atherosclerosis

Atherosclerosis is typically asymptomatic for decades because the arteries enlarge at all plaque locations, thus there is no effect on blood flow.{{cite journal | vauthors = Ross R | title = The pathogenesis of atherosclerosis: a perspective for the 1990s | journal = Nature | volume = 362 | issue = 6423 | pages = 801–809 | date = April 1993 | pmid = 8479518 | doi = 10.1038/362801a0 | bibcode = 1993Natur.362..801R }} Even most plaque ruptures do not produce symptoms until enough narrowing or closure of an artery, due to clots, occurs. Signs and symptoms only happen after severe narrowing or closure impedes blood flow to different organs enough to induce symptoms.Atherosclerosis. Harvard Health Publications Harvard Health Publications. Health Topics A – Z, (2011) Most of the time, patients realize that they have the disease only when they experience other cardiovascular disorders such as stroke or heart attack. These symptoms, however, still vary depending on which artery or organ is affected.{{cite web | title = Atherosclerosis | publisher = National Heart, Lung, and Blood Institute | url = http://www.nhlbi.nih.gov/health/health-topics/topics/atherosclerosis/signs.html | year = 2011 }}

Early atherosclerotic processes likely begin in childhood. Fibrous and gelatinous lesions have been observed in the coronary arteries of children.{{cite journal | vauthors = Velican D, Velican C | title = Study of fibrous plaques occurring in the coronary arteries of children | journal = Atherosclerosis | volume = 33 | issue = 2 | pages = 201–205 | date = June 1979 | pmid = 475879 | doi = 10.1016/0021-9150(79)90117-5 }} Fatty streaks have been observed in the coronary arteries of juveniles. While coronary artery disease is more prevalent in men than women, atherosclerosis of the cerebral arteries and strokes equally affect both sexes.{{cite journal | vauthors = Flora GC, Baker AB, Loewenson RB, Klassen AC | title = A comparative study of cerebral atherosclerosis in males and females | journal = Circulation | volume = 38 | issue = 5 | pages = 859–869 | date = November 1968 | pmid = 5697685 | doi = 10.1161/01.CIR.38.5.859 | doi-access = free }}

Marked narrowing in the coronary arteries, which are responsible for bringing oxygenated blood to the heart, can produce symptoms such as chest pain of angina and shortness of breath, sweating, nausea, dizziness or lightheadedness, breathlessness or palpitations. Abnormal heart rhythms called arrhythmias—the heart beating either too slowly or too quickly—are another consequence of ischemia.Arrhythmia. Heart and Stroke Foundation. {{cite web |url=http://www.heartandstroke.com/site/c.ikIQLcMWJtE/b.3484057/ |title=Heart disease - Arrhythmia - Heart and Stroke Foundation of Canada |access-date=2014-01-31 |url-status=dead |archive-url=https://web.archive.org/web/20140203120532/http://www.heartandstroke.com/site/c.ikIQLcMWJtE/b.3484057/ |archive-date=2014-02-03 }} (2011)

Carotid arteries supply blood to the brain and neck. Marked narrowing of the carotid arteries can present with symptoms such as a feeling of weakness; being unable to think straight; difficulty speaking; dizziness; difficulty in walking or standing up straight; blurred vision; numbness of the face, arms and legs; severe headache; and loss of consciousness. These symptoms are also related to stroke (death of brain cells). Stroke is caused by marked narrowing or closure of arteries going to the brain; lack of adequate blood supply leads to the death of the cells of the affected tissue.{{cite journal | vauthors = Sims NR, Muyderman H | title = Mitochondria, oxidative metabolism and cell death in stroke | journal = Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease | volume = 1802 | issue = 1 | pages = 80–91 | date = January 2010 | pmid = 19751827 | doi = 10.1016/j.bbadis.2009.09.003 }}

Peripheral arteries, which supply blood to the legs, arms, and pelvis, also experience marked narrowing due to plaque rupture and clots. Symptoms of the narrowing are pain and numbness within the arms or legs. Another significant location for plaque formation is the renal arteries, which supply blood to the kidneys. Plaque occurrence and accumulation lead to decreased kidney blood flow and chronic kidney disease, which, like in all other areas, is typically asymptomatic until late stages.

In 2004, US data indicated that in ~66% of men and ~47% of women, the first symptom of atherosclerotic cardiovascular disease was a heart attack or sudden cardiac death (defined as death within one hour of onset of the symptom).{{cite book |doi=10.1007/978-0-387-78665-0_51 |chapter=Atherosclerotic Burden and Mortality |title=Handbook of Disease Burdens and Quality of Life Measures |date=2010 | vauthors = Roquer J, Ois A |pages=899–918 |isbn=978-0-387-78664-3 }}

Case studies have included autopsies of U.S. soldiers killed in World War II and the Korean War. A much-cited report involved the autopsies of 300 U.S. soldiers killed in Korea. Although the average age of the men was 22.1 years, 77.3 percent had "gross evidence of coronary arteriosclerosis".{{cite journal | vauthors = Enos WF, Holmes RH, Beyer J | title = Coronary disease among United States soldiers killed in action in Korea; preliminary report | journal = Journal of the American Medical Association | volume = 152 | issue = 12 | pages = 1090–1093 | date = July 1953 | pmid = 13052433 | doi = 10.1001/jama.1953.03690120006002 }} The average age was calculated from the ages of 200 of the soldiers. No age was recorded in nearly 100 of the men.

{{See also|Lipoprotein|Lipoprotein (a)}}

File:Blausen 0227 Cholesterol.png

The atherosclerotic process is not well understood.{{update inline|date=November 2024}} Atherosclerosis is associated with inflammatory processes in the endothelial cells of the vessel wall associated with retained low-density lipoprotein (LDL) particles.{{cite journal | vauthors = Li X, Fang P, Li Y, Kuo YM, Andrews AJ, Nanayakkara G, Johnson C, Fu H, Shan H, Du F, Hoffman NE, Yu D, Eguchi S, Madesh M, Koch WJ, Sun J, Jiang X, Wang H, Yang X | title = Mitochondrial Reactive Oxygen Species Mediate Lysophosphatidylcholine-Induced Endothelial Cell Activation | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 36 | issue = 6 | pages = 1090–1100 | date = June 2016 | pmid = 27127201 | pmc = 4882253 | doi = 10.1161/ATVBAHA.115.306964 }}{{cite journal | vauthors = Botts SR, Fish JE, Howe KL | title = Dysfunctional Vascular Endothelium as a Driver of Atherosclerosis: Emerging Insights Into Pathogenesis and Treatment | journal = Frontiers in Pharmacology | volume = 12 | pages = 787541 | date = December 2021 | pmid = 35002720 | pmc = 8727904 | doi = 10.3389/fphar.2021.787541 | doi-access = free }} This retention may be a cause, an effect, or both, of the underlying inflammatory process.{{cite journal | vauthors = Williams KJ, Tabas I | title = The response-to-retention hypothesis of early atherogenesis | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 15 | issue = 5 | pages = 551–561 | date = May 1995 | pmid = 7749869 | pmc = 2924812 | doi = 10.1161/01.ATV.15.5.551 }}

The presence of the plaque induces the muscle cells of the blood vessel to stretch, compensating for the additional bulk. The endothelial lining then thickens, increasing the separation between the plaque and lumen. The thickening somewhat offsets the narrowing caused by the growth of the plaque, but moreover, it causes the wall to stiffen and become less compliant to stretching with each heartbeat.{{cite journal | vauthors = Aviram M, Fuhrman B | title = LDL oxidation by arterial wall macrophages depends on the oxidative status in the lipoprotein and in the cells: role of prooxidants vs. antioxidants | journal = Molecular and Cellular Biochemistry | volume = 188 | issue = 1–2 | pages = 149–159 | date = November 1998 | pmid = 9823020 | doi = 10.1023/A:1006841011201 }}

• Western pattern diet{{Cite web|url=https://www.nhlbi.nih.gov/health/health-topics/topics/atherosclerosis/atrisk|title = Atherosclerosis | NHLBI, NIH| date=24 March 2022 }}
• Abdominal obesity
• Diabetes
• Dyslipidemia
• High blood cholesterol
• Hypertension
• Elevated low-density lipoprotein (LDL){{cite journal|display-authors=3 |vauthors=Ference BA, Ginsberg HN, Graham I, Ray KK, Packard CJ, Bruckert E, Hegele RA, Krauss RM, Raal FJ, Schunkert H, Watts GF, Borén J, Fazio S, Horton JD, Masana L, Nicholls SJ, Nordestgaard BG, van de Sluis B, Taskinen MR, Tokgözoglu L, Landmesser U, Laufs U, Wiklund O, Stock JK, Chapman MJ, Catapano AL |title=Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel |journal=European Heart Journal |volume=38 |issue=32 |pages=2459–2472 |date=August 2017 |pmid=28444290 |pmc=5837225 |doi=10.1093/eurheartj/ehx144}}{{Cite web|date=2020|title=What is the role of lipids in atherosclerosis and how low should we decrease lipid levels?|url=https://www.escardio.org/Journals/E-Journal-of-Cardiology-Practice/Volume-18/what-is-the-role-of-lipids-in-atherosclerosis-and-how-low-should-we-decrease-lip|website=European Society for Cardiology|language=en-GB|archive-date=January 20, 2025|archive-url=https://web.archive.org/web/20250120115242/https://www.escardio.org/Journals/E-Journal-of-Cardiology-Practice/Volume-18/what-is-the-role-of-lipids-in-atherosclerosis-and-how-low-should-we-decrease-lip|url-status=live|quote= Following decades of research in the field, compelling evidence from preclinical investigations, Mendelian randomisation studies, epidemiologic observations, and randomised trials of lipid-modifying medications supports the key causal role of atherogenic lipoproteins, particularly low-density lipoprotein (LDL), in the pathogenesis of ASCVD.}}
• High saturated fat diet{{Cite web|date=2025|title=Atherosclerosis|url=https://www.hopkinsmedicine.org/health/conditions-and-diseases/atherosclerosis|website=Johns Hopkins Medicine|language=en-GB|archive-date=March 18, 2025|archive-url=https://web.archive.org/web/20250318201438/https://www.hopkinsmedicine.org/health/conditions-and-diseases/atherosclerosis|url-status=live}}
• Trans fat{{cite journal|last1=Sacks|first1=Frank M.|last2=Lichtenstein|first2=Alice H.|last3=Wu|first3=Jason H.Y.|last4=Appel|first4=Lawrence J.|last5=Creager|first5=Mark A.|last6=Kris-Etherton|first6=Penny M.|last7=Miller|first7=Michael|last8=Rimm|first8=Eric B.|last9=Rudel|first9=Lawrence L.|last10=Robinson|first10=Jennifer G.|last11=Stone|first11=Neil J.|last12=Van Horn|first12=Linda V.|title=Dietary Fats and Cardiovascular Disease: A Presidential Advisory From the American Heart Association|journal=Circulation|date=June 15, 2017|pages=e1–e23|doi=10.1161/CIR.0000000000000510|pmid=28620111|volume=136|issue=3|s2cid=367602|doi-access=free}}
• Tobacco smoking
• Bacterial infections{{cite journal | vauthors = Campbell LA, Rosenfeld ME | title = Infection and Atherosclerosis Development | journal = Archives of Medical Research | volume = 46 | issue = 5 | pages = 339–350 | date = July 2015 | pmid = 26004263 | pmc = 4524506 | doi = 10.1016/j.arcmed.2015.05.006 }}
• HIV/AIDS{{cite journal | vauthors = Sinha A, Feinstein MJ | title = Coronary Artery Disease Manifestations in HIV: What, How, and Why | journal = The Canadian Journal of Cardiology | volume = 35 | issue = 3 | pages = 270–279 | date = March 2019 | pmid = 30825949 | pmc = 9532012 | doi = 10.1016/j.cjca.2018.11.029 }}
• Psychological stress{{cite journal|vauthors=Gu HF, Tang CK, Yang YZ|year=2012|title=Psychological stress, immune response, and atherosclerosis|journal=Atherosclerosis

|volume=223|issue=1|pages=69-77|doi=10.1016/j.atherosclerosis.2012.01.021|pmid=22304794}}

• Sedentary lifestyle

• Biological sex{{cite journal | vauthors = Mosca L, Barrett-Connor E, Wenger NK | title = Sex/gender differences in cardiovascular disease prevention: what a difference a decade makes | journal = Circulation | volume = 124 | issue = 19 | pages = 2145–2154 | date = November 2011 | pmid = 22064958 | pmc = 3362050 | doi = 10.1161/CIRCULATIONAHA.110.968792 }}
• South Asian descent{{cite journal | vauthors = Enas EA, Kuruvila A, Khanna P, Pitchumoni CS, Mohan V | title = Benefits & risks of statin therapy for primary prevention of cardiovascular disease in Asian Indians - a population with the highest risk of premature coronary artery disease & diabetes | journal = The Indian Journal of Medical Research | volume = 138 | issue = 4 | pages = 461–491 | date = October 2013 | pmid = 24434254 | pmc = 3868060 }}Indian Heart Association Why South Asians Facts Web. 30 April 2015. http://indianheartassociation.org/why-indians-why-south-asians/overview/
• Advanced age{{cite journal | vauthors = Tyrrell DJ, Blin MG, Song J, Wood SC, Zhang M, Beard DA, Goldstein DR | title = Age-Associated Mitochondrial Dysfunction Accelerates Atherogenesis | journal = Circulation Research | volume = 126 | issue = 3 | pages = 298–314 | date = January 2020 | pmid = 31818196 | pmc = 7006722 | doi = 10.1161/CIRCRESAHA.119.315644 }}
• Genetic abnormalities
• Family history
• Coronary anatomy and branch pattern{{cite journal | vauthors = Velican C, Velican D | title = Differences in the pattern of atherosclerotic involvement between non-branched regions and adjacent branching points of human coronary arteries | journal = Atherosclerosis | volume = 54 | issue = 3 | pages = 333–342 | date = March 1985 | pmid = 3994786 | doi = 10.1016/0021-9150(85)90126-1 }}

• Thrombophilia{{cite journal | vauthors = Borissoff JI, Spronk HM, Heeneman S, ten Cate H | title = Is thrombin a key player in the 'coagulation-atherogenesis' maze? | journal = Cardiovascular Research | volume = 82 | issue = 3 | pages = 392–403 | date = June 2009 | pmid = 19228706 | doi = 10.1093/cvr/cvp066 | doi-access = free }}{{cite journal | vauthors = Borissoff JI, Heeneman S, Kilinç E, Kassák P, Van Oerle R, Winckers K, Govers-Riemslag JW, Hamulyák K, Hackeng TM, Daemen MJ, ten Cate H, Spronk HM | title = Early atherosclerosis exhibits an enhanced procoagulant state | journal = Circulation | volume = 122 | issue = 8 | pages = 821–830 | date = August 2010 | pmid = 20697022 | doi = 10.1161/CIRCULATIONAHA.109.907121 | doi-access = free }}{{cite journal | vauthors = Borissoff JI, Spronk HM, ten Cate H | title = The hemostatic system as a modulator of atherosclerosis | journal = The New England Journal of Medicine | volume = 364 | issue = 18 | pages = 1746–1760 | date = May 2011 | pmid = 21542745 | doi = 10.1056/NEJMra1011670 }}
• Elevated triglycerides
• Systemic inflammation{{cite journal | vauthors = Bhatt DL, Topol EJ | title = Need to test the arterial inflammation hypothesis | journal = Circulation | volume = 106 | issue = 1 | pages = 136–140 | date = July 2002 | pmid = 12093783 | doi = 10.1161/01.CIR.0000021112.29409.A2 | doi-access = free }}
• Hyperinsulinemia{{cite journal | vauthors = Griffin M, Frazer A, Johnson A, Collins P, Owens D, Tomkin GH | title = Cellular cholesterol synthesis--the relationship to post-prandial glucose and insulin following weight loss | journal = Atherosclerosis | volume = 138 | issue = 2 | pages = 313–318 | date = June 1998 | pmid = 9690914 | doi = 10.1016/S0021-9150(98)00036-7 }}
• Sleep deprivation{{cite journal | vauthors = King CR, Knutson KL, Rathouz PJ, Sidney S, Liu K, Lauderdale DS | title = Short sleep duration and incident coronary artery calcification | journal = JAMA | volume = 300 | issue = 24 | pages = 2859–2866 | date = December 2008 | pmid = 19109114 | pmc = 2661105 | doi = 10.1001/jama.2008.867 }}
• Air pollution{{cite journal | vauthors = Provost EB, Madhloum N, Int Panis L, De Boever P, Nawrot TS | title = Carotid intima-media thickness, a marker of subclinical atherosclerosis, and particulate air pollution exposure: the meta-analytical evidence | journal = PLOS ONE | volume = 10 | issue = 5 | pages = e0127014 | date = 2015 | pmid = 25970426 | pmc = 4430520 | doi = 10.1371/journal.pone.0127014 | doi-access = free | bibcode = 2015PLoSO..1027014P }}{{cite journal | vauthors = Adar SD, Sheppard L, Vedal S, Polak JF, Sampson PD, Diez Roux AV, Budoff M, Jacobs DR, Barr RG, Watson K, Kaufman JD | title = Fine particulate air pollution and the progression of carotid intima-medial thickness: a prospective cohort study from the multi-ethnic study of atherosclerosis and air pollution | journal = PLOS Medicine | volume = 10 | issue = 4 | pages = e1001430 | date = April 23, 2013 | pmid = 23637576 | pmc = 3637008 | doi = 10.1371/journal.pmed.1001430 | quote = This early analysis from MESA suggests that higher long-term PM2.5 concentrations are associated with increased IMT progression and that greater reductions in PM2.5 are related to slower IMT progression. | doi-access = free }}
• Arsenic poisoning{{cite journal | vauthors = Wang CH, Jeng JS, Yip PK, Chen CL, Hsu LI, Hsueh YM, Chiou HY, Wu MM, Chen CJ | title = Biological gradient between long-term arsenic exposure and carotid atherosclerosis | journal = Circulation | volume = 105 | issue = 15 | pages = 1804–1809 | date = April 2002 | pmid = 11956123 | doi = 10.1161/01.cir.0000015862.64816.b2 | doi-access = free }}
• Hypothyroidism{{cite journal | vauthors = Sadovsky R |title=Treating Hypothyroidism Reduces Atherosclerosis Risk |journal=American Family Physician |volume=69 |issue=3 |date=February 2004 |pages=656–657 |id={{ProQuest|234284553}} |url=https://www.aafp.org/afp/2004/0201/p656.html }}
• Periodontal disease{{cite journal | vauthors = Bale BF, Doneen AL, Vigerust DJ | title = High-risk periodontal pathogens contribute to the pathogenesis of atherosclerosis | journal = Postgraduate Medical Journal | volume = 93 | issue = 1098 | pages = 215–220 | date = April 2017 | pmid = 27899684 | pmc = 5520251 | doi = 10.1136/postgradmedj-2016-134279 }}

The relation between dietary fat and atherosclerosis is controversial. The USDA, in its food pyramid, promotes a diet of about 64% carbohydrates from total calories. The American Heart Association, the American Diabetes Association, and the National Cholesterol Education Program make similar recommendations. In contrast, Prof Walter Willett (Harvard School of Public Health, PI of the second Nurses' Health Study) recommends much higher levels of fat, especially of monounsaturated and polyunsaturated fat.{{cite web|url=http://www.hsph.harvard.edu/nutritionsource/pyramids.html |title=Food Pyramids: Nutrition Source, Harvard School of Public Health |access-date=2007-11-25 |archive-url=https://web.archive.org/web/20071226085222/http://www.hsph.harvard.edu/nutritionsource/pyramids.html |archive-date=26 December 2007 |url-status=dead }} These dietary recommendations reach a consensus, though, against consumption of trans fats.{{citation needed|date=December 2020}}

The role of eating oxidized fats (rancid fats) in humans is not clear.

Rabbits fed rancid fats develop atherosclerosis faster.{{cite journal | vauthors = Staprãns I, Rapp JH, Pan XM, Hardman DA, Feingold KR | title = Oxidized lipids in the diet accelerate the development of fatty streaks in cholesterol-fed rabbits | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 16 | issue = 4 | pages = 533–538 | date = April 1996 | pmid = 8624775 | doi = 10.1161/01.atv.16.4.533 }} Rats fed DHA-containing oils experienced marked disruptions to their antioxidant systems, and accumulated significant amounts of phospholipid hydroperoxide in their blood, livers and kidneys.{{cite journal | vauthors = Song JH, Fujimoto K, Miyazawa T | title = Polyunsaturated (n-3) fatty acids susceptible to peroxidation are increased in plasma and tissue lipids of rats fed docosahexaenoic acid-containing oils | journal = The Journal of Nutrition | volume = 130 | issue = 12 | pages = 3028–3033 | date = December 2000 | pmid = 11110863 | doi = 10.1093/jn/130.12.3028 | doi-access = free }}

Rancid fats and oils taste very unpleasant in even small amounts, so people avoid eating them.{{cite journal | vauthors = Mattes RD | title = Fat taste and lipid metabolism in humans | journal = Physiology & Behavior | volume = 86 | issue = 5 | pages = 691–697 | date = December 2005 | pmid = 16249011 | doi = 10.1016/j.physbeh.2005.08.058 | quote = The rancid odor of an oxidized fat is readily detectable }}

Measuring or estimating the actual human consumption of these substances is challenging.{{cite journal | vauthors = Dobarganes C, Márquez-Ruiz G | title = Oxidized fats in foods | journal = Current Opinion in Clinical Nutrition and Metabolic Care | volume = 6 | issue = 2 | pages = 157–163 | date = March 2003 | pmid = 12589185 | doi = 10.1097/00075197-200303000-00004 }} Highly unsaturated omega-3 rich oils such as fish oil, when being sold in pill form, can hide the taste of oxidized or rancid fat that might be present. In the US, the health food industry's dietary supplements are self-regulated and outside of FDA regulations.{{cite web |url= https://www.fda.gov/Food/DietarySupplements/default.htm |title=Dietary Supplements |website=Food and Drug Administration |date=4 February 2020}} To protect unsaturated fats from oxidation, it is best to keep them cool and in oxygen-free environments.{{cite journal | vauthors = Khan-Merchant N, Penumetcha M, Meilhac O, Parthasarathy S | title = Oxidized fatty acids promote atherosclerosis only in the presence of dietary cholesterol in low-density lipoprotein receptor knockout mice | journal = The Journal of Nutrition | volume = 132 | issue = 11 | pages = 3256–3262 | date = November 2002 | pmid = 12421837 | doi = 10.1093/jn/132.11.3256 | doi-access = free | author-link4 = Sampath Parthasarathy }}

== Pathophysiology ==

Atherogenesis is the developmental process of atheromatous plaques. It is characterized by a remodeling of arteries leading to subendothelial accumulation of fatty substances called plaques. The buildup of an atheromatous plaque is a slow process, developed over several years through a complex series of cellular events occurring within the arterial wall and in response to several local vascular circulating factors. One recent hypothesis suggests that, for unknown reasons, leukocytes, such as monocytes or basophils, begin to attack the endothelium of the artery lumen in cardiac muscle. The ensuing inflammation leads to the formation of atheromatous plaques in the arterial tunica intima, a region of the vessel wall located between the endothelium and the tunica media. Chronic inflammation within the arterial wall, driven by immune cells like macrophages, accelerates atherosclerotic plaque instability by promoting collagen breakdown and thinning the fibrous cap, which increases the likelihood of rupture and thrombosis.{{cite book | vauthors = Shahjehan RD, Sharma S, Bhutta BS |title=StatPearls |date=2024 |publisher=StatPearls Publishing |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK564304/ |chapter=Coronary Artery Disease |pmid=33231974 }} The bulk of these lesions is made of excess fat, collagen, and elastin. At first, as the plaques grow, only wall thickening occurs without narrowing. Stenosis is a late event, which may never happen and is often the result of repeated plaque rupture and healing responses, not just the atherosclerotic process.{{cite web |url= https://www.lecturio.com/concepts/atherosclerosis/ | title= Atherosclerosis

| website= The Lecturio Medical Concept Library |access-date= 2 July 2021}} Autopsy studies have shown that the prevalence of coronary artery atherosclerosis in males from the United States, with an average age of 22.1 years old, who died in war, ranges from 45% to 77.3%.{{cite journal | vauthors = Joseph A, Ackerman D, Talley JD, Johnstone J, Kupersmith J | title = Manifestations of coronary atherosclerosis in young trauma victims--an autopsy study | journal = Journal of the American College of Cardiology | volume = 22 | issue = 2 | pages = 459–467 | date = August 1993 | pmid = 8335815 | doi = 10.1016/0735-1097(93)90050-B }}

File:RCA atherosclerosis.jpg of an artery that supplies the heart showing significant atherosclerosis and marked luminal narrowing. Tissue has been stained using Masson's trichrome.]]

Early atherogenesis is characterized by the adherence of blood circulating monocytes (a type of white blood cell) to the vascular bed lining, the endothelium, then by their migration to the sub-endothelial space, and further activation into monocyte-derived macrophages.{{cite journal | vauthors = Schwartz CJ, Valente AJ, Sprague EA, Kelley JL, Cayatte AJ, Mowery J | title = Atherosclerosis. Potential targets for stabilization and regression | journal = Circulation | volume = 86 | issue = 6 Suppl | pages = III117–III123 | date = December 1992 | pmid = 1424045 }} The primary documented driver of this process is oxidized lipoprotein particles within the wall, beneath the endothelial cells, though upper normal or elevated concentrations of blood glucose also plays a major role and not all factors are fully understood. Fatty streaks may appear and disappear.{{citation needed|date=December 2020}}

Low-density lipoprotein (LDL) particles in blood plasma invade the endothelium and become oxidized, creating risk of cardiovascular disease. A complex set of biochemical reactions regulates the oxidation of LDL, involving enzymes (such as Lp-LpA2) and free radicals in the endothelium.{{cite journal | title = The Role of Lipids and Lipoproteins in Atherosclerosis | journal = Endotext | date = 2000 | pmid = 26844337 | id = {{NCBIBook2|NBK343489}} | vauthors = Feingold KR, Anawalt B, Blackman MR, Boyce A, Chrousos G, Corpas E, De Herder WW, Dhatariya K, Dungan K, Hofland J, Kalra S, Kaltsas G, Kapoor N, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrère B, Levy M, McGee EA, McLachlan R, New M, Purnell J, Sahay R, Shah AS, Singer F, Sperling MA, Stratakis CA, Trence DL }}

Initial damage to the endothelium results in an inflammatory response. Monocytes enter the artery wall from the bloodstream, with platelets adhering to the area of insult. This may be promoted by redox signaling induction of factors such as VCAM-1, which recruits circulating monocytes, and M-CSF, which is selectively required for the differentiation of monocytes to macrophages. The monocytes differentiate into macrophages, which proliferate locally,{{cite journal | vauthors = Robbins CS, Hilgendorf I, Weber GF, Theurl I, Iwamoto Y, Figueiredo JL, Gorbatov R, Sukhova GK, Gerhardt LM, Smyth D, Zavitz CC, Shikatani EA, Parsons M, van Rooijen N, Lin HY, Husain M, Libby P, Nahrendorf M, Weissleder R, Swirski FK | title = Local proliferation dominates lesional macrophage accumulation in atherosclerosis | journal = Nature Medicine | volume = 19 | issue = 9 | pages = 1166–1172 | date = September 2013 | pmid = 23933982 | pmc = 3769444 | doi = 10.1038/nm.3258 }} ingest oxidized LDL, slowly turning into large "foam cells" – so-called because of their changed appearance resulting from the numerous internal cytoplasmic vesicles and resulting high lipid content. Under the microscope, the lesion now appears as a fatty streak. Foam cells eventually die and further propagate the inflammatory process.{{citation needed|date=December 2020}}

In addition to these cellular activities, there is also smooth muscle proliferation and migration from the tunica media into the intima in response to cytokines secreted by damaged endothelial cells. This causes the formation of a fibrous capsule covering the fatty streak. Intact endothelium can prevent this smooth muscle proliferation by releasing nitric oxide.{{citation needed|date=December 2020}}

Calcification forms among vascular smooth muscle cells of the surrounding muscular layer, specifically in the muscle cells adjacent to atheromas and on the surface of atheroma plaques and tissue.{{cite journal | vauthors = Miller JD | title = Cardiovascular calcification: Orbicular origins | journal = Nature Materials | volume = 12 | issue = 6 | pages = 476–478 | date = June 2013 | pmid = 23695741 | doi = 10.1038/nmat3663 | bibcode = 2013NatMa..12..476M }} In time, as cells die, this leads to extracellular calcium deposits between the muscular wall and outer portion of the atheromatous plaques. With the atheromatous plaque interfering with the regulation of calcium deposition, it accumulates and crystallizes. A similar form of intramural calcification, presenting the picture of an early phase of arteriosclerosis, appears to be induced by many drugs that have an antiproliferative mechanism of action (Rainer Liedtke 2008).{{citation needed|date=April 2021}}

Cholesterol is delivered into the vessel wall by cholesterol-containing low-density lipoprotein (LDL) particles. To attract and stimulate macrophages, the cholesterol must be released from the LDL particles and oxidized, a key step in the ongoing inflammatory process. The process is worsened if it is insufficient high-density lipoprotein (HDL), the lipoprotein particle that removes cholesterol from tissues and carries it back to the liver.

The foam cells and platelets encourage the migration and proliferation of smooth muscle cells, which in turn ingest lipids, become replaced by collagen, and transform into foam cells themselves. A protective fibrous cap normally forms between the fatty deposits and the artery lining (the intima).{{citation needed|date=December 2020}}

These capped fatty deposits (now called 'atheromas') produce enzymes that cause the artery to enlarge over time. As long as the artery enlarges sufficiently to compensate for the extra thickness of the atheroma, then no narrowing ("stenosis") of the opening ("lumen") occurs. The artery expands with an egg-shaped cross-section, still with a circular opening. If the enlargement is beyond proportion to the atheroma thickness, then an aneurysm is created.{{cite journal | vauthors = Glagov S, Weisenberg E, Zarins CK, Stankunavicius R, Kolettis GJ | title = Compensatory enlargement of human atherosclerotic coronary arteries | journal = The New England Journal of Medicine | volume = 316 | issue = 22 | pages = 1371–1375 | date = May 1987 | pmid = 3574413 | doi = 10.1056/NEJM198705283162204 }}

File:Atherosclerosis, aorta, gross pathology PHIL 846 lores.jpg. Autopsy specimen.]]

Although arteries are not typically studied microscopically, two plaque types can be distinguished:{{cite web |url=http://www.pathologyatlas.ro/coronary-atherosclerosis-fibrous-plaque.php |title=Coronary atherosclerosis — the fibrous plaque with calcification |publisher=www.pathologyatlas.ro |access-date=2010-03-25 }}

1. The fibro-lipid (fibro-fatty) plaque is characterized by an accumulation of lipid-laden cells underneath the intima of the arteries, typically without narrowing the lumen due to compensatory expansion of the bounding muscular layer of the artery wall. Beneath the endothelium, there is a "fibrous cap" covering the atheromatous "core" of the plaque. The core consists of lipid-laden cells (macrophages and smooth muscle cells) with elevated tissue cholesterol and cholesterol ester content, fibrin, proteoglycans, collagen, elastin, and cellular debris. In advanced plaques, the central core of the plaque usually contains extracellular cholesterol deposits (released from dead cells), which form areas of cholesterol crystals with empty, needle-like clefts. At the periphery of the plaque are younger "foamy" cells and capillaries. These plaques usually produce the most damage to the individual when they rupture. Cholesterol crystals may also play a role.{{cite journal | vauthors = Janoudi A, Shamoun FE, Kalavakunta JK, Abela GS | title = Cholesterol crystal induced arterial inflammation and destabilization of atherosclerotic plaque | journal = European Heart Journal | volume = 37 | issue = 25 | pages = 1959–1967 | date = July 2016 | pmid = 26705388 | doi = 10.1093/eurheartj/ehv653 | doi-access = free }}
2. The fibrous plaque is also localized under the intima, within the arterial wall resulting in thickening and expansion of the wall and, sometimes, spotty localized narrowing of the lumen with some atrophy of the muscular layer. The fibrous plaque contains collagen fibers (eosinophilic), precipitates of calcium (hematoxylinophilic), and rarely, lipid-laden cells.{{citation needed|date=December 2020}}

In effect, the muscular portion of the artery wall forms small aneurysms just large enough to hold the atheroma that are present. The muscular portion of artery walls usually remains strong, even after they have been remodeled to compensate for the atheromatous plaques.{{citation needed|date=December 2020}}

However, atheromas within the vessel wall are soft and fragile with little elasticity. Arteries constantly expand and contract with each heartbeat, i.e., the pulse. In addition, the calcification deposits between the outer portion of the atheroma and the muscular wall, as they progress, lead to a loss of elasticity and stiffening of the artery as a whole.{{citation needed|date=December 2020}}

The calcification deposits,{{cite book | vauthors = Maton A, Hopkins RL, McLaughlin CW, Johnson S, Warner MQ, LaHart D, Wright JD | title = Human Biology and Health | publisher = Prentice Hall | year = 1993 | location = Englewood Cliffs, NJ | isbn = 978-0-13-981176-0 | oclc = 32308337 | url-access = registration | url = https://archive.org/details/humanbiologyheal00scho }} after they have become sufficiently advanced, are partially visible on coronary artery computed tomography or electron beam tomography (EBT) as rings of increased radiographic density, forming halos around the outer edges of the atheromatous plaques, within the artery wall. On CT, >130 units on the Hounsfield scale (some argue for 90 units) has been the radiographic density usually accepted as clearly representing tissue calcification within arteries. These deposits demonstrate unequivocal evidence of the disease, relatively advanced, even though the lumen of the artery is often still normal by angiography.{{citation needed|date=December 2020}}

File:Late complications of atherosclerosis.PNG

Although the disease process tends to be slowly progressive over decades, it usually remains asymptomatic until an atheroma ulcerates, which leads to immediate blood clotting at the site of the atheroma ulcer. This triggers a cascade of events that leads to clot enlargement, which may quickly obstruct blood flow. A complete blockage leads to ischemia of the myocardial (heart) muscle and damage. This process is the myocardial infarction or "heart attack".{{cite web|title=What Are the Signs and Symptoms of Coronary Heart Disease?|url=http://www.nhlbi.nih.gov/health/health-topics/topics/cad/signs|website=www.nhlbi.nih.gov|access-date=2 July 2021|date=September 29, 2014|url-status=dead|archive-url=https://web.archive.org/web/20150224034615/http://www.nhlbi.nih.gov/health/health-topics/topics/cad/signs|archive-date=24 February 2015}}

If the heart attack is not fatal, fibrous organization of the clot within the lumen ensues, covering the rupture but also producing stenosis or closure of the lumen, or over time and after repeated ruptures, resulting in a persistent, usually localized stenosis or blockage of the artery lumen. Stenoses can be slowly progressive, whereas plaque ulceration is a sudden event that occurs specifically in atheromas with thinner/weaker fibrous caps that have become "unstable".

Repeated plaque ruptures, ones not resulting in total lumen closure, combined with the clot patch over the rupture and healing response to stabilize the clot is the process that produces most stenoses over time. The stenotic areas often become more stable despite increased flow velocities at these narrowings. Most major blood-flow-stopping events occur at large plaques, which, before their rupture, produced little if any stenosis.{{citation needed|date=December 2020}}

From clinical trials, 20% is the average stenosis at plaques that subsequently rupture with resulting complete artery closure. Most severe clinical events do not occur at plaques that produce high-grade stenosis. From clinical trials, only 14% of heart attacks occur from artery closure at plaques producing 75% or greater stenosis before the vessel closing.{{Citation needed|date=August 2010}}

If the fibrous cap separating a soft atheroma from the bloodstream within the artery ruptures, tissue fragments are exposed and released. These tissue fragments are very clot-promoting, containing collagen and tissue factor; they activate platelets and activate the system of coagulation. The result is the formation of a thrombus (blood clot) overlying the atheroma, which obstructs blood flow acutely. With the obstruction of blood flow, downstream tissues are starved of oxygen and nutrients. If this is the myocardium (heart muscle) angina (cardiac chest pain) or myocardial infarction (heart attack) develops.{{citation needed|date=December 2020}}

The distribution of atherosclerotic plaques in a part of arterial endothelium is inhomogeneous. The multiple and focal development of atherosclerotic changes is similar to that in the development of amyloid plaques in the brain and age spots on the skin. Misrepair-accumulation aging theory suggests that misrepair mechanisms{{cite journal | vauthors = Wang J, Michelitsch T, Wunderlin A, Mahadeva R |title=Aging as a consequence of misrepair -- A novel theory of aging |journal=Nature Precedings |date=6 April 2009 |doi=10.1038/npre.2009.2988.2 |arxiv=0904.0575 }}{{cite arXiv |title= Aging as a process of accumulation of Misrepairs | vauthors = Wang-Michelitsch J, Michelitsch T |class= q-bio.TO |year=2015 | eprint = 1503.07163 }} play an important role in the focal development of atherosclerosis.{{cite arXiv |title= Misrepair mechanism in the development of atherosclerotic plaques | vauthors = Wang-Michelitsch J, Michelitsch TM |class= q-bio.TO |year=2015 | eprint = 1505.01289 }} The development of a plaque is a result of the repair of the injured endothelium. Because of the infusion of lipids into the sub-endothelium, the repair has to end up with altered remodeling of the local endothelium. This is the manifestation of a misrepair. This altered remodeling increases the susceptibility of the local endothelium to damage and reduces its repair efficiency. Consequently, this part of endothelium has an increased risk of being injured and improperly repaired. Thus, the accumulation of misrepairs of endothelium is focalized and self-accelerating. In this way, the growth of a plaque is also self-accelerating. Within a part of the arterial wall, the oldest plaque is always the biggest and is the most dangerous one to cause blockage of a local artery.{{citation needed|date=December 2020}}

The plaque is divided into three distinct components:

1. The atheroma ("lump of gruel", {{ety|gre|ἀθήρα (athera)|gruel}}), which is the nodular accumulation of a soft, flaky, yellowish material at the center of large plaques, composed of macrophages nearest the lumen of the artery{{citation needed|date=December 2020}}
2. Underlying areas of cholesterol crystals{{citation needed|date=December 2020}}
3. Calcification at the outer base of older or more advanced lesions. Atherosclerotic lesions, or atherosclerotic plaques, are separated into two broad categories: Stable and unstable (also called vulnerable).{{cite journal | vauthors = Ross R | title = Atherosclerosis--an inflammatory disease | journal = The New England Journal of Medicine | volume = 340 | issue = 2 | pages = 115–126 | date = January 1999 | pmid = 9887164 | doi = 10.1056/NEJM199901143400207 }} The pathobiology of atherosclerotic lesions is very complicated, but generally, stable atherosclerotic plaques, which tend to be asymptomatic, are rich in extracellular matrix and smooth muscle cells. On the other hand, unstable plaques are rich in macrophages and foam cells, and the extracellular matrix separating the lesion from the arterial lumen (also known as the fibrous cap) is usually weak and prone to rupture.{{cite journal | vauthors = Finn AV, Nakano M, Narula J, Kolodgie FD, Virmani R | title = Concept of vulnerable/unstable plaque | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 30 | issue = 7 | pages = 1282–1292 | date = July 2010 | pmid = 20554950 | doi = 10.1161/ATVBAHA.108.179739 | doi-access = free }} Ruptures of the fibrous cap expose thrombogenic material, such as collagen,{{cite journal | vauthors = Didangelos A, Simper D, Monaco C, Mayr M | title = Proteomics of acute coronary syndromes | journal = Current Atherosclerosis Reports | volume = 11 | issue = 3 | pages = 188–195 | date = May 2009 | pmid = 19361350 | doi = 10.1007/s11883-009-0030-x }} to the circulation and eventually induce thrombus formation in the lumen. Upon formation, intraluminal thrombi can occlude arteries outright (e.g., coronary occlusion), but more often they detach, move into the circulation, and eventually occlude smaller downstream branches causing thromboembolism.{{citation needed|date=December 2020}}

Apart from thromboembolism, chronically expanding atherosclerotic lesions can cause complete closure of the lumen. Chronically expanding lesions are often asymptomatic until the lumen stenosis is so severe (usually over 80%) that blood supply to downstream tissue(s) is insufficient, resulting in ischemia. These complications of advanced atherosclerosis are chronic, slowly progressive, and cumulative. Most commonly, soft plaque suddenly ruptures (see vulnerable plaque), causing the formation of a thrombus that will rapidly slow or stop blood flow, leading to the death of the tissues fed by the artery in approximately five minutes. This event is called an infarction.{{citation needed|date=December 2020}}

File:CT image of atherosclerosis of the abdominal aorta.svg of atherosclerosis of the abdominal aorta. Woman of 70 years old with hypertension and dyslipidemia.]]

File:Calcificatio atherosclerotica.jpg and eosin stain)]]

Areas of severe narrowing, stenosis, detectable by angiography, and to a lesser extent "stress testing" have long been the focus of human diagnostic techniques for cardiovascular disease, in general. However, these methods focus on detecting only severe narrowing, not the underlying atherosclerosis disease.{{cite journal | vauthors = Tarkin JM, Dweck MR, Evans NR, Takx RA, Brown AJ, Tawakol A, Fayad ZA, Rudd JH | title = Imaging Atherosclerosis | journal = Circulation Research | volume = 118 | issue = 4 | pages = 750–769 | date = February 2016 | pmid = 26892971 | pmc = 4756468 | doi = 10.1161/CIRCRESAHA.115.306247 }} As demonstrated by human clinical studies, most severe events occur in locations with heavy plaque, yet little or no lumen narrowing present before debilitating events suddenly occur. Plaque rupture can lead to artery lumen occlusion within seconds to minutes, potential permanent debility, and sometimes sudden death.{{citation needed|date=December 2020}}

Plaques that have ruptured are called complicated lesions. The extracellular matrix of the lesion breaks, usually at the shoulder of the fibrous cap that separates the lesion from the arterial lumen, where the exposed thrombogenic components of the plaque, mainly collagen, will trigger thrombus formation. The thrombus then travels downstream to other blood vessels, where the blood clot may partially or completely block blood flow. If the blood flow is completely blocked, cell deaths occur due to the lack of oxygen supply to nearby cells, resulting in necrosis.{{cite journal | vauthors = Stary HC, Chandler AB, Dinsmore RE, Fuster V, Glagov S, Insull W, Rosenfeld ME, Schwartz CJ, Wagner WD, Wissler RW | title = A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association | journal = Circulation | volume = 92 | issue = 5 | pages = 1355–1374 | date = September 1995 | pmid = 7648691 | doi = 10.1161/01.CIR.92.5.1355 | doi-access = free | author-link4 = Valentín Fuster }} The narrowing or obstruction of blood flow can occur in any artery within the body. Obstruction of arteries supplying the heart muscle results in a heart attack, while the obstruction of arteries supplying the brain results in an ischaemic stroke.{{citation needed|date=December 2020}}

File:RICA Stenosis 174302500.jpg

Lumen stenosis that is greater than 75% was considered the hallmark of clinically significant disease in the past because recurring episodes of angina and abnormalities in stress tests are only detectable at that particular severity of stenosis. However, clinical trials have shown that only about 14% of clinically debilitating events occur at sites with more than 75% stenosis. Most cardiovascular events that involve sudden rupture of the atheroma plaque do not display any evident luminal narrowing. Thus, greater attention has been focused on "vulnerable plaque" from the late 1990s onwards.{{cite journal | vauthors = Maseri A, Fuster V | title = Is there a vulnerable plaque? | journal = Circulation | volume = 107 | issue = 16 | pages = 2068–2071 | date = April 2003 | pmid = 12719286 | doi = 10.1161/01.CIR.0000070585.48035.D1 | doi-access = free }}

Besides the traditional diagnostic methods such as angiography and stress-testing, other detection techniques have been developed in the past decades for earlier detection of atherosclerotic disease. Some of the detection approaches include anatomical detection and physiologic measurement.{{citation needed|date=December 2020}}

Examples of anatomical detection methods include coronary calcium scoring by CT, carotid IMT (intimal media thickness) measurement by ultrasound, and intravascular imaging techniques, such as intravascular ultrasound (IVUS), and intravascular optical coherence tomography (OCT),{{cite journal | vauthors = Tearney GJ, Regar E, Akasaka T, Adriaenssens T, Barlis P, Bezerra HG, Bouma B, Bruining N, Cho JM, Chowdhary S, Costa MA, de Silva R, Dijkstra J, Di Mario C, Dudek D, Falk E, Feldman MD, Fitzgerald P, Garcia-Garcia HM, Gonzalo N, Granada JF, Guagliumi G, Holm NR, Honda Y, Ikeno F, Kawasaki M, Kochman J, Koltowski L, Kubo T, Kume T, Kyono H, Lam CC, Lamouche G, Lee DP, Leon MB, Maehara A, Manfrini O, Mintz GS, Mizuno K, Morel MA, Nadkarni S, Okura H, Otake H, Pietrasik A, Prati F, Räber L, Radu MD, Rieber J, Riga M, Rollins A, Rosenberg M, Sirbu V, Serruys PW, Shimada K, Shinke T, Shite J, Siegel E, Sonoda S, Suter M, Takarada S, Tanaka A, Terashima M, Thim T, Uemura S, Ughi GJ, van Beusekom HM, van der Steen AF, van Es GA, van Soest G, Virmani R, Waxman S, Weissman NJ, Weisz G | title = Consensus standards for acquisition, measurement, and reporting of intravascular optical coherence tomography studies: a report from the International Working Group for Intravascular Optical Coherence Tomography Standardization and Validation | journal = Journal of the American College of Cardiology | volume = 59 | issue = 12 | pages = 1058–1072 | date = March 2012 | pmid = 22421299 | doi = 10.1016/j.jacc.2011.09.079 }}{{cite journal | vauthors = Pereira VM, Lylyk P, Cancelliere N, Lylyk PN, Lylyk I, Anagnostakou V, Bleise C, Nishi H, Epshtein M, King RM, Shazeeb MS, Puri AS, Liang CW, Hanel RA, Spears J, Marotta TR, Lopes DK, Gounis MJ, Ughi GJ | title = Volumetric microscopy of cerebral arteries with a miniaturized optical coherence tomography imaging probe | journal = Science Translational Medicine | volume = 16 | issue = 747 | pages = eadl4497 | date = May 2024 | pmid = 38748771 | doi = 10.1126/scitranslmed.adl4497 }} allowing direct visualization of atherosclerotic plaques.

Other methods include blood measurements, e.g., lipoprotein subclass analysis, HbA1c, hs-CRP, and homocysteine.{{citation needed|date=December 2020}}

Both anatomic and physiologic methods allow early detection before symptoms show up, disease staging, and tracking of disease progression.

In recent years, developments in nuclear imaging techniques such as PET and SPECT have provided non-invasive ways of estimating the severity of atherosclerotic plaques.

Up to 90% of cardiovascular disease may be preventable if established risk factors are avoided.{{cite journal | vauthors = McGill HC, McMahan CA, Gidding SS | title = Preventing heart disease in the 21st century: implications of the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study | journal = Circulation | volume = 117 | issue = 9 | pages = 1216–1227 | date = March 2008 | pmid = 18316498 | doi = 10.1161/CIRCULATIONAHA.107.717033 | doi-access = free }}{{cite journal | vauthors = McNeal CJ, Dajani T, Wilson D, Cassidy-Bushrow AE, Dickerson JB, Ory M | title = Hypercholesterolemia in youth: opportunities and obstacles to prevent premature atherosclerotic cardiovascular disease | journal = Current Atherosclerosis Reports | volume = 12 | issue = 1 | pages = 20–28 | date = January 2010 | pmid = 20425267 | doi = 10.1007/s11883-009-0072-0 }} Medical management of atherosclerosis first involves modification to risk factors–for example, via smoking cessation and diet restrictions. Prevention is generally by eating a healthy diet, exercising, not smoking, and maintaining a normal weight.

Changes in diet may help prevent the development of atherosclerosis. Tentative evidence suggests that a diet containing dairy products has no effect on or decreases the risk of cardiovascular disease.{{cite journal | vauthors = Rice BH | title = Dairy and Cardiovascular Disease: A Review of Recent Observational Research | journal = Current Nutrition Reports | volume = 3 | issue = 2 | pages = 130–138 | date = 2014 | pmid = 24818071 | pmc = 4006120 | doi = 10.1007/s13668-014-0076-4 }}{{cite journal | vauthors = Kratz M, Baars T, Guyenet S | title = The relationship between high-fat dairy consumption and obesity, cardiovascular, and metabolic disease | journal = European Journal of Nutrition | volume = 52 | issue = 1 | pages = 1–24 | date = February 2013 | pmid = 22810464 | doi = 10.1007/s00394-012-0418-1 }}

A diet high in fruits and vegetables decreases the risk of cardiovascular disease and death.{{cite journal | vauthors = Wang X, Ouyang Y, Liu J, Zhu M, Zhao G, Bao W, Hu FB | title = Fruit and vegetable consumption and mortality from all causes, cardiovascular disease, and cancer: systematic review and dose-response meta-analysis of prospective cohort studies | journal = BMJ | volume = 349 | pages = g4490 | date = July 2014 | pmid = 25073782 | pmc = 4115152 | doi = 10.1136/bmj.g4490 }} Evidence suggests that the Mediterranean diet may improve cardiovascular results.{{cite journal | vauthors = Walker C, Reamy BV | title = Diets for cardiovascular disease prevention: what is the evidence? | journal = American Family Physician | volume = 79 | issue = 7 | pages = 571–578 | date = April 2009 | pmid = 19378874 | url = https://www.aafp.org/link_out?pmid=19378874 | id = {{ProQuest|234120649}} }} There is also evidence that a Mediterranean diet may be better than a low-fat diet in bringing about long-term changes to cardiovascular risk factors (e.g., lower cholesterol level and blood pressure).{{cite journal | vauthors = Nordmann AJ, Suter-Zimmermann K, Bucher HC, Shai I, Tuttle KR, Estruch R, Briel M | title = Meta-analysis comparing Mediterranean to low-fat diets for modification of cardiovascular risk factors | journal = The American Journal of Medicine | volume = 124 | issue = 9 | pages = 841–51.e2 | date = September 2011 | pmid = 21854893 | doi = 10.1016/j.amjmed.2011.04.024 }} A 2024 review highlighted that bioactive compounds found in Mediterranean diet components (such as olive, grape, garlic, rosemary, and saffron) exhibit properties that may contribute to cardiovascular health and atherosclerosis prevention.{{cite journal | vauthors = Anguera-Tejedor M, Garrido G, Garrido-Suárez BB, Ardiles-Rivera A, Bistué-Rovira À, Jiménez-Altayó F, Delgado-Hernández R |title=Exploring the therapeutic potential of bioactive compounds from selected plant extracts of Mediterranean diet constituents for cardiovascular diseases: A review of mechanisms of action, clinical evidence, and adverse effects |journal=Food Bioscience |date=December 2024 |volume=62 |pages=105487 |doi=10.1016/j.fbio.2024.105487 }}

A controlled exercise program combats atherosclerosis by improving the circulation and functionality of the vessels. Exercise is also used to manage weight in patients who are obese, lower blood pressure, and decrease cholesterol. Often lifestyle modification is combined with medication therapy. For example, statins help to lower cholesterol. Antiplatelet medications like aspirin help to prevent clots, and a variety of antihypertensive medications are routinely used to control blood pressure. If the combined efforts of risk factor modification and medication therapy are not sufficient to control symptoms or fight imminent threats of ischemic events, a physician may resort to interventional or surgical procedures to correct the obstruction.{{cite book |chapter= Cardiovascular, Circulatory, and Hematologic Function |pages=730–1047 |chapter-url= https://books.google.com/books?id=SB_-CRXvZPYC&pg=PA730 | veditors = Paul P, Williams B |title=Brunner & Suddarth's Textbook of Canadian Medical-surgical Nursing |date=2009 |publisher=Lippincott Williams & Wilkins |isbn=978-0-7817-9989-8 }}

Treatment of established disease may include medications to lower cholesterol such as statins, blood pressure medication, or medications that decrease clotting, such as aspirin. Many procedures may also be carried out such as percutaneous coronary intervention, coronary artery bypass graft, or carotid endarterectomy.

Medical treatments often focus on alleviating symptoms. However, measures that focus on decreasing underlying atherosclerosis—as opposed to simply treating symptoms—are more effective.{{cite journal | vauthors = Fonarow GC | title = Aggressive treatment of atherosclerosis: the time is now | journal = Cleveland Clinic Journal of Medicine | volume = 70 | issue = 5 | pages = 431–434 | date = May 2003 | pmid = 12785316 | doi = 10.3949/ccjm.70.5.431 | doi-broken-date = 4 December 2024 }} Non-pharmaceutical means are usually the first method of treatment, such as stopping smoking and practicing regular exercise.{{cite journal | vauthors = Ambrose JA, Barua RS | title = The pathophysiology of cigarette smoking and cardiovascular disease: an update | journal = Journal of the American College of Cardiology | volume = 43 | issue = 10 | pages = 1731–1737 | date = May 2004 | pmid = 15145091 | doi = 10.1016/j.jacc.2003.12.047 | doi-access = free }}{{cite journal | vauthors = Pigozzi F, Rizzo M, Fagnani F, Parisi A, Spataro A, Casasco M, Borrione P | title = Endothelial (dys)function: the target of physical exercise for prevention and treatment of cardiovascular disease | journal = The Journal of Sports Medicine and Physical Fitness | volume = 51 | issue = 2 | pages = 260–267 | date = June 2011 | pmid = 21681161 | url = http://www.minervamedica.it/index2.t?show=R40Y2011N02A0260 }} If these methods do not work, medicines are usually the next step in treating cardiovascular diseases and, with improvements, have increasingly become the most effective method over the long term.{{cite journal | vauthors = Gupta KK, Ali S, Sanghera RS | title = Pharmacological Options in Atherosclerosis: A Review of the Existing Evidence | journal = Cardiology and Therapy | volume = 8 | issue = 1 | pages = 5–20 | date = June 2019 | pmid = 30543029 | pmc = 6525235 | doi = 10.1007/s40119-018-0123-0 }}

The key to the more effective approaches is to combine different treatment strategies.{{cite journal | vauthors = Koh KK, Han SH, Oh PC, Shin EK, Quon MJ | title = Combination therapy for treatment or prevention of atherosclerosis: focus on the lipid-RAAS interaction | journal = Atherosclerosis | volume = 209 | issue = 2 | pages = 307–313 | date = April 2010 | pmid = 19800624 | pmc = 2962413 | doi = 10.1016/j.atherosclerosis.2009.09.007 }} In addition, for those approaches, such as lipoprotein transport behaviors, which have been shown to produce the most success, adopting more aggressive combination treatment strategies taken daily and indefinitely has generally produced better results, both before and especially after people are symptomatic.

Statin medications are widely prescribed for treating atherosclerosis. They have shown benefit in reducing cardiovascular disease and mortality in those with high cholesterol with few side effects.{{cite journal | vauthors = Taylor F, Huffman MD, Macedo AF, Moore TH, Burke M, Davey Smith G, Ward K, Ebrahim S | title = Statins for the primary prevention of cardiovascular disease | journal = The Cochrane Database of Systematic Reviews | volume = 2013 | issue = 1 | pages = CD004816 | date = January 2013 | pmid = 23440795 | pmc = 6481400 | doi = 10.1002/14651858.CD004816.pub5 }} Secondary prevention therapy, which includes high-intensity statins and aspirin, is recommended by multi-society guidelines for all patients with a history of ASCVD (atherosclerotic cardiovascular disease) to prevent the recurrence of coronary artery disease, ischemic stroke, or peripheral arterial disease.{{cite journal | vauthors = Virani SS, Smith SC, Stone NJ, Grundy SM | title = Secondary Prevention for Atherosclerotic Cardiovascular Disease: Comparing Recent US and European Guidelines on Dyslipidemia | journal = Circulation | volume = 141 | issue = 14 | pages = 1121–1123 | date = April 2020 | pmid = 32250694 | doi = 10.1161/CIRCULATIONAHA.119.044282 | doi-access = free }}{{cite journal | vauthors = Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, Braun LT, de Ferranti S, Faiella-Tommasino J, Forman DE, Goldberg R, Heidenreich PA, Hlatky MA, Jones DW, Lloyd-Jones D, Lopez-Pajares N, Ndumele CE, Orringer CE, Peralta CA, Saseen JJ, Smith SC, Sperling L, Virani SS, Yeboah J | title = 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines | journal = Journal of the American College of Cardiology | volume = 73 | issue = 24 | pages = e285–e350 | date = June 2019 | pmid = 30423393 | doi = 10.1016/j.jacc.2018.11.003 | hdl-access = free | hdl = 20.500.12749/1738 }} However, prescription of and adherence to these guideline-concordant therapies is lacking, particularly among young patients and women.{{cite journal | vauthors = Nanna MG, Wang TY, Xiang Q, Goldberg AC, Robinson JG, Roger VL, Virani SS, Wilson PW, Louie MJ, Koren A, Li Z, Peterson ED, Navar AM | title = Sex Differences in the Use of Statins in Community Practice | journal = Circulation. Cardiovascular Quality and Outcomes | volume = 12 | issue = 8 | pages = e005562 | date = August 2019 | pmid = 31416347 | pmc = 6903404 | doi = 10.1161/CIRCOUTCOMES.118.005562 }}{{cite journal | vauthors = Lee MT, Mahtta D, Ramsey DJ, Liu J, Misra A, Nasir K, Samad Z, Itchhaporia D, Khan SU, Schofield RS, Ballantyne CM, Petersen LA, Virani SS | title = Sex-Related Disparities in Cardiovascular Health Care Among Patients With Premature Atherosclerotic Cardiovascular Disease | journal = JAMA Cardiology | volume = 6 | issue = 7 | pages = 782–790 | date = July 2021 | pmid = 33881448 | pmc = 8060887 | doi = 10.1001/jamacardio.2021.0683 }}

Statins work by inhibiting HMG-CoA (hydroxymethylglutaryl-coenzyme A) reductase, a hepatic rate-limiting enzyme in cholesterol's biochemical production pathway. Inhibiting this rate-limiting enzyme reduces the body's ability to produce as much cholesterol endogenously, thereby reducing the level of LDL-cholesterol in the blood. This reduced endogenous cholesterol production triggers the body to then pull cholesterol from other cellular sources, enhancing serum HDL-cholesterol.{{citation needed|date=January 2021}} These data are primarily in middle-aged men and the conclusions are less clear for women and people over the age of 70.{{cite journal | vauthors = Vos E, Rose CP | title = Questioning the benefits of statins | journal = CMAJ | volume = 173 | issue = 10 | pages = 1207; author reply 1210 | date = November 2005 | pmid = 16275976 | pmc = 1277053 | doi = 10.1503/cmaj.1050120 }}

When atherosclerosis has become severe and caused irreversible ischemia, such as tissue loss in the case of peripheral artery disease, surgery may be indicated. Vascular bypass surgery can re-establish flow around the diseased segment of the artery, and angioplasty with or without stenting can reopen narrowed arteries and improve blood flow. Coronary artery bypass grafting without manipulation of the ascending aorta has demonstrated reduced rates of postoperative stroke and mortality compared to traditional on-pump coronary revascularization.{{cite journal | vauthors = Zhao DF, Edelman JJ, Seco M, Bannon PG, Wilson MK, Byrom MJ, Thourani V, Lamy A, Taggart DP, Puskas JD, Vallely MP | title = Coronary Artery Bypass Grafting With and Without Manipulation of the Ascending Aorta: A Network Meta-Analysis | journal = Journal of the American College of Cardiology | volume = 69 | issue = 8 | pages = 924–936 | date = February 2017 | pmid = 28231944 | doi = 10.1016/j.jacc.2016.11.071 | doi-access = free }}

There is evidence that some anticoagulants, particularly warfarin, which inhibit clot formation by interfering with Vitamin K metabolism, may promote arterial calcification in the long term despite reducing clot formation in the short term.{{cite journal | vauthors = Vlasschaert C, Goss CJ, Pilkey NG, McKeown S, Holden RM | title = Vitamin K Supplementation for the Prevention of Cardiovascular Disease: Where Is the Evidence? A Systematic Review of Controlled Trials | journal = Nutrients | volume = 12 | issue = 10 | pages = 2909 | date = September 2020 | pmid = 32977548 | pmc = 7598164 | doi = 10.3390/nu12102909 | doi-access = free }}{{cite journal | vauthors = Price PA, Faus SA, Williamson MK | title = Warfarin-induced artery calcification is accelerated by growth and vitamin D | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 20 | issue = 2 | pages = 317–327 | date = February 2000 | pmid = 10669626 | doi = 10.1161/01.ATV.20.2.317 | doi-access = free }}{{cite journal | vauthors = Geleijnse JM, Vermeer C, Grobbee DE, Schurgers LJ, Knapen MH, van der Meer IM, Hofman A, Witteman JC | title = Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: the Rotterdam Study | journal = The Journal of Nutrition | volume = 134 | issue = 11 | pages = 3100–3105 | date = November 2004 | pmid = 15514282 | doi = 10.1093/jn/134.11.3100 | hdl-access = free | doi-access = free | hdl = 1765/10366 }}{{cite web |url=http://lpi.oregonstate.edu/infocenter/vitamins/vitaminK/ |title=Vitamin K |publisher=Linus Pauling Institute at Oregon State University |access-date=2010-03-25 | archive-url= https://web.archive.org/web/20100407093811/http://lpi.oregonstate.edu/infocenter/vitamins/vitaminK/| archive-date= 7 April 2010 | url-status= live}}{{excessive citations inline|date=October 2021}} Also, small molecules such as 3-hydroxybenzaldehyde and protocatechuic aldehyde have shown vasculoprotective effects to reduce risk of atherosclerosis.{{cite journal | vauthors = Kong BS, Cho YH, Lee EJ | title = G protein-coupled estrogen receptor-1 is involved in the protective effect of protocatechuic aldehyde against endothelial dysfunction | journal = PLOS ONE | volume = 9 | issue = 11 | pages = e113242 | date = 2014 | pmid = 25411835 | pmc = 4239058 | doi = 10.1371/journal.pone.0113242 | doi-access = free | bibcode = 2014PLoSO...9k3242K }}{{cite journal | vauthors = Kong BS, Im SJ, Lee YJ, Cho YH, Do YR, Byun JW, Ku CR, Lee EJ | title = Vasculoprotective Effects of 3-Hydroxybenzaldehyde against VSMCs Proliferation and ECs Inflammation | journal = PLOS ONE | volume = 11 | issue = 3 | pages = e0149394 | date = 2016 | pmid = 27002821 | pmc = 4803227 | doi = 10.1371/journal.pone.0149394 | doi-access = free | bibcode = 2016PLoSO..1149394K }}

Cardiovascular disease, which is predominantly the clinical manifestation of atherosclerosis, is one of the leading causes of death worldwide.{{Cite web|url=https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death|title=The top 10 causes of death|website=www.who.int|language=en|access-date=2020-01-26}}

Almost all children older than age 10 in developed countries have aortic fatty streaks, with coronary fatty streaks beginning in adolescence.Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson; & Mitchell, Richard N. (2007). Robbins Basic Pathology (8th ed.). Saunders Elsevier. pp. 348-351 {{ISBN|978-1-4160-2973-1}}{{cite journal | vauthors = Strong JP, McGill HC | title = The pediatric aspects of atherosclerosis | journal = Journal of Atherosclerosis Research | volume = 9 | issue = 3 | pages = 251–265 | date = 1969-05-06 | pmid = 5346899 | doi = 10.1016/S0368-1319(69)80020-7 }}{{cite journal | vauthors = Zieske AW, Malcom GT, Strong JP | title = Natural history and risk factors of atherosclerosis in children and youth: the PDAY study | journal = Pediatric Pathology & Molecular Medicine | volume = 21 | issue = 2 | pages = 213–237 | date = January 2002 | pmid = 11942537 | doi = 10.1080/pdp.21.2.213.237 }}

In 1953, a study was published that examined the results of 300 autopsies performed on U.S. soldiers who had died in the Korean War. Despite the average age of the soldiers being just 22 years old, 77% of them had visible signs of coronary atherosclerosis. This study showed that heart disease could affect people at a younger age and was not just a problem for older individuals.{{cite journal | vauthors = Enos WF, Holmes RH, Beyer J | title = Coronary disease among United States soldiers killed in action in Korea; preliminary report | journal = Journal of the American Medical Association | volume = 152 | issue = 12 | pages = 1090–1093 | date = July 1953 | pmid = 13052433 | doi = 10.1001/jama.1953.03690120006002 }}{{Cite web |title=Stopping Heart Disease in Childhood |url=https://nutritionfacts.org/2014/07/15/stopping-heart-disease-in-childhood/ |access-date=2022-12-08 |website=NutritionFacts.org |date=15 July 2014 |language=en-US}}{{cite book | vauthors = Wilson DP |title=Endotext |date=2000 |publisher=MDText.com, Inc. |chapter-url=http://www.ncbi.nlm.nih.gov/books/NBK395576/ |chapter=Is Atherosclerosis a Pediatric Disease? |pmid=27809437 }}

In 1992, a report showed that microscopic fatty streaks were seen in the left anterior descending artery in over 50% of children aged 10–14 and 8% had even more advanced lesions with more accumulations of extracellular lipid.{{cite journal | vauthors = Strong JP, Malcom GT, Newman WP, Oalmann MC | title = Early lesions of atherosclerosis in childhood and youth: natural history and risk factors | journal = Journal of the American College of Nutrition | volume = 11 | issue = sup1 | pages = 51S–54S | date = June 1992 | pmid = 1619200 | doi = 10.1080/07315724.1992.10737984 }}

A 2005 report of a study done between 1985 and 1995 found that around 87% of aortas and 30% of coronary arteries in the age group 5–14 years had fatty streaks which increased with age.{{cite journal | vauthors = Mendis S, Nordet P, Fernandez-Britto JE, Sternby N |title=Atherosclerosis in children and young adults: An overview of the World Health Organization and International Society and Federation of Cardiology study on Pathobiological Determinants of Atherosclerosis in Youth study (1985–1995) |journal=Global Heart |date=March 2005 |volume=1 |issue=1 |pages=3 |doi=10.1016/j.precon.2005.02.010 |doi-access=free }}

The following terms are similar, yet distinct, in both spelling and meaning, and can be easily confused: arteriosclerosis, arteriolosclerosis, and atherosclerosis. Arteriosclerosis is a general term describing any hardening (and loss of elasticity) of medium or large arteries ({{ety|gre|ἀρτηρία (artēria)|artery||σκλήρωσις (sklerosis)|hardening}}); arteriolosclerosis is any hardening (and loss of elasticity) of arterioles (small arteries); atherosclerosis is a hardening of an artery specifically due to an atheromatous plaque ({{ety|grc| ἀθήρα (athḗra)|gruel}}). The term atherogenic is used for substances or processes that cause the formation of atheroma.{{cite web | title = Atherogenic | url = https://www.merriam-webster.com/dictionary/atherogenic | work = Merriam-Webster Dictionary }}

In 2011, coronary atherosclerosis was one of the top ten most expensive conditions seen during inpatient hospitalizations in the US, with aggregate inpatient hospital costs of $10.4 billion.{{cite journal | title = Costs for Hospital Stays in the United States, 2011. | journal = HCUP Statistical Brief | issue = 168 | date = December 2013 | pmid = 24455786 | url = http://hcup-us.ahrq.gov/reports/statbriefs/sb168-Hospital-Costs-United-States-2011.jsp | publisher = Agency for Healthcare Research and Quality | vauthors = Pfuntner A, Wier LM, Steiner C }}

An indication of the role of high-density lipoprotein (HDL) on atherosclerosis has been with the rare Apo-A1 Milano human genetic variant of this HDL protein. A small short-term trial using bacterial synthesized human Apo-A1 Milano HDL in people with unstable angina produced a fairly dramatic reduction in measured coronary plaque volume in only six weeks vs. the usual increase in plaque volume in those randomized to placebo. The trial was published in JAMA in early 2006.{{Citation needed|date=February 2018}} Ongoing work starting in the 1990s may lead to human clinical trials—probably by about 2008.{{update inline|date=June 2014}} These may use synthesized Apo-A1 Milano HDL directly, or they may use gene-transfer methods to pass the ability to synthesize the Apo-A1 Milano HDLipoprotein.{{Citation needed|date=February 2018}}

Methods to increase HDL particle concentrations, which in some animal studies largely reverses and removes atheromas, are being developed and researched.{{Citation needed|date=February 2018}} However, increasing HDL by any means is not necessarily helpful. For example, the drug torcetrapib is the most effective agent currently known for raising HDL (by up to 60%). However, in clinical trials, it also raised deaths by 60%. All studies regarding this drug were halted in December 2006.{{cite journal | vauthors = Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JJ, Komajda M, Lopez-Sendon J, Mosca L, Tardif JC, Waters DD, Shear CL, Revkin JH, Buhr KA, Fisher MR, Tall AR, Brewer B | title = Effects of torcetrapib in patients at high risk for coronary events | journal = The New England Journal of Medicine | volume = 357 | issue = 21 | pages = 2109–2122 | date = November 2007 | pmid = 17984165 | doi = 10.1056/NEJMoa0706628 | doi-access = free }}

The actions of macrophages drive atherosclerotic plaque progression.

Immunomodulation of atherosclerosis is the term for techniques that modulate immune system function to suppress this macrophage action.{{cite journal | vauthors = Nilsson J, Hansson GK, Shah PK | title = Immunomodulation of atherosclerosis: implications for vaccine development | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 25 | issue = 1 | pages = 18–28 | date = January 2005 | pmid = 15514204 | doi = 10.1161/01.ATV.0000149142.42590.a2 | doi-access = free }}

Involvement of lipid peroxidation chain reaction in atherogenesis{{cite journal | vauthors = Spiteller G | title = The relation of lipid peroxidation processes with atherogenesis: a new theory on atherogenesis | journal = Molecular Nutrition & Food Research | volume = 49 | issue = 11 | pages = 999–1013 | date = November 2005 | pmid = 16270286 | doi = 10.1002/mnfr.200500055 }} triggered research on the protective role of the heavy isotope (deuterated) polyunsaturated fatty acids (D-PUFAs) that are less prone to oxidation than ordinary PUFAs (H-PUFAs). PUFAs are essential nutrients – they are involved in metabolism in that very form as they are consumed with food. In transgenic mice, a model for human-like lipoprotein metabolism, adding D-PUFAs to the diet reduced body weight gain, improved cholesterol handling, and reduced atherosclerotic damage to the aorta.{{cite journal | vauthors = Berbée JF, Mol IM, Milne GL, Pollock E, Hoeke G, Lütjohann D, Monaco C, Rensen PC, van der Ploeg LH, Shchepinov MS | title = Deuterium-reinforced polyunsaturated fatty acids protect against atherosclerosis by lowering lipid peroxidation and hypercholesterolemia | journal = Atherosclerosis | volume = 264 | pages = 100–107 | date = September 2017 | pmid = 28655430 | doi = 10.1016/j.atherosclerosis.2017.06.916 }}{{cite journal | vauthors = Tsikas D | title = Combating atherosclerosis with heavy PUFAs: Deuteron not proton is the first | journal = Atherosclerosis | volume = 264 | pages = 79–82 | date = September 2017 | pmid = 28756876 | doi = 10.1016/j.atherosclerosis.2017.07.018 }}

MicroRNAs (miRNAs) have complementary sequences in the 3' UTR and 5' UTR of target mRNAs of protein-coding genes, and cause mRNA cleavage or repression of translational machinery. In diseased vascular vessels, miRNAs are dysregulated and highly expressed. miR-33 is found in cardiovascular diseases.{{cite journal | vauthors = Chen WJ, Yin K, Zhao GJ, Fu YC, Tang CK | title = The magic and mystery of microRNA-27 in atherosclerosis | journal = Atherosclerosis | volume = 222 | issue = 2 | pages = 314–323 | date = June 2012 | pmid = 22307089 | doi = 10.1016/j.atherosclerosis.2012.01.020 }} It is involved in atherosclerotic initiation and progression including lipid metabolism, insulin signaling and glucose homeostatis, cell type progression and proliferation, and myeloid cell differentiation. It was found in rodents that the inhibition of miR-33 will raise HDL-C levels and the expression of miR-33 is down-regulated in humans with atherosclerotic plaques.{{cite journal | vauthors = Sacco J, Adeli K | title = MicroRNAs: emerging roles in lipid and lipoprotein metabolism | journal = Current Opinion in Lipidology | volume = 23 | issue = 3 | pages = 220–225 | date = June 2012 | pmid = 22488426 | doi = 10.1097/MOL.0b013e3283534c9f }}{{cite journal | vauthors = Bommer GT, MacDougald OA | title = Regulation of lipid homeostasis by the bifunctional SREBF2-miR33a locus | journal = Cell Metabolism | volume = 13 | issue = 3 | pages = 241–247 | date = March 2011 | pmid = 21356514 | pmc = 3062104 | doi = 10.1016/j.cmet.2011.02.004 }}{{cite journal | vauthors = Rayner KJ, Sheedy FJ, Esau CC, Hussain FN, Temel RE, Parathath S, van Gils JM, Rayner AJ, Chang AN, Suarez Y, Fernandez-Hernando C, Fisher EA, Moore KJ | title = Antagonism of miR-33 in mice promotes reverse cholesterol transport and regression of atherosclerosis | journal = The Journal of Clinical Investigation | volume = 121 | issue = 7 | pages = 2921–2931 | date = July 2011 | pmid = 21646721 | pmc = 3223840 | doi = 10.1172/JCI57275 }}

miR-33a and miR-33b are located on intron 16 of human sterol regulatory element-binding protein 2 (SREBP2) gene on chromosome 22 and intron 17 of SREBP1 gene on chromosome 17.{{cite journal | vauthors = Iwakiri Y | title = A role of miR-33 for cell cycle progression and cell proliferation | journal = Cell Cycle | volume = 11 | issue = 6 | pages = 1057–1058 | date = March 2012 | pmid = 22395363 | doi = 10.4161/cc.11.6.19744 | doi-access = free }} miR-33a/b regulates cholesterol/lipid homeostasis by binding in the 3'UTRs of genes involved in cholesterol transport such as ATP binding cassette (ABC) transporters and enhance or represses its expression. Studies have shown that ABCA1 mediates cholesterol transport from peripheral tissues to Apolipoprotein-1. It is also important in the reverse cholesterol transport pathway, where cholesterol is delivered from peripheral tissue to the liver, where it can be excreted into bile or converted to bile acids before excretion. Therefore, ABCA1 prevents cholesterol accumulation in macrophages. By enhancing miR-33 function, the level of ABCA1 is decreased, leading to decreased cellular cholesterol efflux to apoA-1. On the other hand, by inhibiting miR-33 function, the level of ABCA1 is increased and increases the cholesterol efflux to apoA-1. Suppression of miR-33 will lead to less cellular cholesterol and higher plasma HDL level through the regulation of ABCA1 expression.{{cite journal | vauthors = Singaraja RR, Stahmer B, Brundert M, Merkel M, Heeren J, Bissada N, Kang M, Timmins JM, Ramakrishnan R, Parks JS, Hayden MR, Rinninger F | title = Hepatic ATP-binding cassette transporter A1 is a key molecule in high-density lipoprotein cholesteryl ester metabolism in mice | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 26 | issue = 8 | pages = 1821–1827 | date = August 2006 | pmid = 16728652 | doi = 10.1161/01.ATV.0000229219.13757.a2 | doi-access = free }}

Aging is the most important risk factor for cardiovascular problems. The causative basis by which aging mediates its impact, independently of other recognized risk factors, remains to be determined. Evidence has been reviewed for a key role of DNA damage in vascular aging.{{cite journal | vauthors = Wu H, Roks AJ | title = Genomic instability and vascular aging: a focus on nucleotide excision repair | journal = Trends in Cardiovascular Medicine | volume = 24 | issue = 2 | pages = 61–68 | date = February 2014 | pmid = 23953979 | doi = 10.1016/j.tcm.2013.06.005 }}{{cite journal | vauthors = Bautista-Niño PK, Portilla-Fernandez E, Vaughan DE, Danser AH, Roks AJ | title = DNA Damage: A Main Determinant of Vascular Aging | journal = International Journal of Molecular Sciences | volume = 17 | issue = 5 | pages = 748 | date = May 2016 | pmid = 27213333 | pmc = 4881569 | doi = 10.3390/ijms17050748 | doi-access = free }}{{cite journal | vauthors = Shah AV, Bennett MR | title = DNA damage-dependent mechanisms of ageing and disease in the macro- and microvasculature | journal = European Journal of Pharmacology | volume = 816 | pages = 116–128 | date = December 2017 | pmid = 28347738 | doi = 10.1016/j.ejphar.2017.03.050 | url = https://www.repository.cam.ac.uk/handle/1810/264776 }}

8-oxoG, a common type of oxidative damage in DNA, is found to accumulate in plaque vascular smooth muscle cells, macrophages and endothelial cells,{{cite journal | vauthors = Martinet W, Knaapen MW, De Meyer GR, Herman AG, Kockx MM | title = Elevated levels of oxidative DNA damage and DNA repair enzymes in human atherosclerotic plaques | journal = Circulation | volume = 106 | issue = 8 | pages = 927–932 | date = August 2002 | pmid = 12186795 | doi = 10.1161/01.cir.0000026393.47805.21 | doi-access = free }} thus linking DNA damage to plaque formation. DNA strand breaks also increased in atherosclerotic plaques. Werner syndrome (WS) is a premature aging condition in humans.{{cite journal | vauthors = Ishida T, Ishida M, Tashiro S, Yoshizumi M, Kihara Y | title = Role of DNA damage in cardiovascular disease | journal = Circulation Journal | volume = 78 | issue = 1 | pages = 42–50 | year = 2014 | pmid = 24334614 | doi = 10.1253/circj.CJ-13-1194 | doi-access = free }} WS is caused by a genetic defect in a RecQ helicase that is employed in several repair processes that remove damages from DNA. WS patients develop a considerable burden of atherosclerotic plaques in their coronary arteries and aorta: calcification of the aortic valve is also frequently observed. These findings link excessive unrepaired DNA damage to premature aging and early atherosclerotic plaque development (see DNA damage theory of aging).{{citation needed|date=December 2020}}

The microbiota – all the microorganisms in the body, can contribute to atherosclerosis in many ways: modulation of the immune system, changes in metabolism, processing of nutrients and production of certain metabolites that can get into blood circulation.{{cite journal | vauthors = Barrington WT, Lusis AJ | title = Atherosclerosis: Association between the gut microbiome and atherosclerosis | journal = Nature Reviews. Cardiology | volume = 14 | issue = 12 | pages = 699–700 | date = December 2017 | pmid = 29099096 | pmc = 5815826 | doi = 10.1038/nrcardio.2017.169 }} One such metabolite, produced by gut bacteria, is trimethylamine N-oxide (TMAO). Its levels have been associated with atherosclerosis in human studies and animal research suggests that there may be a causal relation. An association between the bacterial genes encoding trimethylamine lyases — the enzymes involved in TMAO generation — and atherosclerosis has been noted.{{cite journal | vauthors = Jie Z, Xia H, Zhong SL, Feng Q, Li S, Liang S, Zhong H, Liu Z, Gao Y, Zhao H, Zhang D, Su Z, Fang Z, Lan Z, Li J, Xiao L, Li J, Li R, Li X, Li F, Ren H, Huang Y, Peng Y, Li G, Wen B, Dong B, Chen JY, Geng QS, Zhang ZW, Yang H, Wang J, Wang J, Zhang X, Madsen L, Brix S, Ning G, Xu X, Liu X, Hou Y, Jia H, He K, Kristiansen K | title = The gut microbiome in atherosclerotic cardiovascular disease | journal = Nature Communications | volume = 8 | issue = 1 | pages = 845 | date = October 2017 | pmid = 29018189 | pmc = 5635030 | doi = 10.1038/s41467-017-00900-1 | bibcode = 2017NatCo...8..845J }}

Vascular smooth muscle cells play a key role in atherogenesis and were historically considered to be beneficial for plaque stability by forming a protective fibrous cap and synthesizing strength-giving extracellular matrix components.{{cite journal | vauthors = Harman JL, Jørgensen HF | title = The role of smooth muscle cells in plaque stability: Therapeutic targeting potential | journal = British Journal of Pharmacology | volume = 176 | issue = 19 | pages = 3741–3753 | date = October 2019 | pmid = 31254285 | pmc = 6780045 | doi = 10.1111/bph.14779 }}{{cite journal | vauthors = Bennett MR, Sinha S, Owens GK | title = Vascular Smooth Muscle Cells in Atherosclerosis | journal = Circulation Research | volume = 118 | issue = 4 | pages = 692–702 | date = February 2016 | pmid = 26892967 | pmc = 4762053 | doi = 10.1161/CIRCRESAHA.115.306361 }} However, in addition to the fibrous cap, vascular smooth muscle cells also give rise to many of the cell types found within the plaque core and can modulate their phenotype to both promote and reduce plaque stability.{{cite journal | vauthors = Gomez D, Shankman LS, Nguyen AT, Owens GK | title = Detection of histone modifications at specific gene loci in single cells in histological sections | journal = Nature Methods | volume = 10 | issue = 2 | pages = 171–177 | date = February 2013 | pmid = 23314172 | pmc = 3560316 | doi = 10.1038/nmeth.2332 }}{{cite journal | vauthors = Wang Y, Dubland JA, Allahverdian S, Asonye E, Sahin B, Jaw JE, Sin DD, Seidman MA, Leeper NJ, Francis GA | title = Smooth Muscle Cells Contribute the Majority of Foam Cells in ApoE (Apolipoprotein E)-Deficient Mouse Atherosclerosis | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 39 | issue = 5 | pages = 876–887 | date = May 2019 | pmid = 30786740 | pmc = 6482082 | doi = 10.1161/ATVBAHA.119.312434 }}{{cite journal | vauthors = Chappell J, Harman JL, Narasimhan VM, Yu H, Foote K, Simons BD, Bennett MR, Jørgensen HF | title = Extensive Proliferation of a Subset of Differentiated, yet Plastic, Medial Vascular Smooth Muscle Cells Contributes to Neointimal Formation in Mouse Injury and Atherosclerosis Models | journal = Circulation Research | volume = 119 | issue = 12 | pages = 1313–1323 | date = December 2016 | pmid = 27682618 | pmc = 5149073 | doi = 10.1161/CIRCRESAHA.116.309799 }} Vascular smooth muscle cells exhibit pronounced plasticity within atherosclerotic plaque and can modify their gene expression profile to resemble various other cell types, including macrophages, myofibroblasts, mesenchymal stem cells and osteochondrocytes.{{cite journal | vauthors = Durham AL, Speer MY, Scatena M, Giachelli CM, Shanahan CM | title = Role of smooth muscle cells in vascular calcification: implications in atherosclerosis and arterial stiffness | journal = Cardiovascular Research | volume = 114 | issue = 4 | pages = 590–600 | date = March 2018 | pmid = 29514202 | pmc = 5852633 | doi = 10.1093/cvr/cvy010 }}{{cite journal | vauthors = Basatemur GL, Jørgensen HF, Clarke MC, Bennett MR, Mallat Z | title = Vascular smooth muscle cells in atherosclerosis | journal = Nature Reviews. Cardiology | volume = 16 | issue = 12 | pages = 727–744 | date = December 2019 | pmid = 31243391 | doi = 10.1038/s41569-019-0227-9 | url = https://www.repository.cam.ac.uk/handle/1810/294564 }} Importantly, genetic lineage-tracing experiments have unequivocally shown that 40-90% of plaque-resident cells are vascular smooth muscle cell-derived, therefore, it is important to research the role of vascular smooth muscle cells in atherosclerosis to identify new therapeutic targets.

The sugar cyclodextrin (CD) removed cholesterol that had built up in the arteries of mice fed a high-fat diet. CD is absorbed into the mouse bloodstream. It increases the production of oxysterols in macrophages and plaques, which causes the activation of LXR in macrophages. This in turn causes the macrophages more capable of cholesterol efflux and makes them more anti-inflammatory.{{cite journal | vauthors = Zimmer S, Grebe A, Bakke SS, Bode N, Halvorsen B, Ulas T, Skjelland M, De Nardo D, Labzin LI, Kerksiek A, Hempel C, Heneka MT, Hawxhurst V, Fitzgerald ML, Trebicka J, Björkhem I, Gustafsson JÅ, Westerterp M, Tall AR, Wright SD, Espevik T, Schultze JL, Nickenig G, Lütjohann D, Latz E | title = Cyclodextrin promotes atherosclerosis regression via macrophage reprogramming | journal = Science Translational Medicine | volume = 8 | issue = 333 | pages = 333ra50 | date = April 2016 | pmid = 27053774 | pmc = 4878149 | doi = 10.1126/scitranslmed.aad6100 }}

• {{lay source |template=cite news|vauthors = Hesman Saey T|url= https://www.sciencenews.org/article/sugar-can-melt-away-cholesterol|title = A sugar can melt away cholesterol|date = April 8, 2016|website = Science News.org }}

{{notelist}}

{{reflist}}

{{commons category|Atherosclerosis}}

• {{wikiquote-inline}}
• [https://pharmacytheory.com/pathophysiology-of-atherosclerosis-types-stages Atherosclerosis] {{Webarchive|url=https://web.archive.org/web/20220122202410/https://pharmacytheory.com/pathophysiology-of-atherosclerosis-types-stages/ |date=2022-01-22 }} pathophysiology-stages and types

{{Medical condition classification and resources

| DiseasesDB = 1039

| ICD10 = {{ICD10|I25.0}},{{ICD10|I25.1}},{{ICD10|I70}}

| ICD9 = {{ICD9|440}}, {{ICD9|414.0}}

| MedlinePlus = 000171

| eMedicineSubj = med

| eMedicineTopic = 182

| MeshID = D050197

| Scholia = Q12252367

}}

{{Vascular diseases}}

{{Authority control}}

Category:Diseases of arteries, arterioles and capillaries

Category:Vascular diseases

Category:Medical conditions related to obesity

Category:Inflammations

Category:Wikipedia medicine articles ready to translate