrios Cardíacos/efectos de los fármacos , Atrios Cardíacos/metabolismo , Atrios Cardíacos/patología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Humanos , Remodelación Atrial/efectos de los fármacosRESUMEN
AIMS: A recently published trial has shown no differences in outcomes between patients with new-onset supraventricular arrhythmia (SVA) in septic shock treated with either propafenone or amiodarone. However, these outcome data have not been evaluated in relation to the presence or absence of a dilated left atrium (LA). METHODS AND RESULTS: Patients with SVA and a left ventricular ejection fraction ≥ 35% were randomized to receive intravenous propafenone (70â mg bolus followed by 400-840â mg/24â h) or amiodarone (300â mg bolus followed by 600-1800â mg/24â h). They were divided into groups based on whether their end-systolic left atrial volume (LAVI) was ≥40â mL/m². The subgroup outcomes assessed were survival at ICU discharge, 1 month, 3 months, 6 months, and 12 months. Propafenone cardioverted earlier (P = 0.009) and with fewer recurrences (P = 0.001) in the patients without LA enlargement (n = 133). Patients with LAVI < 40â mL/m2 demonstrated a mortality benefit of propafenone over the follow-up of 1 year [Cox regression, hazard ratio (HR) 0.6 (95% CI 0.4; 0.9), P = 0.014]. Patients with dilated LA (n = 37) achieved rhythm control earlier in amiodarone (P = 0.05) with similar rates of recurrences (P = 0.5) compared to propafenone. The outcomes for patients with LAVI ≥ 40â mL/m2 were less favourable with propafenone compared to amiodarone at 1 month [HR 3.6 (95% CI 1.03; 12.5), P = 0.045]; however, it did not reach statistical significance at 1 year [HR 1.9 (95% CI 0.8; 4.4), P = 0.138]. CONCLUSION: Patients with non-dilated LA who achieved rhythm control with propafenone in the setting of septic shock had better short-term and long-term outcomes than those treated with amiodarone, which seemed to be more effective in patients with LAVI ≥ 40â mL/m². TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03029169, registered on 24 January 2017.
Asunto(s)
Amiodarona , Antiarrítmicos , Atrios Cardíacos , Propafenona , Choque Séptico , Taquicardia Supraventricular , Humanos , Propafenona/uso terapéutico , Propafenona/administración & dosificación , Amiodarona/uso terapéutico , Amiodarona/administración & dosificación , Choque Séptico/tratamiento farmacológico , Choque Séptico/fisiopatología , Masculino , Femenino , Antiarrítmicos/uso terapéutico , Antiarrítmicos/administración & dosificación , Anciano , Atrios Cardíacos/fisiopatología , Atrios Cardíacos/diagnóstico por imagen , Atrios Cardíacos/efectos de los fármacos , Taquicardia Supraventricular/tratamiento farmacológico , Taquicardia Supraventricular/fisiopatología , Resultado del Tratamiento , Persona de Mediana Edad , Volumen Sistólico/fisiología , Volumen Sistólico/efectos de los fármacosRESUMEN
AIMS: High left ventricular filling pressure increases left atrial volume and causes myocardial fibrosis, which may decrease with spironolactone. We studied clinical and proteomic characteristics associated with left atrial volume indexed by body surface area (LAVi), and whether LAVi influences the response to spironolactone on biomarker expression and clinical variables. METHODS AND RESULTS: In the HOMAGE trial, where people at risk of heart failure were randomized to spironolactone or control, we analysed 421 participants with available LAVi and 276 proteomic measurements (Olink) at baseline, month 1 and 9 (mean age 73 ± 6 years; women 26%; LAVi 32 ± 9 ml/m2). Circulating proteins associated with LAVi were also assessed in asymptomatic individuals from a population-based cohort (STANISLAS; n = 1640; mean age 49 ± 14 years; women 51%; LAVi 23 ± 7 ml/m2). In both studies, greater LAVi was significantly associated with greater left ventricular masses and volumes. In HOMAGE, after adjustment and correction for multiple testing, greater LAVi was associated with higher concentrations of matrix metallopeptidase-2 (MMP-2), insulin-like growth factor binding protein-2 (IGFBP-2) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) (false discovery rates [FDR] <0.05). These associations were externally replicated in STANISLAS (all FDR <0.05). Among these biomarkers, spironolactone decreased concentrations of MMP-2 and NT-proBNP, regardless of baseline LAVi (pinteraction > 0.10). Spironolactone also significantly reduced LAVi, improved left ventricular ejection fraction, lowered E/e', blood pressure and serum procollagen type I C-terminal propeptide (PICP) concentration, a collagen synthesis marker, regardless of baseline LAVi (pinteraction > 0.10). CONCLUSION: In individuals without heart failure, LAVi was associated with MMP-2, IGFBP-2 and NT-proBNP. Spironolactone reduced these biomarker concentrations as well as LAVi and PICP, irrespective of left atrial size.
Asunto(s)
Atrios Cardíacos , Insuficiencia Cardíaca , Antagonistas de Receptores de Mineralocorticoides , Proteómica , Espironolactona , Humanos , Espironolactona/uso terapéutico , Femenino , Masculino , Atrios Cardíacos/fisiopatología , Atrios Cardíacos/patología , Atrios Cardíacos/diagnóstico por imagen , Atrios Cardíacos/metabolismo , Atrios Cardíacos/efectos de los fármacos , Anciano , Proteómica/métodos , Persona de Mediana Edad , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/fisiopatología , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Antagonistas de Receptores de Mineralocorticoides/farmacología , Biomarcadores/sangre , Péptido Natriurético Encefálico/sangre , Metaloproteinasa 2 de la Matriz/sangre , Metaloproteinasa 2 de la Matriz/metabolismo , Fragmentos de Péptidos/sangre , Volumen Sistólico/fisiologíaRESUMEN
OBJECTIVE: This study aims to explore the impact of sodium-glucose cotransporter-2 (SGLT-2) inhibitors, a newer class of oral antidiabetic drugs, on atrial electromechanical delay (EMD) in patients with type 2 diabetes mellitus (DM). This is particularly relevant given the significantly higher incidence of atrial fibrillation (AF) in diabetic patients compared to the general population. Atrial electromechanical delay is recognized as an important factor influencing the development of atrial fibrillation. METHODS: This study included 30 type 2 DM patients (53.3% female, mean age 60.07 ± 10.03 years), initiating treatment with SGLT-2 inhibitors. The patients were assessed using echocardiography at baseline and again at 6 months, focusing on basic echocardiographic parameters and atrial electromechanical delay times (EMD) measured via tissue Doppler imaging. RESULTS: No significant changes were observed in intra-atrial EMD times. However, significant reductions were noted in interatrial EMD times, decreasing from 15.13 ± 5.87 ms to 13.20 ± 6.12 ms (P = 0.029). Statistically significant shortening occurred in lateral pulmonary acceleration (PA) times (from 58.73 ± 6.41 ms to 54.37 ± 6.97 ms, P < 0.001), septal PA times (from 50.90 ± 6.02 ms to 48.23 ± 5), and tricuspid PA times (from 43.60 ± 6.28 ms to 41.30 ± 5.60 ms, P = 0.003). Additionally, there was a significant reduction in the E/e' ratio from 8.13 ± 4.0 to 6.50 ± 2.37 (P = 0.003). CONCLUSION: SGLT-2 inhibitors might positively influence atrial electromechanical conduction, reducing DM-related functional impairments and the risk of arrhythmias, particularly AF.
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Fibrilación Atrial , Diabetes Mellitus Tipo 2 , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Femenino , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/complicaciones , Persona de Mediana Edad , Masculino , Fibrilación Atrial/tratamiento farmacológico , Fibrilación Atrial/fisiopatología , Atrios Cardíacos/diagnóstico por imagen , Atrios Cardíacos/efectos de los fármacos , Atrios Cardíacos/fisiopatología , Anciano , Sistema de Conducción Cardíaco/efectos de los fármacos , Sistema de Conducción Cardíaco/fisiopatología , EcocardiografíaRESUMEN
AIM: Atrial fibrillation (AF), the most common arrhythmia, is characterized by atrial electrical and structural remodeling. Previous studies have found that sodium-glucose cotransporter 2 inhibitor (SGLT2i) can protect myocardium in a glucose independent mechanism. But the role of SGLT2i in regulating AF remains largely unknown. This study, we aimed to investigate the effect of Dapagliflozin (DAPA) in reducing AF susceptibility via inhibiting electrical and structural remodeling. METHOD: The mouse model was established by Angiotensin II (2000 ng/kg/min) infusion for 3 weeks, and an in vitro model was generated by stimulating HL-1 and primary mouse fibroblast with Ang II (1 µM) for 24 h. Programmed electrical stimulation, ECG and whole-cell patch clamp were used to detect DAPA effect on atrial electrical remodeling induced by Ang II. To observe DAPA effect on atrial structural remodeling induced by Ang II, we used echocardiographic, H&E and Masson staining to evaluate atrial dilation. To further explore the protective mechanism of DAPA, we adopt in silico molecular docking approaches to investigate the binding affinity of Ang II and CaMKII at Met-281 site. Western blot was to detect expression level of CaMKII, ox-CaMKII, Nav1.5, Kv4.3, Kv4.2, Kchip2, Kir2.1 and Cx40. RESULTS: Ang II induced AF, atrial dilatation and fibrosis, led to atrial electrical and structural remodeling. However, these effects were markedly abrogated by DAPA treatment, a specific SGLT2i. Our observation of atrial electrical activity in mice revealed that DAPA could rescue the prolonged action potential duration (APD) and the abnormal currents of IK1, Ito and INaL triggered by Ang II infusion. DAPA could reduce the binding affinity of Ang II and CaMKII at Met-281 site, which indicated that DAPA may directly alleviate the activation of CaMKII caused by Ang II. DAPA could reduce the upregulation of ox-CaMKII caused by Ang II infusion in atrial tissues. Moreover, DAPA also ameliorated the aberrant expression levels of electrical activity related proteins (Nav1.5, Kv4.3, Kv4.2, Kchip2, Kir2.1 and Cx40) and fibrosis related signal pathways (TGF-ß1, p-smad/smad) caused by Ang II. Furthermore, we confirmed that DAPA, as well as other SGLT2i (EMPA, CANA), could reverse these abnormalities caused by Ang II incubation in HL-1 cells and primary mouse fibroblasts, respectively. CONCLUSION: Overall, our study identifies DAPA, a widely used SGLT2i, contributes to inhibiting Ang II-induced ox-CaMKII upregulation and electrical and structural remodeling to reduce AF susceptibility, suggesting that DAPA may be a potential therapy of treating AF.
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Angiotensina II , Fibrilación Atrial , Remodelación Atrial , Compuestos de Bencidrilo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina , Glucósidos , Atrios Cardíacos , Simulación del Acoplamiento Molecular , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Animales , Angiotensina II/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Fibrilación Atrial/inducido químicamente , Fibrilación Atrial/metabolismo , Fibrilación Atrial/tratamiento farmacológico , Fibrilación Atrial/fisiopatología , Remodelación Atrial/efectos de los fármacos , Glucósidos/farmacología , Ratones , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Atrios Cardíacos/efectos de los fármacos , Atrios Cardíacos/metabolismo , Atrios Cardíacos/fisiopatología , Atrios Cardíacos/patología , Masculino , Compuestos de Bencidrilo/farmacología , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Línea CelularRESUMEN
Several fungi belonging to the genus Psilocybe, also called "magic mushrooms", contain the hallucinogenic drugs psilocybin and psilocin. They are chemically related to serotonin (5-HT). In addition to being abused as drugs, they are now also being discussed or used as a treatment option for depression. Here, we hypothesized that psilocybin and psilocin may act also on cardiac serotonin receptors and studied them in vitro in atrial preparations of our transgenic mouse model with cardiac myocytes-specific overexpression of the human 5-HT4 receptor (5-HT4-TG) as well as in human atrial preparations. Both psilocybin and psilocin enhanced the force of contraction in isolated left atrial preparations from 5-HT4-TG, increased the beating rate in isolated spontaneously beating right atrial preparations from 5-HT4-TG and augmented the force of contraction in the human atrial preparations. The inotropic and chronotropic effects of psilocybin and psilocin at 10⯵M were smaller than that of 1⯵M 5-HT on the left and right atria from 5-HT4-TG, respectively. Psilocybin and psilocin were inactive in WT. In the human atrial preparations, inhibition of the phosphodiesterase III by cilostamide was necessary to unmask the positive inotropic effects of psilocybin or psilocin. The effects of 10⯵M psilocybin and psilocin were abrogated by 10⯵M tropisetron or by 1⯵M GR125487, a more selective 5-HT4 receptor antagonist. In summary, we demonstrated that psilocin and psilocybin act as agonists on cardiac 5-HT4 receptors.
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Atrios Cardíacos , Ratones Transgénicos , Psilocibina , Receptores de Serotonina 5-HT4 , Psilocibina/farmacología , Psilocibina/análogos & derivados , Animales , Humanos , Receptores de Serotonina 5-HT4/metabolismo , Receptores de Serotonina 5-HT4/genética , Atrios Cardíacos/efectos de los fármacos , Atrios Cardíacos/metabolismo , Masculino , Contracción Miocárdica/efectos de los fármacos , Alucinógenos/farmacología , Alucinógenos/toxicidad , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Ratones , Agonistas del Receptor de Serotonina 5-HT4/farmacología , Frecuencia Cardíaca/efectos de los fármacos , FemeninoRESUMEN
BACKGROUND: Extracellular vesicles (EVs) isolated from human heart-derived cells have shown promise in suppressing inflammation and fibroblast proliferation. However, their precise benefits in atrial fibrillation (AF) prevention and the role of their antifibrotic/anti-inflammatory properties remain unclear. OBJECTIVES: The purpose of this study was to conduct a head-to-head comparison of antiarrhythmic strategies to prevent postoperative AF using a rat model of sterile pericarditis. Specifically, we aimed to assess the efficacy of amiodarone (a classic antiarrhythmic drug), colchicine (an anti-inflammatory agent), and EVs derived from human heart-derived cells, which possess anti-inflammatory and antifibrotic properties, on AF induction, inflammation, and fibrosis progression. METHODS: Heart-derived cells were cultured from human atrial appendages under serum-free xenogen-free conditions. Middle-aged Sprague Dawley rats were randomized into different groups, including sham operation, sterile pericarditis with amiodarone treatment, sterile pericarditis with colchicine treatment (2 dose levels), and sterile pericarditis with intra-atrial injection of EVs or vehicle. Invasive electrophysiological testing was performed 3 days after surgery before sacrifice. RESULTS: Sterile pericarditis increased the likelihood of inducing AF. Colchicine and EVs exhibited anti-inflammatory effects, but only EV treatment significantly reduced AF probability, whereas colchicine showed a positive trend without statistical significance. EVs and high-dose colchicine reduced atrial fibrosis by 46% ± 2% and 26% ± 2%, respectively. Amiodarone prevented AF induction but had no effect on inflammation or fibrosis. CONCLUSIONS: In this study, both amiodarone and EVs prevented AF, whereas treatment with colchicine was ineffective. The additional anti-inflammatory and antifibrotic effects of EVs suggest their potential as a comprehensive therapeutic approach for AF prevention, surpassing the effects of amiodarone or colchicine.
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Amiodarona , Antiarrítmicos , Fibrilación Atrial , Colchicina , Fibrosis , Ratas Sprague-Dawley , Fibrilación Atrial/tratamiento farmacológico , Colchicina/farmacología , Colchicina/uso terapéutico , Amiodarona/farmacología , Amiodarona/uso terapéutico , Animales , Ratas , Antiarrítmicos/farmacología , Antiarrítmicos/uso terapéutico , Humanos , Masculino , Atrios Cardíacos/efectos de los fármacos , Atrios Cardíacos/patología , Inflamación/tratamiento farmacológico , Complicaciones Posoperatorias/prevención & control , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Pericarditis/tratamiento farmacológico , Vesículas Extracelulares/efectos de los fármacos , Modelos Animales de Enfermedad , Células CultivadasRESUMEN
Age is an independent risk factor for atrial fibrillation (AF), and curcumin can delay aging related disease through reducing oxidative stress and inflammation. However, its target in aging-related AF remains unclear. Transfer RNA-derived small RNA (tsRNA) is a novel short non-coding RNA (sncRNA), and exerts a potential regulatory function in aging. This study was to explore the therapeutic targets of curcumin in atrium of aged mice by PANDORA-seq. Aged mice (18 month) were treated with curcumin (100 mg/kg). Rapid transjugular atrial pacing was performed to observe AF inducibility. SA-ß-gal staining, reactive oxygen species (ROS) detection and qRT-PCR were used to assess the degree of aging and oxidative stress/inflammation levels. PANDORA-seq was performed to reveal the differentially expressed sncRNAs in the atrium of mice. The results showed that curcumin reduced the susceptibility AF of aged mice by improving aging-related atrial fibrosis. Compared to young mice (5 month) group, aged mice yielded 473 significantly altered tsRNA sequences, while 947 tsRNA sequences were significantly altered after treated with curcumin. Enrichment analysis revealed that the target genes were mainly related to DNA damage and protein modification. Compared with the 5 month group, the expression levels of mature-mt_tRNA-Val-TAC_CCA_end, mature-mt_tRNA-Glu-TTC_CCA_end, and mature-tRNA-Asp-GTC_CCA_end were up-regulated in the 18 month group, while the expression of mature-mt_tRNA-Thr-TGT_5_end was down-regulated. This trend was reversed in the 18 month + curcumin group. Increased cellular ROS levels, inflammation expression and senescence in aged mice atrium were improved by the down-regulation of mature-mt_tRNA-Val-TAC_CCA_end. In conclusion, our findings identified mature-mt_tRNA-Val-TAC_CCA_end participated in the mechanism of aging-related atrial fibrosis, providing new intervention target of aging-related AF.
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Envejecimiento , Fibrilación Atrial , Curcumina , Atrios Cardíacos , Estrés Oxidativo , Animales , Curcumina/farmacología , Fibrilación Atrial/genética , Fibrilación Atrial/metabolismo , Fibrilación Atrial/tratamiento farmacológico , Ratones , Envejecimiento/efectos de los fármacos , Envejecimiento/genética , Atrios Cardíacos/efectos de los fármacos , Atrios Cardíacos/metabolismo , Atrios Cardíacos/patología , Estrés Oxidativo/efectos de los fármacos , ARN de Transferencia/genética , ARN de Transferencia/metabolismo , Masculino , ARN Pequeño no Traducido/genética , ARN Pequeño no Traducido/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Fibrosis , Modelos Animales de Enfermedad , Ratones Endogámicos C57BLRESUMEN
OBJECTIVE: This study aimed to elucidate the molecular mechanisms by which BRD4 play a role in atrial fibrillation (AF). METHODS AND RESULTS: We used a discovery-driven approach to detect BRD4 expression in the atria of patients with AF and in various murine models of atrial fibrosis. We used a BRD4 inhibitor (JQ1) and atrial fibroblast (aFB)-specific BRD4-knockout mice to elucidate the role of BRD4 in AF. We further examined the underlying mechanisms using RNA-seq and ChIP-seq analyses in vitro, to identify key downstream targets of BRD4. We found that BRD4 expression is significantly increased in patients with AF, with accompanying atrial fibrosis and aFB differentiation. We showed that JQ1 treatment and shRNA-based molecular silencing of BRD4 blocked ANG-II-induced extracellular matrix production and cell-cycle progression in aFBs. BRD4-related RNA-seq and ChIP-seq analyses in aFBs demonstrated enrichment of a subset of promoters related to the expression of profibrotic and proliferation-related genes. The pharmacological inhibition of BRD4 in vivo or in aFB-specific BRD4-knockout in mice limited ANG-II-induced atrial fibrosis, atrial enlargement, and AF susceptibility. CONCLUSION: Our findings suggest that BRD4 plays a key role in pathological AF, at least partially by activating aFB proliferation and ECM synthesis. This study provides mechanistic insights into the development of BRD4 inhibitors as targeted antiarrhythmic therapies.