Remodelado estructural y de gap junctions en un modelo 3D de aurícula humana

Introducción: la fibrilación auricular (AF), es la más común de la arritmia cardiaca sostenida y un factor de riesgo para el accidente cerebro vascular y otras morbilidades, si no es tratada. Estudios epidemiológicos muestran que la AF tiende a perpetuarse con el tiempo, generando cambios electrofisiológicos y anatómicos denominados: remodelados auriculares. Se ha demostrado que estos cambios provocan variaciones de la velocidad de conducción (CV), en el tejido auricular. Objetivo: estudiar el efecto del remodelado de gap junctions en la propagación del potencial de acción, implementando un modelo 3D de aurícula humana altamente realista. Materiales y Métodos: se incorporaron los cambios generados por el remodelado eléctrico a un modelo de... Ver más

Guardado en:

1657-9550

2462-960X

10

2022-03-17

48

56

http://purl.org/coar/access_right/c_abf2

info:eu-repo/semantics/openAccess

Revista Biosalud - 2011

id abc05e59803c2f2addd86b413cf21b65
record_format ojs
spelling Remodelado estructural y de gap junctions en un modelo 3D de aurícula humana
Ruiz-Villa C, Tobón C, Rodriguez FJ, Heidenreich E. Efecto de la dilatación auricular sobre la vulnerabilidad a reentradas. In: Congreso Anual de la Sociedad española de Ingeniería Biomédica; 2008. Valladolid.
Allessie M, Ausma J, Schotten U. Electrical, contractile and structural remodeling during atrial fibrillation. Cardiovasc Res 2002; 54(2):230-46.
Ho SY, Sanchez-Quintana D, Anderson RH. Can anatomy define electric pathways? In: International Workshop on Computer Simulation and Experimental Assessment of Electrical Cardiac Function; 1998. Lausanne, Switzerland.
Hansson A, Holm M, Blomstrom P, Johansson R, Luhrs C, Brandt J, et al. Right atrial free wall conduction velocity and degree of anisotropy in patients with stable sinus rhythm studied during open heart surgery. Eur Heart J 1998; 19(2):293-300.
Feld GK, Mollerus M, Birgersdotter-Green U, Fujimura O, Bahnson TD, Boyce K, et al. Conduction velocity in the tricuspid valve-inferior vena cava isthmus is slower in patients with type I atrial flutter compared to those without a history of atrial flutter. J Cardiovasc Electrophysiol 1997; 8(12):1338-48.
Cohen GI, White M, Sochowski RA, Klein AL, Bridge PD, Stewart WJ, et al. Reference values for normal adult transesophageal echocardiographic measurements. J Am Soc Echocardiogr 1995; 8(3):221-30.
Wang K, Ho SY, Gibson DG, Anderson RH. Architecture of atrial musculature in humans. Br Heart J 1995; 73(6):559-65.
Ruiz-Villa C, Tobón C, Heidenreich E, Hornero F. Propagación de potencial de acción en un modelo 3D realista de Aurícula Humana. In: Congreso Anual de la Sociedad Española de Ingeniería Biomédica; 2006. Pamplona.
Bosch RF, Zeng X, Grammer JB, Popovic K, Mewis C, Kuhlkamp V. Ionic mechanisms of electrical remodeling in human atrial fibrillation. Cardiovasc Res 1999; 44(1):121-31.
Jacquemet V, Virag N, Ihara Z, Dang L, Blanc O, Zozor S, et al. Study of unipolar electrogram morphology in a computer model of atrial fibrillation. J Cardiovasc Electrophysiol 2003; 14(Suppl. 10):S172-9.
Virag N, Jacquemet V, Henriquez CS, Zozor S, Blanc O, Vesin JM, et al. Study of atrial arrhythmias in a computer model based on magnetic resonance images of human atria. Chaos 2002; 12(3):754-763.
Tieleman RG, De Langen C, Van Gelder IC, de Kam PJ, Grandjean J, Bel KJ, et al. Verapamil reduces tachycardia-induced electrical remodeling of the atria. Circulation 1997; 95(7):1945-53.
Elvan A, Wylie K, Zipes DP. Pacing-induced chronic atrial fibrillation impairs sinus node function in dogs. Electrophysiological remodeling. Circulation 1996; 94(11):2953-60.
Konings KT, Kirchhof CJ, Smeets JR, Wellens HJ, Penn OC, Allessie MA. High-density mapping of electrically induced atrial fibrillation in humans. Circulation 1994; 89(4):1665-80.
Kirchhof C, Chorro F, Scheffer GJ, Brugada J, Konings K, Zetelaki Z, et al. Regional entrainment of atrial fibrillation studied by high-resolution mapping in open-chest dogs. Circulation 1993; 88(2):736-49.
Cox JL, Canavan TE, Schuessler RB, Cain ME, Lindsay BD, Stone C, et al. The surgical treatment of atrial fibrillation. II. Intraoperative electrophysiologic mapping and description of the electrophysiologic basis of atrial flutter and atrial fibrillation. J Thorac Cardiovasc Surg 1991; 101(3):406-26.
Nygren A, Fiset C, Firek L, Clark JW, Lindblad DS, Clark RB, et al. Mathematical model of an adult human atrial cell: the role of K+ currents in repolarization. Circ Res 1998; 82(1):63-81.
Workman AJ, Kane KA, Rankin AC. The contribution of ionic currents to changes in refractoriness of human atrial myocytes associated with chronic atrial fibrillation. Cardiovasc Res 2001; 52(2):226-35.
Zimerman L, Fenelon G, Martinelli Filho M, Grupi C, Atié J, Lorga Filho A. Diretrizes brasileiras de fibrilação atrial. Arq Bras Cardiol 2009; 92(6 Suppl. 1):1-39.
http://purl.org/coar/resource_type/c_6501
Text
http://purl.org/coar/access_right/c_abf2
info:eu-repo/semantics/openAccess
http://purl.org/coar/version/c_970fb48d4fbd8a85
info:eu-repo/semantics/publishedVersion
http://purl.org/redcol/resource_type/ART
http://purl.org/coar/resource_type/c_2df8fbb1
info:eu-repo/semantics/article
Takeuchi S, Akita T, Takagishi Y, Watanabe E, Sasano C, Honjo H, et al. Disorganization of gap junction distribution in dilated atria of patients with chronic atrial fibrillation. Circ J 2006; 70(5):575-82.
Kharche S, Zhang H. Simulating the effects of atrial fibrillation induced electrical remodeling: A comprehensive simulation study. In: Engineering in Medicine and Biology Society, 2008. EMBS 2008. 30th Annual International Conference of the IEEE; 2008. p. 593-5.
Seemann G, Bustamante PC, Ponto S, Wilhelms M, Scholz EP, Do, et al. Atrial fibrillation-based electrical remodeling in a computer model of the human atrium. In: Computing in Cardiology, 2010; 2010 26-29 Sept. 2010; 2010. p. 417-420.
Wilders R. Computer modelling of the sinoatrial node. Med Biol Eng Comput 2007; 45(2):189-207.
Boyett MR, Honjo H, Kodama I. The sinoatrial node, a heterogeneous pacemaker structure. Cardiovasc Res 2000; 47(4):658-87.
Spach MS, Heidlage JF, Dolber PC, Barr RC. Electrophysiological effects of remodeling cardiac gap junctions and cell size: experimental and model studies of normal cardiac growth. Circ Res 2000; 86(3):302-11.
Kostin S, Rieger M, Dammer S, Hein S, Richter M, Klovekorn WP, et al. Gap junction remodeling and altered connexin 43 expression in the failing human heart. Mol Cell Biochem 2003; 242(1-2):135-44.
Jongsma HJ, Wilders R. Gap junctions in cardiovascular disease. Circ Res 2000; 86(12):1193-7.
Fuenmayor A, Fuenmayor A. Tratamiento no farmacológico de la fibrilación auricular. Avances Cardiológicos 2009;29:286-95.
Lloyd-Jones D, Adams RJ, Brown TM, Carnethon M, Dai S, De Simone G, et al. Heart disease and stroke statistics--2010 update: a report from the American Heart Association. Circulation 2010; 121(7):e46-e215.
Coyne KS, Paramore C, Grandy S, Mercader M, Reynolds M, Zimetbaum P. Assessing the direct costs of treating nonvalvular atrial fibrillation in the United States. Value Health 2006; 9(5):348-56.
Artículo de revista
Introducción: la fibrilación auricular (AF), es la más común de la arritmia cardiaca sostenida y un factor de riesgo para el accidente cerebro vascular y otras morbilidades, si no es tratada. Estudios epidemiológicos muestran que la AF tiende a perpetuarse con el tiempo, generando cambios electrofisiológicos y anatómicos denominados: remodelados auriculares. Se ha demostrado que estos cambios provocan variaciones de la velocidad de conducción (CV), en el tejido auricular. Objetivo: estudiar el efecto del remodelado de gap junctions en la propagación del potencial de acción, implementando un modelo 3D de aurícula humana altamente realista. Materiales y Métodos: se incorporaron los cambios generados por el remodelado eléctrico a un modelo de potencial de acción (AP) de miocito auricular, acoplado con un modelo tridimensional anatómicamente realista de aurícula humana dilatada. Mediante simulaciones de la propagación del AP en condiciones de remodelado eléctrico y anatómico, y de remodelado de gap junctions, se midieron las ventanas vulnerables de generación de reentradas en la base de las venas pulmonares izquierdas de la aurícula. Resultados: los resultados obtenidos indican que la ventana vulnerable en el remodelado de gap junctions, se desplazó 38 ms con relación al modelo dilatado, lo que nos muestra el impacto de la dilatación con remodelado de gap junction. Conclusiones: el remodelado eléctrico generó una disminución del 70 % en la duración del potencial de acción y una disminución de las velocidades de conducción entre un 14.6 y un 26 %, que fueron medidas en diferentes regiones de la aurícula dilatada. El foco disparado en la base de las venas pulmonares izquierdas, generó un frente de onda que mantiene una actividad reentrante debido a la anatomía subyacente de las venas pulmonares.
Ruiz Villa, Carlos A.
Castaño Vélez, Andrés P.
Heidenreich, Elvio A.
fibrilación auricular
gap junctions
modelo 3D
potencial de acción
reentrada
remodelado eléctrico
10
Núm. 2 , Año 2011 : Julio - Diciembre
2
Publication
https://revistasojs.ucaldas.edu.co/index.php/biosalud/article/view/4739
Revista Biosalud - 2011
https://creativecommons.org/licenses/by-nc-sa/4.0/
Español
Biosalud
Universidad de Caldas
application/pdf
reentry
action potential
3D model
gap junctions
Atrial fibrillation
Introduction: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and a significant risk factor for cerebrovascular accident and other morbidities if left untreated. Epidemiological studies show that AF tends to persist over time, creating electrophysiological and anatomical changes called atrial remodeling. It has been shown that these changes result in variations in conduction velocity (CV) in the atrial tissue. Objective: to study the effect of remodeling of gap junctions in the propagation of the action potential by implementing a highly realistic 3D human atrial model. Materials and methods: the changes caused by electrical remodeling were incorporated in an atrial myocyte action potential (AP) model coupled with an anatomically realistic three-dimensional model of dilated human atria. Through simulations of the AP spread in variations of anatomical and electrical remodeling and of gap junctions remodeling, vulnerable windows of reentry generation were measured at the base of the atrium left pulmonary veins. Results: the results obtained indicate that vulnerable window in the gap junctions remodeling moved 38 ms in relation with the expanded model which shows the impact of the dilatation gap junction remodeling. Conclusions: the electrical remodeling produced 70% decrease in action potential duration and decreased conduction velocities between 14.6 and 26 %, which were measured in different regions of the dilated atrium. The focus shot at the base of the left pulmonary veins created a wave which maintains a reentering activity due to the underlying anatomy of the pulmonary veins.
electrical remodeling
Structural remodeling and of gap junctions in a 3D model of human atrial
Journal article
56
48
2462-960X
2022-03-17
https://revistasojs.ucaldas.edu.co/index.php/biosalud/article/view/4739
https://revistasojs.ucaldas.edu.co/index.php/biosalud/article/download/4739/4325
1657-9550
2022-03-17T00:36:52Z
2022-03-17T00:36:52Z
institution UNIVERSIDAD DE CALDAS
thumbnail https://nuevo.metarevistas.org/UNIVERSIDADDECALDAS/logo.png
country_str Colombia
collection Biosalud
title Remodelado estructural y de gap junctions en un modelo 3D de aurícula humana
spellingShingle Remodelado estructural y de gap junctions en un modelo 3D de aurícula humana
Ruiz Villa, Carlos A.
Castaño Vélez, Andrés P.
Heidenreich, Elvio A.
fibrilación auricular
gap junctions
modelo 3D
potencial de acción
reentrada
remodelado eléctrico
reentry
action potential
3D model
gap junctions
Atrial fibrillation
electrical remodeling
title_short Remodelado estructural y de gap junctions en un modelo 3D de aurícula humana
title_full Remodelado estructural y de gap junctions en un modelo 3D de aurícula humana
title_fullStr Remodelado estructural y de gap junctions en un modelo 3D de aurícula humana
title_full_unstemmed Remodelado estructural y de gap junctions en un modelo 3D de aurícula humana
title_sort remodelado estructural y de gap junctions en un modelo 3d de aurícula humana
title_eng Structural remodeling and of gap junctions in a 3D model of human atrial
description Introducción: la fibrilación auricular (AF), es la más común de la arritmia cardiaca sostenida y un factor de riesgo para el accidente cerebro vascular y otras morbilidades, si no es tratada. Estudios epidemiológicos muestran que la AF tiende a perpetuarse con el tiempo, generando cambios electrofisiológicos y anatómicos denominados: remodelados auriculares. Se ha demostrado que estos cambios provocan variaciones de la velocidad de conducción (CV), en el tejido auricular. Objetivo: estudiar el efecto del remodelado de gap junctions en la propagación del potencial de acción, implementando un modelo 3D de aurícula humana altamente realista. Materiales y Métodos: se incorporaron los cambios generados por el remodelado eléctrico a un modelo de potencial de acción (AP) de miocito auricular, acoplado con un modelo tridimensional anatómicamente realista de aurícula humana dilatada. Mediante simulaciones de la propagación del AP en condiciones de remodelado eléctrico y anatómico, y de remodelado de gap junctions, se midieron las ventanas vulnerables de generación de reentradas en la base de las venas pulmonares izquierdas de la aurícula. Resultados: los resultados obtenidos indican que la ventana vulnerable en el remodelado de gap junctions, se desplazó 38 ms con relación al modelo dilatado, lo que nos muestra el impacto de la dilatación con remodelado de gap junction. Conclusiones: el remodelado eléctrico generó una disminución del 70 % en la duración del potencial de acción y una disminución de las velocidades de conducción entre un 14.6 y un 26 %, que fueron medidas en diferentes regiones de la aurícula dilatada. El foco disparado en la base de las venas pulmonares izquierdas, generó un frente de onda que mantiene una actividad reentrante debido a la anatomía subyacente de las venas pulmonares.
description_eng Introduction: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and a significant risk factor for cerebrovascular accident and other morbidities if left untreated. Epidemiological studies show that AF tends to persist over time, creating electrophysiological and anatomical changes called atrial remodeling. It has been shown that these changes result in variations in conduction velocity (CV) in the atrial tissue. Objective: to study the effect of remodeling of gap junctions in the propagation of the action potential by implementing a highly realistic 3D human atrial model. Materials and methods: the changes caused by electrical remodeling were incorporated in an atrial myocyte action potential (AP) model coupled with an anatomically realistic three-dimensional model of dilated human atria. Through simulations of the AP spread in variations of anatomical and electrical remodeling and of gap junctions remodeling, vulnerable windows of reentry generation were measured at the base of the atrium left pulmonary veins. Results: the results obtained indicate that vulnerable window in the gap junctions remodeling moved 38 ms in relation with the expanded model which shows the impact of the dilatation gap junction remodeling. Conclusions: the electrical remodeling produced 70% decrease in action potential duration and decreased conduction velocities between 14.6 and 26 %, which were measured in different regions of the dilated atrium. The focus shot at the base of the left pulmonary veins created a wave which maintains a reentering activity due to the underlying anatomy of the pulmonary veins.
author Ruiz Villa, Carlos A.
Castaño Vélez, Andrés P.
Heidenreich, Elvio A.
author_facet Ruiz Villa, Carlos A.
Castaño Vélez, Andrés P.
Heidenreich, Elvio A.
topicspa_str_mv fibrilación auricular
gap junctions
modelo 3D
potencial de acción
reentrada
remodelado eléctrico
topic fibrilación auricular
gap junctions
modelo 3D
potencial de acción
reentrada
remodelado eléctrico
reentry
action potential
3D model
gap junctions
Atrial fibrillation
electrical remodeling
topic_facet fibrilación auricular
gap junctions
modelo 3D
potencial de acción
reentrada
remodelado eléctrico
reentry
action potential
3D model
gap junctions
Atrial fibrillation
electrical remodeling
citationvolume 10
citationissue 2
citationedition Núm. 2 , Año 2011 : Julio - Diciembre
publisher Universidad de Caldas
ispartofjournal Biosalud
source https://revistasojs.ucaldas.edu.co/index.php/biosalud/article/view/4739
language Español
format Article
rights http://purl.org/coar/access_right/c_abf2
info:eu-repo/semantics/openAccess
Revista Biosalud - 2011
https://creativecommons.org/licenses/by-nc-sa/4.0/
references Ruiz-Villa C, Tobón C, Rodriguez FJ, Heidenreich E. Efecto de la dilatación auricular sobre la vulnerabilidad a reentradas. In: Congreso Anual de la Sociedad española de Ingeniería Biomédica; 2008. Valladolid.
Allessie M, Ausma J, Schotten U. Electrical, contractile and structural remodeling during atrial fibrillation. Cardiovasc Res 2002; 54(2):230-46.
Ho SY, Sanchez-Quintana D, Anderson RH. Can anatomy define electric pathways? In: International Workshop on Computer Simulation and Experimental Assessment of Electrical Cardiac Function; 1998. Lausanne, Switzerland.
Hansson A, Holm M, Blomstrom P, Johansson R, Luhrs C, Brandt J, et al. Right atrial free wall conduction velocity and degree of anisotropy in patients with stable sinus rhythm studied during open heart surgery. Eur Heart J 1998; 19(2):293-300.
Feld GK, Mollerus M, Birgersdotter-Green U, Fujimura O, Bahnson TD, Boyce K, et al. Conduction velocity in the tricuspid valve-inferior vena cava isthmus is slower in patients with type I atrial flutter compared to those without a history of atrial flutter. J Cardiovasc Electrophysiol 1997; 8(12):1338-48.
Cohen GI, White M, Sochowski RA, Klein AL, Bridge PD, Stewart WJ, et al. Reference values for normal adult transesophageal echocardiographic measurements. J Am Soc Echocardiogr 1995; 8(3):221-30.
Wang K, Ho SY, Gibson DG, Anderson RH. Architecture of atrial musculature in humans. Br Heart J 1995; 73(6):559-65.
Ruiz-Villa C, Tobón C, Heidenreich E, Hornero F. Propagación de potencial de acción en un modelo 3D realista de Aurícula Humana. In: Congreso Anual de la Sociedad Española de Ingeniería Biomédica; 2006. Pamplona.
Bosch RF, Zeng X, Grammer JB, Popovic K, Mewis C, Kuhlkamp V. Ionic mechanisms of electrical remodeling in human atrial fibrillation. Cardiovasc Res 1999; 44(1):121-31.
Jacquemet V, Virag N, Ihara Z, Dang L, Blanc O, Zozor S, et al. Study of unipolar electrogram morphology in a computer model of atrial fibrillation. J Cardiovasc Electrophysiol 2003; 14(Suppl. 10):S172-9.
Virag N, Jacquemet V, Henriquez CS, Zozor S, Blanc O, Vesin JM, et al. Study of atrial arrhythmias in a computer model based on magnetic resonance images of human atria. Chaos 2002; 12(3):754-763.
Tieleman RG, De Langen C, Van Gelder IC, de Kam PJ, Grandjean J, Bel KJ, et al. Verapamil reduces tachycardia-induced electrical remodeling of the atria. Circulation 1997; 95(7):1945-53.
Elvan A, Wylie K, Zipes DP. Pacing-induced chronic atrial fibrillation impairs sinus node function in dogs. Electrophysiological remodeling. Circulation 1996; 94(11):2953-60.
Konings KT, Kirchhof CJ, Smeets JR, Wellens HJ, Penn OC, Allessie MA. High-density mapping of electrically induced atrial fibrillation in humans. Circulation 1994; 89(4):1665-80.
Kirchhof C, Chorro F, Scheffer GJ, Brugada J, Konings K, Zetelaki Z, et al. Regional entrainment of atrial fibrillation studied by high-resolution mapping in open-chest dogs. Circulation 1993; 88(2):736-49.
Cox JL, Canavan TE, Schuessler RB, Cain ME, Lindsay BD, Stone C, et al. The surgical treatment of atrial fibrillation. II. Intraoperative electrophysiologic mapping and description of the electrophysiologic basis of atrial flutter and atrial fibrillation. J Thorac Cardiovasc Surg 1991; 101(3):406-26.
Nygren A, Fiset C, Firek L, Clark JW, Lindblad DS, Clark RB, et al. Mathematical model of an adult human atrial cell: the role of K+ currents in repolarization. Circ Res 1998; 82(1):63-81.
Workman AJ, Kane KA, Rankin AC. The contribution of ionic currents to changes in refractoriness of human atrial myocytes associated with chronic atrial fibrillation. Cardiovasc Res 2001; 52(2):226-35.
Zimerman L, Fenelon G, Martinelli Filho M, Grupi C, Atié J, Lorga Filho A. Diretrizes brasileiras de fibrilação atrial. Arq Bras Cardiol 2009; 92(6 Suppl. 1):1-39.
Takeuchi S, Akita T, Takagishi Y, Watanabe E, Sasano C, Honjo H, et al. Disorganization of gap junction distribution in dilated atria of patients with chronic atrial fibrillation. Circ J 2006; 70(5):575-82.
Kharche S, Zhang H. Simulating the effects of atrial fibrillation induced electrical remodeling: A comprehensive simulation study. In: Engineering in Medicine and Biology Society, 2008. EMBS 2008. 30th Annual International Conference of the IEEE; 2008. p. 593-5.
Seemann G, Bustamante PC, Ponto S, Wilhelms M, Scholz EP, Do, et al. Atrial fibrillation-based electrical remodeling in a computer model of the human atrium. In: Computing in Cardiology, 2010; 2010 26-29 Sept. 2010; 2010. p. 417-420.
Wilders R. Computer modelling of the sinoatrial node. Med Biol Eng Comput 2007; 45(2):189-207.
Boyett MR, Honjo H, Kodama I. The sinoatrial node, a heterogeneous pacemaker structure. Cardiovasc Res 2000; 47(4):658-87.
Spach MS, Heidlage JF, Dolber PC, Barr RC. Electrophysiological effects of remodeling cardiac gap junctions and cell size: experimental and model studies of normal cardiac growth. Circ Res 2000; 86(3):302-11.
Kostin S, Rieger M, Dammer S, Hein S, Richter M, Klovekorn WP, et al. Gap junction remodeling and altered connexin 43 expression in the failing human heart. Mol Cell Biochem 2003; 242(1-2):135-44.
Jongsma HJ, Wilders R. Gap junctions in cardiovascular disease. Circ Res 2000; 86(12):1193-7.
Fuenmayor A, Fuenmayor A. Tratamiento no farmacológico de la fibrilación auricular. Avances Cardiológicos 2009;29:286-95.
Lloyd-Jones D, Adams RJ, Brown TM, Carnethon M, Dai S, De Simone G, et al. Heart disease and stroke statistics--2010 update: a report from the American Heart Association. Circulation 2010; 121(7):e46-e215.
Coyne KS, Paramore C, Grandy S, Mercader M, Reynolds M, Zimetbaum P. Assessing the direct costs of treating nonvalvular atrial fibrillation in the United States. Value Health 2006; 9(5):348-56.
type_driver info:eu-repo/semantics/article
type_coar http://purl.org/coar/resource_type/c_6501
type_version info:eu-repo/semantics/publishedVersion
type_coarversion http://purl.org/coar/version/c_970fb48d4fbd8a85
type_content Text
publishDate 2022-03-17
date_accessioned 2022-03-17T00:36:52Z
date_available 2022-03-17T00:36:52Z
url https://revistasojs.ucaldas.edu.co/index.php/biosalud/article/view/4739
url_doi https://revistasojs.ucaldas.edu.co/index.php/biosalud/article/view/4739
issn 1657-9550
eissn 2462-960X
citationstartpage 48
citationendpage 56
url2_str_mv https://revistasojs.ucaldas.edu.co/index.php/biosalud/article/download/4739/4325
_version_ 1797157589300019200