Temporal Progression of Aortic Valve Pathogenesis in a Mouse Model of Osteogenesis Imperfecta.

Organization of extracellular matrix (ECM) components, including collagens, proteoglycans, and elastin, is essential for maintaining the structure and function of heart valves throughout life. Mutations in ECM genes cause connective tissue disorders, including Osteogenesis Imperfecta (OI), and progressive debilitating heart valve dysfunction is common in these patients. Despite this, effective treatment options are limited to end-stage interventions. Mice with a homozygous frameshift mutation in col1a2 serve as a murine model of OI (oim/oim), and therefore, they were used in this study to examine the pathobiology of aortic valve (AoV) disease in this patient population at structural, functional, and molecular levels. Temporal echocardiography of oim/oim mice revealed AoV dysfunction by the late stages of disease in 12-month-old mice. However, structural and proteomic changes were apparent much earlier, at 3 months of age, and were associated with disturbances in ECM homeostasis primarily related to collagen and proteoglycan abnormalities and disorganization. Together, findings from this study provide insights into the underpinnings of late onset AoV dysfunction in connective tissue disease patients that can be used for the development of mechanistic-based therapies administered early to halt progression, thereby avoiding late-stage surgical intervention.

Valve Endothelial Cell Exposure to High Levels of Flow Oscillations Exacerbates Valve Interstitial Cell Calcification.

The aortic valve facilitates unidirectional blood flow to the systemic circulation between the left cardiac ventricle and the aorta. The valve's biomechanical function relies on thin leaflets to adequately open and close over the cardiac cycle. A monolayer of valve endothelial cells (VECs) resides on the outer surface of the aortic valve leaflet. Deeper within the leaflet are sublayers of valve interstitial cells (VICs). Valve tissue remodeling involves paracrine signaling between VECs and VICs. Aortic valve calcification can result from abnormal paracrine communication between these two cell types. VECs are known to respond to hemodynamic stimuli, and, specifically, flow abnormalities can induce VEC dysfunction. This dysfunction can subsequently change the phenotype of VICs, leading to aortic valve calcification. However, the relation between VEC-exposed flow oscillations under pulsatile flow to the progression of aortic valve calcification by VICs remains unknown. In this study, we quantified the level of flow oscillations that VECs were exposed to under dynamic culture and then immersed VICs in VEC-conditioned media. We found that VIC-induced calcification was augmented under maximum flow oscillations, wherein the flow was fully forward for half the cardiac cycle period and fully reversed for the other half. We were able to computationally correlate this finding to specific regions of the aortic valve that experience relatively high flow oscillations and that have been shown to be associated with severe calcified deposits. These findings establish a basis for future investigations on engineering calcified human valve tissues and its potential for therapeutic discovery of aortic valve calcification.

S2 Heart Sound Detects Aortic Valve Calcification Independent of Hemodynamic Changes in Mice.

Background: Calcific aortic valve disease (CAVD) is often undiagnosed in asymptomatic patients, especially in underserved populations. Although artificial intelligence has improved murmur detection in auscultation exams, murmur manifestation depends on hemodynamic factors that can be independent of aortic valve (AoV) calcium load and function. The aim of this study was to determine if the presence of AoV calcification directly influences the S2 heart sound. Methods: Adult C57BL/6J mice were assigned to the following 12-week-long diets: (1) Control group (n = 11) fed a normal chow, (2) Adenine group (n = 4) fed an adenine-supplemented diet to induce chronic kidney disease (CKD), and (3) Adenine + HP (n = 9) group fed the CKD diet for 6 weeks, then supplemented with high phosphate (HP) for another 6 weeks to induce AoV calcification. Phonocardiograms, echocardiogram-based valvular function, and AoV calcification were assessed at endpoint. Results: Mice on the Adenine + HP diet had detectable AoV calcification (9.28 ± 0.74% by volume). After segmentation and dimensionality reduction, S2 sounds were labeled based on the presence of disease: Healthy, CKD, or CKD + CAVD. The dataset (2,516 S2 sounds) was split subject-wise, and an ensemble learning-based algorithm was developed to classify S2 sound features. For external validation, the areas under the receiver operating characteristic curve of the algorithm to classify mice were 0.9940 for Healthy, 0.9717 for CKD, and 0.9593 for CKD + CAVD. The algorithm had a low misclassification performance of testing set S2 sounds (1.27% false positive, 1.99% false negative). Conclusion: Our ensemble learning-based algorithm demonstrated the feasibility of using the S2 sound to detect the presence of AoV calcification. The S2 sound can be used as a marker to identify AoV calcification independent of hemodynamic changes observed in echocardiography.

Prevalencia de acantosis nigricans y factores asociados con el síndrome metabólico en Nobsa (Boyacá, Colombia) / Prevalence of Acanthosis Nigricans and Associated Factors to Metabolic Syndrome in Nobsa (Boyacá, Colombia) / Prevalência de acantose nigricans e fatores associados com a síndrome metabólica em Nobsa (Boyacá, Colômbia)

Introducción: El síndrome metabólico es un conjunto de anormalidades fisiológicas que manifiestan resistencia a la insulina, de la que se derivan complicaciones micro y macrovasculares de alto costo en salud. Objetivo: Estimar la prevalencia de la acantosis nigricans y los factores sociodemográficos asociados en una pobla-ción con síndrome metabólico del municipio de Nobsa (Boyacá, Colombia) en el periodo agosto de 2017-agosto de 2018. Método: Estudio transversal analítico en una muestra de 82 pacientes del programa de crónicos del municipio de Nobsa. Se recolectó información sobre la presencia o ausencia de acantosis nigricans en la exploración física, junto con medidas antropométricas, fototipo de piel y presión arterial; así como concentración sérica de glucosa en ayuno, creatinina y perfil lipídico. Los datos se analizaron mediante la prueba de chi cuadrado. Resultados: En una muestra de 82 pacientes con edad media de 62 años, de los cuales el 91 % fueron mujeres, se encontró una prevalencia de acantosis nigricans del 41,5 % con asociación estadísticamente significativa para niveles elevados de glucosa (p = 0,008) y un odds ratio de 3,75 (IC95 %: 1,3-10,2). Para las demás variables en estudio no se evidenció asociación con significancia estadística. Conclusiones: la acantosis nigricans es un signo clínico indicador de resistencia a la insulina y de niveles alterados de glucemia

Introduction: The metabolic syndrome is a set of physiological abnormalities that manifest insulin resistance, from which high cost micro- and macrovascular complications in health derive. Objective: To estimate the prevalence of acanthosis nigricans and the sociodemographic factors asso-ciated with the population with metabolic syndrome in the municipality of Nobsa (Boyacá, Colombia), from August 2017 to August 2018. Method: Analytical cross-sectional study in a sample of 82 patients from the Nobsa municipality chronic program. Information was collected on the presence or absence of acanthosis nigricans in the physical examination together with anthropometric measurements, skin phototype and blood pres-sure, as well as serum concentration of fasting glucose, creatinine, and lipid profile. The data were analyzed using the Chi square test. Results: In a sample of 82 patients with a mean age of 62 years, of which 91% were women, a pre-valence of acanthosis nigricans of 41.5% was found with a statistically significant association for high glucose levels (p = 0.008) and an Odds Ratio of 3.75 (95% CI: 1.3-10.2). For the other variables under study, no association with statistical significance was evidenced. Conclusions: Acanthosis nigricans is a clinical sign of insulin resistance and altered blood glucose levels

Introdução: A síndrome metabólica é um conjunto de anomalias fisiológicas que manifestam resis-tência à insulina, da qual derivam complicações micro e macro vasculares de alto custo em saúde. Objetivo: Estimar a prevalecia de acantose nigricans e os fatores sociodemográficos associados, a uma população com síndrome metabólica no município de Nobsa (Boyacá, Colômbia) no período de Agosto de 2017 ­ Agosto de 2018. Método: Estudo analítico transversal com uma amostra de 82 pacientes do Programa de crónicos no município de Nobsa. Foram recolhidas informações sobre a presença ou ausência de acantose nigri-cans no exame físico, juntamente com medições antropométricas, fotótipo de pele e pressão sanguí-nea; bem como a concentração sérica da glicose em jejum, creatinina e perfil lipídico. Os dados foram analisados utilizando o teste do qui-quadrado. Resultados: Uma amostra de 82 pacientes com idade meia de 62 anos, 91 % dos quais eram mulhe-res, foi identificada uma prevalência de acantose nigricans de 41,5 % com associação estatisticamente significativa para níveis elevadas de glicose (p = 0,008) e um odds ratio de 3,75 (IC95 %: 1,3-10,2). Para as outras variáveis em estudo, não foi evidenciada associação estatisticamente significativa. Conclusões: A acantose nigricans é um sinal clinico indicador de resistência à insulina e níveis eleva-dos de glicose no sangue

A Method to Quantify Tensile Biaxial Properties of Mouse Aortic Valve Leaflets.

Understanding aortic valve (AV) mechanics is crucial in elucidating both the mechanisms that drive the manifestation of valvular diseases as well as the development of treatment modalities that target these processes. Genetically modified mouse models have become the gold standard in assessing biological mechanistic influences of AV development and disease. However, very little is known about mouse aortic valve leaflet (MAVL) tensile properties due to their microscopic size (∼500 µm long and 45 µm thick) and the lack of proper mechanical testing modalities to assess uniaxial and biaxial tensile properties of the tissue. We developed a method in which the biaxial tensile properties of MAVL tissues can be assessed by adhering the tissues to a silicone rubber membrane utilizing dopamine as an adhesive. Applying equiaxial tensile loads on the tissue-membrane composite and tracking the engineering strains on the surface of the tissue resulted in the characteristic orthotropic response of AV tissues seen in human and porcine tissues. Our data suggest that the circumferential direction is stiffer than the radial direction (n = 6, P = 0.0006) in MAVL tissues. This method can be implemented in future studies involving longitudinal mechanical stimulation of genetically modified MAVL tissues bridging the gap between cellular biological mechanisms and valve mechanics in popular mouse models of valve disease.

Elastin-Dependent Aortic Heart Valve Leaflet Curvature Changes During Cyclic Flexure.

The progression of calcific aortic valve disease (CAVD) is characterized by extracellular matrix (ECM) remodeling, leading to structural abnormalities and improper valve function. The focus of the present study was to relate aortic valve leaflet axial curvature changes as a function of elastin degradation, which has been associated with CAVD. Circumferential rectangular strips (L × W = 10 × 2.5 mm) of normal and elastin-degraded (via enzymatic digestion) porcine AV leaflets were subjected to cyclic flexure (1 Hz). A significant increase in mean curvature (p < 0.05) was found in elastin-degraded leaflet specimens in comparison to un-degraded controls at both the semi-constrained (50% of maximum flexed state during specimen bending and straightening events) and fully-constrained (maximally-flexed) states. This significance did not occur in all three flexed configurations when measurements were performed using either minimum or maximum curvature. Moreover, the mean curvature increase in the elastin-degraded leaflets was most pronounced at the instance of maximum flexure, compared to un-degraded controls. We conclude that the mean axial curvature metric can detect distinct spatial changes in aortic valve ECM arising from the loss in bulk content and/or structure of elastin, particularly when there is a high degree of tissue bending. Therefore, the instance of maximum leaflet flexure during the cardiac cycle could be targeted for mean curvature measurements and serve as a potential biomarker for elastin degradation in early CAVD remodeling.

Alteración de superficies de implantes de ti comercialmente puro a través de métodos físicos y / o químicos. Estudios experimentales: una revisión de literatura / Implants surface alteration of commercial pure through chemical and/or physical methods. Experimental studies: a review of literature

La obtimización de la calidad de interfase creada entre huesos de implante, ha sido objeto de múltiples investigaciones debido a la demanda funcional y biomecnica que esta interfase tiene a ser sometida a cargas oclusales. Dicho mejoramiento se ha hecho a costa del manejo de diferentes biomateriales para cubrimiento de la superficie y de la alteración de las características microestructurales de la superficie de los implantes de Ti comercialmente puro. Esto último se ha realizado con el fin de eliminar o aumentar la cantidad de rugosidad superficial de tal manera que se modifique la cantidad de superficie de contacto entre el hueso e implante para que se produzca un ancláje adecuado del implante al hueso que le permita soportar cargas. Las alteraciones de la topografía superficial se realiza a través de procedimientos físicos tales como el arenodo con partículas de dixido de titanio o de dixido de aluminio de diferentes tamaños, electropulimiento, o por medio de grabado cido con diferentes soluciones y diferentes tiempos. La eficacia de dichos procedimientos sobre las interfase hueso-implante ha sido evaluada por medio de cultivos celulares invitro, análisis histomorfomátricos, y análisis de resistencia al torque reverso. Observando en la mayoria de los estudios que la reacción de rugosidades con diferentes tratamientos puede aumentar la superficie de contacto entre hueso e implante, mejorando a su vez las propiedades biomecánicas de dicha interfase.