RESUMEN
The cardiac outflow tract (OFT) transiently links the ventricles to the aortic sac and forms the arterial valves. Abnormalities in these valves, such as bicuspid aortic valve (BAV), are common congenital anomalies. GATA6-inactivating variants cause cardiac OFT defects and BAV, but their mechanisms are unclear. We generated Gata6STOP/+ mice using CRISPR-Cas9, which show highly penetrant BAV (70%) and membranous ventricular septal defects (43%). These mice exhibited decreased proliferation and increased ISL1-positive progenitor cells in the OFT, indicating abnormal cardiovascular differentiation. Gata6 deletion with the Mef2cCre driver line recapitulated Gata6STOP/+ phenotypes, indicating a cell-autonomous role for Gata6 in the second heart field. Gata6STOP/+ mice showed reduced OFT length and caliber, associated with deficient cardiac neural crest cell contribution, which may cause valvulo-septal defects. RNA-sequencing analysis showed depletion in pathways related to cell proliferation and migration, highlighting Cxcr7 (also known as Ackr3) as a candidate gene. Reduced mesenchymal cell migration and invasion were observed in Gata6STOP/+ OFT tissue. CXCR7 agonists reduced mesenchymal cell migration and increased invasion in wild-type but not in Gata6STOP/+ explants, indicating the GATA6-dependent role of CXCR7 in OFT development and its potential link to BAV.
Asunto(s)
Enfermedad de la Válvula Aórtica Bicúspide , Proliferación Celular , Factor de Transcripción GATA6 , Receptores CXCR , Transducción de Señal , Animales , Factor de Transcripción GATA6/metabolismo , Factor de Transcripción GATA6/genética , Enfermedad de la Válvula Aórtica Bicúspide/patología , Receptores CXCR/metabolismo , Receptores CXCR/genética , Cresta Neural/metabolismo , Cresta Neural/patología , Ratones , Movimiento Celular , Válvula Aórtica/anomalías , Válvula Aórtica/patología , Válvula Aórtica/metabolismo , Enfermedades de las Válvulas Cardíacas/patología , Enfermedades de las Válvulas Cardíacas/metabolismo , Enfermedades de las Válvulas Cardíacas/genética , Fenotipo , Ratones Endogámicos C57BLRESUMEN
Bicuspid aortic valve (BAV), the most common congenital heart defect, is a major cause of aortic valve disease requiring valve interventions and thoracic aortic aneurysms predisposing to acute aortic dissections. The spectrum of BAV ranges from early onset valve and aortic complications (EBAV) to sporadic late onset disease. Rare genomic copy number variants (CNVs) have previously been implicated in the development of BAV and thoracic aortic aneurysms. We determined the frequency and gene content of rare CNVs in EBAV probands (n = 272) using genome-wide SNP microarray analysis and three complementary CNV detection algorithms (cnvPartition, PennCNV, and QuantiSNP). Unselected control genotypes from the Database of Genotypes and Phenotypes were analyzed using identical methods. We filtered the data to select large genic CNVs that were detected by multiple algorithms. Findings were replicated in a BAV cohort with late onset sporadic disease (n = 5040). We identified 3 large and rare (< 1,1000 in controls) CNVs in EBAV probands. The burden of CNVs intersecting with genes known to cause BAV when mutated was increased in case-control analysis. CNVs intersecting with GATA4 and DSCAM were enriched in cases, recurrent in other datasets, and segregated with disease in families. In total, we identified potentially pathogenic CNVs in 9% of EBAV cases, implicating alterations of candidate genes at these loci in the pathogenesis of BAV.
Asunto(s)
Válvula Aórtica , Enfermedad de la Válvula Aórtica Bicúspide , Variaciones en el Número de Copia de ADN , Enfermedades de las Válvulas Cardíacas , Polimorfismo de Nucleótido Simple , Humanos , Variaciones en el Número de Copia de ADN/genética , Válvula Aórtica/anomalías , Válvula Aórtica/patología , Enfermedad de la Válvula Aórtica Bicúspide/genética , Enfermedades de las Válvulas Cardíacas/genética , Masculino , Femenino , Persona de Mediana Edad , Predisposición Genética a la Enfermedad , Adulto , Estudios de Casos y Controles , Anciano , Enfermedad de la Válvula Aórtica/genética , Factor de Transcripción GATA4/genética , Estudio de Asociación del Genoma CompletoRESUMEN
BACKGROUND: Medical therapy for aortic stenosis (AS) remains an elusive goal. OBJECTIVES: This study sought to establish whether evogliptin, a dipeptidyl peptidase-4 inhibitor, could reduce AS progression. METHODS: A total of 228 patients (age 67 ± 11 years; 33% women) with AS were randomly assigned to receive placebo (n = 75), evogliptin 5 mg (n = 77), or evogliptin 10 mg (n = 76). The primary endpoint was the 96-week change in aortic valve calcium volume (AVCV) on computed tomography. Secondary endpoints included the 48-week change in active calcification volume measured using 18F-sodium fluoride positron emission tomography (18F-NaF PET). RESULTS: There were no significant differences in the 96-week changes in AVCV between evogliptin 5 mg and placebo (-5.27; 95% CI: -55.36 to 44.82; P = 0.84) or evogliptin 10 mg and placebo (-18.83; 95% CI: -32.43 to 70.10; P = 0.47). In the placebo group, the increase in AVCV between 48 weeks and 96 weeks was higher than that between baseline and 48 weeks (136 mm3; 95% CI: 108-163 vs 102 mm3; 95% CI: 75-129; P = 0.0485). This increasing trend in the second half of the study was suppressed in both evogliptin groups. The 48-week change in active calcification volume on 18F-NaF PET was significantly lower in both the evogliptin 5 mg (-1,325.6; 95% CI: -2,285.9 to -365.4; P = 0.008) and 10-mg groups (-1,582.2; 95% CI: -2,610.8 to -553.5; P = 0.0038) compared with the placebo group. CONCLUSIONS: This exploratory study did not demonstrate the protective effect of evogliptin on AV calcification. Favorable 18F-NaF PET results and possible suppression of aortic valve calcification with longer medication use in the evogliptin groups suggest the need for larger confirmatory trials. (A Multicenter, Double-blind, Placebo-controlled, Stratified-randomized, Parallel, Therapeutic Exploratory Clinical Study to Evaluate the Efficacy and Safety of DA-1229 in Patients With Calcific Aortic Valve Disease; NCT04055883).
Asunto(s)
Estenosis de la Válvula Aórtica , Válvula Aórtica , Calcinosis , Progresión de la Enfermedad , Humanos , Femenino , Masculino , Anciano , Calcinosis/tratamiento farmacológico , Calcinosis/diagnóstico por imagen , Estenosis de la Válvula Aórtica/tratamiento farmacológico , Estenosis de la Válvula Aórtica/diagnóstico por imagen , Persona de Mediana Edad , Válvula Aórtica/diagnóstico por imagen , Válvula Aórtica/patología , Método Doble Ciego , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Tomografía de Emisión de Positrones/métodos , Resultado del Tratamiento , Tomografía Computarizada por Rayos X , PiperazinasRESUMEN
BACKGROUND: Membranoproliferative glomerulonephritis is a rare entity which can be a result from autoimmune diseases, caused by various medications and infections. CASE PRESENTATION: We herein present the case of a 62-year-old male patient who presented with fatigue and was found to have severe anemia, impaired renal function, and nephrotic syndrome. A renal biopsy revealed membranoproliferative glomerulonephritis (MPGN) of the immune complex type with activation of the classical complement pathway. Further investigations led to the diagnosis of a chronic Coxiella burnetii-infection (Q fever), likely acquired during cycling trips in a region known for intensive sheep farming. Additionally, the patient was found to have a post endocarditic destructive bicuspid aortic valve caused by this pathogen. Treatment with hydroxychloroquine and doxycycline was administered for a duration of 24 months. The aortic valve was replaced successfully and the patient recovered completely. CONCLUSIONS: Early detection and targeted treatment of this life-threatening disease is crucial for complete recovery of the patient.
Asunto(s)
Endocarditis Bacteriana , Glomerulonefritis Membranoproliferativa , Fiebre Q , Humanos , Masculino , Fiebre Q/complicaciones , Fiebre Q/tratamiento farmacológico , Fiebre Q/diagnóstico , Glomerulonefritis Membranoproliferativa/etiología , Glomerulonefritis Membranoproliferativa/complicaciones , Glomerulonefritis Membranoproliferativa/tratamiento farmacológico , Persona de Mediana Edad , Endocarditis Bacteriana/complicaciones , Endocarditis Bacteriana/tratamiento farmacológico , Hidroxicloroquina/uso terapéutico , Enfermedad Crónica , Doxiciclina/uso terapéutico , Válvula Aórtica/patología , Válvula Aórtica/diagnóstico por imagen , Antibacterianos/uso terapéutico , Enfermedad de la Válvula Aórtica Bicúspide/complicacionesRESUMEN
Calcific aortic valve disease (CAVD) primarily involves osteogenic differentiation in human aortic valve interstitial cells (hVICs). Schisandrol B (SolB), a natural bioactive constituent, has known therapeutic effects on inflammatory and fibrotic disorders. However, its impact on valve calcification has not been reported. We investigated the effect of SolB on osteogenic differentiation of hVICs. Transcriptome sequencing was used to analyze potential molecular pathways affected by SolB treatment. The study also included an in vivo murine model using aortic valve wire injury surgery to observe SolB's effect on valve calcification. SolB inhibited the osteogenic differentiation of hVICs, reversing the increase in calcified nodule formation and osteogenic proteins. In the murine model, SolB significantly decreased the peak velocity of the aortic valve post-injury and reduced valve fibrosis and calcification. Transcriptome sequencing identified the p53 signaling pathway as a key molecular target of SolB, demonstrating its role as a molecular glue in the mouse double minute 2 (MDM2)-p53 interaction, thereby promoting p53 ubiquitination and degradation, which further inhibited p53-related inflammatory and senescence response. These results highlighted therapeutic potential of SolB for CAVD via inhibiting p53 signaling pathway and revealed a new molecular mechanism of SolB which provided a new insight of theraputic mechanism for CAVD.
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Estenosis de la Válvula Aórtica , Válvula Aórtica , Calcinosis , Ciclooctanos , Lignanos , Proteína p53 Supresora de Tumor , Animales , Humanos , Masculino , Ratones , Válvula Aórtica/patología , Válvula Aórtica/efectos de los fármacos , Válvula Aórtica/metabolismo , Estenosis de la Válvula Aórtica/tratamiento farmacológico , Estenosis de la Válvula Aórtica/patología , Calcinosis/tratamiento farmacológico , Calcinosis/patología , Calcinosis/metabolismo , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Senescencia Celular/efectos de los fármacos , Ciclooctanos/farmacología , Modelos Animales de Enfermedad , Inflamación/tratamiento farmacológico , Inflamación/patología , Inflamación/metabolismo , Lignanos/farmacología , Ratones Endogámicos C57BL , Osteogénesis/efectos de los fármacos , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Transducción de Señal/efectos de los fármacos , Proteína p53 Supresora de Tumor/metabolismoAsunto(s)
Estenosis de la Válvula Aórtica , Válvula Aórtica , Humanos , Estenosis de la Válvula Aórtica/diagnóstico , Estenosis de la Válvula Aórtica/diagnóstico por imagen , Estenosis de la Válvula Aórtica/fisiopatología , Válvula Aórtica/diagnóstico por imagen , Válvula Aórtica/patología , Índice de Severidad de la EnfermedadRESUMEN
Background Quantifying the fibrotic and calcific composition of the aortic valve at CT angiography (CTA) can be useful for assessing disease severity and outcomes of patients with aortic stenosis (AS); however, it has not yet been validated against quantitative histologic findings. Purpose To compare quantification of aortic valve fibrotic and calcific tissue composition at CTA versus histologic examination. Materials and Methods This prospective study included patients who underwent CTA before either surgical aortic valve replacement for AS or orthotopic heart transplant (controls) at two centers between January 2022 and April 2023. At CTA, fibrotic and calcific tissue composition were quantified using automated Gaussian mixture modeling applied to the density of aortic valve tissue components, calculated as [(volume/total tissue volume) × 100]. For histologic evaluation, explanted valve cusps were stained with Movat pentachrome as well as hematoxylin and eosin. For each cusp, three 5-µm slices were obtained. Fibrotic and calcific tissue composition were quantified using a validated artificial intelligence tool and averaged across the aortic valve. Correlations were assessed using the Spearman rank correlation coefficient. Intermodality and interobserver variability were measured using the intraclass correlation coefficient (ICC) and Bland-Altman plots. Results Twenty-nine participants (mean age, 63 years ± 10 [SD]; 23 male) were evaluated: 19 with severe AS, five with moderate AS, and five controls. Fibrocalcific tissue composition strongly correlated with histologic findings (r = 0.92; P < .001). The agreement between CTA and histologic findings for fibrocalcific tissue quantification was excellent (ICC, 0.94; P = .001), with underestimation of fibrotic composition at CTA (bias, -4.9%; 95% limits of agreement [LoA]: -18.5%, 8.7%). Finally, there was excellent interobserver repeatability for fibrotic (ICC, 0.99) and calcific (ICC, 0.99) aortic valve tissue volume measurements, with no evidence of a difference in measurements between readers (bias, -0.04 cm3 [95% LoA: -0.27 cm3, 0.19 cm3] and 0.02 cm3 [95% LoA: -0.14 cm3, 0.19 cm3], respectively). Conclusion In a direct comparison, standardized quantitative aortic valve tissue characterization at CTA showed excellent concordance with histologic findings and demonstrated interobserver reproducibility. Clinical trial registration no. NCT06136689 Published under a CC BY 4.0 license. Supplemental material is available for this article. See also the editorial by Almeida in this issue.
Asunto(s)
Estenosis de la Válvula Aórtica , Válvula Aórtica , Calcinosis , Angiografía por Tomografía Computarizada , Fibrosis , Humanos , Masculino , Estudios Prospectivos , Femenino , Válvula Aórtica/diagnóstico por imagen , Válvula Aórtica/patología , Persona de Mediana Edad , Estenosis de la Válvula Aórtica/diagnóstico por imagen , Estenosis de la Válvula Aórtica/patología , Estenosis de la Válvula Aórtica/cirugía , Calcinosis/diagnóstico por imagen , Calcinosis/patología , Fibrosis/diagnóstico por imagen , Angiografía por Tomografía Computarizada/métodos , AncianoRESUMEN
BACKGROUND: Left ventricular (LV) hypertrophy occurs in both aortic stenosis (AS) and systemic hypertension (HTN) in response to wall stress. However, differentiation of hypertrophy due to these 2 etiologies is lacking. The aim was to study the 3-dimensional geometric remodeling pattern in severe AS pre- and postsurgical aortic valve replacement and to compare with HTN and healthy controls. METHODS: Ninety-one subjects (36 severe AS, 19 HTN, and 36 healthy controls) underwent cine cardiac magnetic resonance. Cardiac magnetic resonance was repeated 8 months post-aortic valve replacement (n=18). Principal component analysis was performed on the 3-dimensional meshes reconstructed from 109 cardiac magnetic resonance scans of 91 subjects at end-diastole. Principal component analysis modes were compared across experimental groups together with conventional metrics of shape, strain, and scar. RESULTS: A unique AS signature was identified by wall thickness linked to a LV left-right axis shift and a decrease in short-axis eccentricity. HTN was uniquely linked to increased septal thickness. Combining these 3 features had good discriminative ability between AS and HTN (area under the curve, 0.792). The LV left-right axis shift was not reversible post-aortic valve replacement, did not associate with strain, age, or sex, and was predictive of postoperative LV mass regression (R2=0.339, P=0.014). CONCLUSIONS: Unique remodeling signatures might differentiate the etiology of LV hypertrophy. Preliminary findings suggest that LV axis shift is characteristic in AS, is not reversible post-aortic valve replacement, predicts mass regression, and may be interpreted to be an adaptive mechanism.
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Estenosis de la Válvula Aórtica , Implantación de Prótesis de Válvulas Cardíacas , Hipertensión , Hipertrofia Ventricular Izquierda , Imagen por Resonancia Cinemagnética , Función Ventricular Izquierda , Remodelación Ventricular , Humanos , Estenosis de la Válvula Aórtica/fisiopatología , Estenosis de la Válvula Aórtica/cirugía , Estenosis de la Válvula Aórtica/complicaciones , Estenosis de la Válvula Aórtica/diagnóstico por imagen , Femenino , Masculino , Imagen por Resonancia Cinemagnética/métodos , Persona de Mediana Edad , Hipertensión/fisiopatología , Hipertensión/complicaciones , Anciano , Hipertrofia Ventricular Izquierda/fisiopatología , Hipertrofia Ventricular Izquierda/etiología , Hipertrofia Ventricular Izquierda/diagnóstico por imagen , Función Ventricular Izquierda/fisiología , Estudios de Casos y Controles , Valor Predictivo de las Pruebas , Resultado del Tratamiento , Diagnóstico Diferencial , Análisis de Componente Principal , Índice de Severidad de la Enfermedad , Válvula Aórtica/cirugía , Válvula Aórtica/diagnóstico por imagen , Válvula Aórtica/fisiopatología , Válvula Aórtica/patología , Factores de Tiempo , Imagenología TridimensionalAsunto(s)
Válvula Aórtica , Calcinosis , Transducción de Señal , Quinasas Asociadas a rho , Humanos , Quinasas Asociadas a rho/metabolismo , Calcinosis/etiología , Calcinosis/metabolismo , Válvula Aórtica/patología , Válvula Aórtica/metabolismo , Enfermedad de la Válvula Aórtica/metabolismo , Proteína de Unión al GTP rhoA/metabolismo , Estenosis de la Válvula Aórtica/etiología , Estenosis de la Válvula Aórtica/metabolismoRESUMEN
In developed countries, calcific aortic stenosis (CAS) has become the most common acquired valvular disease and cause for valve replacement. The prevalence of the disease increases with age, reaching over 5 % in adults over 75 years of age. The cases of CAS are classified as either of a previously normal (tricuspid) aortic valve (senile, syn. age - related, "sclerotic" type), or based on a congenitally malformed, usually bicuspid aortic valve. This paper is a brief summary of our 5 previous publications from the years 2007 - 2021, devoted to histopathology of CAS, namely to vascularization, inflammatory infiltrate and metaplastic ossification of the valve, and also to topography of these lesions in individual valve cusps. We conclude that calcification of the aortic valve is not a passive degenerative lesion, but an active multifactorial inflammatory process driven by cells native to the aortic valve. Pathogenesis of CAS is similar to that of atherosclerosis.
Asunto(s)
Estenosis de la Válvula Aórtica , Válvula Aórtica , Calcinosis , Humanos , Estenosis de la Válvula Aórtica/patología , Estenosis de la Válvula Aórtica/etiología , Calcinosis/patología , Válvula Aórtica/patología , Válvula Aórtica/anomalías , Inflamación/patologíaRESUMEN
Transcatheter aortic heart valve thrombosis (THVT) affects long-term valve durability, transvalvular pressure gradient and leaflet mobility. In this study, we conduct high-fidelity fluid-structure interaction simulations to perform Lagrangian particle tracing in a generic model with larger aortic diameters (THVT model) with and without neo-sinus which is compared to a model of unaffected TAVI patients (control model). Platelet activation indices are computed for each particle to assess the risk of thrombus formation induced by high shear stresses followed by flow stagnation. Particle tracing indicates that fewer particles contribute to sinus washout of the THVT model with and without neo-sinus compared to the control model (-34.9%/-34.1%). Stagnating particles in the native sinus of the THVT model show higher platelet activation indices than for the control model (+39.6% without neo-sinus, +45.3% with neo-sinus). Highest activation indices are present for particles stagnating in the neo-sinus of the larger aorta representing THVT patients (+80.2% compared to control). This fluid-structure interaction (FSI) study suggests that larger aortas lead to less efficient sinus washout in combination with higher risk of platelet activation among stagnating particles, especially within the neo-sinus. This could explain (a) a higher occurrence of thrombus formation in transcatheter valves compared to surgical valves without neo-sinus and (b) the neo-sinus as the prevalent region for thrombi in TAV. Pre-procedural identification of larger aortic roots could contribute to better risk assessment of patients and improved selection of a patient-specific anti-coagulation therapy.
Asunto(s)
Válvula Aórtica , Modelos Cardiovasculares , Activación Plaquetaria , Trombosis , Humanos , Trombosis/fisiopatología , Trombosis/patología , Activación Plaquetaria/fisiología , Válvula Aórtica/patología , Válvula Aórtica/cirugía , Reemplazo de la Válvula Aórtica Transcatéter , Aorta/fisiopatologíaRESUMEN
BACKGROUND: Aortic stenosis (AS) is driven by progressive inflammatory and fibrocalcific processes regulated by circulating inflammatory and valve resident endothelial and interstitial cells. The impact of platelets, platelet-derived mediators, and platelet-monocyte interactions on the acceleration of local valvular inflammation and mineralization is presently unknown. METHODS: We prospectively enrolled 475 consecutive patients with severe symptomatic AS undergoing aortic valve replacement. Clinical workup included repetitive echocardiography, analysis of platelets, monocytes, chemokine profiling, aortic valve tissue samples for immunohistochemistry, and gene expression analysis. RESULTS: The patients were classified as fast-progressive AS by the median ∆Vmax of 0.45 m/s per year determined by echocardiography. Immunohistological aortic valve analysis revealed enhanced cellularity in fast-progressive AS (slow- versus fast-progressive AS; median [interquartile range], 247 [142.3-504] versus 717.5 [360.5-1234]; P<0.001) with less calcification (calcification area, mm2: 33.74 [27.82-41.86] versus 20.54 [13.52-33.41]; P<0.001). MIF (macrophage migration inhibitory factor)-associated gene expression was significantly enhanced in fast-progressive AS accompanied by significantly elevated MIF plasma levels (mean±SEM; 6877±379.1 versus 9959±749.1; P<0.001), increased platelet activation, and decreased intracellular MIF expression indicating enhanced MIF release upon platelet activation (CD62P, %: median [interquartile range], 16.8 [11.58-23.8] versus 20.55 [12.48-32.28], P=0.005; MIF, %: 4.85 [1.48-9.75] versus 2.3 [0.78-5.9], P<0.001). Regression analysis confirmed that MIF-associated biomarkers are strongly associated with an accelerated course of AS. CONCLUSIONS: Our findings suggest a key role for platelet-derived MIF and its interplay with circulating and valve resident monocytes/macrophages in local and systemic thromboinflammation during accelerated AS. MIF-based biomarkers predict an accelerated course of AS and represent a novel pharmacological target to attenuate progression of AS.
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Estenosis de la Válvula Aórtica , Válvula Aórtica , Biomarcadores , Progresión de la Enfermedad , Oxidorreductasas Intramoleculares , Factores Inhibidores de la Migración de Macrófagos , Tromboinflamación , Humanos , Estenosis de la Válvula Aórtica/genética , Estenosis de la Válvula Aórtica/patología , Estenosis de la Válvula Aórtica/metabolismo , Estenosis de la Válvula Aórtica/sangre , Factores Inhibidores de la Migración de Macrófagos/sangre , Factores Inhibidores de la Migración de Macrófagos/genética , Factores Inhibidores de la Migración de Macrófagos/metabolismo , Masculino , Femenino , Anciano , Estudios Prospectivos , Válvula Aórtica/patología , Válvula Aórtica/metabolismo , Válvula Aórtica/diagnóstico por imagen , Oxidorreductasas Intramoleculares/genética , Oxidorreductasas Intramoleculares/metabolismo , Oxidorreductasas Intramoleculares/sangre , Biomarcadores/sangre , Tromboinflamación/genética , Tromboinflamación/patología , Tromboinflamación/metabolismo , Plaquetas/metabolismo , Plaquetas/patología , Anciano de 80 o más Años , Monocitos/metabolismo , Persona de Mediana Edad , Implantación de Prótesis de Válvulas Cardíacas , Factores de Tiempo , Índice de Severidad de la Enfermedad , Calcinosis/patología , Calcinosis/genética , Calcinosis/sangre , Calcinosis/metabolismoRESUMEN
Severe aortic valve stenosis (AS) often coexists with mitral valve stenosis (MS). MS aggravation after transcatheter aortic valve replacement (TAVR) is common, and its etiology is multifactorial. We hypothesized that geometric changes in the mitral complex (mitral valvular and annular deformities) are adjunctive factors aggravating MS after TAVR, particularly in older adults with a smaller left ventricle (LV). This study aimed to evaluate the mitral complex geometric changes before and after TAVR and to assess the important predictors of MS aggravation after TAVR. This retrospective study enrolled consecutive adult patients who underwent TAVR and surgical AVR (SAVR) for severe AS. The mitral valve area (MVA), the angle between the anterior mitral valve leaflet (AMVL) and left ventricular outflow tract (LVOT), AMVL length, mitral annular diameter, presence of mitral annular calcification, and LV size were evaluated using transthoracic echocardiography. This study included 258 patients who underwent TAVR and SAVR. MVA index decreased from 2.3 ± 0.6 cm² to 1.9 ± 0.5 cm² in the TAVR group. The angle between the AMVL and LVOT was 56.3 ± 9.7° preoperatively and increased to 67.3 ± 11.5° after TAVR. In multivariate analysis, the most important predictive factors of MS aggravation after TAVR were a smaller mitral annular diameter, restricted AMVL mobility, and implantation depth (odds ratio: 4.5, 5.3,3.0; 95% confidence interval: 1.6-14, 1.9-17, 1.0-8.9; and p = 0.005, p = 0.001, p = 0.042, respectively). The reduction in MVA after TAVR was related to the restriction of AMVL opening, depth of implantation and narrowing of the mitral annulus.
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Estenosis de la Válvula Aórtica , Válvula Aórtica , Estenosis de la Válvula Mitral , Válvula Mitral , Índice de Severidad de la Enfermedad , Reemplazo de la Válvula Aórtica Transcatéter , Humanos , Estudios Retrospectivos , Femenino , Masculino , Estenosis de la Válvula Aórtica/diagnóstico por imagen , Estenosis de la Válvula Aórtica/cirugía , Estenosis de la Válvula Aórtica/fisiopatología , Estenosis de la Válvula Mitral/diagnóstico por imagen , Estenosis de la Válvula Mitral/fisiopatología , Estenosis de la Válvula Mitral/cirugía , Estenosis de la Válvula Mitral/etiología , Anciano , Válvula Mitral/diagnóstico por imagen , Válvula Mitral/fisiopatología , Válvula Mitral/cirugía , Reemplazo de la Válvula Aórtica Transcatéter/efectos adversos , Resultado del Tratamiento , Anciano de 80 o más Años , Factores de Riesgo , Válvula Aórtica/diagnóstico por imagen , Válvula Aórtica/cirugía , Válvula Aórtica/fisiopatología , Válvula Aórtica/patología , Factores de Tiempo , Prótesis Valvulares CardíacasRESUMEN
Chronic kidney disease (CKD) is linked to greater prevalence and rapid progression of calcific aortic valve disease (CAVD) characterized by valvular leaflet fibrosis and calcification. Fibroblast growth factor 23 (FGF23) level is elevated, and anti-aging protein Klotho is reduced in CKD patients. However, the roles of FGF23 and Klotho in the mechanism of aortic valve fibrosis and calcification remain unclear. We hypothesized that FGF23 mediates CKD-induced CAVD by enhancing aortic valve interstitial cell (AVIC) fibrosis and calcification, while soluble Klotho inhibits FGF23 effect. Methods and Results: In an old mouse model of CKD, kidney damages were accompanied by aortic valve thickening and calcification. FGF23 levels in plasma and aortic valve were increased, while Klotho levels were decreased. Recombinant FGF23 elevated the inflammatory, fibrogenic, and osteogenic activities in AVICs. Neutralizing antibody or shRNA targeting FGF23 suppressed the pathobiological activities in AVICs from valves affected by CAVD. FGF23 exerts its effects on AVICs via FGF receptor (FGFR)/Yes-associated protein (YAP) signaling, and inhibition of FGFR/YAP reduced FGF23's potency in AVICs. Recombinant Klotho downregulated the pathobiological activities in AVICs exposed to FGF23. Incubation of FGF23 with Klotho formed complexes and decreased FGF23's potency. Further, treatment of CKD mice with recombinant Klotho attenuated aortic valve lesions. Conclusion: This study demonstrates that CKD induces FGF23 accumulation, Klotho insufficiency and aortic valve lesions in old mice. FGF23 upregulates the inflammatory, fibrogenic and osteogenic activities in AVICs via the FGFR/YAP signaling pathway. Soluble Klotho suppresses FGF23 effect through molecular interaction and is capable of mitigating CKD-induced CAVD.
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Válvula Aórtica , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos , Glucuronidasa , Proteínas Klotho , Insuficiencia Renal Crónica , Proteínas Klotho/metabolismo , Factor-23 de Crecimiento de Fibroblastos/metabolismo , Animales , Insuficiencia Renal Crónica/metabolismo , Glucuronidasa/metabolismo , Factores de Crecimiento de Fibroblastos/metabolismo , Ratones , Válvula Aórtica/metabolismo , Válvula Aórtica/patología , Calcinosis/metabolismo , Masculino , Transducción de Señal , Ratones Endogámicos C57BL , Humanos , Estenosis de la Válvula Aórtica/metabolismo , Modelos Animales de EnfermedadRESUMEN
BACKGROUND: Calcific aortic valve disease (CAVD) is one of the most common forms of valvulopathy, with a 50 % elevated risk of a fatal cardiovascular event, and greater than 15,000 annual deaths in North America alone. The treatment standard is valve replacement as early diagnostic, mitigation, and drug strategies remain underdeveloped. The development of early diagnostic and therapeutic strategies requires the fabrication of effective in vitro valve mimetic models to elucidate early CAVD mechanisms. METHODS: In this study, we developed a multilayered physiologically relevant 3D valve-on-chip (VOC) system that incorporated aortic valve mimetic extracellular matrix (ECM), porcine aortic valve interstitial cell (VIC) and endothelial cell (VEC) co-culture and dynamic mechanical stimuli. Collagen and glycosaminoglycan (GAG) based hydrogels were assembled in a bilayer to mimic healthy or diseased compositions of the native fibrosa and spongiosa. Multiphoton imaging and proteomic analysis of healthy and diseased VOCs were performed. RESULTS: Collagen-based bilayered hydrogel maintained the phenotype of the VICs. Proteins related to cellular processes like cell cycle progression, cholesterol biosynthesis, and protein homeostasis were found to be significantly altered and correlated with changes in cell metabolism in diseased VOCs. This study suggested that diseased VOCs may represent an early, adaptive disease initiation stage, which was corroborated by human aortic valve proteomic assessment. CONCLUSIONS: In this study, we developed a collagen-based bilayered hydrogel to mimic healthy or diseased compositions of the native fibrosa and spongiosa layers. When the gels were assembled in a VOC with VECs and VICs, the diseased VOCs revealed key insights about the CAVD initiation process. STATEMENT OF SIGNIFICANCE: Calcific aortic valve disease (CAVD) elevates the risk of death due to cardiovascular pathophysiology by 50 %, however, prevention and mitigation strategies are lacking, clinically. Developing tools to assess early disease would significantly aid in the prevention of disease and in the development of therapeutics. Previously, studies have utilized collagen and glycosaminoglycan-based hydrogels for valve cell co-cultures, valve cell co-cultures in dynamic environments, and inorganic polymer-based multilayered hydrogels; however, these approaches have not been combined to make a physiologically relevant model for CAVD studies. We fabricated a bi-layered hydrogel that closely mimics the aortic valve and used it for valve cell co-culture in a dynamic platform to gain mechanistic insights into the CAVD initiation process using proteomic and multiphoton imaging assessment.
Asunto(s)
Estenosis de la Válvula Aórtica , Válvula Aórtica , Calcinosis , Colesterol , Dispositivos Laboratorio en un Chip , Válvula Aórtica/patología , Válvula Aórtica/metabolismo , Calcinosis/patología , Calcinosis/metabolismo , Animales , Colesterol/metabolismo , Estenosis de la Válvula Aórtica/patología , Estenosis de la Válvula Aórtica/metabolismo , Ciclo Celular , Humanos , Porcinos , Homeostasis , Progresión de la Enfermedad , Hidrogeles/química , Técnicas de Cocultivo , Matriz Extracelular/metabolismo , Células Endoteliales/metabolismo , Células Endoteliales/patología , Sistemas MicrofisiológicosRESUMEN
BACKGROUND: Aortic-valve-stenosis (AS) is a frequent degenerative valvular-disease and carries dismal outcome under-medical-treatment. Transvalvular pressure gradient reflects severity of the valve-disease but is highly dependent on flow-conditions and on other valvular/aortic characteristics. Alternatively, aortic-valve-area (AVA) represents a measure of aortic-valve lesion severity conceptually essential and practically widely-recognized but exhibits multiple-limitations. METHODS: We analyzed the 4D multi-detector computed tomography(MDCT) of 20 randomly selected patients with severe AS. For each-patient, we generated the 3D-model of the valve and of its calcifications, and we computed the anatomical AVA accounting for the 3D-morphology of the leaflets in three-different-ways. Finally, we compared our results vs. Doppler-based AVAE measurements and vs. 2D-planimetric AVA-measurements. RESULTS: 3D-reconstruction and identification of the cusps were successful in 90% of the cases. The calcification patterns where highly-variable over patients, ranging from multiple small deposits to wide and c-shaped deposits running from commissure-to-commissure. AVAE was 82 ± 15 mm2. When segmenting 18 image planes, AVATight, AVAProj-Ann, AVAProj-Tip and their average AVAAve were equal to 80 ± 16, 88 ± 20, 93 ± 21 and 87 ± 19 mm2, respectively, while AVAPlan was equal to 143 ± 50 mm2. Linear-regression of the three measurements vs. AVAE yielded regression slopes equal to 1.26, 1.13 and 0.93 for AVAProj-Ann, AVAProj-Tip and AVATight, respectively. The respective Pearson-coefficients were 0.85,0.86 and 0.90. Conversely, when comparing AVAPlan vs. AVAE, linear regression yielded a slope of 1.73 and a Pearson coefficient of 0.53. CONCLUSIONS: We described a new-method to obtain a set of flow-independent quantifications that complement pressure gradient measurements and combine the advantages of previously proposed methods, while bypassing the corresponding-limitations.
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Estenosis de la Válvula Aórtica , Válvula Aórtica , Imagenología Tridimensional , Tomografía Computarizada Multidetector , Humanos , Estenosis de la Válvula Aórtica/diagnóstico por imagen , Tomografía Computarizada Multidetector/métodos , Masculino , Femenino , Válvula Aórtica/diagnóstico por imagen , Válvula Aórtica/patología , Anciano , Proyectos Piloto , Imagenología Tridimensional/métodos , Anciano de 80 o más Años , Persona de Mediana EdadRESUMEN
BACKGROUND: Aortic stenosis (AS) and transthyretin (ATTR) cardiac amyloidosis (CA) share the same clinical profiles and cardiac phenotype. Amyloid deposits have been frequently reported in aortic valves of patients with severe AS referred for surgical aortic valve replacement (SAVR). The aim of this study was to determine the clinical and myocardial status of patients with aortic valve amyloidosis after aortic valve surgery. METHODS AND RESULTS: We performed a retrospective descriptive study of 46 patients who underwent SAVR for severe AS with amyloid deposits upon histological analysis. All patients were screened for cardiac involvement. Amyloid deposits typing was successful in 35 (76%) patients and 28 (80%) were ATTR. Two (4%) had positive bone scintigraphy and among the 5 myocardial biopsies performed during surgery, 80% were positive for ATTR deposits. CONCLUSION: ATTR is the predominant type in the presence of amyloid deposits on the aortic valve after surgery for severe AS but is only rarely accompanied by cardiac uptake on bone scintigraphy. Early stages of myocardial involvement are frequent and myocardial biopsy is more sensitive for detection of mild amyloid deposits than bone scintigraphy.
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Neuropatías Amiloides Familiares , Estenosis de la Válvula Aórtica , Válvula Aórtica , Humanos , Masculino , Femenino , Estudios Retrospectivos , Anciano , Válvula Aórtica/patología , Válvula Aórtica/cirugía , Válvula Aórtica/diagnóstico por imagen , Estenosis de la Válvula Aórtica/patología , Estenosis de la Válvula Aórtica/cirugía , Estenosis de la Válvula Aórtica/diagnóstico por imagen , Persona de Mediana Edad , Neuropatías Amiloides Familiares/patología , Neuropatías Amiloides Familiares/cirugía , Neuropatías Amiloides Familiares/diagnóstico por imagen , Anciano de 80 o más Años , Miocardio/patología , Biopsia , Implantación de Prótesis de Válvulas Cardíacas , Cardiomiopatías/patología , Índice de Severidad de la EnfermedadRESUMEN
Importance: There are currently no pharmacological treatments available to slow hemodynamic progression of aortic stenosis. Plasma lipoprotein(a) concentrations predict incident aortic stenosis but its association with hemodynamic progression is controversial. Objective: To determine the association between plasma lipoprotein(a) concentrations and hemodynamic progression in patients with aortic stenosis. Design, Settings and Participants: The study included patients with aortic stenosis from 5 longitudinal clinical studies conducted from March 2001 to March 2023 in Canada and the UK. Of 757 total patients, data on plasma lipoprotein(a) concentrations and rates of hemodynamic progression assessed by echocardiography were available for 710, who were included in this analysis. Data were analyzed from March 2023 to April 2024. Exposure: Cohort-specific plasma lipoprotein(a) concentration tertiles. Main Outcomes and Measures: Hemodynamic aortic stenosis progression on echocardiography as assessed by annualized change in peak aortic jet velocity, mean transvalvular gradient, and aortic valve area. Results: Among the included patients, 497 (70%) were male and 213 (30%) were female. The mean (SD) age was 65.2 (13.1) years. Patients in the top lipoprotein(a) tertile demonstrated 41% (estimate, 1.41; 95% CI, 1.13-1.75) faster progression of peak aortic jet velocity and 57% (estimate, 1.57; 95% CI, 1.18-2.10) faster progression of mean transvalvular gradient than patients in the bottom tertile. There was no evidence of heterogeneity across the individual cohorts. Progression of aortic valve area was comparable between groups (estimate, 1.23; 95% CI, 0.71-2.12). Similar results were observed when plasma lipoprotein(a) concentrations were treated as a continuous variable. Conclusions and Relevance: In this study, higher plasma lipoprotein(a) concentrations were associated with faster rates of hemodynamic progression in patients with aortic stenosis. Lowering plasma lipoprotein(a) concentrations warrants further investigation in the prevention and treatment of aortic stenosis.
Asunto(s)
Estenosis de la Válvula Aórtica , Válvula Aórtica , Calcinosis , Progresión de la Enfermedad , Lipoproteína(a) , Estenosis de la Válvula Aórtica/sangre , Estenosis de la Válvula Aórtica/fisiopatología , Estenosis de la Válvula Aórtica/diagnóstico por imagen , Humanos , Lipoproteína(a)/sangre , Calcinosis/sangre , Calcinosis/fisiopatología , Calcinosis/diagnóstico por imagen , Válvula Aórtica/diagnóstico por imagen , Válvula Aórtica/patología , Ecocardiografía , Hemodinámica/fisiología , Femenino , MasculinoRESUMEN
BACKGROUND AND AIMS: Inflammation is initiates the propagation phase of aortic valve calcification. The activation of NLRP3 signaling in macrophages plays a crucial role in the progression of calcific aortic valve stenosis (CAVS). IFN-γ regulates NLRP3 activity in macrophages. This study aimed to explore the mechanism of IFN-γ regulation and its impact on CAVS progression and valve interstitial cell transdifferentiation. METHODS AND RESULTS: The number of Th1 cells and the expression of IFN-γ and STAT1 in the aortic valve, spleen and peripheral blood increased significantly as CAVS progressed. To explore the mechanisms underlying the roles of Th1 cells and IFN-γ, we treated CAVS mice with IFN-γ-AAV9 or an anti-IFN-γ neutralizing antibody. While IFN-γ promoted aortic valve calcification and dysfunction, it significantly decreased NLRP3 signaling in splenic macrophages and Ly6C+ monocytes. In vitro coculture showed that Th1 cells inhibited NLPR3 activation in ox-LDL-treated macrophages through the IFN-γR1/IFN-γR2-STAT1 pathway. Compared with untreated medium, conditioned medium from Th1-treated bone marrow-derived macrophages reduced the osteogenic calcification of valvular interstitial cells. CONCLUSION: Inhibition of the NLRP3 inflammasome by Th1 cells protects against valvular interstitial cell calcification as a negative feedback mechanism of adaptive immunity toward innate immunity. This study provides a precision medicine strategy for CAVS based on the targeting of anti-inflammatory mechanisms.