Atherosclerosis PDF

Atherosclerosis Dr. Aleksandrs Vasiļjevs  Endothelium As the major regulator of vascular homeostasis, the endothelium exerts a number of vasoprotective effes, sctuch as vasodilation, suppression of smooth muscle cell growth, and inhibition of inflammatory responses. Many of these effec...

Atherosclerosis Dr. Aleksandrs Vasiļjevs  Endothelium As the major regulator of vascular homeostasis, the endothelium exerts a number of vasoprotective effes, sctuch as vasodilation, suppression of smooth muscle cell growth, and inhibition of inflammatory responses. Many of these effects are largely mediated by nitric oxide, the most potent endogenous vasodilator. Nitric oxide opposes the effects of endothelium-derived vasoconstrictors and inhibits oxidation of low-density lipoprotein. Circulation Volume 109, Issue 23_suppl_1, 15 June 2004; Pages III-27-III-32 https://doi.org/10.1161/01.CIR.0000131515.03336.f8 Jean Davignon, MD and Peter Ganz, MD  A defect in the production or activity of nitric oxide leads to endothelial dysfunction, signaled by impaired endothelium-dependent vasodilation. Many of the risk factors that predispose to atherosclerosis can also cause endothelial dysfunction, and the presence of multiple risk factors has been found to predict endothelial dysfunction. A number of clinical trials have shown that 3-hydroxy- 3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) improve endothelial dysfunction in patients with coronary risk factors beyond what could be attributed to their impact on plasma lipids. Endothelium functions Although only a simple monolayer, the healthy endothelium is optimally placed and is able to respond to physical and chemical signals by production of a wide range of factors that regulate vascular tone, cellular adhesion, thromboresistance, smooth muscle cell proliferation, and vessel wall inflammation. CirculationVolume 115, Issue 10, 13 March 2007; Pages 1285- 1295 https://doi.org/10.1161/CIRCULATIONAHA.106.652859 John E. Deanfield, MB, BCh, FRCP, Julian P. Halcox, MD, MA, MRCP, and Ton J. Rabelink, MD, PhD  This is achieved by production and release of several vasoactive molecules that relax or constrict the vessel, as well as by response to and modification of circulating vasoactive mediators such as bradykinin and thrombin. This vasomotion plays a direct role in the balance of tissue oxygen supply and metabolic demand by regulation of vessel tone and diameter and is also involved in the remodeling of vascular structure and long-term organ perfusion. The endothelium modulates vasomotion, not only by release of vasodilator substances, but also by an increase in constrictor tone via generation of endothelin and vasoconstrictor prostanoids, as well as via conversion of angiotensin I to angiotensin II at the endothelial surface.  ENDOTHELIAL ACTIVATION AND ATHEROSCLEROSIS What is generally referred to as endothelial dysfunction should more appropriately be considered as endothelial activation, which may eventually contribute to arterial disease when certain conditions are fulfilled. CirculationVolume 115, Issue 10, 13 March 2007; Pages 1285- 1295 https://doi.org/10.1161/CIRCULATIONAHA.106.652859 John E. Deanfield, MB, BCh, FRCP, Julian P. Halcox, MD, MA, MRCP, and Ton J. Rabelink, MD, PhD  Endothelial activation represents a switch from a quiescent phenotype toward one that involves the host defense response. Indeed, most cardiovascular risk factors activate molecular machinery in the endothelium that results in expression of chemokines, cytokines, and adhesion molecules designed to interact with leukocytes and platelets and target inflammation to specific tissues to clear microorganisms.  ENDOTHELIAL INJURY AND REPAIR Prolonged and/or repeated exposure to cardiovascular risk factors can ultimately exhaust the protective effect of endogenous anti- inflammatory systems within endothelial cells. As a consequence, the endothelium not only becomes dysfunctional, but endothelial cells can also lose integrity, progress to senescence, and detach into the circulation CirculationVolume 115, Issue 10, 13 March 2007; Pages 1285-1295 https://doi.org/10.1161/CIRCULATIONAHA.106.652859 John E. Deanfield, MB, BCh, FRCP, Julian P. Halcox, MD, MA, MRCP, and Ton J. Rabelink, MD, PhD  Endothelial integrity depends not only on the extent of injury, but also on the endogenous capacity for repair. Adjacent mature endothelial cells can replicate locally and replace the lost and damaged cells. Circulating endothelial progenitor cells are an alternative mechanism for maintenance and repair of the endothelium. These cells are recruited from the bone marrow, circulate in the peripheral blood, and can differentiate into mature cells with endothelial characteristics.  Arterio-sclerosis General term: “arterial hardening” Changes in arterial walls leading to loss of elasticity Main types: Atherosclerosis Monckeberg medial calcific sclerosis Arteriolosclerosis  Medial calcific sclerosis Calcifications in the walls of muscular arteries, mainly in aged people (older than 50 years) Can be palpable Can be seen radiologically Do not narrow the vascular lumen Arteriolosclerosis Affects the small arteries and arterioles Types: Hyaline Hyperplastic Related to arterial hypertension and the development of delayed complications of diabetes mellitus  Atherosclerosis Clinically significant Represented by intimal damage and formation of atherosclerotic plaques that narrow the vascular lumen; influence haemodynamics / blood flow; weaken the tunica media.  Definition: Chronic inflammatory condition that can be converted into an acute clinical event by plaque rupture and thrombosis. Atherosclerosis, a disease of the large arteries, is the primary cause of heart disease and stroke. In westernized societies, it is the underlying cause of about 50% of all deaths. Published in final edited form as: Nature. 2000 September 14; 407(6801): 233–241. doi:10.1038/35025203. Aldons J. Lusis The most frequent location of atherosclerotic plaques Elastic arteries: aorta, a. carotis, a. iliaca Large and medium – sized muscular arteries: coronary arteries of the heart, arteries supplying the leg or abdominal organs High-pressure arteries Branching points of the arteries The target organs Heart Brain Kidney Leg Intestines The damage of internal organs can develop either slowly or rapidly Coronary heart disease 90% of myocardial ischemia is due to atherosclerosis of coronary arteries Ischemia – dysbalance between the supply of oxygenated blood and the metabolic demands of the tissue Ischemia is more dangerous than hypoxemia as the lack of oxygen is associated with suppresion of metabolism and accumulation of waste products The pathogenesis of coronary heart disease General factor – decreased blood perfusion in coronary arteries The components of pathogenesis: Atherosclerosis Thrombosis Aggregation of thrombocytes Vasospasm Endothelium Thrombocytes Erythrocytes Thrombus Lipid core Fibrous cap Formation of thrombus on ruptured Atherosclerotic plaque atherosclerotic plaque Dr.Vasiļjevs Photo – I.Strumfa Stenosis Stenosis Stenosis Stenosis Dr.Vasiļjevs  Thrombus Thrombus Dr.Vasiļjevs Total occlusion prior and Dr.Vasiļjevs post PCI  To sum up Atherosclerosis nowadays seen as chronic inflammation reaction caused by endothelial activation. Important role of risk factors as hypertension, diabetes myelitis, smoking, hyperlipidemia especially LDL.  Atherosclerosis usually develops clinically silently till blood vessels have a severe stenosis or acute thrombosis/embolization happens. Atherosclerosis is a diffuse process, so if patient has a peripheral artery disease, consider checking other blood vessels ( coronary, brachiocephalic) and vice versa. It is important to control risk factors, to stabilize atherosclerotic plaque – reducing lipid core, increasing fibrin around to prevent rupture of a plaque and acute situation. Causes: Modifiable Nonmodifiable Hyperlipidemia (Constitutional) Hypertension Genetic abnormalities Cigarette Family history smoking Increasing age Diabetes Male gender Inflammation Richard N. Mitchell and Marc K. Halushka Robbins & Cotran Pathologic Basis of Disease, Chapter 11, 485-525 Studies shows that modifiable factors has higher impact on the cardio-vascular health! Lifestyle, not genetics, explains most premature heart disease. Physical inactivity, smoking, high blood pressure, diabetes, and high cholesterol play a greater role than genetics in many young patients with heart disease, according to research presented today at ESC Congress 2019 together with the World Congress of Cardiology. https://www.escardio.org/The-ESC/Press-Office/Press- releases/lifestyle-not-genetics-explains-most-premature- heart-disease  The findings show that healthy behaviours should be a top priority for reducing heart disease even in those with a family history of early onset. “Genetics are an important contributor to premature heart disease but should not be used as an excuse to say it is inevitable,” said study author Dr João A. Sousa of Funchal Hospital, Portugal. The study enrolled 1,075 patients under 50, of whom 555 had coronary artery disease (known as premature CAD). Specific conditions included stable angina, heart attack, and unstable angina. The average age was 45 and 87% were men. Risk factor levels and genetics in patients were compared to a control group of 520 healthy volunteers (average age 44, and 86% men). Patients and controls were recruited from the Genes in Madeira and Coronary Disease (GENEMACOR) database. Risk factors and risk classification The main causal and modifiable ASCVD risk factors are bloodapolipoprotein-B-containing lipoproteins [of which low-density lipoprotein (LDL) is most abundant], high BP, cigarette smoking, and DM. Another important risk factor is adiposity, which increases CVD risk via both major conventional risk factors and other mechanisms. Air pollution. 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice. https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines/2021- ESC-Guidelines-on-cardiovascular-disease-prevention-in-clinical-practice Modifiable Major Risk Factors Hyperlipidemia —and more specifically hypercholesterolemia—is a major risk factor for atherosclerosis; even in the absence of other risk factors, hypercholesterolemia is sufficient to initiate lesion development. The major component of serum cholesterol associated with increased risk is LDL cholesterol (“bad cholesterol”). Richard N. Mitchell and Marc K. Halushka Robbins & Cotran Pathologic Basis of Disease, Chapter 11, 485-525  Hypertension can increase the risk of ischemic heart disease by approximately 60% versus normotensive populations. Cigarette smoking , and in particular prolonged (years) use, doubles the death rate from ischemic heart disease. Diabetes mellitus induces hypercholesterolemia and markedly increases the risk of atherosclerosis. Other factors being equal, the incidence of myocardial infarction is twice as high in diabetics relative to normoglycemic individuals. Inflammation. Inflammation is present during all stages of atherogenesis and is intimately linked with atherosclerotic plaque formation and rupture.  Cholesterol The causal role of LDL-C, and other apo-B- containing lipoproteins,in the development of ASCVD is demonstrated beyond any doubt by genetic, observational, and interventional studies. The key attributes of LDL-C as a risk factor for ASCVD are: 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice. https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines/2021-ESC- Guidelines-on-cardiovascular-disease-prevention-in-clinical-practice  Prolonged lower LDL-C is associated with lower risk of ASCVD throughout the range studied, and the results of randomized controlled trials (RCTs) indicate that lowering LDL-C safely reduces CVD risk even at low LDL-C levels [e.g. LDL-C