RESUMEN
AIMS: Heart failure with preserved ejection fraction (HFpEF) causes substantial morbidity and mortality. Importantly, atrial remodelling and atrial fibrillation are frequently observed in HFpEF. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have recently been shown to improve clinical outcomes in HFpEF, and post-hoc analyses suggest atrial anti-arrhythmic effects. We tested if isolated human atrial cardiomyocytes from patients with HFpEF exhibit an increased Na influx, which is known to cause atrial arrhythmias, and if that is responsive to treatment with the SGTL2i empagliflozin. METHODS AND RESULTS: Cardiomyocytes were isolated from atrial biopsies of 124 patients (82 with HFpEF) undergoing elective cardiac surgery. Na influx was measured with the Na-dye Asante Natrium Green-2 AM (ANG-2). Compared to patients without heart failure (NF), Na influx was doubled in HFpEF patients (NF vs. HFpEF: 0.21 ± 0.02 vs. 0.38 ± 0.04â mmol/L/min (N = 7 vs. 18); P = 0.0078). Moreover, late INa (measured via whole-cell patch clamp) was significantly increased in HFpEF compared to NF. Western blot and HDAC4 pulldown assay indicated a significant increase in CaMKII expression, CaMKII autophosphorylation, CaMKII activity, and CaMKII-dependent NaV1.5 phosphorylation in HFpEF compared to NF, whereas NaV1.5 protein and mRNA abundance remained unchanged. Consistently, increased Na influx was significantly reduced by treatment not only with the CaMKII inhibitor autocamtide-2-related inhibitory peptide (AIP), late INa inhibitor tetrodotoxin (TTX) but also with sodium/hydrogen exchanger 1 (NHE1) inhibitor cariporide. Importantly, empagliflozin abolished both increased Na influx and late INa in HFpEF. Multivariate linear regression analysis, adjusting for important clinical confounders, revealed HFpEF to be an independent predictor for changes in Na handling in atrial cardiomyocytes. CONCLUSION: We show for the first time increased Na influx in human atrial cardiomyocytes from HFpEF patients, partly due to increased late INa and enhanced NHE1-mediated Na influx. Empagliflozin inhibits Na influx and late INa, which could contribute to anti-arrhythmic effects in patients with HFpEF.
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Potenciales de Acción , Compuestos de Bencidrilo , Glucósidos , Insuficiencia Cardíaca , Miocitos Cardíacos , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Volumen Sistólico , Humanos , Glucósidos/farmacología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Miocitos Cardíacos/enzimología , Masculino , Femenino , Anciano , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/patología , Persona de Mediana Edad , Compuestos de Bencidrilo/farmacología , Volumen Sistólico/efectos de los fármacos , Potenciales de Acción/efectos de los fármacos , Sodio/metabolismo , Atrios Cardíacos/metabolismo , Atrios Cardíacos/efectos de los fármacos , Atrios Cardíacos/fisiopatología , Atrios Cardíacos/patología , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Función Ventricular Izquierda/efectos de los fármacos , Células Cultivadas , Función del Atrio Izquierdo/efectos de los fármacos , Intercambiador 1 de Sodio-HidrógenoRESUMEN
Trastuzumab is widely used in HER2 breast cancer. However, it may cause left ventricular (LV) dysfunction. A decrease in LV global longitudinal strain (GLS) has been previously demonstrated to be a good predictor of subsequent cancer therapy related dysfunction (CTRCD). Left atrial morphological remodeling during Trastuzumab therapy has also been shown. The aim of this study is exploring the relationship between early changes in left atrial function and the development of Trastuzumab-induced cardiotoxicity. Consecutive patients with diagnosis of HER2+non-metastatic breast cancer treated with Trastuzumab were prospectively enrolled. A clinical, conventional, and advanced echocardiographic assessment was performed at baseline and every three months, until a one-year follow-up was reached. One-hundred-sixteen patients completed the 12 months follow-up, 10 (9%) cases of CTRCD were observed, all after the sixth month. GLS and LVEF significantly decreased in the CTRCD group at 6 months of follow-up, with an earlier (3 months) significant worsening in left atrial morpho-functional parameters. Systolic blood pressure, early peak atrial longitudinal strain (PALS), peak atrial contraction (PACS) and left atrial volume (LAVI) changes resulted independent predictors of CTRCD at multivariable logistic regression analysis. Moreover, early changes in PALS and PACS resulted good predictors of CTRCD development (AUC 0.85; p = 0.008, p < 0.001 and 0.77; p = 0.008, respectively). This prospective study emphasizes that the decline in PALS and PACS among trastuzumab-treated patients could possibly increase the accuracy in identifying future CTRCD in non-metastatic HER2 breast cancer cases, adding predictive value to conventional echocardiographic assessment.
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Antineoplásicos Inmunológicos , Función del Atrio Izquierdo , Neoplasias de la Mama , Cardiotoxicidad , Receptor ErbB-2 , Trastuzumab , Función Ventricular Izquierda , Humanos , Trastuzumab/efectos adversos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Persona de Mediana Edad , Receptor ErbB-2/metabolismo , Estudios Prospectivos , Antineoplásicos Inmunológicos/efectos adversos , Función Ventricular Izquierda/efectos de los fármacos , Función del Atrio Izquierdo/efectos de los fármacos , Adulto , Factores de Tiempo , Factores de Riesgo , Resultado del Tratamiento , Anciano , Valor Predictivo de las Pruebas , Medición de Riesgo , Remodelación Atrial/efectos de los fármacos , Cardiopatías/inducido químicamente , Cardiopatías/fisiopatología , Cardiopatías/diagnóstico por imagen , Disfunción Ventricular Izquierda/inducido químicamente , Disfunción Ventricular Izquierda/fisiopatología , Disfunción Ventricular Izquierda/diagnóstico por imagen , Atrios Cardíacos/efectos de los fármacos , Atrios Cardíacos/fisiopatología , Atrios Cardíacos/diagnóstico por imagen , Volumen Sistólico/efectos de los fármacosRESUMEN
ABSTRACT: This study seeks to identify the anticoagulant efficacy of rivaroxaban treatment on thrombi detected using echocardiography of the left atrial appendage in 275 patients with persistent atrial fibrillation. During follow-up after 9-24 weeks of rivaroxaban treatment, patients were divided into "effective group" (n = 143) and "ineffective group" (n = 132) according to the thrombolytic effect of the drug. Left atrial diameter (LAD), left atrial ejection fraction (LAEF), left ventricular ejection fraction (LVEF), mean diameter of left atrial appendage (LAAD mean ), angle between left atrial appendage and left atrium (LAA-A), velocity of blood flow in left atrial appendage (LAA-v), and thrombus size were compared before and after drug administration. Following treatment, LAEF, LVEF, and LAA-v values were greater and LAD and LAAD mean values were lower in the effective ( P < 0.05). Logistic regression analysis showed significant correlations of LAD, LAEF, LVEF, LAA-A, and LAA-v with anticoagulant efficacy ( P < 0.05). The efficacy of rivaroxaban in treatment of left atrial auricular thrombosis in patients with persistent AF was correlated with LAD, LAEF, LVEF, LAA-A, and LAA-v. Multivariate logistic regression analysis further revealed LAEF [odds ratio (OR) 1.7, 95% confidence interval (CI), 0.45-16.9, P = 0.008], 3D-EF (OR 6.4, 95% CI, 1.06-16.9, P = 0.039) and left ventricular global longitudinal strain (OR 18.0, 95% CI, 1.38-35.68, P = 0.028) as factors related to left atrial appendage thrombus. Echocardiography with global longitudinal strain assessment could be effectively utilized to evaluate the functional parameters of LAA and thus aid in predicting the safety of rivaroxaban as an anticoagulation agent.
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Apéndice Atrial , Fibrilación Atrial , Ecocardiografía Tridimensional , Inhibidores del Factor Xa , Rivaroxabán , Humanos , Fibrilación Atrial/tratamiento farmacológico , Fibrilación Atrial/fisiopatología , Fibrilación Atrial/diagnóstico por imagen , Fibrilación Atrial/diagnóstico , Femenino , Masculino , Rivaroxabán/uso terapéutico , Rivaroxabán/administración & dosificación , Anciano , Persona de Mediana Edad , Resultado del Tratamiento , Apéndice Atrial/diagnóstico por imagen , Apéndice Atrial/fisiopatología , Apéndice Atrial/efectos de los fármacos , Inhibidores del Factor Xa/efectos adversos , Inhibidores del Factor Xa/uso terapéutico , Trombosis/diagnóstico por imagen , Trombosis/tratamiento farmacológico , Trombosis/fisiopatología , Valor Predictivo de las Pruebas , Función del Atrio Izquierdo/efectos de los fármacos , Terapia Trombolítica , Función Ventricular Izquierda/efectos de los fármacos , Factores de TiempoAsunto(s)
Antineoplásicos , Función del Atrio Izquierdo , Cardiotoxicidad , Valor Predictivo de las Pruebas , Humanos , Función del Atrio Izquierdo/efectos de los fármacos , Femenino , Factores de Riesgo , Antineoplásicos/efectos adversos , Masculino , Persona de Mediana Edad , Cardiopatías/inducido químicamente , Cardiopatías/diagnóstico por imagen , Cardiopatías/fisiopatología , Medición de Riesgo , Anciano , Atrios Cardíacos/diagnóstico por imagen , Atrios Cardíacos/efectos de los fármacos , Atrios Cardíacos/fisiopatologíaRESUMEN
INTRODUCTION: Cardiac organ damage like left ventricular (LV) hypertrophy and left atrial (LA) enlargement is more prevalent in women than men with hypertension, but the mechanisms underlying this gender difference remain unclear. METHODS: We tested the association of drug nonadherence with the presence of LV hypertrophy and LA enlargement by echocardiography in 186 women and 337 men with uncontrolled hypertension defined as daytime systolic blood pressure (BP) ≥ 135mmHg despite the prescription of at least two antihypertensive drugs. Drug adherence was assessed by measurements of serum drug concentrations interpreted by an experienced pharmacologist. Aldosterone-renin-ratio (ARR) was measured on actual medication. RESULTS: Women had a higher prevalence of LV hypertrophy (46% vs. 33%) and LA enlargement (79% vs 65%, both p < 0.05) than men, while drug nonadherence (8% vs. 9%, p > 0.514) did not differ. Women were older and had lower serum renin concentration and higher ARR than men, while 24-h systolic BP (141 ± 9 mmHg vs. 142 ± 9 mmHg), and the prevalences of obesity (43% vs. 50%) did not differ (all p > 0.10). In multivariable analyses, female gender was independently associated with a two-fold increased risk of LV hypertrophy (OR 2.01[95% CI 1.30-3.10], p = 0.002) and LA enlargement (OR 1.90 [95% CI 1.17-3.10], p = 0.010), while no association with drug nonadherence was found. Higher ARR was independently associated with LV hypertrophy in men only (OR 2.12 [95% CI 1.12-4.00] p = 0.02). CONCLUSIONS: Among patients with uncontrolled hypertension, the higher prevalence of LV hypertrophy and LA enlargement in women was not explained by differences in drug nonadherence. REGISTRATION: URL: https://www. CLINICALTRIALS: gov ; Unique identifier: NCT03209154.
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Antihipertensivos , Hipertensión , Hipertrofia Ventricular Izquierda , Cumplimiento de la Medicación , Renina , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Aldosterona/sangre , Antihipertensivos/uso terapéutico , Presión Arterial/efectos de los fármacos , Función del Atrio Izquierdo/efectos de los fármacos , Remodelación Atrial/efectos de los fármacos , Biomarcadores/sangre , Estudios Transversales , Disparidades en el Estado de Salud , Hipertensión/tratamiento farmacológico , Hipertensión/fisiopatología , Hipertensión/epidemiología , Hipertrofia Ventricular Izquierda/epidemiología , Hipertrofia Ventricular Izquierda/fisiopatología , Hipertrofia Ventricular Izquierda/diagnóstico por imagen , Prevalencia , Renina/sangre , Medición de Riesgo , Factores de Riesgo , Factores Sexuales , Resultado del Tratamiento , Función Ventricular Izquierda/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacosRESUMEN
[Figure: see text].
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Antiarrítmicos/uso terapéutico , Fibrilación Atrial/terapia , Función del Atrio Izquierdo/efectos de los fármacos , Remodelación Atrial/efectos de los fármacos , Ablación por Catéter , Atrios Cardíacos , Imagen por Resonancia Magnética , Venas Pulmonares , Tomografía Computarizada por Rayos X , Potenciales de Acción/efectos de los fármacos , Anciano , Antiarrítmicos/efectos adversos , Fibrilación Atrial/diagnóstico por imagen , Fibrilación Atrial/fisiopatología , Ablación por Catéter/efectos adversos , Femenino , Atrios Cardíacos/diagnóstico por imagen , Atrios Cardíacos/efectos de los fármacos , Atrios Cardíacos/fisiopatología , Atrios Cardíacos/cirugía , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Prospectivos , Venas Pulmonares/diagnóstico por imagen , Venas Pulmonares/fisiopatología , Venas Pulmonares/cirugía , Recurrencia , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Although the benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on cardiovascular events have been reported in patients with type 2 diabetes mellitus (T2DM) with or without heart failure (HF), the impact of SGLT2i on cardiac remodelling remains to be established. METHODS: We searched the PubMed, Embase, Cochrane Library and Web of Science databases up to November 16th, 2020, for randomized controlled trials reporting the effects of SGLT2i on parameters of cardiac structure, cardiac function, plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) level or the Kansas City Cardiomyopathy Questionnaire (KCCQ) score in T2DM patients with or without chronic HF. The effect size was expressed as the mean difference (MD) or standardized mean difference (SMD) and its 95% confidence interval (CI). Subgroup analyses were performed based on the stage A-B or stage C HF population and HF types. RESULTS: Compared to placebo or other antidiabetic drugs, SGLT2i showed no significant effects on left ventricular mass index, left ventricular end diastolic volume index, left ventricular end systolic volume index, or left atrial volume index. SGLT2i improved left ventricular ejection fraction only in the subgroup of HF patients with reduced ejection fraction (MD 3.16%, 95% CI 0.11 to 6.22, p = 0.04; I2 = 0%), and did not affect the global longitudinal strain in the overall analysis including stage A-B HF patients. SGLT2i showed benefits in the E/e' ratio (MD - 0.45, 95% CI - 0.88 to - 0.03, p = 0.04; I2 = 0%), plasma NT-proBNP level (SMD - 0.09, 95% CI - 0.16 to - 0.03, p = 0.004; I2 = 0%), and the KCCQ score (SMD 3.12, 95% CI 0.76 to 5.47, p = 0.01; I2 = 0%) in the overall population. CONCLUSION: The use of SGLT2i was associated with significant improvements in cardiac diastolic function, plasma NT-proBNP level, and the KCCQ score in T2DM patients with or without chronic HF, but did not significantly affect cardiac structural parameters indexed by body surface area. The LVEF level was improved only in HF patients with reduced ejection fraction.
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Función del Atrio Izquierdo/efectos de los fármacos , Remodelación Atrial/efectos de los fármacos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Insuficiencia Cardíaca/tratamiento farmacológico , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Función Ventricular Izquierda/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacos , Anciano , Biomarcadores/sangre , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Enfermedad Crónica , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/diagnóstico , Femenino , Insuficiencia Cardíaca/diagnóstico por imagen , Insuficiencia Cardíaca/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Péptido Natriurético Encefálico/sangre , Fragmentos de Péptidos/sangre , Recuperación de la Función , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversos , Volumen Sistólico/efectos de los fármacos , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Sodium-glucose linked transporter type 2 (SGLT-2) inhibition has been shown to reduce cardiovascular mortality in heart failure independently of glycemic control and prevents the onset of atrial arrhythmias, a common co-morbidity in heart failure with preserved ejection fraction (HFpEF). The mechanism behind these effects is not fully understood, and it remains unclear if they could be further enhanced by additional SGLT-1 inhibition. We investigated the effects of chronic treatment with the dual SGLT-1&2 inhibitor sotagliflozin on left atrial (LA) remodeling and cellular arrhythmogenesis (i.e. atrial cardiomyopathy) in a metabolic syndrome-related rat model of HFpEF. METHODS: 17 week-old ZSF-1 obese rats, a metabolic syndrome-related model of HFpEF, and wild type rats (Wistar Kyoto), were fed 30 mg/kg/d sotagliflozin for 6 weeks. At 23 weeks, LA were imaged in-vivo by echocardiography. In-vitro, Ca2+ transients (CaT; electrically stimulated, caffeine-induced) and spontaneous Ca2+ release were recorded by ratiometric microscopy using Ca2+-sensitive fluorescent dyes (Fura-2) during various experimental protocols. Mitochondrial structure (dye: Mitotracker), Ca2+ buffer capacity (dye: Rhod-2), mitochondrial depolarization (dye: TMRE) and production of reactive oxygen species (dye: H2DCF) were visualized by confocal microscopy. Statistical analysis was performed with 2-way analysis of variance followed by post-hoc Bonferroni and student's t-test, as applicable. RESULTS: Sotagliflozin ameliorated LA enlargement in HFpEF in-vivo. In-vitro, LA cardiomyocytes in HFpEF showed an increased incidence and amplitude of arrhythmic spontaneous Ca2+ release events (SCaEs). Sotagliflozin significantly reduced the magnitude of SCaEs, while their frequency was unaffected. Sotagliflozin lowered diastolic [Ca2+] of CaT at baseline and in response to glucose influx, possibly related to a ~ 50% increase of sodium sodium-calcium exchanger (NCX) forward-mode activity. Sotagliflozin prevented mitochondrial swelling and enhanced mitochondrial Ca2+ buffer capacity in HFpEF. Sotagliflozin improved mitochondrial fission and reactive oxygen species (ROS) production during glucose starvation and averted Ca2+ accumulation upon glycolytic inhibition. CONCLUSION: The SGLT-1&2 inhibitor sotagliflozin ameliorated LA remodeling in metabolic HFpEF. It also improved distinct features of Ca2+-mediated cellular arrhythmogenesis in-vitro (i.e. magnitude of SCaEs, mitochondrial Ca2+ buffer capacity, diastolic Ca2+ accumulation, NCX activity). The safety and efficacy of combined SGLT-1&2 inhibition for the treatment and/or prevention of atrial cardiomyopathy associated arrhythmias should be further evaluated in clinical trials.
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Arritmias Cardíacas/prevención & control , Función del Atrio Izquierdo/efectos de los fármacos , Remodelación Atrial/efectos de los fármacos , Glicósidos/farmacología , Atrios Cardíacos/efectos de los fármacos , Insuficiencia Cardíaca/tratamiento farmacológico , Transportador 1 de Sodio-Glucosa/antagonistas & inhibidores , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Transportador 2 de Sodio-Glucosa/metabolismo , Animales , Arritmias Cardíacas/etiología , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatología , Señalización del Calcio/efectos de los fármacos , Modelos Animales de Enfermedad , Atrios Cardíacos/metabolismo , Atrios Cardíacos/fisiopatología , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/fisiopatología , Síndrome Metabólico/complicaciones , Mitocondrias Cardíacas/efectos de los fármacos , Mitocondrias Cardíacas/metabolismo , Mitocondrias Cardíacas/patología , Dinámicas Mitocondriales/efectos de los fármacos , Dilatación Mitocondrial/efectos de los fármacos , Ratas Endogámicas WKY , Ratas Zucker , Especies Reactivas de Oxígeno/metabolismo , Intercambiador de Sodio-Calcio/metabolismo , Transportador 1 de Sodio-Glucosa/metabolismoRESUMEN
Survivors of childhood cancer are at risk of cancer therapy-related cardiac dysfunction (CTRCD) characterized by systolic impairment, with little known about diastolic function. Left atrial strain (LAS) is a surrogate measure of left ventricular filling. We hypothesized that survivors (1) have lower LAS versus controls, and (2) survivors exposed to higher anthracycline dosage have even lower LAS. Cross-sectional study of 45 survivors exposed to anthracyclines ≥ 1 year after chemotherapy and 45 healthy controls. Echo variables included mitral spectral and tissue Doppler, left ventricular ejection fraction (LV EF), LV dimension, LA volume, LV global longitudinal strain (GLS), and LAS. Peak strain (Æ) and strain rate (SR) at three phases were obtained: atrial contraction (ac), reservoir (res), and conduit (con). Two sub-analyses of cancer survivors were performed: (1) those with anthracycline dosage ≥ 250 mg/m2, and (2) those with Æres in the lowest quartile. On the whole, survivors had lower Æres and Æcon values. The majority of survivors had relatively normal LAS, while a subset had very low LAS values and were more likely to be older. Survivors exposed to ≥ 250 mg/m2 anthracycline also had lower Æres than those < 250 mg/m2. There were no differences in mitral spectral/tissue Doppler, LV dimension, left atrial volume, or GLS. A subset of childhood cancer survivors have lower LAS than their healthy counterparts, while most are essentially normal. Those exposed to higher anthracycline dosage have even lower Æres. Longitudinal study of LAS may prove useful in monitoring for CTRCD.
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Antraciclinas/efectos adversos , Antibióticos Antineoplásicos/efectos adversos , Función del Atrio Izquierdo/efectos de los fármacos , Supervivientes de Cáncer , Ecocardiografía Doppler , Atrios Cardíacos/efectos de los fármacos , Cardiopatías/inducido químicamente , Neoplasias/tratamiento farmacológico , Adolescente , Estudios de Casos y Controles , Niño , Estudios Transversales , Femenino , Atrios Cardíacos/diagnóstico por imagen , Atrios Cardíacos/fisiopatología , Cardiopatías/diagnóstico por imagen , Cardiopatías/fisiopatología , Humanos , Masculino , Valor Predictivo de las Pruebas , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Ibrutinib is a Bruton tyrosine kinase inhibitor with remarkable efficacy against B-cell cancers. Ibrutinib also increases the risk of atrial fibrillation (AF), which remains poorly understood. METHODS: We performed electrophysiology studies on mice treated with ibrutinib to assess inducibility of AF. Chemoproteomic analysis of cardiac lysates identified candidate ibrutinib targets, which were further evaluated in genetic mouse models and additional pharmacological experiments. The pharmacovigilance database, VigiBase, was queried to determine whether drug inhibition of an identified candidate kinase was associated with increased reporting of AF. RESULTS: We demonstrate that treatment of mice with ibrutinib for 4 weeks results in inducible AF, left atrial enlargement, myocardial fibrosis, and inflammation. This effect was reproduced in mice lacking Bruton tyrosine kinase, but not in mice treated with 4 weeks of acalabrutinib, a more specific Bruton tyrosine kinase inhibitor, demonstrating that AF is an off-target side effect. Chemoproteomic profiling identified a short list of candidate kinases that was narrowed by additional experimentation leaving CSK (C-terminal Src kinase) as the strongest candidate for ibrutinib-induced AF. Cardiac-specific Csk knockout in mice led to increased AF, left atrial enlargement, fibrosis, and inflammation, phenocopying ibrutinib treatment. Disproportionality analyses in VigiBase confirmed increased reporting of AF associated with kinase inhibitors blocking Csk versus non-Csk inhibitors, with a reporting odds ratio of 8.0 (95% CI, 7.3-8.7; P<0.0001). CONCLUSIONS: These data identify Csk inhibition as the mechanism through which ibrutinib leads to AF. Registration: URL: https://ww.clinicaltrials.gov; Unique identifier: NCT03530215.
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Adenina/análogos & derivados , Antineoplásicos/toxicidad , Fibrilación Atrial/inducido químicamente , Función del Atrio Izquierdo/efectos de los fármacos , Proteína Tirosina Quinasa CSK/antagonistas & inhibidores , Atrios Cardíacos/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Piperidinas/toxicidad , Inhibidores de Proteínas Quinasas/toxicidad , Potenciales de Acción/efectos de los fármacos , Adenina/toxicidad , Agammaglobulinemia Tirosina Quinasa/deficiencia , Agammaglobulinemia Tirosina Quinasa/genética , Animales , Fibrilación Atrial/enzimología , Fibrilación Atrial/fisiopatología , Proteína Tirosina Quinasa CSK/genética , Proteína Tirosina Quinasa CSK/metabolismo , Bases de Datos Genéticas , Atrios Cardíacos/enzimología , Atrios Cardíacos/fisiopatología , Humanos , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Ratones Noqueados , Medición de Riesgo , Factores de RiesgoRESUMEN
Atrial structural and electrical remodelling play important roles in atrial fibrillation (AF). Sacubitril/valsartan attenuates cardiac remodelling in heart failure. However, the effect of sacubitril/valsartan on AF is unclear. The aim of this study was to evaluate the effect of sacubitril/valsartan on atrial electrical and structural remodelling in AF and investigate the underlying mechanism of action. Thirty-three rabbits were randomized into sham, RAP, and sac/val groups. HL-1 cells were subjected to control treatment or rapid pacing with or without LBQ657 and valsartan. Echocardiography, atrial electrophysiology, and histological examination were performed. The concentration of Ca2+ and expression levels of calcineurin, NFAT, p-NFAT, Cav1.2, collagen â and â ¢, ANP, BNP, CNP, NT-proBNP, and ST2 in HL-1 cells, and IcaL in left atrial cells, were determined. We observed that compared to that in the sham group, the atrium and right ventricle were enlarged, myocardial fibrosis was markedly higher, AF inducibility was significantly elevated, and atrial effective refractory periods were shortened in the RAP group. These effects were significantly reversed by sacubitril/valsartan. Compared to that in the sham group, collagen â and â ¢, NT-proBNP, ST2, calcineurin, and NFAT were significantly up-regulated, while p-NFAT and Cav1.2 were down-regulated in the RAP group, and sacubitril/valsartan inhibited these changes. Ca2+ concentration increased and ICaL density decreased in in vivo and in vitro AF models, reversed by sacubitril/valsartan. Sacubitril/valsartan attenuates atrial electrical remodelling and ameliorates structure remodelling in AF. This study paves the way for the possibility of clinical use of sacubitril/valsartan in AF patients.
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Aminobutiratos/farmacología , Antiarrítmicos/farmacología , Fibrilación Atrial/tratamiento farmacológico , Función del Atrio Izquierdo/efectos de los fármacos , Remodelación Atrial/efectos de los fármacos , Atrios Cardíacos/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Tetrazoles/farmacología , Potenciales de Acción/efectos de los fármacos , Animales , Fibrilación Atrial/metabolismo , Fibrilación Atrial/fisiopatología , Compuestos de Bifenilo , Señalización del Calcio/efectos de los fármacos , Modelos Animales de Enfermedad , Combinación de Medicamentos , Fibrosis , Atrios Cardíacos/metabolismo , Atrios Cardíacos/fisiopatología , Masculino , Conejos , ValsartánRESUMEN
OBJECTIVES: - To evaluate the effect of a single dose of pimobendan on left atrial (LA) function in healthy cats. ANIMALS: - Eleven client owned healthy cats. MATERIAL AND METHODS: - Standardized and repeated echocardiographic examinations were performed on healthy and conscious cats before and after a single dose of orally administered pimobendan (1.25 mg/cat). Left atrial systolic functional parameters were assessed. RESULTS: - Some of the tested parameters of LA function showed significant improvement after pimobendan administration, whereas no significant effect on left ventricular function was observed. In particular, LA minimal diameters obtained from M-mode images in short (p=0.018) and long (p=0.009) axis reduced after pimobendan administration, whereas LA fractional shortening from short (p=0.027) and long (p=0.042) axis and LA appendage emptying velocity (p<0.001) significantly increased. A mild increase in heart rate (p=0.001), and a transient increase on the peak systolic wave pulmonary vein velocity (p=0.008) were also recorded as a possible effect. CONCLUSIONS: - A single dose of pimobendan appears to impact LA function in healthy cats. However, because of the small number of cats included, and the absence of a placebo group, these results cannot be definitively separated from the effect of time. Additional studies are needed to understand if similar effects are observed in cats with cardiomyopathy and LA dilatation.
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Función del Atrio Izquierdo/efectos de los fármacos , Piridazinas/farmacología , Animales , Velocidad del Flujo Sanguíneo/efectos de los fármacos , Gatos , Ecocardiografía/veterinaria , Femenino , Atrios Cardíacos/diagnóstico por imagen , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Proyectos Piloto , Venas Pulmonares , Piridazinas/administración & dosificación , Función Ventricular Izquierda/efectos de los fármacosRESUMEN
This study aimed to assess the effects of atenolol on left ventricular (LV) and left atrial (LA) function in healthy cats and investigate the relationship between atenolol administration and LA enlargement (LAE) in cats with hypertrophic cardiomyopathy (HCM). In study 1, nine experimental cats were used to assess the effects of atenolol in healthy subjects. Cats were administered one of three medication protocols for 7 days: atenolol 6.25 mg/cat twice daily, 12.5 mg/cat twice daily, or placebo (biofermin) 1 tab/cat twice daily. In study 2, cats with HCM were retrospectively recruited and divided into four groups according to atenolol administration [(control group (Cont) or atenolol administration group (Ate)] and the presence or absence of LAE as follows: Cont LAE (-) group (n=42), Cont LAE (+) group (n=20), Ate LAE (-) group (n=17), and Ate LAE (+) group (n=12). LV and LA functions were compared in both studies. LV and LA functions were decreased by atenolol administration in study 1. In study 2, the peak myocardial velocity during early diastole (E') was significantly decreased in the Cont LAE (+), Ate LAE (-), and Ate LAE (+) groups compared to that in the Cont LAE (-) group, but there were no significant differences between LAE (+) groups. Multivariate logistic analysis revealed that atenolol administration was not associated with LAE. Diastolic dysfunction may be associated with LAE; however, atenolol administration did not affect LAE in cats with HCM.
Asunto(s)
Antagonistas de Receptores Adrenérgicos beta 1/farmacología , Atenolol/farmacología , Función del Atrio Izquierdo/efectos de los fármacos , Cardiomiopatía Hipertrófica/veterinaria , Función Ventricular Izquierda/efectos de los fármacos , Animales , Remodelación Atrial/efectos de los fármacos , Cardiomiopatía Hipertrófica/tratamiento farmacológico , Enfermedades de los Gatos/tratamiento farmacológico , Gatos , Ecocardiografía/veterinaria , Femenino , Masculino , Estudios RetrospectivosRESUMEN
BACKGROUND: Previous studies demonstrated impaired lipid metabolism and augmented aerobic glycolysis in AF. The authors aimed to investigate whether the use of metformin, an AMPK activator, could reverse this metabolic remodeling in chronic AF and to explore the underlying mechanisms. METHODS: We conducted chronic AF animal models with 18 beagle dogs and divided them into SR (pacemaker implanted without pacing), AF (pacemaker implanted with sustained pacing at a frequency of 400 beats/min for 6 weeks), and metformin+AF group (daily oral administration of metformin was initiated 1 week before surgery and continued throughout the study period). After electrophysiological measurements, the left atrial appendage tissue samples were taken from the beating heart for further analysis. Protein expression, histological analysis, and biochemical measurements were conducted. RESULTS: The AF groups showed decreased expression of FAT/CD36, CPT-1, VLCAD, increased concentration of free fatty acid and triglyceride, and increased lipid deposition. The activation of AMPK/PGC-1α/PPARα pathway was decreased. The key factors of the Warburg effect, including HIF-1α, GLUT-1, PDK1, HK, and LDH, increased in AF group compared to SR group. The expression of PDH decreased significantly, accompanied by increased atrial lactate production. The extent of fibrosis increased significantly in the left atrial appendage of AF group. dERP, ∑WOV, and AF inducibility increased while ERP decreased in AF group compared to SR group. The use of metformin attenuated all these changes effectively. CONCLUSIONS: Metformin improves lipid metabolism and reverses the Warburg effect in chronic AF via AMPK activation. It attenuates atrial electrical and structural remodeling.
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Proteínas Quinasas Activadas por AMP/metabolismo , Apéndice Atrial/efectos de los fármacos , Fibrilación Atrial/tratamiento farmacológico , Metabolismo Energético/efectos de los fármacos , Activadores de Enzimas/farmacología , Metabolismo de los Lípidos/efectos de los fármacos , Metformina/farmacología , Animales , Apéndice Atrial/enzimología , Apéndice Atrial/fisiopatología , Fibrilación Atrial/enzimología , Fibrilación Atrial/fisiopatología , Función del Atrio Izquierdo/efectos de los fármacos , Remodelación Atrial/efectos de los fármacos , Enfermedad Crónica , Modelos Animales de Enfermedad , Perros , Activación Enzimática , Frecuencia Cardíaca/efectos de los fármacos , MasculinoRESUMEN
Both diabetes mellitus (DM) and atrial fibrillation (AF) are usually associated with enhanced inflammatory response. The effect of the "NACHT, LRR and PYD domain containing protein 3" (NLRP3)-inflammasome/caspase-1/galectin-3 pathway and the potential benefits of NLRP3-inflammasome inhibitor glibenclamide (GLB) on atrial remodeling in the DM state are still unknown. Here, we demonstrated that higher AF inducibility and conduction inhomogeneity, slower epicardial conduction velocity, and increased amount of fibrosis in diabetic rabbits as against normal ones were markedly reduced by GLB. Atrial caspase-1 activity as well as serum IL-1ß and IL-18 levels were elevated in diabetic animals but suppressed by GLB. Moreover, GLB decreased the DM-induced protein expression enhancement of NLRP3, Gal-3, TGF-ß1, and CaV1.2 according to western blot analysis. Summarily, our findings indicate that the NLRP3-inflammasome/caspase-1/Gal-3 signaling pathway is related to the pathogenesis of AF in the diabetic state. NLRP3-inflammasome inhibitor GLB prevents AF inducibility and moderates atrial structural remodeling in DM.
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Fibrilación Atrial/etiología , Función del Atrio Izquierdo , Remodelación Atrial , Caspasa 1/metabolismo , Diabetes Mellitus Experimental/complicaciones , Galectina 3/metabolismo , Atrios Cardíacos/metabolismo , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Aloxano , Animales , Antiinflamatorios/farmacología , Fibrilación Atrial/metabolismo , Fibrilación Atrial/fisiopatología , Fibrilación Atrial/prevención & control , Función del Atrio Izquierdo/efectos de los fármacos , Remodelación Atrial/efectos de los fármacos , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatología , Fibrosis , Gliburida/farmacología , Atrios Cardíacos/efectos de los fármacos , Atrios Cardíacos/fisiopatología , Frecuencia Cardíaca , Inflamasomas/antagonistas & inhibidores , Preparación de Corazón Aislado , Masculino , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Conejos , Transducción de SeñalRESUMEN
Background: Left atrial (LA) function is an important determinant of the left ventricular (LV) filling, playing a key role in maintaining optimal cardiac performance. Pimobendan is a phosphodiesterase III inhibitor with positive inotropic and vasodilator effects. The present study aims to investigate the effects of pimobendan on LA function in dogs with stage B2 myxomatous mitral valve disease (MMVD). Aim: The aim of this investigation was to study the effects of pimobendan on LA function in dogs with preclinical MMVD. Methods: Twenty-seven dogs with stage B2 MMVD were retrospectively included. LA function was assessed before and 1-6 months following pimobendan initiation. For each dog, two-dimensional (2D) echocardiography was performed to assess LA diameter and volume for each phase of the LA cycle and to assess complete, passive, and active LA function. Pulsed-wave tissue Doppler imaging (TDI) of the left ventricular longitudinal myocardial velocity associated with atrial contraction (A'), both at the level of the interventricular septum and the LV free wall, was also used as an indicator of LA function. Results: There were no significant differences in any of the left atrial variables pre- and posttreatment. Conclusion: Echocardiographic estimates of LA function by 2D diameters and volumes and TDI A' in dogs with MMVD do not change after treatment with pimobendan.
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Función del Atrio Izquierdo/efectos de los fármacos , Enfermedades de los Perros/tratamiento farmacológico , Enfermedades de las Válvulas Cardíacas/veterinaria , Piridazinas/farmacología , Vasodilatadores/farmacología , Animales , Cardiotónicos/farmacología , Perros , Femenino , Enfermedades de las Válvulas Cardíacas/tratamiento farmacológico , Masculino , Inhibidores de Fosfodiesterasa/farmacologíaAsunto(s)
Artritis Reumatoide/complicaciones , Función del Atrio Izquierdo , Remodelación Atrial , Cardiopatías/etiología , Psoriasis/etiología , Accidente Cerebrovascular/etiología , Antiinflamatorios/uso terapéutico , Antirreumáticos/uso terapéutico , Artritis Reumatoide/diagnóstico , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/fisiopatología , Función del Atrio Izquierdo/efectos de los fármacos , Remodelación Atrial/efectos de los fármacos , Factores de Riesgo de Enfermedad Cardiaca , Cardiopatías/diagnóstico , Cardiopatías/fisiopatología , Cardiopatías/prevención & control , Humanos , Pronóstico , Psoriasis/diagnóstico , Psoriasis/tratamiento farmacológico , Psoriasis/fisiopatología , Medición de Riesgo , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/fisiopatología , Accidente Cerebrovascular/prevención & controlRESUMEN
OBJECTIVES: The aim of this study was to assess the effect of congestion and decongestive therapy on left atrial (LA) mechanics and to determine the relationship between LA improvement after decongestive therapy and clinical outcome in immediate or chronic heart failure with reduced ejection fraction (HFrEF). BACKGROUND: LA mechanics are affected by volume/pressure overload in decompensated HFrEF. METHODS: A total of 31 patients with HFrEF and immediate heart failure (age 64 ± 15 years, 74% male, left ventricular ejection fraction 20 ± 12%) underwent serial echocardiography during decongestive therapy with simultaneous hemodynamic monitoring. LA function was assessed by strain (rate) imaging. Patients were re-evaluated 6 weeks after discharge and prospectively followed up for the composite endpoint of heart failure readmission and all-cause mortality. RESULTS: LA reservoir function was markedly reduced at baseline and improved with decongestion (peak atrial longitudinal strain from 6.4 ± 2.2% to 8.8 ± 3.0% and strain rate from 0.29 ± 0.11 s-1 to 0.38 ± 0.13 s-1), independent of changes in left ventricular global longitudinal strain, LA end-diastolic volume, and mitral regurgitation severity (p < 0.001). Both measures continued to rise at 6 weeks (up to 13.4 ± 6.1% and 0.50 ± 0.19 s-1, respectively; p < 0.001). LA pump strain rate only increased 6 weeks after discharge (-0.25 ± 0.12 s-1 to -0.55 ± 0.29 s-1; p < 0.010). Changes in LA mechanics correlated with changes in wedge pressure (r = -0.61; p < 0.001). Lower peak atrial longitudinal strain values after decongestion were associated with increased risk for the composite endpoint of heart failure and mortality (p < 0.019). CONCLUSIONS: LA reservoir and booster function, while severely impaired during immediate decompensation, significantly improve during and after decongestive therapy. Poor LA reservoir function after decongestion is associated with worse outcome.
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Función del Atrio Izquierdo , Ecocardiografía , Insuficiencia Cardíaca/diagnóstico por imagen , Monitorización Hemodinámica , Hemodinámica , Anciano , Función del Atrio Izquierdo/efectos de los fármacos , Fármacos Cardiovasculares/uso terapéutico , Progresión de la Enfermedad , Femenino , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/mortalidad , Insuficiencia Cardíaca/fisiopatología , Hemodinámica/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Readmisión del Paciente , Valor Predictivo de las Pruebas , Estudios Prospectivos , Recuperación de la Función , Factores de Tiempo , Resultado del TratamientoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Arnebiae Radix, a common herbal medicine in China, is often utilized to treat blood-heat syndrome and has been reported to exert an effect on the heart. AIM OF THE STUDY: The combination of acetylcholine (Ach) and CaCl2 has been widely used to induce atrial fibrillation (AF) in animals. However, whether Arnebiae Radix displays any preventive action on Ach-CaCl2 induced AF in rats remains uncertain. In our study, we attempted to investigate the protective effects of Arnebiae Radix on Ach-CaCl2 induced AF compared to amiodarone, which was employed as the positive control. MATERIALS AND METHODS: To establish the AF model, SD rats were treated with a mixture of 0.1 mL/100â¯g Ach-CaCl2 (60⯵g/mL Ach and 10â¯mg/mL CaCl2) by tail vein injection for 7 days. Rats were also given a gavage of Arnebiae Radix (0.18â¯g/mL) one week before or concurrently with the establishment of the AF model. At the end of the experimental period, the induction, duration and timing of AF were monitored using electrocardiogram recordings. Left atrial tissues were stained to observe the level of fibrosis. Electrophysiological measurements were used to examine atrial size and function. RESULTS: In Ach-CaCl2-induced AF rats, Arnebiae Radix decreased AF induction, duration and susceptibility to AF. In addition, Arnebiae Radix significantly reduced atrial fibrosis and inhibited atrial enlargement induced by Ach-CaCl2. Moreover, there was an apparent improvement in cardiac function in the Arnebiae Radix-treated group. CONCLUSIONS: Our findings indicate that Arnebiae Radix treatment can attenuate Ach-CaCl2-induced atrial injury and serve as an effective therapeutic strategy for the treatment of AF in the future.
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Antiarrítmicos/farmacología , Fibrilación Atrial/prevención & control , Función del Atrio Izquierdo/efectos de los fármacos , Remodelación Atrial/efectos de los fármacos , Boraginaceae , Frecuencia Cardíaca/efectos de los fármacos , Extractos Vegetales/farmacología , Acetilcolina , Animales , Antiarrítmicos/aislamiento & purificación , Fibrilación Atrial/inducido químicamente , Fibrilación Atrial/fisiopatología , Boraginaceae/química , Cloruro de Calcio , Modelos Animales de Enfermedad , Fibrosis , Masculino , Extractos Vegetales/aislamiento & purificación , Ratas Sprague-Dawley , Función Ventricular Izquierda/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacosRESUMEN
BACKGROUND: Diabetes mellitus is an important risk factor for atrial fibrillation (AF) development. Sodium-glucose co-transporter-2 (SGLT-2) inhibitors are used for the treatment of type 2 diabetes mellitus (T2DM). Their cardioprotective effects have been reported but whether they prevent AF in T2DM patients are less well-explored. We tested the hypothesis that the SGLT-2 inhibitor, empagliflozin, can prevent atrial remodeling in a diabetic rat model. METHODS: High-fat diet and low-dose streptozotocin (STZ) treatment were used to induce T2DM. A total of 96 rats were randomized into the following four groups: (i) control (ii) T2DM, (iii) low-dose empagliflozin (10 mg/kg/day)/T2DM; and (iv) high-dose empagliflozin (30 mg/kg/day)/T2DM by the intragastric route for 8 weeks. RESULTS: Compared with the control group, left atrial diameter, interstitial fibrosis and the incidence of AF inducibility were significantly increased in the DM group. Moreover, atrial mitochondrial respiratory function, mitochondrial membrane potential, and mitochondrial biogenesis were impaired. Empagliflozin treatment significantly prevented the development of these abnormalities in DM rats, likely via the peroxisome proliferator-activated receptor-c coactivator 1α (PGC-1α)/nuclear respiratory factor-1 (NRF-1)/mitochondrial transcription factor A (Tfam) signaling pathway. CONCLUSIONS: Empagliflozin can ameliorate atrial structural and electrical remodeling as well as improve mitochondrial function and mitochondrial biogenesis in T2DM, hence may be potentially used in the prevention of T2DM-related atrial fibrillation.