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RESEARCH PRODUCT

Cuantificación del calcio mineral en la ateromatosis carotídea mediante angiografía por tomografía computarizada: perfil evolutivo y relación con la progresión del grado de estenosis volumétrica

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Antecedentes: La cuantificación y caracterización del calcio (Ca) mineral (hidroxiapatita) en la bifurcación carotídea con AngioTC, y su relación con la sintomatología neurológica, en un estudio preliminar de casos y controles (Miralles y cols. Eur J Vasc Endovasc Surg 2006), constituye la base conceptual del presente estudio. Sus resultados, al igual que los de otras publicaciones, sugerían un posible papel protector del calcio en el desarrollo de eventos neurológicos. Sin embargo, su relación con la progresión de la ateromatosis carotídea ha sido escasamente analizado. Objetivos: Principales: 1. Diseñar un método de medición volumétrica de la ateromatosis (AE) carotídea y contenido de Ca mediante AngioTC. 2. Analizar el grado de calcificación arterial y su relación con la progresión de la ateromatosis carotídea. Secundarios: 3. Evaluar la relación entre calcificación arterial carotídea y descalcificación ósea, así como su posible conexión a través de los factores humorales implicados en la regulación del metabolismo Ca-P. 4. Estudiar un posible mecanismo genético común: relación entre los polimorfismos del gen de la OPG y la progresión de la calcificación en la placa de ateroma. Pacientes y método: Diseño: Cohortes, medidas repetidas. Pacientes: 54 pacientes, neurológicamente asintomáticos con estenosis de la arteria carótida interna (ECI) >50% (eco-Doppler). Determinaciones: Medición del grado de ECI mediante eco-Doppler y proyecciones MIP 2D de AngioTC. Medición del Volumen del molde de contraste y contenido de Ca (AngioTC cuantitativa: Agatston score modificado: volumen de Ca (mm3) x densidad radiológica (unidades Hounsfield, UH) en reconstrucción volumétrica (volume rendering) de la bifurcación carotídea (volumen de contraste entre 2 cm por debajo y 1 cm por encima de la bifurcación [VBif] y su cociente con un segmento de 1 cm en carótida primitiva [VCP]) (n=45). En todos los pacientes se repitió la exploración a los 122 meses para valorar la variación en el contenido de Ca y en el grado de estenosis volumétrica de la bifurcación, como medición indirecta de la progresión/regresión de la AE carotídea. Densitometría ósea de columna y fémur (n=32), (basal y a los 122 meses). Bioquímica y metabolismo Ca-P (Ca, P, vit D, PTH). Determinación de osteopontina (OPN) y osteoprotegerina (OPG) sérica y distribución de 7 SNPs del gen de la OPG seleccionados sobre bases bibiliométricas (n=48). Análisis estadístico: descriptivo (media [DE]); concordancia intra e interobservador (gráficos de Bland-Altman) y coeficiente de correlación intraclase (CCI), precisión eco-Doppler/AngioTC y Volumetría 3D/MIP 2D: sensibilidad (Sens), especificidad (Esp), índice kappa, curvas operador receptor (COR), comparación de medias (prueba T), análisis de regresión uni y multivariable. Resultados: 1. La medición volumétrica de la bifurcación carotídea mostró una concordancia intra e interobservador con un CCI de 0,96 (IC 95%: 0,904-0,985) y 0,94 (IC 95%: 0,822-0,977), respectivamente. El VBif/VCP del grupo de ECI50% (p=0,001). El punto de corte óptimo de la relación VBif/VCP se identificó a partir de la curva COR en 4,1 (Sens=0,75; Esp=0,75, kappa=0,46). 2. La medición mediante AngioTC demostró, a los 12 meses, un aumento del volumen promedio de pared arterial (disminución del volumen de la columna de contraste), respecto al valor basal (475,45 [155,6] mm3xUH vs 501,3 [171,9] mm3xUH, p=0,04), así como un aumento del Ca intraplaca (56,8 [52,3] vs 64,58 [57,8] mm3xUH, p=0,002). El análisis univariable demostró una correlación inversa entre el contenido basal de Ca y progresión de estenosis volumétrica de la bifurcación (r=-0,481; p50% (duplex scanning). Determinations: Measurement of CAS grade with duplex scanning and MIP 2D projections of AngioCT. Volume measurement of contrast medium and Ca content (quantitative AngioCT: Agatston score: Ca volume (mm3) x radiological density (Hounsfield units, HU) in volume reconstruction of the carotid bifurcation [contrast volume between 2 cm below and 1 cm above the bifurcation (BifV) and its ratio with that from 1 cm segment in common carotid artery (CCV)] (n=45). In all patients, the scans was repeated at 12±2 months to assess the variation in Ca content and the degree of bifurcation volumetric stenosis as an indirect measure of carotid AE progression / regression. Bone and spine densitometry (n=32), where obtained at baseline and after 12±2 months, as well as Biochemistry and Ca-P metabolism parameters (Ca, P, vit D, PTH). Determination of plasma levels of osteopontin (OPN) and osteoprotegerin (OPG) where compared with the distribution of 7 SNPs of the OPG gene selected on bibiliometrics bases (n=48). Statistical analysis: descriptive [mean (SD)]; Intra and interobserver agreement (Bland-Altman plots and intraclass correlation coefficient (ICC), duplex scanning / AngioCT precision and 3D Volumetry / MIP 2D: Sensitivity (S), specificity (E), kappa index, ROC curves, means comparison (T test), univariate and multivariate regression analysis. Results: 1.The volumetric measurement of the carotid bifurcation showed intra and interobserver agreement with a ICC of 0.96 (95% CI: 0.904-0.985) and 0.94 (95% CI: 0.822-0.977), respectively. The BifV/CCV of the CAS > 50% group was 5.2±1.8 vs 3.8 ±1.3 in the CAS >50% group (p=0.001). The optimum cutoff point for the BifV/CCV relation was identified from the ROC curve at 4,1 (S=0.75, E=0.75, kappa=0.46). 2. AngioCT measurement showed, at 12 months, an increase in mean arterial wall volume (decrease in contrast column volume), compared to baseline (475.45 [155.6] mm3xHU vs 501.3 [171.9] mm3xHU, p=0.04), as well as an increase in intraplaque Ca (56.8 [52.3] vs 64.58 [57.8] mm3xHU, p=0.002). Univariate analysis showed an inverse correlation between basal Ca content and progression of bifurcation volumetric stenosis (r=-0.481; p<0.001). The multiple regression analysis allowed to fit a linear regression model between the reduction of bifurcation volume (carotid AE progression) and the baseline intraplaque content of Ca, adjusted for body mass index (BMI). 3. A statistically significant decrease in bone density was observed with respect to the baseline determination (2.08 [0.22] vs 2.06 [0.23] g/cm2, p=0.013), as well as increased intraplaque Ca as compared with baseline values (79.2 [55] vs 64.58 [49.2] mm3xHU, p=0.12). However, a positive correlation was identified between the relative variation of Ca content and the relative variation of bone density (r=0.574, p=0.003). In other words, a greater tendency to osteoporosis was associated with a lower tendency to progression of intraplaque calcium. Likewise, a relationship between Vit D plasma levels and baseline densitometry (r=-0.459, p=0.036) and between plasma HDL-cholesterol levels and the relative variation, relative to baseline values, were observed. Bone density (r=-0.579, p=0.009). The univariate analysis showed an inverse correlation between the basal Ca content and the progression of bifurcation volumetric stenosis (r=-0.481; p<0.001), as well as between the increase in the intra-plaque calcium content and plasma levels of vit D (R=0.4, p=0.025) and femur Z score (r=0.378, p=0.047). Only the urine P concentration presented a moderate positive correlation with the increase of intra-plaque Ca (r=0.488, p=0.015). No other variable, among Ca-P metabolism parameters, was related to arterial calcification. 4. There were no differences between the distribution of SNPs in patients and control group. There was also no relationship between genotype and serum OPG concentration. Conclusions: 1. The volumetric measurement of the carotid bifurcation is a new concept based on the assessment of the plaque load rather than on its hemodynamic effect or maximal stenosis. Given its accuracy in detecting small variations in arterial lumen, this method may be especially useful in plaque progression studies. 2. The results of this study suggest that a higher content of Ca confers greater stability against the progression of carotid AE and, eventually, its capacity to generate symptomatology. 3. We found an independent tendency to progressive arterial calcification and bone decalcification. However, the results suggest a direct temporal relationship in the evolution of the calcium deposit in both locations, so it is not possible to rule out that its modulation is controlled by similar mechanisms. 4. The results are inconclusive with regard to the role of OPG in AE plaque calcification. No significant relationship between the distribution of SNPs analyzed and OPG levels in the studied patients was observed.