Editing Coronary artery disease (section)

==Risk factors==
[[File:Blausen 0257 CoronaryArtery Plaque.png|thumb|Illustration depicting atherosclerosis in a coronary artery]]
Coronary artery disease is characterized by heart problems that result from atherosclerosis.<ref>Institute of Medicine (US) Committee on Social Security Cardiovascular Disability Criteria. (2010). ''Cardiovascular Disability: Updating the Social Security Listings''. "[https://www.ncbi.nlm.nih.gov/books/NBK209964/ Ischemic Heart Disease]". NCBI, National Academies Press (US).</ref> Atherosclerosis is a type of arteriosclerosis which is the "chronic inflammation of the arteries which causes them to harden and accumulate cholesterol plaques (atheromatous plaques) on the artery walls".<ref>Tenas, M. S. & Torres, M. F. (2018) "[https://www.clinicbarcelona.org/en/assistance/diseases/ischemic-heart-disease/definition What is Ischaemic Heart Disease?]" Clinic Barcelona.</ref> CAD has several well-determined risk factors contributing to atherosclerosis. These risk factors for CAD include "smoking, diabetes, high blood pressure (hypertension), abnormal (high) amounts of cholesterol and other fat in the blood (dyslipidemia), type 2 diabetes and being overweight or obese (having excess body fat)" due to lack of exercise and a poor diet.<ref name="doi.org">Nordestgaard, B. G. & Palmer, T. M. & Benn, M. & Zacho, J & Tybjærg-Hansen, A. & Smith, G. D. & Timpson, N. J. (2012). "The Effect of Elevated Body Mass Index on Ischemic Heart Disease Risk: Causal Estimates from a Mendelian Randomisation Approach". ''PLoS Medicine'' vol. 9,5 e1001212. {{doi|10.1371/journal.pmed.1001212}}.</ref> Some other risk factors include [[hypertension|high blood pressure]], [[tobacco smoking|smoking]], [[diabetes mellitus|diabetes]], lack of exercise, [[obesity]], [[hypercholesterolaemia|high blood cholesterol]], poor diet, [[major depressive disorder|depression]], [[Family history (medicine)|family history]], [[psychological stress]] and excessive [[ethanol|alcohol]].<ref name=WHO2011/><ref name=Meh2014/><ref name=Char2013/> About half of cases are linked to genetics.<ref>{{cite journal | vauthors = Dai X, Wiernek S, Evans JP, Runge MS | title = Genetics of coronary artery disease and myocardial infarction | journal = World Journal of Cardiology | volume = 8 | issue = 1 | pages = 1–23 | date = January 2016 | pmid = 26839654 | pmc = 4728103 | doi = 10.4330/wjc.v8.i1.1 | doi-access = free }}</ref> Apart from these classical risk factors, several unconventional risk factors have also been studied including high serum fibrinogen, high c-reactive protein (CRP), chronic inflammatory conditions, hypovitaminosis D, high lipoprotein A levels, serum homocysteine etc.<ref>{{Cite journal |last=Ullah |first=Himayat |date=2022-04-29 |title=High Sensitivity C-Reactive Protein Level and Ischemic Heart Disease |url=https://pjmhsonline.com/index.php/pjmhs/article/view/648 |journal=Pakistan Journal of Medical & Health Sciences |language=en |volume=16 |issue=4 |pages=34–35 |doi=10.53350/pjmhs2216434 |issn=2957-899X}}</ref><ref>{{Cite journal |last1=Yuan |first1=Deshan |last2=Jiang |first2=Ping |last3=Zhu |first3=Pei |last4=Jia |first4=Sida |last5=Zhang |first5=Ce |last6=Liu |first6=Yue |last7=Liu |first7=Ru |last8=Xu |first8=Jingjing |last9=Tang |first9=Xiaofang |last10=Zhao |first10=Xueyan |last11=Gao |first11=Runlin |last12=Yang |first12=Yuejin |last13=Xu |first13=Bo |last14=Gao |first14=Zhan |last15=Yuan |first15=Jinqing |date=2021-07-16 |title=Prognostic value of fibrinogen in patients with coronary artery disease and prediabetes or diabetes following percutaneous coronary intervention: 5-year findings from a large cohort study |journal=Cardiovascular Diabetology |volume=20 |issue=1 |pages=143 |doi=10.1186/s12933-021-01335-1 |doi-access=free |issn=1475-2840 |pmc=8283976 |pmid=34271936}}</ref> Smoking and obesity are associated with about 36% and 20% of cases, respectively.<ref name=Kivi2012/> Smoking just one cigarette per day about doubles the risk of CAD.<ref>{{cite journal | vauthors = Hackshaw A, Morris JK, Boniface S, Tang JL, Milenković D | title = Low cigarette consumption and risk of coronary heart disease and stroke: meta-analysis of 141 cohort studies in 55 study reports | journal = BMJ | volume = 360 | pages = j5855 | date = January 2018 | pmid = 29367388 | pmc = 5781309 | doi = 10.1136/bmj.j5855 }}</ref> Lack of exercise has been linked to 7–12% of cases.<ref name=Kivi2012/><ref>{{cite journal | vauthors = Lee IM, Shiroma EJ, Lobelo F, Puska P, Blair SN, Katzmarzyk PT | title = Effect of physical inactivity on major non-communicable diseases worldwide: an analysis of burden of disease and life expectancy | journal = Lancet | volume = 380 | issue = 9838 | pages = 219–29 | date = July 2012 | pmid = 22818936 | pmc = 3645500 | doi = 10.1016/S0140-6736(12)61031-9 }}</ref> Exposure to the [[herbicide]] [[Agent Orange]] may increase risk.<ref>{{cite web |title=Agent Orange presumptive conditions |url=https://www.publichealth.va.gov/exposures/publications/agent-orange/agent-orange-2020/presumptive.asp |website=US Department of Veterans Affairs, Veterans Health Administration }}</ref> Rheumatologic diseases such as [[rheumatoid arthritis]], [[systemic lupus erythematosus]], [[psoriasis]], and [[psoriatic arthritis]] are independent risk factors as well.<ref>{{cite journal | vauthors = Esdaile JM, Abrahamowicz M, Grodzicky T, Li Y, Panaritis C, du Berger R, Côte R, Grover SA, Fortin PR, Clarke AE, Senécal JL | display-authors = 6 | title = Traditional Framingham risk factors fail to fully account for accelerated atherosclerosis in systemic lupus erythematosus | journal = Arthritis and Rheumatism | volume = 44 | issue = 10 | pages = 2331–37 | date = October 2001 | pmid = 11665973 | doi = 10.1002/1529-0131(200110)44:10<2331::aid-art395>3.0.co;2-i }}</ref><ref>{{cite journal | vauthors = Kerola AM, Kauppi MJ, Kerola T, Nieminen TV | title = How early in the course of rheumatoid arthritis does the excess cardiovascular risk appear? | journal = Annals of the Rheumatic Diseases | volume = 71 | issue = 10 | pages = 1606–15 | date = October 2012 | pmid = 22736093 | doi = 10.1136/annrheumdis-2012-201334 | s2cid = 8419145 }}</ref><ref name="Roubille2013">{{cite journal | vauthors = Roubille C, Richer V, Starnino T, McCourt C, McFarlane A, Fleming P, Siu S, Kraft J, Lynde C, Pope J, Gulliver W, Keeling S, Dutz J, Bessette L, Bissonnette R, Haraoui B | display-authors = 6 | title = The effects of tumour necrosis factor inhibitors, methotrexate, non-steroidal anti-inflammatory drugs and corticosteroids on cardiovascular events in rheumatoid arthritis, psoriasis and psoriatic arthritis: a systematic review and meta-analysis | journal = Annals of the Rheumatic Diseases | volume = 74 | issue = 3 | pages = 480–89 | date = March 2015 | pmid = 25561362 | pmc = 4345910 | doi = 10.1136/annrheumdis-2014-206624 | type = Systematic Review & Meta-Analysis }}</ref><ref name="Garshick2017">{{cite journal | vauthors = Garshick M, Underberg JA | title = The Use of Primary Prevention Statin Therapy in Those Predisposed to Atherosclerosis | journal = Current Atherosclerosis Reports | volume = 19 | issue = 12 | pages = 48 | date = October 2017 | pmid = 29038899 | doi = 10.1007/s11883-017-0685-7 | type = Review | s2cid = 4630668 }}</ref>{{excessive citations inline|date=October 2021}}

Job stress appears to play a minor role accounting for about 3% of cases.<ref name=Kivi2012>{{cite journal | vauthors = Kivimäki M, Nyberg ST, Batty GD, Fransson EI, Heikkilä K, Alfredsson L, Bjorner JB, Borritz M, Burr H, Casini A, Clays E, De Bacquer D, Dragano N, Ferrie JE, Geuskens GA, Goldberg M, Hamer M, Hooftman WE, Houtman IL, Joensuu M, Jokela M, Kittel F, Knutsson A, Koskenvuo M, Koskinen A, Kouvonen A, Kumari M, Madsen IE, Marmot MG, Nielsen ML, Nordin M, Oksanen T, Pentti J, Rugulies R, Salo P, Siegrist J, Singh-Manoux A, Suominen SB, Väänänen A, Vahtera J, Virtanen M, Westerholm PJ, Westerlund H, Zins M, Steptoe A, Theorell T | display-authors = 6 | title = Job strain as a risk factor for coronary heart disease: a collaborative meta-analysis of individual participant data | journal = Lancet | volume = 380 | issue = 9852 | pages = 1491–97 | date = October 2012 | pmid = 22981903 | pmc = 3486012 | doi = 10.1016/S0140-6736(12)60994-5 }}</ref> In one study, females who were free of stress from work life saw an increase in the diameter of their blood vessels, leading to decreased progression of atherosclerosis.<ref name=Wang07>{{cite journal | vauthors = Wang HX, Leineweber C, Kirkeeide R, Svane B, Schenck-Gustafsson K, Theorell T, Orth-Gomér K | title = Psychosocial stress and atherosclerosis: family and work stress accelerate progression of coronary disease in women. The Stockholm Female Coronary Angiography Study | journal = Journal of Internal Medicine | volume = 261 | issue = 3 | pages = 245–54 | date = March 2007 | pmid = 17305647 | doi = 10.1111/j.1365-2796.2006.01759.x | s2cid = 38337323 | doi-access = free }}</ref> In contrast, females who had high levels of work-related stress experienced a decrease in the diameter of their blood vessels and significantly increased disease progression.<ref name=Wang07/>

=== Air pollution ===
[[Air pollution]], both [[Household air pollution|indoor]] and outdoor, is responsible for roughly 28% of deaths from CAD. This varies by region: In highly developed areas, this is approximately 10%, whereas in Southern, East and West Africa, and [[South Asia]], approximately 40% of deaths from CAD can be attributed to unhealthy air.<ref name="HEI_2024_p3-4">{{Cite book |last1=Health Effects Institute |author-link1=Health Effects Institute |url=https://www.stateofglobalair.org/resources/report/state-global-air-report-2024 |title=State of Global Air Report 2024: A Special Report on Global Exposure to Air Pollution and its Health Impacts with a Focus on Children's Health. |last2=Institute for Health Metrics and Evaluation |author-link2=Institute for Health Metrics and Evaluation |last3=UNICEF |author-link3=UNICEF |date=2024 |publisher=Health Effects Institute |pages=27 |issn=2578-6873}}</ref> In particular, [[Particulate pollution|fine particle pollution]] (PM<sub>2.5</sub>), which comes mostly from the burning of [[Fossil fuel|fossil fuels]], is a key risk factor for CAD.<ref>{{Cite journal |last1=Montone |first1=Rocco A. |last2=Rinaldi |first2=Riccardo |last3=Bonanni |first3=Alice |last4=Severino |first4=Anna |last5=Pedicino |first5=Daniela |last6=Crea |first6=Filippo |last7=Liuzzo |first7=Giovanna |date=2023-02-01 |title=Impact of air pollution on ischemic heart disease: Evidence, mechanisms, clinical perspectives |journal=Atherosclerosis |language=English |volume=366 |pages=22–31 |doi=10.1016/j.atherosclerosis.2023.01.013 |issn=0021-9150 |pmid=36696748|doi-access=free }}</ref>

===Blood fats===
The consumption of different types of [[fat]]s including [[trans fat]] (trans unsaturated), and [[saturated fat]], in a diet "influences the level of cholesterol that is present in the bloodstream".<ref name="ib.bioninja.com.au">{{Cite web |title=Lipid Health Risks {{!}} BioNinja |url=https://ib.bioninja.com.au/standard-level/topic-2-molecular-biology/23-carbohydrates-and-lipids/lipid-health-risks.html |access-date=2023-12-12 |website=ib.bioninja.com.au |archive-date=19 October 2023 |archive-url=https://web.archive.org/web/20231019125341/https://ib.bioninja.com.au/standard-level/topic-2-molecular-biology/23-carbohydrates-and-lipids/lipid-health-risks.html |url-status=dead }}</ref> Unsaturated fats originate from plant sources (such as oils). There are two types of unsaturated fats, cis and trans isomers. Cis unsaturated fats are bent in molecular structure and trans are linear. Saturated fats originate from animal sources (such as animal fats) and are also molecularly linear in structure.<ref>{{Cite web |title=Types of Fatty Acids {{!}} BioNinja |url=https://ib.bioninja.com.au/standard-level/topic-2-molecular-biology/23-carbohydrates-and-lipids/types-of-fatty-acids.html |access-date=2023-12-12 |website=ib.bioninja.com.au |archive-date=19 October 2023 |archive-url=https://web.archive.org/web/20231019125734/https://ib.bioninja.com.au/standard-level/topic-2-molecular-biology/23-carbohydrates-and-lipids/types-of-fatty-acids.html |url-status=dead }}</ref> The linear configurations of unsaturated trans and saturated fats allow them to easily accumulate and stack at the arterial walls when consumed in high amounts (and other positive measures towards physical health are not met).
* Fats and cholesterol are insoluble in blood and thus are amalgamated with proteins to form lipoproteins for transport. Low-density lipoproteins (LDL) transport cholesterol from the liver to the rest of the body and raise blood cholesterol levels. The consumption of "saturated fats increases LDL levels within the body, thus raising blood cholesterol levels".<ref name="ib.bioninja.com.au"/>
* High-density lipoproteins (HDL) are considered 'good' lipoproteins as they search for excess cholesterol in the body and transport it back to the liver for disposal. Trans fats also "increase LDL levels whilst decreasing HDL levels within the body, significantly raising blood cholesterol levels".<ref name="ib.bioninja.com.au"/>

High levels of cholesterol in the bloodstream lead to atherosclerosis. With increased levels of LDL in the bloodstream, "LDL particles will form deposits and accumulate within the arterial walls, which will lead to the development of plaques, restricting blood flow".<ref name="ib.bioninja.com.au"/> The resultant reduction in the heart's blood supply due to atherosclerosis in coronary arteries "causes shortness of breath, angina pectoris (chest pains that are usually relieved by rest), and potentially fatal heart attacks (myocardial infarctions)".<ref name="doi.org"/>

===Genetics===
The [[heritability]] of coronary artery disease has been estimated between 40% and 60%.<ref>{{cite journal | vauthors = McPherson R, Tybjaerg-Hansen A | title = Genetics of Coronary Artery Disease | journal = Circulation Research | volume = 118 | issue = 4 | pages = 564–78 | date = February 2016 | pmid = 26892958 | doi = 10.1161/circresaha.115.306566 }}</ref> [[Genome-wide association studies]] have identified over 160 genetic susceptibility loci for coronary artery disease.<ref>{{cite journal | vauthors = van der Harst P, Verweij N | title = Identification of 64 Novel Genetic Loci Provides an Expanded View on the Genetic Architecture of Coronary Artery Disease | journal = Circulation Research | volume = 122 | issue = 3 | pages = 433–43 | date = February 2018 | pmid = 29212778 | pmc = 5805277 | doi = 10.1161/circresaha.117.312086 | publisher = Ovid Technologies (Wolters Kluwer Health) }}</ref>

===[[Transcriptome]]===
Several [[RNA|RNA Transcripts]] associated with CAD - [[FoxP1]], [[ICOSLG]], [[IKZF4/Eos]], [[SMYD3]], [[TRIM28]], and [[TCF3/E2A]] are likely markers of [[regulatory T cells]] (Tregs), consistent with known reductions in Tregs in CAD.<ref>{{cite journal | vauthors = McCaffrey TA, Toma I, Yang Z, Katz R, Reiner J, Mazhari R, Shah P, Tackett M, Jones D, Jepson T, Falk Z, Wargodsky R, Shtakalo D, Antonets D, Ertle J, Kim JH, Lai Y, Arslan Z, Aledort E, Alfaraidy M, Laurent GS | title = RNA sequencing of blood in coronary artery disease: involvement of regulatory T cell imbalance | journal = BMC Med Genomics | volume = 14 | issue = 216 | date = September 2021 | page = 216 | pmid = 34479557 | pmc = 8414682 | doi = 10.1186/s12920-021-01062-2 | doi-access = free }}</ref>

[[Image:Schematic representation of Treg-related TRACs identified by RNAseq.jpg|thumb|300px|Transcripts associated with CAD identified by [[RNA-seq]]. The differentially expressed genes identified by RNAseq were curated by automated and manual analysis to identify the molecular pathways involved. The resulting pattern points to changes in the 'immune synapse', which involves both endocytic pathways of T cell receptor-containing vesicles, as well as ciliary protrusions that couple to intracellular signaling pathways.]]

The RNA changes are mostly related to ciliary and endocytic transcripts, which in the circulating immune system would be related to the [[immune synapse]].<ref>{{cite journal | vauthors = McCaffrey TA, Toma I, Yang Z, Katz R, Reiner J, Mazhari R, Shah P, Falk Z, Wargowsky R, Goldman J, Jones D, Shtokalo D, Antonets D, Tisha Jepson T, Fetisova A, Jaatinen K, Ree N, Ri M| title = RNAseq profiling of blood from patients with coronary artery disease: Signature of a T cell imbalance | journal = Journal of Molecular and Cellular Cardiology Plus | volume = 4 | date = June 2023 | page = 100033 | doi = 10.1016/j.jmccpl.2023.100033| pmid = 37303712 | pmc = 10256136 | s2cid = 257761467 }}</ref> One of the most differentially expressed genes, [[fibromodulin]] (FMOD), which is increased 2.8-fold in CAD, is found mainly in connective tissue<ref>{{cite journal | pmc=9986681 | date=2023 | title=Fibromodulin, a Multifunctional Matricellular Modulator | journal=Journal of Dental Research | volume=102 | issue=2 | pages=125–34 | doi=10.1177/00220345221138525 | pmid=36515321 | vauthors = Zheng Z, Granado HS, Li C }}</ref> and is a modulator of the TGF-beta signaling pathway. However, not all RNA changes may be related to the immune synapse. For example, [[Nebulette]], the most down-regulated transcript (2.4-fold), is found in cardiac muscle; it is a 'cytolinker' that connects actin and desmin to facilitate cytoskeletal function and vesicular movement. The endocytic pathway is further modulated by changes in [[tubulin]], a key microtubule protein, and [[fidgetin]], a tubulin-severing enzyme that is a marker for cardiovascular risk identified by [[genome-wide association study]]. Protein recycling would be modulated by changes in the proteasomal regulator [[SIAH3]], and the ubiquitin ligase [[MARCHF10]]. On the ciliary aspect of the immune synapse, several of the modulated transcripts are related to ciliary length and function. [[STRC|Stereocilin]] is a partner to [[mesothelin]], a related [[superhelix|super-helical]] protein, whose transcript is also modulated in CAD. [[DCDC2]], a double-cortin protein, modulates ciliary length. In the signaling pathways of the immune synapse, numerous transcripts are directly related to T-cell function and the control of differentiation. [[Butyrophilin]] is a co-regulator for T cell activation. [[Fibromodulin]] modulates the TGF-beta signaling pathway, a primary determinant of Tre differentiation. Further impact on the [[TGF-beta]] pathway is reflected in concurrent changes in the BMP receptor 1B RNA (BMPR1B), because the bone morphogenic proteins are members of the TGF-beta superfamily, and likewise impact Treg differentiation. Several of the transcripts ([[TMEM98]], [[NRCAM]], [[SFRP5]], [[SHISA2]]) are elements of the Wnt signaling pathway, which is a major determinant of Treg differentiation.

===Other===
* [[Endometriosis]] in females under the age of 40.<ref>{{cite journal | vauthors = Mu F, Rich-Edwards J, Rimm EB, Spiegelman D, Missmer SA | title = Endometriosis and Risk of Coronary Heart Disease | journal = Circulation: Cardiovascular Quality and Outcomes | volume = 9 | issue = 3 | pages = 257–64 | date = May 2016 | pmid = 27025928 | pmc = 4940126 | doi = 10.1161/CIRCOUTCOMES.115.002224 }}</ref>
* Depression and hostility appear to be risks.<ref>{{cite journal | vauthors = Albus C | title = Psychological and social factors in coronary heart disease | journal = Annals of Medicine | volume = 42 | issue = 7 | pages = 487–94 | date = October 2010 | pmid = 20839918 | doi = 10.3109/07853890.2010.515605 | s2cid = 25144107 | doi-access = free }}</ref>
* The number of categories of [[adverse childhood experiences]] (psychological, physical, or sexual abuse; violence against mother; or living with household members who used substances, mentally ill, suicidal, or incarcerated) showed a graded correlation with the presence of adult diseases including coronary artery (ischemic heart) disease.<ref>{{cite journal | vauthors = Felitti VJ, Anda RF, Nordenberg D, Williamson DF, Spitz AM, Edwards V, Koss MP, Marks JS | display-authors = 6 | title = Relationship of childhood abuse and household dysfunction to many of the leading causes of death in adults. The Adverse Childhood Experiences (ACE) Study | journal = American Journal of Preventive Medicine | volume = 14 | issue = 4 | pages = 245–58 | date = May 1998 | pmid = 9635069 | doi = 10.1016/S0749-3797(98)00017-8 | s2cid = 26055600 | doi-access = free }}</ref>
* Hemostatic factors: High levels of fibrinogen and coagulation factor VII are associated with an increased risk of CAD.<ref name=Grant2003>{{cite journal | vauthors = Grant PJ | title = The genetics of atherothrombotic disorders: a clinician's view | journal = Journal of Thrombosis and Haemostasis | volume = 1 | issue = 7 | pages = 1381–90 | date = July 2003 | pmid = 12871271 | doi = 10.1046/j.1538-7836.2003.00276.x | df = dmy-all | type = Review | s2cid = 20395787 | doi-access = free }}</ref>
* Low hemoglobin.<ref>{{cite journal |id={{Gale|A261829143}} | vauthors = Padmanaban P, Toora B |title=Hemoglobin: Emerging marker in stable coronary artery disease |journal=Chronicles of Young Scientists |date=2011 |volume=2 |issue=2 |pages=109 |doi=10.4103/2229-5186.82971 |url=https://ddtjournal.net/?view-pdf=1&embedded=true&article=2acc68c5a97079e54b6b7b584b3de7261Zs4oQ%3D%3D | doi-access = free }}</ref>
* In the Asian population, the b fibrinogen gene G-455A polymorphism was associated with the risk of CAD.<ref>{{cite journal | vauthors = Fajar JK |title=The β fibrinogen gene G-455A polymorphism in Asian subjects with coronary heart disease: A meta analysis |journal=Egyptian Journal of Medical Human Genetics |date=2017-02-27 |volume=18 |issue=1 |pages=19–28 |doi=10.1016/j.ejmhg.2016.06.002 |url=https://www.ajol.info/index.php/ejhg/article/view/152188 |doi-access=free }}</ref>
* Patient-specific vessel ageing or remodelling determines endothelial cell behaviour and thus disease growth and progression. Such 'hemodynamic markers' are patient-specific risk surrogates.<ref name=Adikari2022>{{cite journal | vauthors = Adikari D | title = A new and automated risk prediction of coronary artery disease using clinical endpoints and medical imaging-derived patient-specific insights: protocol for the retrospective GeoCAD cohort study | journal = British Medical Journal | volume = 12 | date = June 2022 | issue = 6 | pages = e054881 | doi = 10.1136/bmjopen-2021-054881 | pmid = 35725256 | pmc = 9214399 | df = dmy-all | type = Prospective study | doi-access = free }}</ref>
* [[HIV/AIDS|HIV]] is a known risk factor for developing atherosclerosis and coronary artery disease.<ref name="Sinha2019">{{cite journal |last1=Sinha |first1=A |last2=Feinstein |first2=MJ |title=Coronary Artery Disease Manifestations in HIV: What, How, and Why |journal=The Canadian Journal of Cardiology |date=March 2019 |volume=35 |issue=3 |pages=270–79 |doi=10.1016/j.cjca.2018.11.029 |pmid=30825949 |pmc=9532012 }}</ref>