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  1. Atherosclerosis Sophie Tatishvili
  2. Mechanisms of Inflammation in Atherogenesis • A fundamental role for inflammation in atherogenesis; – The macrophage foam cells recruited to the artery wall early in this process serve as a reservoir for excess lipid. In the established atherosclerotic lesion, these cells also provide a rich source of proinflammatory mediators—proteins such as cytokines and chemokines and various eicosanoids and lipids such as platelet-activating factor. Brawnwald Heart Diseases. 10th. edition
  3. Representation of formation of foam cells and initiation of atherogenesis LDL particles enter arterial wall through endothelium; monocytes are recruited and once in the wall, differentiate into macrophages. These macrophages will capture LDL particles and the result will be foam cells Published in Healthcare Technology Letters; Received on 4th December 2013; Revised on 10th February 2014; Accepted on 11th February 2014
  4. The endothelial thrombotic balance. This diagram depicts the anticoagulant profibrinolytic functions of the endothelial cell (left) and certain procoagulant and antifibrinolytic functions (right). PAi = plasminogen activator inhibitor; PGI2 = prostacyclin; t-PA = tissue type plasminogen activator; vWf = von Willebrand factor.
  5. Mechanisms of Inflammation in Atherogenesis Innate and adaptive immunity in atherosclerosis. A diagram of the pathways of innate (left) and adaptive (right) immunity operating during atherogenesis. MF = macrophage, IFN-g = interferon gamma, Th = T helper. (Adapted from Hansson G, Libby P, Schoenbeck U, Yan Z-Q: Innate and adaptive immunity in the pathogenesis of atherosclerosis. Circ Res 91:281-291, 2002.)
  6. Schematic of the evolution of the atherosclerotic plaque 1, Accumulation of lipoprotein particles in the intima. The modification of these lipoproteins is depicted by the darker color. Modifications include oxidation and glycation. 2, Oxidative stress including products found in modified lipoproteins can induce local cytokine elaboration. 3, The cytokines thus induced increase expression of adhesion molecules for leukocytes that cause their attachment and chemoattractant molecules that direct their migration into the intima. 4, Blood monocytes, on entering the artery wall in response to chemoattractant cytokines such as monocyte chemoattractant protein 1 (MCP-1), encounter stimuli such as macrophage colony-stimulating factor (M-CSF) that can augment their expression of scavenger receptors. 5, Scavenger receptors mediate the uptake of modified lipoprotein particles and promote the development of foam cells. Macrophage foam cells are a source of mediators such as more cytokines and effector molecules such as hypochlorous acid, superoxide anion (O2 -), and matrix metalloproteinases. 6, SMCs in the intima divide, other SMCs migrate into the intima from the media. 7, SMCs can then divide and elaborate extracellular matrix promoting extracellular matrix accumulation in the growing atherosclerotic plaque. In this manner, the fatty streak can evolve into a fibro-fatty lesion. 8, In later stages, calcification can occur (not depicted), and fibrosis continues, sometimes accompanied by SMC death (including programmed cell death, or apoptosis) yielding a relatively acellular fibrous capsule surrounding a lipid-rich core that may also contain dying or dead cells and their detritus. IL-1 = interleukin- 1; LDL = low-density lipoprotein, SMCs = smooth muscle cells
  7. ANTIOXIDANTS & REDOX SIGNALING Volume 25, Number 7, 2016 Mary Ann Liebert, Inc. DOI: 10.1089/ars.2015.6493
  8. A schematic relating extracellular matrix metabolism to intimal inflammation during atherogenesis. The lymphocyte can elaborate gamma interferon (IFN–γ) that inhibits SMC collagen production. The lymphocyte can also signal either by elaboration of soluble mediators or by contact activation of macrophages. Other cytokines produced in response to products of oxidized lipoproteins, among other stimuli, can further activate the macrophage. The activated phagocyte can release collagen degrading matrix metalloproteinases, and elastolytic enzymes including certain nonmetalloenzymes, such as cathepsins S and K. These enzymes promote matrix catabolism. Thus, in states characterized by heightened intimal inflammation, the extracellular matrix that confers biomechanical strength to the plaque's fibrous cap is under double attack: decreased synthesis and increased degradation. This results in a weakening and thinning of the fibrous cap, features associated in pathological studies with fatal atheromatous plaque disruptions and thrombosis. TNF–α = tumor necrosis factor-alpha; M-CSF = macrophage colony stimulating factor; MCP-1 = monocyte chemoattractant protein-1. (Reproduced from Libby P: The molecular bases of the acute coronary syndromes. Circulation 91:2844-2850, 1995.)
  9. Positive remodelling • During the first part of the life history of an atheromatous lesion, growth of the plaque is outward, in an abluminal direction, rather than inward in a way that would lead to luminal stenosis. • This outward growth of the intima leads to an increase in caliber of the entire artery. This so-called positive remodeling or compensatory enlargement must involve turnover of extracellular matrix molecules to accommodate the circumferential growth of the artery. • Luminal stenosis tends to occur only after the plaque burden exceeds about 40 percent of the cross-sectional area of the artery. Brawnwald Heart Diseases. 10th. edition
  10. Positive remodelling Atherosclerotic vessel growth model used in the computational simulations. A: schematic description of the positive coronary remodeling described by Glagov et al. (14) and included in our model. Plathick, plaque thickness; Remodindex, arterial remodeling index. B: for a given remodeling index, the main parameters describing plaque morphology, i.e., cap thickness (Capthick), necrotic core thickness (Corethick), and necrotic core arc angle (Coreangle), were varied. A total of 5,500 distinct plaque geometries were considered. Dark gray, arterial wall; gray, fibrosis; light gray, necrotic core. Published 2008 in American journal of physiology. Heart and… DOI:10.1152/ajpheart.00005.2008
  11. Classification of coronary lesions Schematic representation of the histopathologic classification of coronary lesions proposed by the AHA. Adapted from Stary et al.15
  12. Evolution and progression of atherosclerotic lesions
  13. Cont Am J Cardiol 1998
  14. Coronary thrombosis • This evolution in our view of the pathogenesis of the acute coronary syndromes places new emphasis on thrombosis as the critical mechanism of transition from chronic to acute atherosclerosis. • Understanding of the mechanisms of coronary thrombosis has advanced considerably. We now appreciate that a physical disruption of the atherosclerotic plaque commonly causes acute thrombosis. Several major modes of plaque disruption provoke most coronary thrombi.[ • The first mechanism, accounting for nearly two-thirds of acute myocardial infarctions, involves a fracture of the fibrous cap of the plaque . • Another mode involves a superficial erosion of the intima, accounting for up to one-quarter of acute myocardial infarctions in highly selected referral cases from medical examiners on individuals who have succumbed to sudden cardiac death. • Superficial erosion appears more frequently in women than in men as a mechanism of sudden cardiac death.[ Brawnwald Heart Diseases. 10th. edition
  15. Vulnerable Plaques American Journal of Biomedical Engineering 2012, 2(2): 1-6 DOI: 10.5923/j.ajbe.20120202.01
  16. Coronary Stenosis severity
  17. Coronary Lesions Libby-Th%C3%A9roux/51e09844c05e9b252161a116de06113b0ae294d6
  18. Coronary Arteries
  19. Supply/Demand Progress in Cardiovascular Diseases Volume 57, Issue 5, March–April 2015, Pages 443-453
  20. Coronary Flow
  21. Coronary Flow cont. Phasic coronary arterial inflow and venous outflow at rest and during adenosine vasodilation. Arterial inflow primarily occurs during diastole. During systole (dotted vertical lines), arterial inflow declines as venous outflow peaks, reflecting the compression of micocirculatory vessels during systole. After adenosine administration, the phasic variations in venous outflow are more pronounced. (Modified from Canty JM Jr, Brooks A: Phasic volumetric coronary venous outflow patterns in conscious dogs. Am J Physiol 258:H1457, 1990.)
  22. Coronary flow and oxygen consumption Fick equation and the relation between heart rate (HR)–systolic blood pressure (SBP) double product and myocardial oxygen consumption (MVO2). A, Increases in MVO2 are primarily met by increases in coronary flow and linearly related to the double product. A doubling of HR, SBP, or contractility each results in approximately 50% increases in myocardial oxygen consumption. B, Beta blockade allows the same external workload to be accomplished at a lower cardiac workload (MVO2) by reducing the double product and myocardial contractility. CaO2 = coronary arterial oxygen content; CBF = coronary blood flow; CvO2 = coronary venous oxygen content. Brawnwald Heart Diseases. 10th. edition
  23. Coronary Autoregulatoin Autoregulatory relation under basal conditions and after metabolic stress (e.g., tachycardia). Left, The normal heart maintains coronary blood flow constant as regional coronary pressure is varied over a wide range when the global determinants of oxygen consumption are kept constant (red lines). Below the lower autoregulatory pressure limit (approximately 40 mm Hg), subendocardial vessels are maximally vasodilated and myocardial ischemia develops. During vasodilation (blue lines), flow increases four to five times above resting values at a normal arterial pressure. Coronary flow ceases at a pressure higher than right atrial pressure (PRA), called zero flow pressure (Pf=0), which is the effective back pressure to flow in the absence of coronary collaterals. Right, After stress, tachycardia increases the compressive determinants of coronary resistance by decreasing the time available for diastolic perfusion and thus reduces maximum vasodilated flow. LV hypertrophy and microvascular disease also limit maximal blood flow per gram of myocardium. In addition, increases in myocardial oxygen demand or reductions in arterial oxygen content (e.g., from anemia or hypoxemia) increase resting flow. These changes reduce coronary flow reserve, the ratio between dilated and resting coronary flow, and cause ischemia to develop at higher coronary pressures. Hb = hemoglobin; HR = heart rate; SBP = systolic blood pressure. Brawnwald Heart Diseases. 10th. edition
  24. Effects of extravascular tissue pressure on transmural perfusion. Compressive effects during diastole (A) are related to tissue pressures that decrease from the subendocardium (Endo) to subepicardium (Epi). At diastolic LV pressures greater than 20 mm Hg, preload determines the effective back pressure to coronary diastolic perfusion. During systole (B), cardiac contraction increases intramyocardial tissue pressure surrounding compliant arterioles and venules. This produces a concealed arterial “backflow” that reduces systolic epicardial artery inflow, as depicted in Figure 49-1. Compression of venules accelerates venous outflow. (Modified from Hoffman JI, Spaan JA: Pressure-flow relations in the coronary circulation. Physiol Rev 70:331, 1990.) Brawnwald Heart Diseases. 10th. edition
  25. Schematic of components of coronary vascular resistance with and without a coronary stenosis R1 is epicardial conduit artery resistance, which normally is insignificant; R2 is resistance secondary to metabolic and autoregulatory adjustments in flow and occurs in arterioles and small arteries; and R3 is the time- varying compressive resistance that is higher in subendocardial than subepicardial layers. In the normal heart (upper panel), R2 > R3 ≫ R1. The development of a proximal stenosis or pharmacologic vasodilation reduces arteriolar resistance (R2). In the presence of a severe epicardial stenosis (lower panel), R1 > R3 > R2. Brawnwald Heart Diseases. 10th. edition
  26. Schematic representation of biochemical processes of plaque formation, key molecules and cells, endothelium junctions and intima + media Published in Healthcare Technology Letters; Received on 4th December 2013; Revised on 10th February 2014; Accepted on 11th February 2014
  27. Coronary Flow
  28. Schematic representation of the role of arterial stiffness in assuring blood flow through the peripheral circulation Kidney International August 2, 2012Volume 82, Issue 4, Pages 388– 400
  29. Endothelium-dependent control of vascular tone. Brawnwald Heart Diseases. John M. Canty Jr.,, Dirk J. Duncker In the normal coronary circulation, endothelium-dependent vasodilation occurs after increases in luminal flow or shear stress, as well as in response to agonists (e.g., released from platelets or cardiac nerves) that bind to receptors on the endothelial surface. These stimulate the production of NO, EDHF, or EETs (epoxyeicosatrienoic acid products), which diffuse into vascular smooth muscle and cause relaxation. Prostacyclin, or prostaglandin I2 (PGI2), is produced in the coronary endothelium of collateral vessels and causes tonic vasodilation. The endothelium also produces endothelin (ET), which activates protein kinase C in vascular smooth muscle to produce coronary constriction and competes with endothelium-derived relaxing factors. Impaired endothelium-dependent vasodilation can result from the lack of production of relaxing factors (e.g., disrupted endothelium) or by inactivation of nitric oxide in disease states associated with oxidative stress and superoxide anion production (e.g., NO and O2 − combining to produce peroxynitrite). In these circumstances, the effect of autacoids on vascular tone can be converted to vasoconstriction because of their direct effects on vascular smooth muscle (not shown). AA = arachidonic acid; ACh = acetylcholine; Bk = bradykinin; 5-HT = 5-hydroxytryptamine [serotonin]; KCa = calcium-activated potassium channel; TGFβ = transforming growth factor-beta-1; Thr = thrombin.
  30. As the plaque burden increases, the atherosclerotic mass tends to stay external to the lumen, which allows the diameter of the lumen to be maintained; this is known as the Glagov effect, or positive remodeling.1As plaque encroaches into the lumen, the coronary artery diameter decreases. Myocardial ischemia results from a discordant ratio of coronary blood supply to myocardial oxygen consumption. Luminal narrowing of more than 65 to 75 percent may result in transient ischemia and angina. In acute coronary syndromes, vulnerable plaque is a more important factor than is the degree of stenosis; acute coronary events result from ulceration or erosion of the fibrous cap, with subsequent intraluminal thrombosis.2,3 Vulnerable plaque within the vessel wall may not be obstructive and thus may remain clinically silent until it causes rupture and associated consequences. (The figure has been modified from Greenland et al.,4 with permission.) Typical Progression of Coronary Atherosclerosis. N Engl J Med 2005; 352:2524-2533 DOI: 10.1056/NEJMcp042317
  31. Imaging modalities Education in Heart Non-invasive imaging Volume 97, Issue 4
  32. CAD Likelihood
  33. European Heart Journal (2007) 28, 1598–1660 doi:10.1093/eurheartj/ehm161

Notas do Editor

  1. Brawnwald Heart Diseases. 10th. edition