Atherosclerosis: Pathogenesis, Genetics and Experimental Models

Abstract

Atherosclerosis is a progressive disease of the arteries that results in the development of heart disease and stroke – the most common causes of death in developed countries and a growing socioeconomic burden in developing countries. Atherosclerosis results from an initial injury to the artery endothelium caused by mechanical and environmental factors, resulting in an inflammatory response in the vessel wall. The location and morphology of the atherosclerotic lesions predict the nature of the resulting vascular disease. Many risk factors for the disease are well known, and current therapies are largely directed at modifying them; however, the large array of poorly understood polygenetic factors affects the development of atherosclerosis. Recent developments in genetic studies have been applied to atherosclerosis and are beginning to rapidly reveal the genetic factors that modulate the pathogenesis of this disease.

Key Concepts

  • Atherosclerosis is a common, costly and deadly vascular disease that affects peoples of developed countries and increasingly burdens developing countries.
  • Atherosclerosis is an inflammatory disease of the arterial vascular wall.
  • The pathogenesis of atherosclerosis is complex but is generally explained by the ‘response to injury’ hypothesis for which recent studies in the field extend such hypothesis towards the degree of the inflammatory response to such injury.
  • Atherosclerotic lesions in humans have distinctive morphological characteristics and complications that differ in current animal models, the clinical manifestations correlate mostly with lesion type and location.
  • Both environmental and heritable risk factors modulate atherosclerosis development.
  • Candidate gene and linkage analysis studies have failed to identify previously unknown pathways in the pathogenesis of atherosclerosis.
  • Recent genome‐wide association studies have reproducibly identified several loci involved in the pathogenesis of atherosclerosis, and most of the identified genes are newly implicated in the disease process.
  • Rodent models such as APOE‐ and LDLR‐deficient mice are widely used to study the pathogenesis of atherosclerosis because of its reproducibility and genetic manipulation; however, recent studies with novel and bigger animal models more accurately resemble human disease.

Keywords: atheroma; atherosclerosis; coronary artery disease; endothelial dysfunction; foam cell; hyperlipidaemia; hypertension; myocardial infarct; stroke; vascular inflammation

Figure 1. Obstructive atherosclerotic disease in many vascular beds in a single individual. Angiography carried out in a 40‐year‐old male shows diffuse disease in the right (a) and left (b) coronary arteries, as well as focal lesions in the right iliac (c) and right renal arteries (d).
Figure 2. Human and animal atherosclerotic pathogenesis. Representation of the major features found in human atherosclerotic plaque versus animal models. The major differences are the factors that contribute to plaque instability in humans: fibrous cap, lipid‐rich necrotic core and intraplaque haemorrhage. Only select animal models recapitulate these individual components. The overlapping features between animal and human disease include endothelial dysfunction with immune cell rolling and extravasation, endothelial to mesenchymal transformation, neointimal hyperplasia with vascular smooth muscle cell (VSMC) migration and proliferation, foam cell formation, neoangiogenesis, LDL and very‐low‐density lipoprotein (VLDL) accumulation and inflammatory cell accumulation.
close

References

Abul‐Husn NS, Manickam K, Jones LK, et al. (2016) Genetic identification of familial hypercholesterolemia within a single U.S. health care system. Science 354 (6319): aaf7000.

Al‐Mashhadi RH, Sorensen CB, Kragh PM, et al. (2013) Familial hypercholesterolemia and atherosclerosis in cloned minipigs created by DNA transposition of a human PCSK9 gain‐of‐function mutant. Science Translational Medicine 5 (166): 166ra161.

Assimes TL and Roberts R (2016) Genetics: implications for prevention and management of coronary artery disease. Journal of the American College of Cardiology 68 (25): 2797–2818.

Babu AS, Veluswamy SK, Brubaker PH, et al. (2014) Prevention and control of atherosclerosis: why are exercise and physical activity not getting the respect they deserve? Journal of the American College of Cardiology 64 (16): 1760–1761.

Badimon L and Vilahur G (2014) Thrombosis formation on atherosclerotic lesions and plaque rupture. Journal of Internal Medicine 276 (6): 618–632.

Baumgartner C, Brandl J, Munch G, et al. (2016) Rabbit models to study atherosclerosis and its complications ‐ transgenic vascular protein expression in vivo. Progress in Biophysics and Molecular Biology 121 (2): 131–141.

Bjorklund MM, Hollensen AK, Hagensen MK, et al. (2014) Induction of atherosclerosis in mice and hamsters without germline genetic engineering. Circulation Research 114 (11): 1684–1689.

te Boekhorst BC, Bovens SM, Hellings WE, et al. (2011) Molecular MRI of murine atherosclerotic plaque targeting NGAL: a protein associated with unstable human plaque characteristics. Cardiovascular Research 89 (3): 680–688.

Bowen MS, Kolor K, Dotson WD, et al. (2012) Public health action in genomics is now needed beyond newborn screening. Public Health Genomics 15 (6): 327–334.

Burton PR, Clayton D, Cardon LR, et al. (2007) Genome‐wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447 (7145): 661–678.

Chen PY, Qin L, Baeyens N, et al. (2015) Endothelial‐to‐mesenchymal transition drives atherosclerosis progression. Journal of Clinical Investigation 125 (12): 4514–4528.

Cuchel M, Bruckert E, Ginsberg HN, et al. (2014) Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. European Heart Journal 35 (32): 2146–2157.

Davis BT, Wang XJ, Rohret JA, et al. (2014) Targeted disruption of LDLR causes hypercholesterolemia and atherosclerosis in Yucatan miniature pigs. PLoS One 9 (4): e93457.

Deloukas P, Kanoni S, Willenborg C, ARDIoGRAMplusC4D Consortium, et al. (2013) Large‐scale association analysis identifies new risk loci for coronary artery disease. Nature Genetics 45 (1): 25–33.

Dunham I, Kundaje A, Aldred SF, et al. (2012) An integrated encyclopedia of DNA elements in the human genome. Nature 489 (7414): 57–74.

Emini Veseli B, Perrotta P, De Meyer GRA, et al. (2017) Animal models of atherosclerosis. European Journal of Pharmacology. pii: S0014‐2999(17)30320‐5.

Finn AV, Nakano M, Narula J, et al. (2010) Concept of vulnerable/unstable plaque. Arteriosclerosis, Thrombosis, and Vascular Biology 30 (7): 1282–1292.

Girelli D, Piubelli C, Martinelli N, et al. (2017) A decade of progress on the genetic basis of coronary artery disease. Practical insights for the internist. European Journal of Internal Medicine 41: 10–17.

Hamamdzic D and Wilensky RL (2013) Porcine models of accelerated coronary atherosclerosis: role of diabetes mellitus and hypercholesterolemia. Journal of Diabetes Research 2013: 761415.

Helgadottir A, Thorleifsson G, Manolescu A, et al. (2007) A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science 316 (5830): 1491–1493.

Herrera VL, Makrides SC, Xie HX, et al. (1999) Spontaneous combined hyperlipidemia, coronary heart disease and decreased survival in Dahl salt‐sensitive hypertensive rats transgenic for human cholesteryl ester transfer protein. Nature Medicine 5 (12): 1383–1389.

Herrera VM, Didishvili T, Lopez LV, et al. (2001) Hypertension exacerbates coronary artery disease in transgenic hyperlipidemic Dahl salt‐sensitive hypertensive rats. Molecular Medicine 7 (12): 831–844.

Herrera VL, Tsikoudakis A, Didishvili T, et al. (2004) Analysis of gender‐specific atherosclerosis susceptibility in transgenic[hCETP]25DS rat model. Atherosclerosis 177 (1): 9–18.

Herrington W, Lacey B, Sherliker P, et al. (2016) Epidemiology of atherosclerosis and the potential to reduce the global burden of atherothrombotic disease. Circulation Research 118 (4): 535–546.

Hetterich H, Webber N, Willner M, et al. (2016) AHA classification of coronary and carotid atherosclerotic plaques by grating‐based phase‐contrast computed tomography. European Radiology 26 (9): 3223–3233.

Hindorff LA, Sethupathy P, Junkins HA, et al. (2009) Potential etiologic and functional implications of genome‐wide association loci for human diseases and traits. Proceedings of the National Academy of Sciences of the United States of America 106 (23): 9362–9367.

Holdt LM and Teupser D (2013) From genotype to phenotype in human atherosclerosis – recent findings. Current Opinion in Lipidology 24 (5): 410–418.

Iannaccone PM and Jacob HJ (2009) Rats!. Disease Models & Mechanisms 2 (5–6): 206–210.

Ishibashi S, Brown MS, Goldstein JL, et al. (1993) Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus‐mediated gene delivery. Journal of Clinical Investigation 92 (2): 883–893.

Ishibashi F, Yokoyama S, Miyahara K, et al. (2007) Quantitative colorimetry of atherosclerotic plaque using the L*a*b* color space during angioscopy for the detection of lipid cores underneath thin fibrous caps. International Journal of Cardiovascular Imaging 23 (6): 679–691.

Kathiresan S, Voight BF, Purcell S, Myocardial Infarction Genetics, Consortium, et al. (2009) Genome‐wide association of early‐onset myocardial infarction with single nucleotide polymorphisms and copy number variants. Nature Genetics 41 (3): 334–341.

Khera AV, Won HH, Peloso GM, et al. (2016) Diagnostic yield and clinical utility of sequencing familial hypercholesterolemia genes in patients with severe hypercholesterolemia. Journal of the American College of Cardiology 67 (22): 2578–2589.

Kojima Y, Downing K, Kundu R, et al. (2014) Cyclin‐dependent kinase inhibitor 2B regulates efferocytosis and atherosclerosis. Journal of Clinical Investigation 124 (3): 1083–1097.

Lotta LA (2010) Genome‐wide association studies in atherothrombosis. European Journal of Internal Medicine 21 (2): 74–78.

Malarstig A and Hamsten A (2010) Genetics of atherothrombosis and thrombophilia. Current Atherosclerosis Reports 12 (3): 159–166.

McCarthy MI, Abecasis GR, Cardon LR, et al. (2008) Genome‐wide association studies for complex traits: consensus, uncertainty and challenges. Nature Reviews Genetics 9 (5): 356–369.

McPherson R, Pertsemlidis A, Kavaslar N, et al. (2007) A common allele on chromosome 9 associated with coronary heart disease. Science 316 (5830): 1488–1491.

Morales‐Villegas E (2014) Coronary atherosclerosis the implications of being a woman. Current Hypertension Reviews 9: 297–309.

Morgan TM, Krumholz HM, Lifton RP, et al. (2007) Nonvalidation of reported genetic risk factors for acute coronary syndrome in a large‐scale replication study. JAMA 297 (14): 1551–1561.

Mozaffarian D, Benjamin EJ, Go AS, et al. (2016) Heart Disease and Stroke Statistics‐2016 Update: A Report From the American Heart Association. Circulation 133 (4): e38–360.

Nakazato R, Park HB, Gransar H, et al. (2016) Additive diagnostic value of atherosclerotic plaque characteristics to non‐invasive FFR for identification of lesions causing ischaemia: results from a prospective international multicentre trial. EuroIntervention 12 (4): 473–481.

Niimi M, Yang D, Kitajima S, et al. (2016) ApoE knockout rabbits: a novel model for the study of human hyperlipidemia. Atherosclerosis 245: 187–193.

Nikpay M, Goel A, Won HH, et al. (2015) A comprehensive 1,000 genomes‐based genome‐wide association meta‐analysis of coronary artery disease. Nature Genetics 47 (10): 1121–1130.

Nordestgaard BG, Chapman MJ, Humphries SE, et al. (2013) Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. European Heart Journal 34 (45): 3478–3490.

Paynter NP, Ridker PM and Chasman DI (2016) Are genetic tests for atherosclerosis ready for routine clinical use? Circulation Research 118 (4): 607–619.

Piedrahita JA, Zhang SH, Hagaman JR, et al. (1992) Generation of mice carrying a mutant apolipoprotein E gene inactivated by gene targeting in embryonic stem cells. Proceedings of the National Academy of Sciences 89: 4471–4475.

Piepoli MF, Hoes AW, Agewall S, et al. (2016) European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts) Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). European Heart Journal 37 (29): 2315–2381.

Prescott MF, McBride CH, Hasler‐Rapacz J, et al. (1991) Development of complex atherosclerotic lesions in pigs with inherited hyper‐LDL cholesterolemia bearing mutant alleles for apolipoprotein B. American Journal of Pathology 139 (1): 139–147.

Reitsma PH (2007) No praise for folly: genomics will never be useful in arterial thrombosis. Journal of Thrombosis and Haemostasis 5 (3): 454–457.

Roche‐Molina M, Sanz‐Rosa D, Cruz FM, et al. (2015) Induction of sustained hypercholesterolemia by single adeno‐associated virus‐mediated gene transfer of mutant hPCSK9. Arteriosclerosis, Thrombosis, and Vascular Biology 35 (1): 50–59.

Ross R (1993) The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 362 (6423): 801–809.

Ross R (1999) Atherosclerosis – an inflammatory disease. New England Journal of Medicine 340 (2): 115–126.

Samani NJ, Erdmann J, Hall AS, et al. (2007) Genomewide association analysis of coronary artery disease. New England Journal of Medicine 357 (5): 443–453.

Schunkert H, Konig IR, Kathiresan S, et al. (2011) Large‐scale association analysis identifies 13 new susceptibility loci for coronary artery disease. Nature Genetics 43 (4): 333–338.

Seneviratne A, Hulsmans M, Holvoet P, et al. (2013) Biomechanical factors and macrophages in plaque stability. Cardiovascular Research 99 (2): 284–293.

Shim J, Al‐Mashhadi RH, Sorensen CB, et al. (2016) Large animal models of atherosclerosis – new tools for persistent problems in cardiovascular medicine. Journal of Pathology 238 (2): 257–266.

Slavkin HC (1999) Atherosclerosis, Russell Ross and the passion of science. Journal of the American Dental Association 130 (8): 1219–1222.

Thim T, Hagensen MK, Drouet L, et al. (2010) Familial hypercholesterolaemic downsized pig with human‐like coronary atherosclerosis: a model for preclinical studies. EuroIntervention 6 (2): 261–268.

Torres N, Guevara‐Cruz M, Velazquez‐Villegas LA, et al. (2015) Nutrition and atherosclerosis. Archives of Medical Research 46 (5): 408–426.

Van der Donckt C, Van Herck JL, Schrijvers DM, et al. (2015) Elastin fragmentation in atherosclerotic mice leads to intraplaque neovascularization, plaque rupture, myocardial infarction, stroke, and sudden death. European Heart Journal 36 (17): 1049–1058.

Van Herck JL, De Meyer GR, Martinet W, et al. (2009) Impaired fibrillin‐1 function promotes features of plaque instability in apolipoprotein E‐deficient mice. Circulation 120 (24): 2478–2487.

Visel A, Zhu Y, May D, et al. (2010) Targeted deletion of the 9p21 non‐coding coronary artery disease risk interval in mice. Nature 464 (7287): 409–412.

Watanabe Y (1980) Serial inbreeding of rabbits with hereditary hyperlipidemia (WHHL‐rabbit). Atherosclerosis 36 (2): 261–268.

Webb TR, Erdmann J, Stirrups KE, et al. (2017) Systematic evaluation of pleiotropy identifies 6 further loci associated with coronary artery disease. Journal of the American College of Cardiology 69 (7): 823–836.

Wei S, Zhang Y, Su L, et al. (2015) Apolipoprotein E‐deficient rats develop atherosclerotic plaques in partially ligated carotid arteries. Atherosclerosis 243 (2): 589–592.

Winkel LC, Hoogendoorn A, Xing R, et al. (2015) Animal models of surgically manipulated flow velocities to study shear stress‐induced atherosclerosis. Atherosclerosis 241 (1): 100–110.

Xiangdong L, Yuanwu L, Hua Z, et al. (2011) Animal models for the atherosclerosis research: a review. Protein & Cell 2 (3): 189–201.

Yusuf S, Reddy S, Ounpuu S, et al. (2001a) Global burden of cardiovascular diseases: part I: general considerations, the epidemiologic transition, risk factors, and impact of urbanization. Circulation 104 (22): 2746–2753.

Yusuf S, Reddy S, Ounpuu S, et al. (2001b) Global burden of cardiovascular diseases: part II: variations in cardiovascular disease by specific ethnic groups and geographic regions and prevention strategies. Circulation 104 (23): 2855–2864.

Further Reading

Chen Y, Rollins J, Paigen B, et al. (2007) Genetic and genomic insights into the molecular basis of atherosclerosis. Cell Metabolism 6: 164–179.

Laffont B and Rayner KJ (2017) MicroRNAs in the pathobiology and therapy of atherosclerosis. Canadian Journal of Cardiology 33 (3): 313–324.

Libby P (2012) Inflammation in atherosclerosis. Arteriosclerosis, Thrombosis, and Vascular Biology 32 (9): 2045–2051.

Lusis AJ (2012) Genetics of atherosclerosis. Trends in Genetics 28 (6): 267–275.

Mann D, Zipes D, Libby P and Bonow R (2014) Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, 10th edn. Philadelphia: Saunders/Elsevier.

Ramsey SA, Gold ES and Aderem A (2010) A systems biology approach to understanding atherosclerosis. EMBO Molecular Medicine 2: 79–89.

Rocha VZ and Libby P (2009) Obesity, inflammation, and atherosclerosis. Nature Reviews Cardiology 6: 399–409.

Weakley SM, Jiang J, Kougias P, et al. (2010) Role of somatic mutations in vascular disease formation. Expert Review of Molecular Diagnostics 10: 173–185.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Mota, Roberto, Homeister, Jonathon W, Willis, Monte S, and Bahnson, Edward M(Oct 2017) Atherosclerosis: Pathogenesis, Genetics and Experimental Models. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005998.pub3]