RESUMEN
BACKGROUND: Atrial fibrillation has an estimated prevalence of 1.5-2%, making it the most common cardiac arrhythmia. The processes that cause and sustain the disease are still not completely understood. An association between atrial fibrillation and systemic, as well as local, inflammatory processes has been reported. However, the exact mechanisms underlying this association have not been established. While it is understood that inflammatory macrophages can influence cardiac electrophysiology, a direct, causative relationship to atrial fibrillation has not been described. This study investigated the pro-arrhythmic effects of activated M1 macrophages on human induced pluripotent stem cell (hiPSC)-derived atrial cardiomyocytes, to propose a mechanistic link between inflammation and atrial fibrillation. METHODS: Two hiPSC lines from healthy individuals were differentiated to atrial cardiomyocytes and M1 macrophages and integrated in an isogenic, pacing-free, atrial fibrillation-like coculture model. Electrophysiology characteristics of cocultures were analysed for beat rate irregularity, electrogram amplitude and conduction velocity using multi electrode arrays. Cocultures were additionally treated using glucocorticoids to suppress M1 inflammation. Bulk RNA sequencing was performed on coculture-isolated atrial cardiomyocytes and compared to meta-analyses of atrial fibrillation patient transcriptomes. RESULTS: Multi electrode array recordings revealed M1 to cause irregular beating and reduced electrogram amplitude. Conduction analysis further showed significantly lowered conduction homogeneity in M1 cocultures. Transcriptome sequencing revealed reduced expression of key cardiac genes such as SCN5A, KCNA5, ATP1A1, and GJA5 in the atrial cardiomyocytes. Meta-analysis of atrial fibrillation patient transcriptomes showed high correlation to the in vitro model. Treatment of the coculture with glucocorticoids showed reversal of phenotypes, including reduced beat irregularity, improved conduction, and reversed RNA expression profiles. CONCLUSIONS: This study establishes a causal relationship between M1 activation and the development of subsequent atrial arrhythmia, documented as irregularity in spontaneous electrical activation in atrial cardiomyocytes cocultured with activated macrophages. Further, beat rate irregularity could be alleviated using glucocorticoids. Overall, these results point at macrophage-mediated inflammation as a potential AF induction mechanism and offer new targets for therapeutic development. The findings strongly support the relevance of the proposed hiPSC-derived coculture model and present it as a first of its kind disease model.
Asunto(s)
Fibrilación Atrial , Técnicas de Cocultivo , Células Madre Pluripotentes Inducidas , Macrófagos , Miocitos Cardíacos , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Células Madre Pluripotentes Inducidas/citología , Miocitos Cardíacos/metabolismo , Fibrilación Atrial/metabolismo , Fibrilación Atrial/patología , Macrófagos/metabolismo , Fenotipo , Diferenciación Celular , Atrios Cardíacos/patología , Atrios Cardíacos/metabolismo , Atrios Cardíacos/citologíaRESUMEN
Atrial fibrillation (AF) is the most common sustained arrhythmia and carries an increased risk of stroke and heart failure. Here we investigated how the immune infiltrate of human epicardial adipose tissue (EAT), which directly overlies the myocardium, contributes to AF. Flow cytometry analysis revealed an enrichment of tissue-resident memory T (TRM) cells in patients with AF. Cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) and single-cell T cell receptor (TCR) sequencing identified two transcriptionally distinct CD8+ TRM cells that are modulated in AF. Spatial transcriptomic analysis of EAT and atrial tissue identified the border region between the tissues to be a region of intense inflammatory and fibrotic activity, and the addition of TRM populations to atrial cardiomyocytes demonstrated their ability to differentially alter calcium flux as well as activate inflammatory and apoptotic signaling pathways. This study identified EAT as a reservoir of TRM cells that can directly modulate vulnerability to cardiac arrhythmia.
Asunto(s)
Tejido Adiposo , Fibrilación Atrial , Células T de Memoria , Pericardio , Fibrilación Atrial/inmunología , Fibrilación Atrial/genética , Fibrilación Atrial/patología , Fibrilación Atrial/metabolismo , Humanos , Pericardio/metabolismo , Pericardio/patología , Pericardio/inmunología , Tejido Adiposo/metabolismo , Tejido Adiposo/inmunología , Tejido Adiposo/patología , Células T de Memoria/inmunología , Células T de Memoria/metabolismo , Masculino , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Transcriptoma , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Miocitos Cardíacos/inmunología , Femenino , Persona de Mediana Edad , Perfilación de la Expresión Génica , Anciano , Fenotipo , Señalización del Calcio , Apoptosis , Memoria Inmunológica , Transcripción Genética , Estudios de Casos y Controles , Atrios Cardíacos/patología , Atrios Cardíacos/inmunología , Atrios Cardíacos/metabolismo , Fibrosis/patología , Tejido Adiposo EpicárdicoRESUMEN
BACKGROUND: Obesity increases the risk of atrial fibrillation (AF). We hypothesize that 'obese' epicardial adipose tissue (EAT) is, regardless of comorbidities, associated with markers of AF vulnerability. METHODS: Patients >40y of age undergoing bariatric surgery and using <2 antihypertensive drugs and no insulin were prospectively included. Study investigations were conducted before and 1y after surgery. Heart rhythm and p-wave duration were measured through ECGs and 7-d-holters. EAT-volume and attenuation were determined on non-enhanced CT scans. Serum markers were quantified by ELISA. RESULTS: Thirty-seven patients underwent surgery (age: 52.1 ± 5.9y; 27 women; no AF). Increased p-wave duration correlated with higher BMI, larger EAT volumes, and lower EAT attenuations (p < 0.05). Post-surgery, p-wave duration decreased from 109 ± 11 to 102 ± 11ms. Concurrently, EAT volume decreased from 132 ± 49 to 87 ± 52ml, BMI from 43.2 ± 5.2 to 28.9 ± 4.6kg/m2, and EAT attenuation increased from -76.1 ± 4.0 to -71.7 ± 4.4HU (p <0.001). Adiponectin increased from 8.7 ± 0.8 to 14.2 ± 1.0 µg/ml (p <0.001). However, decreased p-wave durations were not related to changed EAT characteristics, BMI or adiponectin. CONCLUSION: In this explorative study, longer p-wave durations related to higher BMIs, larger EAT volume, and lower EAT attenuations. P-wave duration and EAT volume decreased, and EAT attenuation increased upon drastic weightloss. However, there was no relation between decreased p-wave duration and changed BMI or EAT characteristics.
Asunto(s)
Tejido Adiposo , Fibrilación Atrial , Pericardio , Pérdida de Peso , Humanos , Fibrilación Atrial/metabolismo , Fibrilación Atrial/fisiopatología , Femenino , Persona de Mediana Edad , Masculino , Tejido Adiposo/metabolismo , Pericardio/metabolismo , Pericardio/patología , Obesidad/metabolismo , Estudios Prospectivos , Adiponectina/metabolismo , Adiponectina/sangre , Cirugía Bariátrica , Índice de Masa Corporal , Tejido Adiposo EpicárdicoRESUMEN
Catheter ablation (CA) is an essential method for the interventional treatment of atrial fibrillation (AF), and it is very important to reduce long-term recurrence after CA. The mechanism of recurrence after CA is still unclear. We established a long-term model of beagle canines after circumferential pulmonary vein ablation (CPVA). The transcriptome and proteome were obtained using high-throughput sequencing and TMT-tagged LC-MS/LC analysis, respectively. Differentially expressed genes and proteins were screened and enriched, and the effect of fibrosis was found and verified in tissues. A downregulated protein, neuropeptide Y (NPY), was selected for validation and the results suggest that NPY may play a role in the long-term reinduction of AF after CPVA. Then, the molecular mechanism of NPY was further investigated. The results showed that the atrial effective refractory period (AERP) was shortened and fibrosis was increased after CPVA. Atrial myocyte apoptosis was alleviated by NPY intervention, and Akt activation was inhibited in cardiac fibroblasts. These results suggest that long-term suppression of NPY after CPVA may lead to induction of AF through promoting cardiomyocyte apoptosis and activating the Akt pathway in cardiac fibroblasts, which may make AF more likely to reinduce.
Asunto(s)
Apoptosis , Fibrilación Atrial , Ablación por Catéter , Miocardio , Neuropéptido Y , Venas Pulmonares , Animales , Perros , Apoptosis/efectos de los fármacos , Fibrilación Atrial/metabolismo , Fibrilación Atrial/cirugía , Fibrilación Atrial/patología , Ablación por Catéter/métodos , Modelos Animales de Enfermedad , Fibrosis , Atrios Cardíacos/metabolismo , Atrios Cardíacos/patología , Multiómica , Miocardio/metabolismo , Miocardio/patología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Neuropéptido Y/metabolismo , Proteoma/metabolismo , Proteómica/métodos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Venas Pulmonares/metabolismo , Venas Pulmonares/cirugía , TranscriptomaRESUMEN
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
BACKGROUND: Atrial cardiomyopathy (ACM) is responsible for atrial fibrillation (AF) and thromboembolic events. Diabetes mellitus (DM) is an important risk factor for ACM. However, the potential mechanism between ACM and DM remains elusive. METHODS: Atrial tissue samples were obtained from patients diagnosed with AF or sinus rhythm (SR) to assess alterations in NR4A3 expression, and then two distinct animal models were generated by subjecting Nr4a3-/- mice and WT mice to a high-fat diet (HFD) and Streptozotocin (STZ), while db/db mice were administered AAV9-Nr4a3 or AAV9-ctrl. Subsequently, in vivo and in vitro experiments were conducted to assess the impact of NR4A3 on diabetes-induced atrial remodeling through electrophysiological, biological, and histological analyses. RNA sequencing (RNA-seq) and metabolomics analysis were employed to unravel the downstream mechanisms. FINDINGS: The expression of NR4A3 was significantly decreased in atrial tissues of both AF patients and diabetic mice compared to their respective control groups. NR4A3 deficiency exacerbated atrial hypertrophy and atrial fibrosis, and increased susceptibility to pacing-induced AF. Conversely, overexpression of NR4A3 alleviated atrial structural remodeling and reduced AF induction rate. Mechanistically, we confirmed that NR4A3 improves mitochondrial energy metabolism and reduces oxidative stress injury by preserving the transcriptional expression of Sdha, thereby exerting a protective influence on atrial remodeling induced by diabetes. INTERPRETATION: Our data confirm that NR4A3 plays a protective role in atrial remodeling caused by diabetes, so it may be a new target for treating ACM. FUNDING: This study was supported by the major research program of National Natural Science Foundation of China (NSFC) No: 82370316 (to Q-S. W.), No. 81974041 (to Y-P. W.), and No. 82270447 (to Y-P. W.) and Fundation of Shanghai Hospital Development Center (No. SHDC2022CRD044 to Q-S. W.).
Asunto(s)
Diabetes Mellitus Experimental , Metabolismo Energético , Estrés Oxidativo , Animales , Ratones , Humanos , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/complicaciones , Masculino , Ratones Noqueados , Receptores de Hormona Tiroidea/metabolismo , Receptores de Hormona Tiroidea/genética , Atrios Cardíacos/metabolismo , Atrios Cardíacos/patología , Fibrilación Atrial/metabolismo , Fibrilación Atrial/etiología , Fibrilación Atrial/prevención & control , Modelos Animales de Enfermedad , Mitocondrias/metabolismo , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/etiología , Cardiomiopatías Diabéticas/genética , Cardiomiopatías Diabéticas/patología , Cardiomiopatías Diabéticas/prevención & control , Cardiomiopatías/etiología , Cardiomiopatías/metabolismo , Remodelación Atrial , Proteínas de Unión al ADN , Receptores de EsteroidesRESUMEN
Atrial fibrosis is associated with the occurrence of atrial fibrillation (AF) and regulated by the transforming growth factor-ß1 (TGF-ß1)/Smad2/3 signalling pathway. Unfortunately, the mechanisms of regulation of TGF-ß1/Smad2/3-induced atrial fibrosis and vulnerability to AF remain still unknown. Previous studies have shown that sirtuin3 (SIRT3) sulfhydration has strong anti-fibrotic effects. We hypothesised that SIRT3 sulfhydration inhibits angiotensin II (Ang-II)-induced atrial fibrosis via blocking the TGF-ß1/Smad2/3 signalling pathway. In this study, we found that SIRT3 expression was decreased in the left atrium of patients with AF compared to that in those with sinus rhythm (SR). In vitro, SIRT3 knockdown by small interfering RNA significantly expanded Ang-II-induced atrial fibrosis and TGF-ß1/Smad2/3 signalling pathway activation, whereas supplementation with Sodium Hydrosulfide (NaHS, exogenous hydrogen sulfide donor and sulfhydration agonist) and SIRT3 overexpression using adenovirus ameliorated Ang-II-induced atrial fibrosis. Moreover, we observed suppression of the TGF-ß1/Smad2/3 pathway when Ang-II was combined with NaHS treatment, and the effect of this co-treatment was consistent with that of Ang-II combined with LY3200882 (Smad pathway inhibitor) on reducing atrial fibroblast proliferation and cell migration in vitro. Supplementation with dithiothreitol (DTT, a sulfhydration inhibitor) and adenovirus SIRT3 shRNA blocked the ameliorating effect of NaHS and AngII co-treatment on atrial fibrosis in vitro. Finally, continued treatment with NaHS in rats ameliorated atrial fibrosis and remodelling, and further improved AF vulnerability induced by Ang-II, which was reversed by DTT and adenovirus SIRT3 shRNA, suggesting that SIRT3 sulfhydration might be a potential therapeutic target in atrial fibrosis and AF.
Asunto(s)
Angiotensina II , Fibrilación Atrial , Fibrosis , Atrios Cardíacos , Sulfuro de Hidrógeno , Transducción de Señal , Sirtuina 3 , Proteína Smad2 , Proteína smad3 , Factor de Crecimiento Transformador beta1 , Angiotensina II/farmacología , Sirtuina 3/metabolismo , Sirtuina 3/genética , Fibrilación Atrial/metabolismo , Fibrilación Atrial/patología , Fibrilación Atrial/prevención & control , Factor de Crecimiento Transformador beta1/metabolismo , Transducción de Señal/efectos de los fármacos , Proteína smad3/metabolismo , Animales , Proteína Smad2/metabolismo , Atrios Cardíacos/efectos de los fármacos , Atrios Cardíacos/metabolismo , Atrios Cardíacos/patología , Sulfuro de Hidrógeno/farmacología , Sulfuro de Hidrógeno/metabolismo , Masculino , Humanos , Ratas , Ratas Sprague-Dawley , Femenino , Persona de Mediana Edad , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacosRESUMEN
Obesity is linked to an increased risk of atrial fibrillation (AF) via increased oxidative stress. While NADPH oxidase 2 (NOX2), a major source of oxidative stress and reactive oxygen species (ROS) in the heart, predisposes to AF, the underlying mechanisms remain unclear. Here, we studied NOX2-mediated ROS production in obesity-mediated AF using Nox2-knockout mice and mature human induced pluripotent stem cell-derived atrial cardiomyocytes (hiPSC-aCMs). Diet-induced obesity (DIO) mice and hiPSC-aCMs treated with palmitic acid (PA) were infused with a NOX blocker (apocynin) and a NOX2-specific inhibitor, respectively. We showed that NOX2 inhibition normalized atrial action potential duration and abrogated obesity-mediated ion channel remodeling with reduced AF burden. Unbiased transcriptomics analysis revealed that NOX2 mediates atrial remodeling in obesity-mediated AF in DIO mice, PA-treated hiPSC-aCMs, and human atrial tissue from obese individuals by upregulation of paired-like homeodomain transcription factor 2 (PITX2). Furthermore, hiPSC-aCMs treated with hydrogen peroxide, a NOX2 surrogate, displayed increased PITX2 expression, establishing a mechanistic link between increased NOX2-mediated ROS production and modulation of PITX2. Our findings offer insights into possible mechanisms through which obesity triggers AF and support NOX2 inhibition as a potential novel prophylactic or adjunctive therapy for patients with obesity-mediated AF.
Asunto(s)
Fibrilación Atrial , Ratones Noqueados , Miocitos Cardíacos , NADPH Oxidasa 2 , Obesidad , NADPH Oxidasa 2/genética , NADPH Oxidasa 2/metabolismo , Fibrilación Atrial/genética , Fibrilación Atrial/metabolismo , Fibrilación Atrial/patología , Fibrilación Atrial/etiología , Fibrilación Atrial/enzimología , Animales , Obesidad/genética , Obesidad/metabolismo , Obesidad/patología , Ratones , Humanos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Miocitos Cardíacos/enzimología , Especies Reactivas de Oxígeno/metabolismo , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Células Madre Pluripotentes Inducidas/metabolismo , Masculino , Estrés Oxidativo , Remodelación AtrialRESUMEN
Atrial fibrillation (AF) is the most prevalent sustained tachyarrhythmia in patients with cardiovascular diseases. Recently, it has been discovered that oxidative stress is an important contributor to AF. Therefore, antioxidant therapies for AF have great potential for clinical applications. Methionine, a sulfur-containing amino acid residue other than cysteine, is recognized as a functional redox switch, which could be rescued from the reversible oxidation of methionine sulfoxide by methionine sulfoxide reductase A (MsrA). S-Methyl-L-cysteine (SMLC), a natural analogue of Met, which is abundantly found in garlic and cabbage, could substitute for Met oxidations and mediate MsrA to scavenge free radicals. However, whether SMLC alleviates AF is unclear. This study aims to clarify the effects of SMLC on AF and elucidate the underlying pharmacological and molecular mechanisms. In vivo, SMLC (70, 140 and 280 mg kg-1 day-1) was orally administered to mice for 4 weeks with angiotensin II (Ang II) by subcutaneous infusion using osmotic pumps to induce AF. Ang II significantly prompted high AF susceptibility and atrial remodeling characterized by oxidative stress, conductive dysfunction and fibrosis. SMLC played a remarkable protective role in Ang II-induced atrial remodeling dose-dependently. Moreover, RNA sequencing was performed on atrial tissues to identify the differentially expressed mRNA, which was to screen out MSRA, CAMK2 and MAPK signaling pathways. Western blots confirmed that Ang II-induced downregulation of MsrA and upregulation of oxidized CaMKII (ox-CaMKII) and p38 MAPK could be reversed in a concentration-dependent manner by SMLC. To investigate the underlying mechanisms, HL-1 cells (mouse atria-derived cardiomyocytes) treated with Ang II were used for an in vitro model. SMLC alleviated Ang II-induced cytotoxicity, mitochondrial damage and oxidative stress. Additionally, knockdown MsrA could attenuate the protective effects of SMLC, which were eliminated by the p38 MAPK inhibitor SB203580. In summary, the present study demonstrates that SMLC protects against atrial remodeling in AF by inhibiting oxidative stress through the mediation of the MsrA/p38 MAPK signaling pathway.
Asunto(s)
Angiotensina II , Remodelación Atrial , Ratones Endogámicos C57BL , Estrés Oxidativo , Proteínas Quinasas p38 Activadas por Mitógenos , Animales , Ratones , Estrés Oxidativo/efectos de los fármacos , Angiotensina II/farmacología , Angiotensina II/análogos & derivados , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Masculino , Remodelación Atrial/efectos de los fármacos , Metionina Sulfóxido Reductasas/metabolismo , Metionina Sulfóxido Reductasas/genética , Fibrilación Atrial/tratamiento farmacológico , Fibrilación Atrial/metabolismo , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Cisteína/análogos & derivados , Cisteína/farmacologíaRESUMEN
BACKGROUND: Atrial fibrillation (AF) is associated with increased risk of stroke and mortality. It has been reported that the process of atrial fibrosis was regulated by ß-catenin in rats with AF. However, pathophysiological mechanisms of this process in human with AF remain unclear. This study aims to investigate the possible mechanisms of ß-catenin in participating in the atrial fibrosis using human right atrial appendage (hRAA) tissues . METHODS: We compared the difference of ß-catenin expression in hRAA tissues between the patients with AF and sinus rhythm (SR). The possible function of ß-catenin in the development of AF was also explored in mice and primary cells. RESULTS: Firstly, the space between the membrane of the gap junctions of cardiomyocytes was wider in the AF group. Secondly, the expression of the gap junction function related proteins, Connexin40 and Connexin43, was decreased, while the expression of ß-catenin and its binding partner E-cadherin was increased in hRAA and cardiomyocytes of the AF group. Thirdly, ß-catenin colocalized with E-cadherin on the plasma membrane of cardiomyocytes in the SR group, while they were dissociated and accumulated intracellularly in the AF group. Furthermore, the expression of glycogen synthase kinase 3ß (GSK-3ß) and Adenomatous Polyposis Coli (APC), which participated in the degradation of ß-catenin, was decreased in hRAA tissues and cardiomyocytes of the AF group. Finally, the development of atrial fibrosis and AF were proved to be prevented after inhibiting ß-catenin expression in the AF model mice. CONCLUSIONS: Based on human atrial pathological and molecular analyses, our findings provided evidence that ß-catenin was associated with atrial fibrosis and AF progression.
Asunto(s)
Fibrilación Atrial , Fibrosis , Atrios Cardíacos , Miocitos Cardíacos , beta Catenina , Anciano , Animales , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , Fibrilación Atrial/patología , Fibrilación Atrial/metabolismo , beta Catenina/metabolismo , Cadherinas/metabolismo , Conexina 43/metabolismo , Uniones Comunicantes/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Atrios Cardíacos/metabolismo , Atrios Cardíacos/patología , Ratones Endogámicos C57BL , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patologíaRESUMEN
BACKGROUND: Atrial fibrosis is associated with the pathogenesis of atrial fibrillation (AF). This study aims to discuss the function of circ_0079480 in atrial fibrosis and its underlying mechanism. METHODS: In vitro and in vivo models of atrial fibrosis were established by using angiotensin II (Ang II) to treat human atrial fibroblasts (HAFs) and C57/B6J mice. qRT-PCR and western blot were used to examine the mRNA and protein expression levels. CCK-8, EdU, cell strach, and transwell assays were performed to determine the proliferation and migration of HAFs. Dual-luciferase reporter and RIP/RNA pull-down assays were explored to identify the interaction of miR-338-3p and circ_0079480/THBS1. HE and Masson's trichrome staining experiments were performed to analyze the histopathological change in mice atrial tissues. RESULTS: Circ_0079480 expression was increased in AF patients' atrial tissues and Ang II-treated HAFs. Silencing circ_0079480 inhibited cell proliferation and migration and reduced fibrosis-associated gene expression in Ang II-treated HAFs. Circ_0079480 could target miR-338-3p to repress its expression. MiR-338-3p inhibitor blocked the inhibitory effects of circ_0079480 knockdown on HAFs proliferation, migration, and fibrosis. Thrombospondin-1 (THBS1) was confirmed as a downstream target of miR-338-3p, and circ_0079480 could sponge miR-338-3p to upregulate THBS1 expression. Moreover, silencing THBS1 suppressed Ang II-induced proliferation, migration, and fibrosis in HAFs. More importantly, depletion of circ_0079480 inactivated the THBS1/TGF-ß1/Smad3 signaling by upregulating miR-338-3p. Mice experiments also confirmed the suppression of circ_0079480 knockdown on atrial fibrosis. CONCLUSION: Circ_0079480 acts as a sponge of miR-338-3p to upregulate THBS1 expression and activate the TGF-ß1/Smad3 signaling, finally promoting Ang II-induced atrial fibrosis.
Asunto(s)
Fibrilación Atrial , Movimiento Celular , Proliferación Celular , Fibroblastos , Fibrosis , Atrios Cardíacos , Ratones Endogámicos C57BL , MicroARNs , ARN Circular , Transducción de Señal , Proteína smad3 , Trombospondina 1 , Factor de Crecimiento Transformador beta1 , Fibrilación Atrial/genética , Fibrilación Atrial/metabolismo , Fibrilación Atrial/patología , MicroARNs/genética , MicroARNs/metabolismo , Animales , Proteína smad3/metabolismo , Proteína smad3/genética , Ratones , Proliferación Celular/fisiología , Humanos , Factor de Crecimiento Transformador beta1/metabolismo , Trombospondina 1/genética , Trombospondina 1/metabolismo , Trombospondina 1/biosíntesis , Movimiento Celular/fisiología , ARN Circular/genética , ARN Circular/metabolismo , Fibroblastos/metabolismo , Fibroblastos/patología , Atrios Cardíacos/patología , Atrios Cardíacos/metabolismo , Transducción de Señal/fisiología , Masculino , Células CultivadasRESUMEN
BACKGROUND: The biological functions of mitochondrial complexes are closely related to the development of atrial fibrillation (AF). Calcium binding and coiled-coil domain 2 (CALCOCO2) is a novel and specific receptor for mitophagy; however, its function in AF remains unknown. Therefore, this study aimed to investigate the role and molecular mechanisms of CALCOCO2 in AF, especially its regulatory mechanism in mitophagy and mitochondrial stress. METHODS: Mice and HL-1 cells were treated with AngII to establish in vitro and in vivo AF models. Additionally, we examined the effect of CALCOCO2 or DAP3 Binding Cell Death Enhancer 1 (DELE1) overexpression on mitophagy and mitochondrial stress in AF models. To investigate the role of mitophagy in the regulatory effects of CALCOCO2 in AF, HL-1 cells were treated with chloroquine, a mitophagy inhibitor. Moreover, mitochondrial parameters were examined using specific fluorescent probes, transmission electron microscopy, western blotting, immunohistochemistry, and confocal microscopy. RESULTS: AngII severely impaired the normal morphology and function of mitochondria; inhibited mitophagy; promoted atrial mitochondrial stress, fibrosis, and oxidative stress; and accelerated the progression of atrial remodeling in atrial myocytes. However, CALCOCO2 overexpression reversed/ameliorated these AF-induced changes. Additionally, CALCOCO2 overexpression restored mitochondrial homeostasis in atrial muscle by activating mitophagy and ameliorating mitochondrial stress. Mechanistically, DELE1 overexpression increased mitochondrial reactive oxygen species level and the expression of mitochondrial stress proteins (HRI, eIF2α, and ATF4) even in CALCOCO2-expressing in vitro AF models.. CONCLUSIONS: CALCOCO2 may serve as a potential target for AF therapy to prevent or reverse the progression of atrial remodeling by regulating mitophagy and DELE1-mediated mitochondrial stress.
Asunto(s)
Angiotensina II , Fibrilación Atrial , Remodelación Atrial , Mitofagia , Animales , Humanos , Masculino , Ratones , Fibrilación Atrial/metabolismo , Proteínas de Unión al Calcio/metabolismo , Proteínas de Unión al Calcio/genética , Línea Celular , Modelos Animales de Enfermedad , Atrios Cardíacos/metabolismo , Atrios Cardíacos/patología , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , Mitofagia/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Estrés OxidativoRESUMEN
The E-twenty-six variant 1 (ETV1)-dependent transcriptome plays an important role in atrial electrical and structural remodelling and the occurrence of atrial fibrillation (AF), but the underlying mechanism of ETV1 in AF is unclear. In this study, cardiomyocyte-specific ETV1 knockout (ETV1f/fMyHCCre/+, ETV1-CKO) mice were constructed to observe the susceptibility to AF and the underlying mechanism in AF associated with ETV1-CKO mice. AF susceptibility was examined by intraesophageal burst pacing, induction of AF was increased obviously in ETV1-CKO mice than WT mice. Electrophysiology experiments indicated shortened APD50 and APD90, increased incidence of DADs, decreased density of ICa,L in ETV1-CKO mice. There was no difference in VINACT,1/2 and VACT,1/2, but a significantly longer duration of the recovery time after inactivation in the ETV1-CKO mice. The recording of intracellular Ca2+ showed that there was significantly increased in the frequency of calcium spark, Ca2+ transient amplitude, and proportion of SCaEs in ETV1-CKO mice. Reduction of Cav1.2 rather than NCX1 and SERCA2a, increase RyR2, p-RyR2 and CaMKII was reflected in ETV1-CKO group. This study demonstrates that the increase in calcium spark and SCaEs corresponding to Ca2+ transient amplitude may trigger DAD in membrane potential in ETV1-CKO mice, thereby increasing the risk of AF.
Asunto(s)
Fibrilación Atrial , Calcio , Atrios Cardíacos , Ratones Noqueados , Miocitos Cardíacos , Factores de Transcripción , Animales , Miocitos Cardíacos/metabolismo , Ratones , Fibrilación Atrial/metabolismo , Fibrilación Atrial/genética , Calcio/metabolismo , Atrios Cardíacos/metabolismo , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Señalización del Calcio , Potenciales de Acción , Potenciales de la Membrana , MasculinoRESUMEN
BACKGROUND: Direct oral anticoagulants (DOACs) have high potency against their therapeutic target and are widely used in the treatment of atrial fibrillation (AF). Most DOACs are often claimed to have adverse effects due to off-target inhibition of essential proteins. Human serum paraoxonase 1 (PON1), one of the essential proteins, known for its anti-inflammatory and antioxidant properties, could be affected by DOACs. Thus, a comparative evaluation of DOACs and their effect on PON1 protein will aid in recommending the most effective DOACs for AF treatment. This study aimed to assess the impact of DOACs on PON1 through a combination of computational and experimental analyses. METHODS: We focus on apixaban, dabigatran, and rivaroxaban, the most recommended DOACs in AF treatment, for their impact on PON1 through molecular docking and molecular dynamics (MD) simulation to elucidate the binding affinity and drug-protein structural stability. This investigation revealed the most influential DOACs on the PON1 protein. Then experimental validation was performed in DOAC-treated AF participants (n = 42; 19 treated with dabigatran and 23 treated with rivaroxaban) compared to a healthy control group (n = 22) through gene expression analysis in peripheral blood mononuclear cells (PBMC) and serum enzyme concentration. RESULTS: Our computational investigation showed rivaroxaban (-4.24 kcal/mol) exhibited a lower affinity against the PON1 protein compared to apixaban (-5.97 kcal/mol) and dabigatran (-9.03 kcal/mol) through molecular docking. Dabigatran holds complex interactions with PON1 at GLU53, TYR197, SER193, and ASP269 by forming hydrogen bonds. Additionally, MD simulation revealed that dabigatran disrupts PON1 stability, which may contribute functional changes. Further experimental validation revealed a significant down-regulation (p < 0.05) of PON1 gene expression in PBMC and decreased serum PON1 enzyme concentration on DOAC treatment. Rivaroxaban as about 48% has inhibitory percentage and dabigatran as about 75% of inhibitory percentage compared to healthy control. CONCLUSION: Overall, our computational and experimental results clearly show the higher inhibitory effect of dabigatran than rivaroxaban. Hence, rivaroxaban will be a better drug candidate for improving the outcome of AF.
Asunto(s)
Arildialquilfosfatasa , Fibrilación Atrial , Dabigatrán , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Piridonas , Rivaroxabán , Humanos , Fibrilación Atrial/tratamiento farmacológico , Fibrilación Atrial/metabolismo , Arildialquilfosfatasa/sangre , Rivaroxabán/uso terapéutico , Masculino , Piridonas/uso terapéutico , Pirazoles/farmacología , Pirazoles/uso terapéutico , Pirazoles/química , Administración Oral , Anticoagulantes/farmacología , Anticoagulantes/química , Femenino , Anciano , Persona de Mediana EdadRESUMEN
Atrial fibrillation (AF) is the most common clinical arrhythmia, however there is limited understanding of its pathophysiology including the cellular and ultrastructural changes rendered by the irregular rhythm, which limits pharmacological therapy development. Prior work has demonstrated the importance of reactive oxygen species (ROS) and mitochondrial dysfunction in the development of AF. Mitochondrial structure, interactions with other organelles such as sarcoplasmic reticulum (SR) and T-tubules (TT), and degradation of dysfunctional mitochondria via mitophagy are important processes to understand ultrastructural changes due to AF. However, most analysis of mitochondrial structure and interactome in AF has been limited to two-dimensional (2D) modalities such as transmission electron microscopy (EM), which does not fully visualize the morphological evolution of the mitochondria during mitophagy. Herein, we utilize focused ion beam-scanning electron microscopy (FIB-SEM) and perform reconstruction of three-dimensional (3D) EM from murine left atrial samples and measure the interactions of mitochondria with SR and TT. We developed a novel 3D quantitative analysis of FIB-SEM in a murine model of AF to quantify mitophagy stage, mitophagosome size in cardiomyocytes, and mitochondrial structural remodeling when compared with control mice. We show that in our murine model of spontaneous and continuous AF due to persistent late sodium current, left atrial cardiomyocytes have heterogenous mitochondria, with a significant number which are enlarged with increased elongation and structural complexity. Mitophagosomes in AF cardiomyocytes are located at Z-lines where they neighbor large, elongated mitochondria. Mitochondria in AF cardiomyocytes show increased organelle interaction, with 5X greater contact area with SR and are 4X as likely to interact with TT when compared to control. We show that mitophagy in AF cardiomyocytes involves 2.5X larger mitophagosomes that carry increased organelle contents. In conclusion, when oxidative stress overcomes compensatory mechanisms, mitophagy in AF faces a challenge of degrading bulky complex mitochondria, which may result in increased SR and TT contacts, perhaps allowing for mitochondrial Ca2+ maintenance and antioxidant production.
Asunto(s)
Fibrilación Atrial , Mitocondrias , Mitofagia , Miocitos Cardíacos , Animales , Ratones , Fibrilación Atrial/metabolismo , Fibrilación Atrial/patología , Miocitos Cardíacos/ultraestructura , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Mitocondrias/ultraestructura , Mitocondrias/metabolismo , Mitocondrias/patología , Retículo Sarcoplasmático/metabolismo , Retículo Sarcoplasmático/ultraestructura , Retículo Sarcoplasmático/patología , Mitocondrias Cardíacas/ultraestructura , Mitocondrias Cardíacas/metabolismo , Mitocondrias Cardíacas/patología , Imagenología Tridimensional/métodos , Masculino , Modelos Animales de Enfermedad , Microscopía Electrónica de Rastreo/métodosRESUMEN
Atrial fibrillation (AF) emerges as a critical complication following acute myocardial infarction (AMI) and is associated with a significant increased risk of heart failure, stroke and mortality. Ataxia telangiectasia mutated (ATM), a key player in DNA damage repair (DDR), has been implicated in multiple cardiovascular conditions, however, its involvement in the development of AF following AMI remains unexplored. This study seeks to clarify the contribution of the ATM/p53 pathway in the onset of AF post-AMI and to investigate the underlying mechanisms. The rat model of AMI was established by ligating left anterior descending coronary artery in the presence or absence of Ku55933 (an ATM kinase inhibitor, 5 mg/kg/d) treatment. Rats receiving Ku55933 were further divided into the early administration group (administered on days 1, 2, 4, and 7 post-AMI) and the late administration group (administered on days 8, 9, 11 and 14 post-AMI). RNA-sequencing was performed 14 days post-operation. In vitro, H2O2-challenged HL-1 atrial muscle cells were utilized to evaluate the potential effects of different ATM inhibition schemes, including earlier, middle, and late periods of intervention. Fourteen days post-AMI injury, the animals exhibited significantly increased AF inducibility, exacerbated atrial electrical/structural remodeling, reduced ventricular function and exacerbated atrial DNA damage, as evidenced by enhanced ATM/p53 signaling as well as γH2AX level. These effects were partially consistent with the enrichment results of bioinformatics analysis. Notably, the deleterious effects were ameliorated by early, but not late, administration of Ku55933. Mechanistically, inhibition of ATM signaling successfully suppressed atrial NLRP3 inflammasome-mediated pyroptotic pathway. Additionally, the results were validated in the in vitro experiments demonstrating that early inhibition of Ku55933 not only attenuated cellular ATM/p53 signaling, but also mitigated inflammatory response by reducing NLRP3 activation. Collectively, hyperactivation of ATM/p53 contributed to the pathogenesis of AF following AMI. Early intervention with ATM inhibitors substantially mitigated AF susceptibility and atrial electrical/structural remodeling, highlighting a novel therapeutic avenue against cardiac arrhythmia following AMI.
Asunto(s)
Proteínas de la Ataxia Telangiectasia Mutada , Fibrilación Atrial , Remodelación Atrial , Infarto del Miocardio , Transducción de Señal , Proteína p53 Supresora de Tumor , Animales , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Proteínas de la Ataxia Telangiectasia Mutada/antagonistas & inhibidores , Infarto del Miocardio/metabolismo , Infarto del Miocardio/complicaciones , Proteína p53 Supresora de Tumor/metabolismo , Fibrilación Atrial/metabolismo , Fibrilación Atrial/etiología , Ratas , Remodelación Atrial/efectos de los fármacos , Masculino , Transducción de Señal/efectos de los fármacos , Ratas Sprague-Dawley , Morfolinas/farmacología , TioxantenosRESUMEN
BACKGROUND: Aging is one of the most potent risk determinants for the onset of atrial fibrillation (AF). Sirts (sirtuins) have been implicated in the pathogenesis of cardiovascular disease, and their expression declines with aging. However, whether Sirts involved in age-related AF and its underlying mechanisms remain unknown. The present study aims to explore the role of Sirts in age-related AF and delineate the underlying molecular mechanisms. METHODS: Sirt1 levels in the atria of both elderly individuals and aging rats were evaluated using quantitative real-time polymerase chain reaction and Western blot analysis. Mice were engineered to specifically knockout Sirt1 in the atria and right ventricle (Sirt1mef2c/mef2c). Various techniques, such as echocardiography, atrial electrophysiology, and protein acetylation modification omics were employed. Additionally, coimmunoprecipitation was utilized to substantiate the interaction between Sirt1 and RIPK1 (receptor-interacting protein kinase 1). RESULTS: We discerned that among the diverse subtypes of sirtuin proteins, only Sirt1 expression was significantly diminished in the atria of elderly people and aged rats. The Sirt1mef2c/mef2c mice exhibited an enlarged atrial diameter and heightened vulnerability to AF. Acetylated proteomics and cell experiments identified that Sirt1 deficiency activated atrial necroptosis through increasing RIPK1 acetylation and subsequent pseudokinase MLKL (mixed lineage kinase domain-like protein) phosphorylation. Consistently, necroptotic inhibitor necrosulfonamide mitigated atrial necroptosis and diminished both the atrial diameter and AF susceptibility of Sirt1mef2c/mef2c mice. Resveratrol prevented age-related AF in rats by activating atrial Sirt1 and inhibiting necroptosis. CONCLUSIONS: Our findings first demonstrated that Sirt1 exerts significant efficacy in countering age-related AF by impeding atrial necroptosis through regulation of RIPK1 acetylation, highlighting that the activation of Sirt1 or the inhibition of necroptosis could potentially serve as a therapeutic strategy for age-related AF.
Asunto(s)
Fibrilación Atrial , Modelos Animales de Enfermedad , Atrios Cardíacos , Ratones Noqueados , Necroptosis , Proteína Serina-Treonina Quinasas de Interacción con Receptores , Sirtuina 1 , Anciano , Animales , Femenino , Humanos , Masculino , Ratones , Ratas , Acetilación , Factores de Edad , Envejecimiento/metabolismo , Envejecimiento/patología , Fibrilación Atrial/metabolismo , Fibrilación Atrial/genética , Fibrilación Atrial/fisiopatología , Fibrilación Atrial/prevención & control , Fibrilación Atrial/patología , Atrios Cardíacos/metabolismo , Atrios Cardíacos/patología , Atrios Cardíacos/fisiopatología , Ratones Endogámicos C57BL , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Ratas Sprague-Dawley , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con Receptores/genética , Transducción de Señal , Sirtuina 1/metabolismo , Sirtuina 1/genéticaRESUMEN
Healthy aging results in cardiac structural and electrical remodeling that increase susceptibility to cardiovascular diseases. Relaxin has shown broad cardioprotective effects including anti-fibrotic, anti-arrhythmic and anti-inflammatory outcomes in multiple models. This paper focuses on the cardioprotective effects of Relaxin in a rat model of aging. Sustained atrial or ventricular fibrillation are readily induced in the hearts of aged but not young control animals. Treatment with Relaxin suppressed this arrhythmogenic response by increasing conduction velocity, decreasing fibrosis and promoting substantial cardiac remodeling. Relaxin treatment resulted in a significant increase in the levels of: Nav1.5, Cx43, ßcatenin and Wnt1 in rat hearts. In isolated cardiomyocytes, Relaxin increased Nav1.5 expression. These effects were mimicked by CHIR 99021, a pharmacological activator of canonical Wnt signaling, but blocked by the canonical Wnt inhibitor Dickkopf1. Relaxin prevented TGF-ß-dependent differentiation of cardiac fibroblasts into myofibroblasts while increasing the expression of Wnt1; the effects of Relaxin on cardiac fibroblast differentiation were blocked by Dickkopf1. RNASeq studies demonstrated reduced expression of pro-inflammatory cytokines and an increase in the expression of α- and ß-globin in Relaxin-treated aged males. Relaxin reduces arrhythmogenicity in the hearts of aged rats by reduction of fibrosis and increased conduction velocity. These changes are accompanied by substantial remodeling of the cardiac tissue and appear to be mediated by increased canonical Wnt signaling. Relaxin also exerts significant anti-inflammatory and anti-oxidant effects in the hearts of aged rodents. The mechanisms by which Relaxin increases the expression of Wnt ligands, promotes Wnt signaling and reprograms gene expression remain to be determined.
Asunto(s)
Envejecimiento , Fibrilación Atrial , Fibrosis , Relaxina , Animales , Relaxina/farmacología , Masculino , Ratas , Fibrilación Atrial/metabolismo , Fibrilación Atrial/tratamiento farmacológico , Fibrilación Atrial/prevención & control , Envejecimiento/efectos de los fármacos , Inflamación/metabolismo , Inflamación/tratamiento farmacológico , Ratas Endogámicas F344RESUMEN
Left atrial strain (LAS) measured by two-dimensional speckle tracking echocardiography (2DSTE) is considered to be a marker of LA structural remodeling, but it remains unsettled. We investigated the potential usefulness and clinical relevance of LAS to detect atrial remodeling including fibrosis by analyzing gene expression in cardiovascular surgery patients. Preoperative 2DSTE was performed in 131 patients (92 patients with sinus rhythm [SR] patients including paroxysmal AF [PAF], 39 atrial fibrillation [AF]) undergoing cardiovascular surgery. Atrial samples were obtained from the left atrial appendages, and mRNA expression level was analyzed by real-time reverse transcription polymerase chain reaction (RT-PCR) in 59 cases (24 PAF, 35 AF). Mean value of left atrial reservoir strain (mLASr) correlated with left atrial volume index (LAVI), and left atrial conduit strain (mLAScd). mLASr also correlated with left atrial contractile strain (mLASct) in SR patients including PAF. mLASr was significantly lower, and LAVI was higher, in the AF group, compared with SR patients including PAF. The expression of COL1A1 mRNA encoding collagen type I α1 significantly increased in AF patients (p = 0.031). mLASr negatively correlated with COL1A1 expression level, and multivariate regression analysis showed that mLASr was an independent predictor of atrial COL1A1 expression level, even after adjusting for age, sex, and BMI. But, neither mLAScd / mLASct nor LAVI (bp) correlated with COL1A1 gene expression. The expression level of COL1A1 mRNA strongly correlated with ECM-related genes (COL3A1, FN1). It also correlated ECM degradation-related genes (MMP2, TIMP1, and TIMP2), pro-fibrogenic cytokines (TGFB1 encoding TGFß1, END1, PDGFD, CTGF), oxidant stress-related genes (NOX2, NOX4), ACE, inflammation-related genes (NLRP, IL1B, MCP-1), and apoptosis (BAX). Among the fibrosis-related genes examined, univariable regression analysis showed that log (COL1A1) was associated with log (TGFB1) (adjusted R2 = 0.685, p<0.001), log (NOX4) (adjusted R2 = 0.622, p<0.001), log (NOX2) (adjusted R2 = 0.611, p<0.001), suggesting that TGFB1 and NOX4 was the potent independent determinants of COL1A1 expression level. mLASr negatively correlated with the ECM-related genes, and fibrosis-related gene expression level including TGFB1, NOX2, and NLRP3 in PAF patients. PAF patients with low mLASr had higher expression of the fibrosis-related gene expression, compared with those with high mLASr. These results suggest that LASr correlates with atrial COL1A1 gene expression associated with fibrosis-related gene expression. Patients with low LASr exhibit increased atrial fibrosis-related gene expression, even those with PAF, highlighting the utility of LAS as a marker for LA fibrosis in cardiovascular surgery patients.
Asunto(s)
Fibrilación Atrial , Remodelación Atrial , Fibrosis , Atrios Cardíacos , Humanos , Masculino , Femenino , Remodelación Atrial/genética , Anciano , Persona de Mediana Edad , Atrios Cardíacos/metabolismo , Atrios Cardíacos/patología , Fibrilación Atrial/genética , Fibrilación Atrial/metabolismo , Fibrilación Atrial/cirugía , Fibrilación Atrial/patología , Fibrilación Atrial/fisiopatología , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Ecocardiografía , Cadena alfa 1 del Colágeno Tipo I , Biomarcadores/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Función del Atrio IzquierdoRESUMEN
Atrial fibrillation (AF) is the most common form of cardiac arrhythmia, often evolving from paroxysmal episodes to persistent stages over an extended timeframe. While various factors contribute to this progression, the precise biophysical mechanisms driving it remain unclear. Here we explore how rapid firing of cardiomyocytes at the outlet of the pulmonary vein of the left atria can create a substrate for a persistent re-entry wave. This is grounded in a recently formulated mathematical model of the regulation of calcium ion channel density by intracellular calcium concentration. According to the model, the number of calcium channels is controlled by the intracellular calcium concentration. In particular, if the concentration increases above a certain target level, the calcium current is weakened to restore the target level of calcium. During rapid pacing, the intracellular calcium concentration of the cardiomyocytes increases leading to a substantial reduction of the calcium current across the membrane of the myocytes, which again reduces the action potential duration. In a spatially resolved cell-based model of the outlet of the pulmonary vein of the left atria, we show that the reduced action potential duration can lead to re-entry. Initiated by rapid pacing, often stemming from paroxysmal AF episodes lasting several days, the reduction in calcium current is a critical factor. Our findings illustrate how such episodes can foster a conducive environment for persistent AF through electrical remodeling, characterized by diminished calcium currents. This underscores the importance of promptly addressing early AF episodes to prevent their progression to chronic stages.