Abstract
We present here a mathematical model describing the primary mechanisms that drive the early stages of atherosclerosis. This involves the interactions between modified low density lipoprotein (LDL), monocytes/macrophages, cytokines and foam cells. This model suggests that there is an initial inflammatory phase associated with atherosclerotic lesion development and a longer, quasi-static process of plaque development inside the arterial wall that follows the initial transient. We will show results that show how different LDL concentrations in the blood stream and different immune responses can affect the development of a plaque. Through numerical bifurcation analysis, we show the existence of a fold bifurcation when the flux of LDL from the blood is sufficiently high. By analysing the model presented in this paper, we gain a greater insight into this inflammatory response qualitatively and quantitatively.
Similar content being viewed by others
References
Andersson J, Libby P, Hansson G (2010) Adaptive immunity and atherosclerosis. Clin Immunol 134(1, SI):33–46
Berg A, Scherer P (2005) Adipose tissue, inflammation, and cardiovascular disease. Circ Res 96(9):939–949
Bulelzai M, Dubbeldam J (2012) Long time evolution of atherosclerotic plaques. J Theor Biol 297:1–10
Bulelzai M, Dubbeldam J, Meijer H (2014) Bifurcation analysis of a model for atherosclerotic plaque evolution. Phys D-Nonlinear Phenom 278:31–43
Calvez V, Ebde A, Meunier N, Raoult A (2009) Mathematical modelling of the atherosclerotic plaque formation. ESAIM Proc 28:1–12
Calvez V, Houot J, Meunier N, Raoult A, Rusnakova G (2010) Mathematical and numerical modeling of early atherosclerotic lesions. ESAIM Proc 30:1–14
Channon K (2002) The endothelium and the pathogenesis of atherosclerosis. Medicine 30(4):54–58
Charo I, Taubman M (2004) Chemokines in the pathogenesis of vascular disease. Circ Res 95(9):858–866
Cilla M, Pena E, Martinez M (2014) Mathematical modelling of atheroma plaque formation and development in coronary arteries. J R Soc Int 11(90):20130866
Cobbold C, Sherratt J, Maxwell S (2002) Lipoprotein oxidation and its significance for atherosclerosis: a mathematical approach. Bull Math Biol 64(1):65–95
Cohen A, Myerscough M, Thompson R (2014) Athero-protective effects of high density lipoproteins (HDL): an ODE model of the early stages of atherosclerosis. Bull Math Biol 76(5):1117–1142
Dabagh M, Jalali P, Tarbell J (2009) The transport of LDL across the deformable arterial wall: the effect of endothelial cell turnover and intimal deformation under hypertension. Am J Physiol-Heart Circ Physiol 297(3):H983–H996
Di Vito L, Porto I, Burzotta F, Trani C, Pirozzolo G, Niccoli G, Leone AM, Crea F (2013) Radial artery intima-media ratio predicts presence of coronary thin-cap fibroatheroma: A frequency domain-optical coherence tomography study. Int J Cardiol 168(3):1917–1922
Doedel E, Champneys A, Fairgrieve T, Kuznetsov Y, Oldeman B, Paffenroth R, Sandstede B, Wang X, Zhang C (2007) AUTO-07P: continuation and bifurcation software for ordinary differential equations. http://cmvl.cs.concordia.ca/. Accessed Oct 2012
Dutta P, Courties G, Wei Y, Leuschner F, Gorbatov R, Robbins C, Iwamoto Y, Thompson B, Carlson A, Heidt T, Majmudar M, Lasitschka F, Etzrodt M, Waterman P, Waring M, Chicoine A, van der Laan A, Niessen H, Piek J, Rubin B, Butany J, Stone J, Katus H, Murphy S, Morrow D, Sabatine M, Vinegoni C, Moskowitz M, Pittet M, Libby P, Lin C, Swirski F, Weissleder R, Nahrendorf M (2012) Myocardial infarction accelerates atherosclerosis. Nature 487(7407):325–329
El Khatib N, Genieys S, Volpert V (2007) Atherosclerosis initiation modeled as an inflammatory process. Math Model Nat Phenom 2(2):126–141
El Khatib N, Genieys S, Kazmierczak B, Volpert V (2009) Mathematical modelling of atherosclerosis as an inflammatory disease. Philos Trans R Soc A-Math Phys Eng Sci 367(1908):4877–4886
El Khatib N, Genieys S, Kazmierczak B, Volpert V (2012) Reaction–diffusion model of atherosclerosis development. J Math Biol 65(2):349–374
Filipovic N, Rosic M, Tanaskovic I, Milosevic Z, Nikolic D, Zdravkovic N, Peulic A, Kojic M, Fotiadis D, Parodi O (2012) ARTreat project: three-dimensional numerical simulation of plaque formation and development in the arteries. IEEE Trans Inf Technol Biomed 16(2, SI):272–278
Filipovic N, Nikolic D, Saveljic I, Milosevic Z, Exarchos T, Pelosi G, Parodi O (2013) Computer simulation of three-dimensional plaque formation and progression in the coronary artery. Comput Fluids 88:826–833
Fok P (2012) Mathematical model of intimal thickening in atherosclerosis: vessel stenosis as a free boundary problem. J Theor Biol 314:23–33
Furchgott R (1999) Endothelium-derived relaxing factor: discovery, early studies, and identification as nitric oxide. Biosci Rep 19(4):235–251
Galkina E, Ley K (2007) Vascular adhesion molecules in atherosclerosis. Arterioscler Thromb Vasc Biol 27(11):2292–2301
Galkina E, Ley K (2009) Immune and inflammatory mechanisms of atherosclerosis. Ann Rev Immunol 27:165–197
Gessaghi V, Raschi M, Tanoni D, Perazzo C, Larreteguy A (2011) Growth model for cholesterol accumulation in the wall of a simplified 3D geometry of the carotid bifurcation. Comput Methods Appl Mech Eng 200(23–24):2117–2125
Han K, Hong K, Park J, Ko J, Kang D, Choi K, Hong M, Park S, Park S (2004) C-reactive protein promotes monocyte chemoattractant protein-1-mediated chemotaxis through upregulating CC chemokine receptor 2 expression in human monocytes. Circulation 109(21):2566–2571
Hansson G, Libby P (2006) The immune response in atherosclerosis: a double-edged sword. Nat Rev Immunol 6(7):508–519
Hidalgo A, Tello L, Toro E (2014) Numerical and analytical study of an atherosclerosis inflammatory disease model. J Math Biol 68(7):1785–1814
Ibragimov A, McNeal C, Ritter L, Walton J (2005) A mathematical model of atherogenesis as an inflammatory response. Math Med Biol-A J IMA 22(4):305–333
Kharbanda R, MacAllister R (2005) The atherosclerosis time-line and the role of the endothelium. Curr Med Chem Immunol Endocr Metab Agents 5(1):47–52
Libby P (2002) Inflammation in atherosclerosis. Nature 420(6917):868–874
Libby P, Ridker P (2006) Inflammation and atherothrombosis–from population biology and bench research to clinical practice. J Am Coll Cardiol 48(9, Suppl. A):A33–A46
Little M, Gola A, Tzoulaki I (2009) A model of cardiovascular disease giving a plausible mechanism for the effect of fractionated low-dose ionizing radiation exposure. PLOS Comput Biol 5(10):e1000539
Llodra J, Angeli V, Liu J, Trogan E, Fisher E, Randolph G (2004) Emigration of monocyte-derived cells from atherosclerotic lesions characterizes regressive, but not progressive, plaques. Proc Natl Acad Sci USA 101(32):11,779–11,784
Lusis A (2000) Atherosclerosis. Nature 407(6801):233–241
McKay C, McKee S, Mottram N, Mulholland T, Wilson S, Kennedy S, Wadsworth R (2004) Towards a model of atherosclerosis. In: Tech. rep. University of Strathclyde
McKellar G, McCarey D, Sattar N, McInnes I (2009) Role for TNF in atherosclerosis? Lessons from autoimmune disease. Nat Rev Cardiol 6(6):410–417
Milonas C, Jernberg T, Lindback J, Agewall S, Wallentin L, Stenestrand U (2010) Effect of angiotensin-converting enzyme inhibition on 1 year mortality and frequency of repeat acute myocardial infarction in patients with acute myocardial infarction. Am J Cardiol 105(9):1229–1234
Napoli C, de Nigris F, Williams-Ignarro S, Pignalosa O, Sica V, Ignarro L (2006) Nitric oxide and atherosclerosis: an update. Nitric Oxide-Biol Chem 15(4):265–279
Newby A (2008) Metalloproteinase expression in monocytes and macrophages and its relationship to atherosclerotic plaque instability. Arterioscler Thromb Vasc Biol 28(12):2108–2114
Newby A, Zaltsman A (1999) Fibrous cap formation or destruction—the critical importance of vascular smooth muscle cell proliferation, migration and matrix formation. Cardiovasc Res 41(2):345–360
Nozawa N, Hibi K, Endo M, Sugano T, Ebina T, Kosuge M, Tsukahara K, Okuda J, Umemura S, Kimura K (2010) Association between circulating monocytes and coronary plaque progression in patients with acute myocardial infarction. Circ J 74(7):1384–1391
Ougrinovskaia A, Thompson R, Myerscough M (2010) An Ode model of early stages of atherosclerosis: mechanisms of the inflammatory response. Bull Math Biol 72(6):1534–1561
Paavola C, Hemmerich S, Grunberger D, Polsky I, Bloom A, Freedman R, Mulkins M, Bhakta S, McCarley D, Wiesent L, Wong B, Jarnagin K, Handel T (1998) Monomeric monocyte chemoattractant protein-1 (MCP-1) binds and activates the MCP-1 receptor CCR2B. J Biol Chem 273(50):33,157–33,165
Pai J, Pischon T, Ma J, Manson J, Hankinson S, Joshipura K, Curhan G, Rifai N, Cannuscio C, Stampfer M, Rimm E (2004) Inflammatory markers and the risk of coronary heart disease in men and women. N Engl J Med 351(25):2599–2610
Pappalardo F, Musumeci S, Motta S (2008) Modeling immune system control of atherogenesis. Bioinformatics 24(15):1715–1721
Parodi O, Exarchos T, Marraccini P, Vozzi F, Milosevic Z, Nikolic D, Sakellarios A, Siogkas P, Fotiadis D, Filipovic N (2012) Patient-specific prediction of coronary plaque growth from CTA angiography: a multiscale model for plaque formation and progression. IEEE Trans Inf Technol Biomed 16(5, SI):952–965
Plank M, Wall D, David T (2007) The role of endothelial calcium and nitric oxide in the localisation of atherosclerosis. Math Biosci 207(1):26–39
Poston R, Poston D (2007) Typical atherosclerotic plaque morphology produced in silico by an atherogenesis model based on self-perpetuating propagating macrophage recruitment. Math Model Nat Phenom 2(2):142–149
Prior JA, Jordan KP, Kadam UT (2014) Associations between cardiovascular disease severity, osteoarthritis co-morbidity and physical health: a population-based study. Rheumatology 53(10):1794–1802
Ross R (1999) Mechanisms of disease—atherosclerosis—an inflammatory disease. N Engl J Med 340(2):115–126
Tabas I (2010) Macrophage death and defective inflammation resolution in atherosclerosis. Nat Rev Immunol 10(1):36–46
Volpert V, Petrovskii S (2009) Reaction–diffusion waves in biology. Phys Life Rev 6(4):267–310
Zohdi T, Holzapfel G, Berger S (2004) A phenomenological model for atherosclerotic plaque growth and rupture. J Theor Biol 227(3):437–443
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Chalmers, A.D., Cohen, A., Bursill, C.A. et al. Bifurcation and dynamics in a mathematical model of early atherosclerosis. J. Math. Biol. 71, 1451–1480 (2015). https://doi.org/10.1007/s00285-015-0864-5
Received:
Revised:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00285-015-0864-5