RESUMEN
We investigated the modulatory effects of aldosterone on atrial remodeling induced by an abdominal aorto-venocaval shunt (AVS) in rats, as patients with primary hyperaldosteronism are suggested to have a higher risk of developing atrial fibrillation (AF). The rats were divided into four groups based on the basis of whether they underwent AVS surgery, received aldosterone using an intraperitoneally implanted osmotic minipump, or both. Aldosterone was started at 0.5 µg/h during the AVS surgery, and morphological and electrophysiological assessments were performed four weeks after AVS creation. The atrial structural changes induced by AVS, including atrial cell hypertrophy and fibrosis, were not modulated by aldosterone, whereas P-wave duration was longer in aldosterone-treated AVS rats than in non-treated rats. Although the average AF duration induced by burst pacing was 10-25 s in the untreated, aldosterone-treated, and AVS rats, the AF duration was approximately 100 s in the aldosterone-treated AVS rats. Meanwhile, there was no significant difference in the atrial effective refractory period among the four experimental groups. Notably, premature atrial contractions (PAC) were frequently observed in aldosterone-treated sham rats, while paroxysmal AF, in addition to PAC, was detected in aldosterone-treated AVS rats, which was not induced in non-treated AVS rats. These findings suggest that aldosterone robustly promotes AF, particularly in the presence of chronic volume overload.
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Aldosterona , Fibrilación Atrial , Atrios Cardíacos , Animales , Aldosterona/sangre , Fibrilación Atrial/etiología , Fibrilación Atrial/fisiopatología , Masculino , Atrios Cardíacos/efectos de los fármacos , Atrios Cardíacos/fisiopatología , Atrios Cardíacos/patología , Remodelación Atrial/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
AIMS: Atrial fibrosis and autonomic remodelling are proposed pathophysiological mechanisms in atrial fibrillation (AF). Their impact on conduction velocity (CV) dynamics and wavefront propagation was evaluated. METHODS AND RESULTS: Local activation times (LATs), voltage, and geometry data were obtained from patients undergoing ablation for persistent AF. LATs were obtained at three pacing intervals (PIs) in sinus rhythm (SR). LATs were used to determine CV dynamics and their relationship to local voltage amplitude. The impact of autonomic modulation- pharmacologically and with ganglionated plexi (GP) stimulation, on CV dynamics, wavefront propagation, and pivot points (change in wavefront propagation of ≥90°) was determined in SR. Fifty-four patients were included. Voltage impacted CV dynamics whereby at non-low voltage zones (LVZs) (≥0.5â mV) the CV restitution curves are steeper [0.03 ± 0.03â m/s ΔCV PI 600-400â ms (PI1), 0.54 ± 0.09â m/s ΔCV PI 400-250â ms (PI2)], broader at LVZ (0.2-0.49â mV) (0.17 ± 0.09â m/s ΔCV PI1, 0.25 ± 0.11â m/s ΔCV PI2), and flat at very LVZ (<0.2â mV) (0.03 ± 0.01â m/s ΔCV PI1, 0.04 ± 0.02â m/s ΔCV PI2). Atropine did not change CV dynamics, while isoprenaline and GP stimulation resulted in greater CV slowing with rate. Isoprenaline (2.7 ± 1.1 increase/patient) and GP stimulation (2.8 ± 1.3 increase/patient) promoted CV heterogeneity, i.e. rate-dependent CV (RDCV) slowing sites. Most pivot points co-located to RDCV slowing sites (80.2%). Isoprenaline (1.3 ± 1.1 pivot increase/patient) and GP stimulation (1.5 ± 1.1 increase/patient) also enhanced the number of pivot points identified. CONCLUSION: Atrial CV dynamics is affected by fibrosis burden and influenced by autonomic modulation which enhances CV heterogeneity and distribution of pivot points. This study provides further insight into the impact of autonomic remodelling in AF.
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Fibrilación Atrial , Fibrosis , Atrios Cardíacos , Humanos , Femenino , Masculino , Fibrilación Atrial/fisiopatología , Fibrilación Atrial/cirugía , Persona de Mediana Edad , Atrios Cardíacos/fisiopatología , Atrios Cardíacos/inervación , Anciano , Potenciales de Acción , Ablación por Catéter , Remodelación Atrial , Frecuencia Cardíaca , Técnicas Electrofisiológicas Cardíacas , Sistema Nervioso Autónomo/fisiopatología , Función del Atrio Izquierdo , Isoproterenol/farmacología , Atropina/farmacología , Factores de Tiempo , Sistema de Conducción Cardíaco/fisiopatología , Resultado del TratamientoRESUMEN
Recent epidemiological studies have shown that patients with right-sided breast cancer (RBC) treated with X-ray irradiation (IR) are more susceptible to developing cardiovascular diseases, such as arrhythmias, atrial fibrillation, and conduction disturbances after radiotherapy (RT). Our aim was to investigate the mechanisms induced by low to moderate doses of IR and to evaluate changes in the cardiac sympathetic nervous system (CSNS), atrial remodeling, and calcium homeostasis involved in cardiac rhythm. To mimic the RT of the RBC, female C57Bl/6J mice were exposed to X-ray doses ranging from 0.25 to 2 Gy targeting 40% of the top of the heart. At 60 weeks after RI, Doppler ultrasound showed a significant reduction in myocardial strain, ejection fraction, and atrial function, with a significant accumulation of fibrosis in the epicardial layer and apoptosis at 0.5 mGy. Calcium transient protein expression levels, such as RYR2, NAK, Kir2.1, and SERCA2a, increased in the atrium only at 0.5 Gy and 2 Gy at 24 h, and persisted over time. Interestingly, 3D imaging of the cleaned hearts showed an early reduction of CSNS spines and dendrites in the ventricles and a late reorientation of nerve fibers, combined with a decrease in SEMA3a expression levels. Our results showed that local heart IR from 0.25 Gy induced late cardiac and atrial dysfunction and fibrosis development. After IR, ventricular CSNS and calcium transient protein expression levels were rearranged, which affected cardiac contractility. The results are very promising in terms of identifying pro-arrhythmic mechanisms and preventing arrhythmias during RT treatment in patients with RBC.
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Calcio , Ratones Endogámicos C57BL , Sistema Nervioso Simpático , Animales , Ratones , Sistema Nervioso Simpático/efectos de la radiación , Sistema Nervioso Simpático/metabolismo , Femenino , Calcio/metabolismo , Rayos X , Corazón/efectos de la radiación , Corazón/fisiopatología , Remodelación Atrial/efectos de la radiaciónRESUMEN
BACKGROUND: The adverse prognostic impact of diabetes on hypertrophic cardiomyopathy (HCM) is poorly understood. We sought to explore the underlying mechanisms in terms of structural and functional remodelling in HCM patients with coexisting diabetes (HCM-DM). METHODS: A total of 45 HCM-DM patients were retrospectively included. Isolated HCM controls (HCM patients without diabetes) were matched to HCM-DM patients in terms of maximal wall thickness, age, and gender distribution. Left ventricular (LV) and atrial (LA) performance were evaluated using cardiac magnetic resonance feature tracking strain analyses. The associations between diabetes and LV/LA impairment were investigated by univariable and multivariable linear regression. RESULTS: Compared with the isolated HCM controls, the HCM-DM patients had smaller end-diastolic volume and stroke volume, lower ejection fraction, larger mass/volume ratio and impaired strains in all three directions (all P < 0.05). In terms of the LA parameters, HCM-DM patients presented impaired LA reservoir and conduit strain/strain rate (all P < 0.05). Among all HCM patients, comorbidity with diabetes was independently associated with a low LV ejection fraction (ß = - 6.05, P < 0.001) and impaired global longitudinal strain (ß = 1.40, P = 0.007). Moreover, compared with the isolated HCM controls, HCM-DM patients presented with more myocardial fibrosis according to late gadolinium enhancement, which was an independent predictor of impaired LV global radial strain (ß = - 45.81, P = 0.008), LV global circumferential strain (ß = 18.25, P = 0.003), LA reservoir strain (ß = - 59.20, P < 0.001) and strain rate (ß = - 2.90, P = 0.002). CONCLUSIONS: Diabetes has adverse effects on LV and LA function in HCM patients, which may be important contributors to severe manifestations and outcomes in those patients. The present study strengthened the evidence of the prevention and management of diabetes in HCM patients.
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Función del Atrio Izquierdo , Cardiomiopatía Hipertrófica , Diabetes Mellitus , Imagen por Resonancia Cinemagnética , Valor Predictivo de las Pruebas , Volumen Sistólico , Función Ventricular Izquierda , Remodelación Ventricular , Humanos , Masculino , Femenino , Persona de Mediana Edad , Cardiomiopatía Hipertrófica/diagnóstico por imagen , Cardiomiopatía Hipertrófica/fisiopatología , Cardiomiopatía Hipertrófica/complicaciones , Estudios Retrospectivos , Anciano , Diabetes Mellitus/epidemiología , Diabetes Mellitus/fisiopatología , Diabetes Mellitus/diagnóstico , Factores de Riesgo , Adulto , Pronóstico , Disfunción Ventricular Izquierda/fisiopatología , Disfunción Ventricular Izquierda/diagnóstico por imagen , Disfunción Ventricular Izquierda/etiología , Comorbilidad , Remodelación AtrialRESUMEN
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.
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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.).
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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
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.
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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.
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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: Left atrial volume index (LAVI) serves as a crucial marker for assessing left atrial (LA) remodeling, particularly in patients with mitral valve regurgitation (MR). Recent guidelines recommend a LAVI exceeding 60 mL/m2 as Class IIa recommendation for mitral valve repair surgery in asymptomatic MR patients with preserved left ventricular function. Traditionally, echocardiography is the standard for assessing LAVI in MR patients. However, cardiac magnetic resonance imaging (CMR) is increasingly recognized for its more precise measurements of cardiac dimensions and volumes. But still, literature remains scarce on comparing the efficacy of both modalities in assessing LAVI measurements. METHODS: This retrospective study included 168 MR patients undergoing both echocardiography and CMR assessments within a six-month period. LAVI measurements were compared using Pearson correlation and Bland-Altman plots. Patients were stratified based on MR grades, and clinical implications were assessed. RESULTS: Mean LAVI differed significantly between echocardiography and CMR (47.1 ± 20.8 mL/m2 versus 70 ± 20.3 mL/m2, p < 0.001, respectively). CMR consistently yielded higher LAVI measurements compared to echocardiography, with a mean difference of approximately 20 mL/m2. CMR measurements resulted in an increased incidence of patients meeting the class IIa LAVI criterion (LAVI >60 mL/m2) by 37%. Variations in LAVI did not differ across MR grades. CONCLUSION: Echocardiography systematically underestimates LAVI compared to CMR in MR patients. While current guidelines rely on echocardiography, CMR's precision suggests the need for CMR-specific LAVI cutoff values to guide clinical management effectively. Establishing such values could refine patient stratification and timing of surgery, potentially improving clinical outcomes for MR patients.
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Remodelación Atrial , Ecocardiografía , Atrios Cardíacos , Imagen por Resonancia Cinemagnética , Insuficiencia de la Válvula Mitral , Humanos , Femenino , Masculino , Estudios Retrospectivos , Persona de Mediana Edad , Ecocardiografía/métodos , Ecocardiografía/normas , Anciano , Remodelación Atrial/fisiología , Atrios Cardíacos/diagnóstico por imagen , Atrios Cardíacos/fisiopatología , Insuficiencia de la Válvula Mitral/diagnóstico por imagen , Insuficiencia de la Válvula Mitral/cirugía , Insuficiencia de la Válvula Mitral/fisiopatología , Imagen por Resonancia Cinemagnética/métodos , Imagen por Resonancia Cinemagnética/normas , Función del Atrio Izquierdo/fisiologíaRESUMEN
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.
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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
BACKGROUND: Sodium-glucose cotransporter-2 (SGLT2) inhibitors have demonstrated reduction in heart failure outcomes in patients with type 2 diabetes mellitus, although the exact mechanism of benefit remains unclear. Alteration in left atrial (LA) function due to chronic pressure or volume overload is a hallmark of heart failure. OBJECTIVE: To evaluate the effect of the SGLT2 inhibitor empagliflozin on LA volume and function. METHODS: 90 patients with coronary artery disease and type 2 diabetes (T2DM) were randomized to empagliflozin (n = 44) or placebo (n = 46), and underwent cardiac magnetic resonance (CMR) imaging at baseline and after 6 months. The main outcome was change in LA volume; LA function, including active and passive components, was also measured by a blinded reader. RESULTS: At baseline, there was no significant difference in LA volumes between the empagliflozin (indexed maximum LA volume 26.4 ± 8.4mL/m2, minimum LA volume 11.1 ± 5.7mL/m2) and placebo (indexed maximum LA volume 28.7 ± 8.2mL/m2, minimum LA volume 12.6 ± 5.0mL/m2) groups. After 6 months, changes in LA volumes did not differ with adjusted difference (empagliflozin minus placebo): 0.99 mL/m2 (95% CI: -1.7 to 3.7 mL/m2; p = 0.47) for indexed maximum LA volume, and 0.87 mL/m2 (95% CI: -0.9 to 2.6 mL/m2; p = 0.32) for indexed minimum LA volume. Changes in total LA emptying fraction were also similar, with between-group adjusted mean difference - 0.01 (95% CI: -0.05 to 0.03, p = 0.59). CONCLUSION: SGLT2 inhibition with empagliflozin for 6 months did not have a significant impact on LA volume and function in patients with T2DM and coronary artery disease. (Effects of Empagliflozin on Cardiac Structure in Patients with Type 2 Diabetes [EMPA-HEART]; NCT02998970).
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Función del Atrio Izquierdo , Compuestos de Bencidrilo , Enfermedad de la Arteria Coronaria , Diabetes Mellitus Tipo 2 , Glucósidos , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Glucósidos/uso terapéutico , Glucósidos/efectos adversos , Compuestos de Bencidrilo/uso terapéutico , Compuestos de Bencidrilo/efectos adversos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/fisiopatología , Diabetes Mellitus Tipo 2/complicaciones , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversos , Masculino , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Enfermedad de la Arteria Coronaria/fisiopatología , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Femenino , Persona de Mediana Edad , Anciano , Función del Atrio Izquierdo/efectos de los fármacos , Resultado del Tratamiento , Factores de Tiempo , Método Doble Ciego , Remodelación Atrial/efectos de los fármacos , Atrios Cardíacos/fisiopatología , Atrios Cardíacos/efectos de los fármacos , Atrios Cardíacos/diagnóstico por imagenRESUMEN
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.
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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
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
BACKGROUND: CHA2DS2-VASc score-related differences have been reported in atrial fibrotic remodeling and prognosis of atrial fibrillation (AF) patients after ablation. There are currently no data on the efficacy of low voltage zone (LVZ)-guided ablation in persistent AF patients according to CHA2DS2-VASc score. We assessed in a cohort of persistent AF patients the extent of LVZ, the regional distribution of LA voltage and the outcome of LA voltage-guided substrate ablation in addition to PVI according to CHA2DS2-VASc score. METHODS: 138 consecutive persistent AF patients undergoing a first voltage-guided catheter ablation were enrolled. 58 patients with CHAD2DS2-VASc score ≥ 3 and 80 patients with CHAD2DS2-VASc score ≤ 2 were included. LA voltage maps were obtained using 3D-electroanatomical mapping system in sinus rhythm. LVZ was defined as < 0.5 mV. RESULTS: In the high CHAD2DS2-VASc score group, LA voltage was lower (1.5 [1.1-2.5] vs. 2.3 [1.5-2.8] mV, p = 0.02) and LVZs were more frequently identified (40% vs. 18%), p < 0.01). Female with CHA2DS2-VASc score ≥ 3 (p = 0.031), LA indexed volume (p = 0.009) and P-wave duration ≥ 150 ms (p = 0.001) were predictors of LVZ. After a 36-month follow-up, atrial arrhythmia-free survival was similar between the two groups (logrank test, P = 0.676). CONCLUSIONS: AF patients with CHAD2DS2-VASc score ≥ 3 display more LA substrate remodeling with lower voltage and more LVZs compared with those with CHAD2DS2-VASc score ≤ 2. Despite this atrial remodeling, they had similar and favorable 36 months results after one single procedure. Unlike male with CHAD2DS2-VASc score ≥ 3, female with CHAD2DS2-VASc score ≥ 3 was predictor of LVZ occurrence.
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Potenciales de Acción , Fibrilación Atrial , Función del Atrio Izquierdo , Remodelación Atrial , Ablación por Catéter , Valor Predictivo de las Pruebas , Humanos , Fibrilación Atrial/fisiopatología , Fibrilación Atrial/cirugía , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/mortalidad , Femenino , Masculino , Ablación por Catéter/efectos adversos , Persona de Mediana Edad , Anciano , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Atrios Cardíacos/fisiopatología , Atrios Cardíacos/cirugía , Frecuencia Cardíaca , Técnicas de Apoyo para la Decisión , Técnicas Electrofisiológicas Cardíacas , Recurrencia , Estudios RetrospectivosRESUMEN
BACKGROUND: It remains unknown to what extent intrinsic atrial cardiomyopathy or left ventricular diastolic dysfunction drive atrial remodeling and functional failure in heart failure with preserved ejection fraction (HFpEF). Computational 3-dimensional (3D) models fitted to cardiovascular magnetic resonance allow state-of-the-art anatomic and functional assessment, and we hypothesized to identify a phenotype linked to HFpEF. METHODS: Patients with exertional dyspnea and diastolic dysfunction on echocardiography (E/e', >8) were prospectively recruited and classified as HFpEF or noncardiac dyspnea based on right heart catheterization. All patients underwent rest and exercise-stress right heart catheterization and cardiovascular magnetic resonance. Computational 3D anatomic left atrial (LA) models were generated based on short-axis cine sequences. A fully automated pipeline was developed to segment cardiovascular magnetic resonance images and build 3D statistical models of LA shape and find the 3D patterns discriminant between HFpEF and noncardiac dyspnea. In addition, atrial morphology and function were quantified by conventional volumetric analyses and deformation imaging. A clinical follow-up was conducted after 24 months for the evaluation of cardiovascular hospitalization. RESULTS: Beyond atrial size, the 3D LA models revealed roof dilation as the main feature found in masked HFpEF (diagnosed during exercise-stress only) preceding a pattern shift to overall atrial size in overt HFpEF (diagnosed at rest). Characteristics of the 3D model were integrated into the LA HFpEF shape score, a biomarker to characterize the gradual remodeling between noncardiac dyspnea and HFpEF. The LA HFpEF shape score was able to discriminate HFpEF (n=34) to noncardiac dyspnea (n=34; area under the curve, 0.81) and was associated with a risk for atrial fibrillation occurrence (hazard ratio, 1.02 [95% CI, 1.01-1.04]; P=0.003), as well as cardiovascular hospitalization (hazard ratio, 1.02 [95% CI, 1.00-1.04]; P=0.043). CONCLUSIONS: LA roof dilation is an early remodeling pattern in masked HFpEF advancing to overall LA enlargement in overt HFpEF. These distinct features predict the occurrence of atrial fibrillation and cardiovascular hospitalization. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03260621.
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Función del Atrio Izquierdo , Remodelación Atrial , Atrios Cardíacos , Insuficiencia Cardíaca , Imagen por Resonancia Cinemagnética , Volumen Sistólico , Función Ventricular Izquierda , Humanos , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/diagnóstico , Femenino , Masculino , Volumen Sistólico/fisiología , Anciano , Atrios Cardíacos/fisiopatología , Atrios Cardíacos/diagnóstico por imagen , Imagen por Resonancia Cinemagnética/métodos , Estudios Prospectivos , Persona de Mediana Edad , Función Ventricular Izquierda/fisiología , Imagenología Tridimensional , Cateterismo Cardíaco , Valor Predictivo de las Pruebas , Disnea/fisiopatología , Disnea/etiología , Disnea/diagnósticoRESUMEN
To characterize utility of atrioventricular block (AVB) dogs as atrial fibrillation (AF) model, we studied remodeling processes occurring in their atria in acute (<2 weeks) and chronic (>4 weeks) phases. Fifty beagle dogs were used. Holter electrocardiogram demonstrated that paroxysmal AF occurred immediately after the production of AVB, of which duration tended to be prolonged in chronic phase. Electrophysiological analysis showed that inter-atrial conduction time and duration of burst pacing-induced AF increased in the chronic phase compared with those in the acute phase, but that atrial effective refractory period was hardly altered. Echocardiographic study revealed that diameters of left atrium, right pulmonary vein and inferior vena cava increased similarly in the acute and chronic phases. Histological evaluation indicated that hypertrophy and fibrosis in atrial tissue increased in the chronic phase. Electropharmacological characterization showed that i.v. pilsicainide effectively suppressed burst pacing-induced AF with increasing atrial conduction time and refractoriness of AVB dogs in chronic phase, but that i.v. amiodarone did not exert such electrophysiological effects. Taken together, AVB dogs in chronic phase appear to possess such pathophysiology as developed in the atria of early-stage AF patients, and therefore they can be used to evaluate drug candidates against early-stage AF.
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Fibrilación Atrial , Remodelación Atrial , Bloqueo Atrioventricular , Modelos Animales de Enfermedad , Atrios Cardíacos , Animales , Perros , Fibrilación Atrial/fisiopatología , Fibrilación Atrial/etiología , Bloqueo Atrioventricular/fisiopatología , Atrios Cardíacos/fisiopatología , Atrios Cardíacos/patología , Remodelación Atrial/fisiología , Masculino , Antiarrítmicos/farmacología , Antiarrítmicos/uso terapéutico , Ecocardiografía , Amiodarona/farmacologíaRESUMEN
Atrial fibrillation (AF) remains challenging to prevent and treat. A key feature of AF is atrial enlargement. However, not all atrial enlargement progresses to AF. Atrial enlargement in response to physiological stimuli such as exercise is typically benign and reversible. Understanding the differences in atrial function and molecular profile underpinning pathological and physiological atrial remodelling will be critical for identifying new strategies for AF. The discovery of molecular mechanisms responsible for pathological and physiological ventricular hypertrophy has uncovered new drug targets for heart failure. Studies in the atria have been limited in comparison. Here, we characterised mouse atria from (1) a pathological model (cardiomyocyte-specific transgenic (Tg) that develops dilated cardiomyopathy [DCM] and AF due to reduced protective signalling [PI3K]; DCM-dnPI3K), and (2) a physiological model (cardiomyocyte-specific Tg with an enlarged heart due to increased insulin-like growth factor 1 receptor; IGF1R). Both models presented with an increase in atrial mass, but displayed distinct functional, cellular, histological and molecular phenotypes. Atrial enlargement in the DCM-dnPI3K Tg, but not IGF1R Tg, was associated with atrial dysfunction, fibrosis and a heart failure gene expression pattern. Atrial proteomics identified protein networks related to cardiac contractility, sarcomere assembly, metabolism, mitochondria, and extracellular matrix which were differentially regulated in the models; many co-identified in atrial proteomics data sets from human AF. In summary, physiological and pathological atrial enlargement are associated with distinct features, and the proteomic dataset provides a resource to study potential new regulators of atrial biology and function, drug targets and biomarkers for AF.
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Fibrilación Atrial , Remodelación Atrial , Atrios Cardíacos , Ratones Transgénicos , Miocitos Cardíacos , Fibrilación Atrial/fisiopatología , Fibrilación Atrial/metabolismo , Fibrilación Atrial/genética , Animales , Atrios Cardíacos/metabolismo , Atrios Cardíacos/fisiopatología , Atrios Cardíacos/patología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Receptor IGF Tipo 1/metabolismo , Receptor IGF Tipo 1/genética , Cardiomiopatía Dilatada/fisiopatología , Cardiomiopatía Dilatada/genética , Cardiomiopatía Dilatada/metabolismo , Cardiomiopatía Dilatada/patología , Modelos Animales de Enfermedad , Fibrosis , Ratones , Humanos , Transducción de Señal , Fosfatidilinositol 3-Quinasas/metabolismo , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/patologíaRESUMEN
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.
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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
BACKGROUND: Prominent multi-scallop systolic leaflet displacement toward the left atrium (atrialization) is typically observed in bileaflet mitral valve prolapse (MVP) with mitral annular disjunction. We hypothesized that mitral leaflet atrialization is associated with an underlying left atrial (LA) myopathy characterized by progressive structural and functional abnormalities, irrespective of mitral regurgitation (MR) severity. METHODS: We identified 334 consecutive patients with MVP, no prior atrial fibrillation, and comprehensive clinical and echocardiographic data. LA function was assessed by LA reservoir strain, LA function index, and LA emptying fraction. We also classified the stage of LA remodeling based on LA enlargement and LA reservoir strain (stage 1: no remodeling; stage 2: mild remodeling; stage 3: moderate remodeling; and stage 4: severe remodeling). The primary end point was the composite risk of sudden arrhythmic death, heart failure hospitalization, or the new onset of atrial fibrillation. RESULTS: Bileaflet MVP with no or mild MR had a lower LA reservoir strain (P=0.04) and LA function index (P<0.001) compared with other MVP subtypes. In multivariable linear regression adjusted for cardiovascular risk factors and MR ≥moderate, bileaflet MVP remained significantly associated with lower LA function parameters (all P<0.05). There was a significant increase in the risk of events as the LA reservoir strain and LA remodeling stage increased (P<0.001). In multivariable analysis, stage 4 of LA remodeling remained significantly associated with a higher risk of events compared with stage 1 (hazard ratio, 6.09 [95% CI, 1.69-21.9]; P=0.006). CONCLUSIONS: In a large MVP registry, bileaflet involvement is associated with reduced LA function regardless of MR severity, suggesting a primary atriopathy in this MVP subtype. Abnormal LA function, particularly when assessed through a multiparametric approach, is linked to a higher risk of cardiovascular events and may improve risk stratification in MVP, even in those without significant MR.
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Función del Atrio Izquierdo , Remodelación Atrial , Prolapso de la Válvula Mitral , Humanos , Prolapso de la Válvula Mitral/fisiopatología , Prolapso de la Válvula Mitral/complicaciones , Prolapso de la Válvula Mitral/diagnóstico por imagen , Femenino , Masculino , Anciano , Persona de Mediana Edad , Atrios Cardíacos/diagnóstico por imagen , Atrios Cardíacos/fisiopatología , Fibrilación Atrial/fisiopatología , Fibrilación Atrial/complicaciones , Factores de Riesgo , Índice de Severidad de la Enfermedad , Estudios Retrospectivos , Válvula Mitral/diagnóstico por imagen , Válvula Mitral/fisiopatología , Ecocardiografía/métodos , Insuficiencia de la Válvula Mitral/fisiopatología , Insuficiencia de la Válvula Mitral/diagnóstico por imagen , Valor Predictivo de las PruebasRESUMEN
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.