SCAI CHAP 1 Atherosclerosis Flashcards
Guess the following with regards to atherosclerosis :
A. A key event in atherogenesis
B. The process of immune cells being drawn to sites of inflammation in atherosclerosis.
C. The transformation of macrophages into lipid-laden cells.
D. Growth resulting from SMC migration, proliferation, and extracellular matrix deposition.
E. Changes in vessel structure due to atherosclerotic processes.
F. An environment rich in lipids and inflammation that initiates atherosclerosis.
G. Early atherosclerotic lesions that develop into plaques.
H. Plaques with micro-calcifications and thin fibrous caps, prone to rupture.
I. An event that leads to thrombosis and acute ischemia due to plaque instability.
A. Extracellular Lipid Accumulation
B. Leukocyte Recruitment
C. Foam Cell Formation
D. Neointimal Growth
E. Vessel Remodeling
F. Proatherogenic Milieu
G. Fatty Streaks
H. Vulnerable Plaques
I. Plaque Rupture
Steps for atherosclerosis ( if you read the sequence, it makes perfect sense and looks easy to remember what comes first )
Guess the following :
A. Key event in the creation of atherosclerotic lesions, occurring within the intima.
B. Processes such as oxidation and glycation.
C. Stimulated by modified lipoproteins from endothelial and smooth muscle cells. Leads to leucocytes recruitment and SMC proliferation
D. Macrophages that ingest lipids and develop a foamy appearance.
E. Receptors like CD36 and macrosialin that bind and internalize modified lipoproteins.
F. Can lead to foam cell death and result in necrotic debris within lesions.
G. Pathways like apoptosis and autophagy that foam cells undergo.
H. Results from foam cell death and contributes to plaque instability.
I. Can expose plaque contents to blood, stimulating thrombus formation.
J. Rapidly stimulated when plaque contents are exposed to blood, potentially obstructing flow.
A. Lipoprotein Accumulation
B. Lipoprotein Modifications
C. Cytokine Production
D. Foam Cells ( hallmark of fatty streaks and initial stage of atherosclerosis ).
E. Scavenger Receptors
F. Oxidized Lipoproteins
G. Programmed Cell Death
H. Necrotic Debris
I. Cap Erosion or Rupture
J. Thrombus Formation
A. Play an important role in atherosclerosis by releasing cytokines and growth factors.
B. Influence atherogenesis, plaque rupture, and thrombosis through their release by leukocytes.
C. Expressed by endothelial cells in response to injury such as lipoprotein accumulation, facilitating leukocyte recruitment.
D. Interacts with ligands on leukocytes to initiate rolling along the vessel surface.
E. The process where leukocytes roll along the vessel surface before stopping.
F. Adhesion molecules that mediate tight binding of leukocytes before diapedesis.
G. The process by which leukocytes migrate through the vessel wall into the plaque.
H. Plasma levels correlate with clinical manifestations of coronary atherosclerosis.
I. Secreted cytokines that induce leukocyte migration to the plaque.
A. Leukocytes ( especially Macrophage )
B. Cytokines and Growth Factors
C. Adhesion Molecules ( like e-selectin)
D. E-selectin
E. Leukocyte Rolling
F. Intergrin Class
G. Diapedesis
H. ICAM-1 ( intracellular adhesion molecule ) and E-selectin
I. Chemokines
A. Secreted cytokines that induce leukocyte migration to the plaque.
B. Chemokine tha participates in the recruitment of monocytes to the plaque.
C. Chemokine that recruits neutrophils to areas of vascular injury.
D. Areas where leukocytes accumulate, increasing vulnerability to rupture.
E. Preferred sites for atherosclerosis development due to turbulent flow.
F. Upregulated in areas of high shear stress, facilitating leukocyte recruitment.
G. Contribute to vascular calcification in response to specific factors like Monocytes-CSF and RANKL ( receptor activator of nuclear factor kappa beta )
H. Occurs in both reactive and orchestrated fashion by vascular SMCs.
I. Associated with increased vulnerability to plaque rupture and cardiovascular events.
J. Involved in the response to monocyte colony-stimulating factor and RANKL.
A. Chemokines
B. MCP-1 (Monocyte Chemoattractant Protein-1)
C. Interleukin-8 (IL-8)
D. “Shoulder” Regions of Plaques
E. Bifurcations and High-Shear-Stress Regions ( maybe low shear for plaque formation and high shear for rupture .. I think it is a mistake in this book )
F. Adhesion Molecules
G. Monocytes
H. Vascular Calcification
I. Micro-calcifications in Plaques
J. NF-κB (Nuclear Factor Kappa Beta)
Question 1: The monocyte is thought to be the first _______ recruited to the incipient _______ after encountering complex signals that include soluble and local _______.
Question 2: Monocytes are stimulated to become _______ after migration into the plaque and may differentiate into specific macrophage _______ based on environmental _______.
Question 3: Type 1 macrophages (M1) are induced by _______ or LPS signaling and display a _______ phenotype, producing high amounts of reactive oxygen species and inflammatory _______.
Question 4: Type 2 macrophages show a high expression of scavenger receptors that produce extracellular matrix components and secrete anti-inflammatory cytokines such as ______, chemokine ligand 18, and ______.
Question 5: The phenotypes of plaque-associated macrophages (PAMs) are _______ because infiltrating monocytes/macrophages express markers of both _______ and _______ macrophages.
Question 6: Macrophages further amplify the inflammatory response through the secretion of cytokines such as _______ and _______.
Question 7: Other cells of the innate immune response that have been implicated in atherosclerosis include _______ cells, natural killer cells, and _______.
Answer 1: leukocyte, atheroma, factors
Answer 2: macrophages, phenotypes, signals
Answer 3: interferon (IFN)-γ, proinflammatory, cytokines ( TNF and IL1B)
Answer 4: IL-1ra, IL-10
Answer 5: mixed, M1, M2-type
Answer 6: TNF-α, IL-1β
Answer 7: mast, neutrophils
Use Chunking strategy to remember important information about the previous card :
M1 Macrophages:
Induced by IFN-γ or LPS.
Proinflammatory phenotype.
Produce reactive oxygen species and cytokines (e.g., TNF, IL-1β).
M2 Macrophages:
Induced by IL-4 or IL-13.
Anti-inflammatory/reparative phenotype.
Secrete cytokines like IL-1ra, chemokine ligand 18, and IL-10.
Plaque-Associated Macrophages (PAMs)
PAMs have mixed phenotypes.
Express markers of both M1 and M2 macrophages.
Cytokine Amplification
Macrophages secrete cytokines to amplify the inflammatory response.
Key cytokines: TNF-α and IL-1β.
Use Verbal Repetition strategy to remember some importnat info about the card
Repetition Strategy:
Monocyte to Macrophage Transition:
Repeat: “Monocytes become macrophages in the plaque.”
Repeat for M1: “M1 macrophages are proinflammatory, induced by IFN-γ or LPS, produce TNF and IL-1β.”
Repeat for M2: “M2 macrophages are anti-inflammatory, induced by IL-4 or IL-13, secrete IL-10.”
Cytokine Amplification:
Repeat: “Macrophages secrete TNF-α and IL-1β to amplify inflammation.”
JEOPARDY Category: Adaptive Immune Response in Atherosclerosis
$100: This type of T cell is the primary cell of the adaptive immune response at atherosclerotic sites, by influencing plaques progression and vulnerability.
$200: This cytokine inhibits the growth of smooth muscle cells (SMCs) and promotes their apoptosis, leading to plaque vulnerability.
$300: This ligand, expressed by CD4+ T cells, influences a variety of cell types to produce a highly procoagulant tissue factor.
$400: These are the predominant types of CD4+ T cells in atherosclerotic lesions believed to promote atherosclerosis.
$500: This type of immune response, involving antibodies to oxidized LDL, acts as a protectant against atherosclerosis.
$600: These cells, present in atherosclerosis, suppress activation of other T cells and may be either pro- or anti-atherogenic.
$700: Infections with agents like Chlamydia pneumonia or viruses can create antibodies with these features that promote atherogenesis.
ANSWERS
$100 : CD4+ T cell
$200 : IFN-γ (Interferon gamma). IFN-γ limits production of structural proteins (collagen and elastin) that SMCs secrete and may lead to the increased risk of plaque rupture
$300: CD40 ligand (soluble factor)
$400: CD4+ TH1 T cells ( CD4+ TH2 T cells, on the other hand, are likely antiatherogenic ).
$500: humoral immune response ( B cells ).
$600: regulatory T cells
$700: auto-immune features
Chose Key words using alphabetical orders for the card/topic above
A: Adaptive - Apoptosis - Atherosclerotic- Antiatherogenic- Activation- Antibodies
Auto-immune
B: B cells
C: CD4+, Cytokines, Collagen, CD40. Chlamydia
D: Density, Death
E: Effects, Elastin
I: IFN-γ
L: LDL (Low-Density Lipoprotein), Ligand, Limits
M: Monocyte
N: Neutralizing
O: Oxidized
P: Plaque, Production, Pneumonia, Procoagulant
R: Response, Receptors, Released, Regulatory
S: Sites, SMCs (Smooth Muscle Cells), Soluble, Secreted, Suppress
Question 1: SMCs and their products are responsible for providing _______ to the mature atherosclerotic _______, which is initially little more than a collection of _______ and foam cells.
Question 2: Under the influence of growth factors and _______ such as platelet-derived growth factors and _______, SMCs migrate out from the media into the _______ where they begin to proliferate.
Question 3: In addition, SMCs produce extracellular matrix _______, including collagen, _______, elastin, fibrinogen, fibronectin, and _______.
Question 4: These proteins often account for a substantial _______ of the plaque and are important in determining the structural _______ of the fibrous _______.
Question 5: There is evidence that these cells express bone matrix _______ that have been subsequently _______ by other investigators. This highlights the role of SMC in vascular _______.
Question 6: SMC migration is influenced by growth factors and _______, such as platelet-derived _______ factors and thrombin, which help them move out from the _______.
Question 7: The extracellular matrix produced by SMCs includes _______, proteoglycans, elastin, _______, and vitronectin, which are crucial for the structural _______ of the plaque.
Question 8: The role of SMCs in vascular calcification has been highlighted by the expression of bone matrix _______, which has been corroborated by other _______ and underscores their role in _______.
Answer 1 : structure, plaque, lipids
Answer 2 : chemoattractants, thrombin, neointima
Answer 3 : constituents, proteoglycans, vitronectin
Answer 4 : volume, integrity, cap
Answer 5 : proteins, corroborated, calcification
Answer 6 : chemoattractants, growth, media
Answer 7 : collagen, fibrinogen, integrity
Answer 8 : proteins, investigators, calcification
Plaque Angiogenesis and Hypoxia:
Question 1: New vasculature, under the influence of angiogenic _______ factors, such as hypoxia inducible factor (HIF)/vascular endothelial growth factor (VEGF), may grow from the _______ within the adventitia into the _______.
Question 2: These vessels may be disrupted and cause plaque _______ independent of plaque _______. In addition, analogous to tumor growth, these vessels may stimulate plaque _______.
Question 3: There is experimental evidence demonstrating inhibition of plaque growth by angiogenic _______ in a murine model of _______. Furthermore, neo vessel density is higher in nonstenotic segments and stenotic noncalcified _______ than in normal segments or calcified lesions.
Question 4: Hypoxemia not only promotes angiogenesis but also contributes to _______ through the promotion of matrix metalloproteinases (MMPs), a family of interstitial collagenases that weaken the fibrous _______ and gelatinases capable of catabolizing nonfibrillar _______.
Question 5: Proteolysis leads to dissolution of the plaque extracellular _______ and plaque vulnerability. Hypoxemia promotes the formation of proinflammatory _______ and leukotrienes and activates the Akt and beta-catenin pathways with subsequent macrophage _______.
Question 6: In addition, conditions resulting in lipid accumulation in macrophages are amplified with accumulation of triglyceride containing cytosolic lipid _______ and adipose differentiation protein (ADRP) expression, even in the absence of exogenous _______.
Question 7: The lipid accumulation is a result of increased triglyceride _______, reduced beta-oxidation of fatty acids, and increased expression of stearoyl-coenzyme A _______ (SCD-1), an enzyme involved in the synthesis of fatty _______.
Question 8: Hypoxemia promotes the formation of proinflammatory cytokines and _______ and activates the Akt and beta-catenin pathways with subsequent _______ activation.
Answer 1: growth, vasa vasorum, plaque
Answer 2: hemorrhage, rupture, growth
Answer 3: inhibitors, atherosclerosis, plaques
Answer 4: proteolysis, cap, collagen
Answer 5: matrix, cytokines, activation
Answer 6: droplets, lipids, expression
Answer 7: biosynthesis, desaturase, acids
Answer 8: leukotrienes, macrophage, pathways
Matching :
A- Angiogenic growth factors such as _______
B- Neovessels may cause plaque _______ independent of rupture
C- Neo vessel density is higher in _______ segments
D- Hypoxemia contributes to _______ through MMPs
E- Proteolysis leads to dissolution of the plaque extracellular _______
F- Hypoxemia promotes proinflammatory _______ and leukotrienes
G- Increased expression of _______ involved in fatty acid synthesis
Answer: A. hypoxia inducible factor (HIF)/VEGF
Answer: B. hemorrhage
Answer: C . noncalcified
Answer: D. proteolysis
Answer: G. matrix
Answer: H. cytokines
Answer: G. stearoyl-coenzyme A desaturase (SCD-1)
Matching :
A- New vasculature may grow from the _______ into the plaque
B- Angiogenic growth factors include _______
C- MMPs are a type of interstitial _______
D- Gelatinases are capable of catabolizing nonfibrillar _______
E- Hypoxemia activates the Akt and beta-catenin _________ with sybsequent ________ activation.
F- Lipid accumulation results in increased triglyceride _______
Answer: A. vasa vasorum
Answer: B. hypoxia inducible factor (HIF)/VEGF
Answer: C. collagenases
Answer: D. collagen
Answer: E. pathways, macrophages
Answer: F. biosynthesis
comment on the picture
Schematic of positive vascular remodeling. Initially, the external elastic lamina (external red circle) enlarges to accommodate plaque growth. As the plaque size increases, the luminal area is compromised. EEM, external elastic membrane, also called external elastic lamina.
The mature plaque:
- A key characteristic of a mature __________ is the presence of a fibrous cap overlying a __________ .
- The Fibrous cap of an atherosclerotic plaque is primarily composed of __________ and various extracellular matrix proteins.
- __________ are a major cellular component of the fibrous cap and contribute to its stability and structural integrity.
- The necrotic lipid core within an atherosclerotic plaque contains free cholesterol ______ , foam cells, and necrotic debris.
- __________ are macrophages that have ingested large amounts of lipids, contributing to the growth and instability of the necrotic core.
- Besides foam cells, other leukocytes such as ______ are found within the atherosclerotic plaque.
- Variations in cap thickness and leukocyte distribution can influence the likelihood of __________ , a critical event in the progression of atherosclerosis.
- __________ are a severe consequence of plaque rupture, often leading to myocardial
infarction or unstable angina. - The stability of the __________ is a critical factor in preventing plaque rupture and subsequent cardiovascular events.
- The accumulation of __________ contributes significantly to the formation and expansion of the necrotic lipid core in atherosclerotic plaques.
- Atherosclerotic Plaque, necrotic lipid core.
- smooth muscle cells
- SMCs
- esters
- Foam Cells
- T cells
- Plaque Rupture
- Acute Coronary Syndromes
- Fibrous Cap
- Cholesterol Esters
Vascular remodeling
- Angiography provides a comprehensive view of the vessel wall architecture, making intravascular imaging unnecessary for detailed plaque characterization.
A) True
B) False - Atherosclerosis is typically a localized disease, easily detectable by angiography even in its early stages.
A) True
B) False - The degree to which a plaque obstructs the lumen is solely determined by the volume of the plaque itself, independent of vascular remodeling.
A) True
B) False - Vascular remodeling is a static process, unaffected by external stimuli such as hypertension or risk factors for atherosclerosis.
A) True
B) False - In the context of hypertension, vascular remodeling might involve an increase in the muscle mass of the vessel wall as a compensatory mechanism.
A) True
B) False - In atherosclerosis, remodeling always leads to a reduction in luminal area.
A) True
B) False - Matrix Metalloproteinases (MMPs) are downregulated in areas of vessel wall remodeling.
A) True
B) False - MMPs are calcium-dependent proteases that play a crucial role in vascular remodeling and plaque rupture.
A) True
B) False - The text suggests that intravascular imaging can identify diffuse atherosclerosis that might be missed by traditional angiography.
A) True
B) False - Vascular remodeling exclusively involves cellular components of the vessel wall and does not affect non-cellular components.
A) True
B) False
ANSWER KEY:
- B) False. Angiography has limitations in visualizing the vessel wall architecture, making intravascular imaging necessary for detailed plaque characterization.
- B) False. Atherosclerosis is often diffuse and difficult to detect without intravascular imaging, especially in its early stages.
- B) False. The amount of impingement is determined by both plaque volume and vascular remodeling.
- B) False. Vascular remodeling is a dynamic process responsive to various stimuli, including risk factors for atherosclerosis and conditions like hypertension.
- A) True. The text explicitly mentions that in hypertension, muscle mass of the vessel wall can increase to normalize wall stress.
- B) False. Remodeling can involve compensatory enlargement to preserve luminal area.
- B) False. MMPs are upregulated in areas of vessel wall remodeling.
- B) False. MMPs are zinc-dependent proteases, not calcium-dependent.
- A) True. The text states atherosclerosis is almost always diffuse, although more difficult to detect without intravascular imaging.
- B) False. Vascular remodeling involves restructuring of both cellular and non-cellular components of the vessel wall.
True or False
Question 1: Angiography is limited in its ability to visualize the vessel wall architecture, making intravascular imaging essential for comprehensive plaque assessment.
Question 2: Intravascular imaging during coronary angiography is primarily used for detecting non-obstructive lesions rather than characterizing flow-obstructing ones.
Question 3: Diffuse atherosclerosis is often easily identifiable without the need for intravascular imaging techniques.
Question 4: Vascular remodeling, influenced by plaque volume growth, can either preserve or reduce the luminal area of the vessel.
Question 5: Vascular remodeling exclusively involves changes to the noncellular components of the vessel wall.
Question 6: In response to hypertension, an increase in vessel wall muscle mass is a mechanism to maintain normal wall stress levels.
Question 7: Compensatory enlargement of the vessel in atherosclerosis is aimed at reducing the luminal area to manage blood flow.
Question 8: MMPs, known for their role in vascular remodeling, are zinc-dependent proteases that are downregulated in areas of vessel wall remodeling.
Question 9: The role of MMPs in plaque rupture is well-documented, highlighting their significance in the progression of atherosclerosis.
Question 10: Vascular remodeling can occur due to various stimuli, which are exclusively unrelated to coronary atherosclerosis risk factors.
Answers with Explanations
Answer 1: True
Explanation: Angiography primarily visualizes the lumen of blood vessels but does not provide detailed images of the vessel wall. Intravascular imaging, such as intravascular ultrasound, is used to assess the plaque and vessel wall architecture in detail.
Answer 2: False
Explanation: Intravascular imaging is used to characterize both non-obstructive and flow-obstructing lesions, providing detailed information about the nature and extent of the plaque.
Answer 3: False
Explanation: Diffuse atherosclerosis is challenging to detect without intravascular imaging, as it may not cause significant lumen narrowing visible on standard angiography.
Answer 4: True
Explanation: Vascular remodeling can involve compensatory enlargement to preserve the luminal area or constrictive remodeling that reduces the lumen size, depending on the plaque characteristics and vessel response.
Answer 5: False
Explanation: Vascular remodeling involves changes in both cellular (e.g., smooth muscle cells) and noncellular (e.g., extracellular matrix) components of the vessel wall.
Answer 6: True
Explanation: In hypertension, the vessel wall may thicken due to increased muscle mass to normalize wall stress and accommodate higher blood pressure.
Answer 7: False
Explanation: Compensatory enlargement aims to preserve the luminal area, not reduce it, ensuring adequate blood flow despite plaque growth.
Answer 8: False
Explanation: MMPs are upregulated in areas of vessel wall remodeling, contributing to the breakdown of extracellular matrix components and facilitating remodeling processes.
Answer 9: True
Explanation: MMPs play a significant role in plaque rupture by degrading the fibrous cap and weakening the structural integrity of the plaque, contributing to the progression of atherosclerosis.
Answer 10: False
Explanation: Vascular remodeling can occur due to a variety of stimuli, many of which are related to coronary atherosclerosis risk factors, such as hypertension and high cholesterol levels.
Progressive Lumen Encroachment and Stable Angina
1- As atherosclerotic lesions grow, they gradually encroah upon the _______ of the vessel, depending on the amount of _________ vascular remodeling.
2- The reduction in flow due to lumen encroachment leads to _______ of the distal _______ to increase flow.
3- The inability of the coronary circulation to increase blood flow in response to demand typically leads to _______ _______.
4- The point at which luminal encroachment causes symptoms depends on factors such as the severity of the _______ and the oxygen-carrying capacity of the _______.
5- Lesions generally begin to produce symptoms when they reach approximately _______ to _______ diameter stenosis.
6- Modern techniques for assessing intracoronary hemodynamics involve the use of _______ and _______ wires.
7- Interventional cardiologists use these techniques to objectively identify lesions that result in _______ _______.
8- The demand of the distal _______ _______ is one of the factors influencing when luminal encroachment causes symptoms.
Answers
1- encroach, compensatory
2- vasodilation, micro-circulation
3- exertional, angina
4- lesion, blood stream
7- 60%, 70%
8- flow, pressure
9- hemodynamic, consequences
10- cardiac, bed
Plaque Rupture, Thrombosis, and the Acute Coronary Syndromes
Question 1: What type of studies provided insights into acute coronary syndromes by using angiography after randomization?
Question 2: According to the angiograms, what was the diameter stenosis of the majority of lesions responsible for myocardial infarction (MI)?
Question 3: How quickly can mild and moderate stenoses progress to produce an MI according to other angiographic studies?
Question 4: In the analysis of four serial angiographic studies, what percentage of acute MIs were found to arise from lesions with degrees of stenosis greater than 60%?
Question 5: What is predominantly responsible for a lesion’s propensity to cause an infarct, according to the text?
Question 6: What often accompanies atherosclerosis and may cause mildly stenotic lesions to represent large plaques by volume?
Answer 1: Studies with mandated angiography after randomization to either placebo or thrombolytic therapy.
Answer 2: The majority of lesions responsible for MI were less than 50% in diameter stenosis.
Answer 3: Mild and moderate stenoses may progress to produce an MI in a matter of weeks to months.
Answer 4: Only 15% of acute MIs were found to arise from lesions with degrees of stenosis greater than 60%.
Answer 5: The vascular biologic state of the lesion is predominantly responsible for its propensity to cause an infarct, rather than then stenosis severity ( noncritical lesions represent a larger population than critical lesions. Tthrombosis, often on a noncritical stenosis, caused by lesion disruption causes the majority of MIs ).
Answer 6: Compensatory enlargement of the vessel often accompanies atherosclerosis, causing mildly stenotic lesions to represent large plaques by volume.
Question 1: What is the proximate event leading to thrombosis at a lesion?
Question 2: What components of the plaque are exposed to blood during plaque rupture?
Question 3: Name one feature identified by histologic studies that is associated with plaques more vulnerable to rupture.
Question 4: Where are inflammatory cells largely concentrated within a vulnerable plaque?
Question 5: What role does inflammation play in the structural integrity of the plaque?
Question 6: What is the name of the trial that examined the natural history of atherosclerosis?
Question 7: How many patients were involved in the PROSPECT study?
Question 8: What diagnostic method was used to check the major epicardial arteries of patients in the PROSPECT study?
Question 9: How many nonculprit lesions were associated with adverse cardiac events in the PROSPECT study?
Question 10: List one correlate that predicted a subsequent adverse cardiac event according to the PROSPECT study.
Answer 1: Plaque rupture leading to exposure of blood to highly thrombotic sub-endothelial components of the plaque.
Answer 2: Highly thrombotic sub-endothelial components of the plaque.
Answer 3: A thin fibrous cap ( also large lipid core and abundance of inflammatory cells ).
Answer 4: Inflammatory cells are largely concentrated at the shoulder regions of the plaque.
Answer 5: Inflammation is a key regulator of the structural integrity of the plaque.
Answer 6: The Providing Regional Observations to Study Predictors of Events in the Coronary Tree (PROSPECT) study.
Answer 7: 697 patients.
Answer 8: Intravascular ultrasound.
Answer 9: One hundred and six nonculprit lesions.
Answer 10: A plaque burden greater than 70% ( others: thin cap FA or TCFA and MLA < 4 mm2)
Characteristics of stable versus vulnerable plaques. Vulnerable plaques have thinner fibrous caps and larger, more inflammatory, cell-rich lipid cores. SMC, smooth muscular cell.
Question 1: What two components is the structural integrity of the plaque dependent on?
Question 2: How is SMC mass balanced within the plaque?
Question 3: What role do cytokines released from inflammatory cells play in cell death?
Question 4: What is the balance of extracellular matrix content dependent on?
Question 5: What inhibits SMC collagen synthesis in the plaque?
Question 6: Name one type of enzyme produced by inflammatory cells that degrades the extracellular matrix.
Question 7: What are two important constituents of the extracellular matrix that can be degraded by enzymes?
Question 8: How do inflammatory cells contribute to plaque weakening?
Question 9: What is the role of activated T cells in the plaque regarding extracellular matrix production?
Question 10: What is the effect of inflammatory cells on SMC mass and extracellular matrix content?
Answer 1: SMC mass and extracellular matrix content.
Answer 2: SMC mass is balanced between SMC cell accumulation (via migration from the media and proliferation) in the neointima and cell death.
Answer 3: Cytokines released from inflammatory cells control apoptosis, or programmed cell death.
Answer 4: Extracellular matrix content is a balance between production from SMCs and degradation by a variety of proteases.
Answer 5: IFN-γ, secreted by activated T cells, inhibits SMC collagen synthesis.
Answer 6: MMP (Matrix Metalloproteinases) and cathepsins.
Answer 7: Collagens and elastin.
Answer 8: Inflammatory cells contribute to plaque weakening by decreasing SMC mass, decreasing extracellular matrix content, and increasing extracellular matrix degradation.
Answer 9: Activated T cells secrete IFN-γ, which inhibits SMC collagen synthesis, affecting extracellular matrix production.
Answer 10: Inflammatory cells decrease SMC mass and extracellular matrix content while increasing extracellular matrix degradation.
Thickness of the fibrous cap is a balance between synthesis of extracellular matrix proteins by smooth muscle cells and the breakdown of these products by degradative enzymes. These processes are largely under the influence of inflammatory cells.
Question 1: There are still several unanswered ______ in this area: most importantly—how and why plaques ______ when they do.
Question 2: The variability of ______ rupture involves a number of postulated ______.
Question 3: These mechanisms include ______ variation, stress ______, and the abrupt release of cortisol.
Question 4: Another machanism is high-circumferential ______ forces act at the shoulder regions of ______.
Question 5: There is an interesting combination of both ______ and biophysical ______ that make plaques prone to rupture.
Question 6: Frank plaque rupture is the major ______ cause of thrombotic ______ of the acute coronary syndromes.
Question 7: Other ______ may also be responsible, such as local superficial ______ of endothelial cells.
Question 8: This denudation may expose the internal ______ membrane, representing an important ______ substrate.
Question 9: This exposure has ______ for therapy due to the lack of ruptured ______.
Question 10: Plaque erosion pathophysiology is more based in ______ adhesion and ______.
Answer 1: questions, rupture
Answer 2: plaque, mechanisms
Answer 3: circadian, events
Answer 4: biomechanical, plaques
Answer 5: biochemical, characteristics
Answer 6: antecedent, complications
Answer 7: processes, denudation
Answer 8: elastic, thrombotic
Answer 9: implications, plaque
Answer 10: platelet, aggregation
Illustration of differences between plaque erosion and plaque rupture as causes of presentation with acute coronary syndrome
MATCHING
1: The event that triggers thrombus formation by exposing blood to the lipid core, which is rich in prothrombotic substances.
2: The process by which the inner lining of the blood vessel is stripped away, often leading to thrombus formation.
3: Often found associated with lipid-laden macrophages.
4: The exposure of this element within a plaque acts as a potent stimulus for the coagulation cascade.
5: A protein that, when present in elevated levels, can increase the risk of thrombus formation and subsequent vessel blockage.
6: An environment in the bloodstream that promotes the breakdown of clots, potentially limiting severe outcomes to forms of angina.
7: Conditions or substances in the blood that enhance the likelihood of thrombus growth, potentially leading to vessel occlusion.
8: A type of thrombus that adheres to the vessel wall but does not completely block blood flow, possibly contributing to plaque enlargement over time.
9: A protein that, when present in elevated levels, can increase the risk of thrombus formation and subsequent vessel blockage.
10: The incorporation of nonocclusive thrombi into the plaque structure, facilitating its enlargement and potential instability.
1: Plaque Rupture
2: Endothelial Denudation
3: Thrombus Formation
4: Lipid Core Exposure
5: Tissue Factor ( prothrombotic )
6: Fibrinolytic Milieu
7: Prothrombotic Factors
8: Mural Thrombus
9: Fibrinogen ( plasminogen activator inhibitor PAI 1)
10: Plaque Growth
1: Numerous trials corroborate its role in the thrombotic paradigm of acute coronary syndromes.
2: Trials support its effectiveness in reducing subsequent coronary events without changing lesion severity.
3: Theories suggest that reducing lipids can decrease the risk of plaque rupture.
4: Lipids within the plaque provide this, crucial for plaque growth and rupture.
5: These lipid-lowering drugs may help stabilize the fibrous cap and reduce thrombogenicity.
6: A beneficial action of statins that helps reduce the risk of plaque rupture.
7: The potential of the plaque’s inner core to promote thrombus formation, reduced by statins.
8 : Lipid-lowering therapy reduces coronary events with essentially no change in this aspect
1: Antiplatelet Therapy
2: Lipid-Lowering Therapy
3: Plaque Vulnerability
4: Inflammatory Stimulus
5: Statin Agents
6: Fibrous Cap Stabilization
7: Thrombogenicity ( lipid core is thrombogenic )
8: Lesion Severity
Question 1: More than three decades ago, Ludmer and colleagues reported that a ______ reaction occurred when acetylcholine was administered ______ to patients with atherosclerosis.
Question 2: Rather than the expected ______ effect normally observed in epicardial coronary arteries, the investigators observed ______ in patients with atherosclerosis.
Question 3: This reaction was observed even in territories without significant ______ narrowing.
Question 4: Acetylcholine had previously been identified as working through an ______-dependent mechanism.
Question 5: Hence, the concept of clinical ______ dysfunction was born.
Answer 1: paradoxical, intracoronary
Answer 2: vasodilatory, vasoconstriction
Answer 3: luminal
Answer 4: endothelial
Answer 5: endothelial
Question 1: The endothelium is a ______ of cells derived from the embryonic ______ that form a continuous layer on the intimal surface of the cardiovascular system.
Question 2: This layer covers the arteries, veins, and heart chambers, known as the ______; the capillary walls consist solely of ______ cells.
Question 3: Endothelial cells have diverse functions crucial for maintaining ______ integrity, including the regulation of vascular ______.
Question 4: They also manage vascular ______, vessel wall inflammation, and ______ through the expression of anticoagulants.
Question 5: Anticoagulants such as ______ sulfate and enzymes that destroy them are expressed by endothelial cells.
Question 6: Rapid repair of the endothelium is vital when damaged, requiring quick replacement of ______ cells by circulating endothelial progenitor cells (EPCs).
Question 7: EPCs are central to ______ throughout our lifespan.
Answer 1: monolayer, mesoderm
Answer 2: endocardium, endothelial
Answer 3: vascular, tone
Answer 4: permeability, thromboresistance
Answer 5: heparin
Answer 6: apoptotic
Answer 7: angiogenesis
Question 1: This molecule, generated from L-arginine by endothelial NO synthase, diffuses to vascular smooth muscle cells to cause vasodilation.
Question 2: This enzyme, activated by nitric oxide in vascular smooth muscle cells, results in cyclic guanosine monophosphate-dependent vasodilation.
Question 3: The endothelium mediates hyperpolarization of vascular smooth muscle cells via a pathway independent of this molecule.
Question 4: These factors, produced by the endothelium, increase potassium conductance and propagate depolarization of vascular smooth muscle cells.
Question 5: This vasoconstrictive molecule leads to vasoconstriction and proliferation through the activation of ETA receptors.
Question 6: These three molecules play roles similar to endothelin 1, inducing smooth muscle cell proliferation.
Question 7: This endothelial protein controls vascular permeability and cell-to-cell communication.
Answer 1: What is Nitric Oxide (NO)?
Answer 2: What is guanylate cyclase?
Answer 3: What is Nitric Oxide (NO)?
Answer 4: What are endothelium-derived hyperpolarizing factors (EDHFs)?
Answer 5: What is endothelin 1?
Answer 6: What are thromboxane A2, serotonin, and angiotensin II?
Answer 7: What is vascular endothelial cadherin?
MATCHING:
1: A gaseous signaling molecule that facilitates vasodilation by activating guanylate cyclase in smooth muscle cells.
2: An enzyme responsible for converting L-arginine into a vasodilatory molecule in the presence of specific cofactors.
3: A cofactor necessary for the proper function of the enzyme that produces a key vasodilatory molecule i.e. NO.
4: An enzyme activated by a gaseous molecule, leading to cyclic GMP-dependent vasodilation.
5: Factors that cause hyperpolarization of vascular smooth muscle cells, increasing potassium conductance.
6: A potent vasoconstrictive peptide that acts through specific receptors to cause vasoconstriction and proliferation.
7: Receptors that mediate the effects of a potent vasoconstrictive peptide, leading to smooth muscle proliferation.
8: A molecule that, along with serotonin and angiotensin II, induces smooth muscle cell proliferation.
9: A protein that plays a critical role in controlling vascular permeability and communication between endothelial cells.
10: The physiological state maintained by the balance of various vasodilatory and vasoconstrictive factors.
1: Nitric Oxide (NO)
2: Endothelial NO Synthase (eNOS)
3: Tetrahydrobiopterin
4: Guanylate Cyclase
5: Endothelium-Derived Hyperpolarizing Factors (EDHFs)
6: Endothelin 1 ( expressed in active plaques )
7: ETA Receptors
8: Thromboxane A2
9: Vascular Endothelial Cadherin
10: Vascular Tone
1: Activate cell signaling and modulate cellular function in endothelial cells.
2: Augmented by upregulated expression of adhesion molecules in response to atherogenic stimuli.
3: Modified through altered production of vasoactive substances by endothelial cells.
4: An early marker of atherosclerotic changes and contributor to cardiovascular events.
5: Widely used methods for assessing endothelial function, focusing on vessels <500 µm in diameter ( not visible ).
6: To activate or block endothelial cell function and measure changes in vascular tone.
7: Methods included in vascular reactivity tests for functional assessment of the microcirculation.
1: Atherogenic Stimuli
2: Endothelial and Immune Cell Interaction
3: Vascular Smooth Muscle Function
4: Dysfunctional Endothelium
5: Vascular Reactivity Tests
6: Aim of Vascular Reactivity Tests ( assess microcirculation )
7: Coronary Flow Reserve (CFR) and Coronary Blood Flow (CBF)
1: Defined as the ratio of near-maximal to basal myocardial flow in response to maximal hyperemia.
2: An amalgamated measure of CBF through both epicardial arteries and microcirculation
3: Produces primarily a vasodilator response.
4: Causes dose-dependent vasoconstriction.
5: Acts on vessels less than 150 µm in diameter, reflecting changes in resistance via adenosine A2 receptors on SMCs.
6: Acetylcholine reflects the former, while adenosine reflects the latter.
7: An increase >50% in CBF with acetylcholine and a CFR ratio >2.5 in response to adenosine.
8: Indicates dysfunction in epicardial AND resistance vessels involving both endothelium-dependent and independent mechanisms.
9: Indicates endothelial-independent dysfunction.
10: Suggests an endothelial-dependent dysfunction.
1: What is CFR (Coronary Flow Reserve)?
2: CFR reflects both epicardial arteries and microcirculation. A decrease in CFR without epicardial vessel obstruction reflects solely on the microcirculation.
3: What is the response of acetylcholine in normal coronaries?
4: What is the response of acetylcholine in coronary artery disease?
5: What is the action of adenosine?
6: What are endothelial-dependent and endothelial-independent mechanisms?
7: What are normal CBF and CFR responses to acetylcholine or adenosine ?
8: What does an abnormal response to both acetylcholine and adenosine indicate?
9: What does an abnormal response to ONLY adenosine indicate?
10: What does an abnormal response to acetylcholine only suggest?
Q1: How is endothelial dysfunction associated with different types of angina and myocardial infarction?
Q2: What did Marks et al. find in their study of patients with ischemic cardiac disease and normal coronary angiograms?
Q3: What were the findings of Brien et al. regarding cardiovascular event rates in patients with normal or minimally diseased coronary arteries?
Q4: What was the focus of Rubinshtein et al.’s study on endothelial dysfunction?
Q5: How many patients were included in Rubinshtein et al.’s study, and what were their characteristics?
Q6: What methods were used to evaluate coronary blood flow and coronary flow reserve in Rubinshtein et al.’s study?
Q7: What relationship did the authors analyze in relation to CBF and CFR in Rubinshtein et al.’s study?
Q8: What were the conclusions of Rubinshtein et al. regarding predictors of reduced CFR in patients without obstructive coronary disease?
A1: Endothelial dysfunction is associated with stable angina, unstable angina, and myocardial infarction, and it is frequently categorized under the clinical umbrella of ischemia with nonobstructive coronary arteries (INOCAs).
A2: Marks et al. found that patients with an abnormal CFR had nearly threefold higher mortality (20% vs 7%; P = .016) over a mean period of 8.5 years compared to those with normal CFR.
A3: Brien et al. noted a more than threefold higher cardiovascular event rate in patients in the lowest tertile of CFR compared to those in the highest tertile (18% vs 5%, P = .019), with 36% of all events related to acute coronary syndrome over an average of 6.5 years.
A4: Rubinshtein et al. focused on evaluating the relationship between the Framingham risk score (FRS), the presence of coronary risk factors, and coronary microcirculatory vasodilator function in patients with early coronary atherosclerosis.
A5: The study included 1063 patients (age: 50 ± 12 years, 676 (64%) females) without significant narrowing (<30%) on coronary angiography who underwent invasive assessment of coronary endothelial function.
A6: Coronary blood flow (CBF) in response to the endothelium-dependent vasodilator acetylcholine and the microvascular (endothelium-independent) CFR in response to intracoronary adenosine were evaluated.
A7: The authors analyzed CBF and CFR in relation to the Framingham risk score (FRS) and the presence of traditional and novel risk factors.
A8: The authors concluded that a higher Framingham risk score (FRS) was an independent predictor of reduced CFR, as was female sex and family history of coronary artery disease
Q1: What are the key principles in managing INOCA ( ischemia with non obstructive CAD ) ?
Q2: What are the current management strategies for INOCA?
Q3: What was the purpose of the CORonary MICrovascular Angina (CorMicA) trial?
Q4: What were the findings of the CorMicA trial regarding stratified medical therapy?
Q5: What tailored therapies were included in the CorMicA trial for different patient conditions?
Q6: What are the ongoing trials related to INOCA, and what insights are they expected to provide?
Q7: How are agents used as coronary vasodilators in the cath lab classified?
A1: The key principles include establishing a diagnosis, evaluating pathophysiological mechanisms (coronary macrovascular vs. microvascular dysfunction), targeted treatment, lifestyle changes, and avoiding exacerbating factors.
A2: Current management focuses on lifestyle modification, cardiac rehabilitation, lipid-lowering agents, angiotensin-converting enzyme inhibitors, angiotensin rennin blockers, β-blockers, L-arginine, ranolazine, xanthine derivatives, and enhanced external counterpulsation.
A3: The CorMicA trial evaluated stratified medical therapy with an interventional diagnostic procedure, including an assessment of CFR followed by vasoreactivity testing with acetylcholine, versus standard care with a sham procedure in patients with INOCA.
A4: The trial found that stratified medical therapy following an interventional diagnostic procedure was feasible and improved angina severity at 6 months, with marked improvements in angina and overall quality of life persisting at 1 year.
A5: Tailored therapy included calcium channel blockers and long-acting nitrates for those with documented vasospasm; beta-blockers, ACE inhibitors, and statins for those with coronary microvascular dysfunction; and discontinuation of antianginal therapy for those with normal testing.
A6: The ongoing trials are iCorMicA and the Women’s Ischemia Trial to Reduce Events in Non-obstructive Coronary Artery Disease (WARRIOR), which should provide further insights into the optimal management of INOCA patients.
A7: They are classified as endothelial-dependent or independent
Endothelium-Independent Vasodilators
Mnemonic: “Direct Sodium and Metabolic Smoothies”
Endothelium-Dependent Vasodilators
Mnemonic: “Active 5 Brady”
Endothelium-Independent Vasodilators
Mnemonic: “Direct Sodium and Metabolic Smoothies”
Direct NO Donors:
“Direct” - NO Gas
“Sodium” - Sodium (Na) Nitroprusside, Na Trioxodinitrate
NO Donors Requiring Metabolism: “Metabolic” - Nitroglycerin, Isosorbide Dinitrate, Amyl Nitrate, Nicorandil
Smooth Muscle Cell Relaxers: “Smoothies” - Calcium Channel Blockers
Endothelium-Dependent Vasodilators : Mnemonic: “Active 5 Brady”
“Active” - Acetylcholine
“5” - 5-Hydroxytryptamine
“Brady” - Bradykinin
Q1: What is the focus of medical therapy for atherosclerosis?
Q2: What are first-line antianginal therapies?
Q3: What is the foundation of atherosclerotic treatment?
Q4: What trial demonstrated the benefit of adding ezetimibe to statin therapy in pattients with ACS ?
Q5: What do PCSK9 inhibitors do?
Q6: Which trial evaluated the efficacy of evolocumab with statin therapy in stable CAD ?
Q7: What did the ODYSSEY OUTCOMES trial investigate?
Q8: What additional effects of statins are suggested beyond LDL lowering?
Q9: Which trial linked inflammation reduction to statin therapy benefits?
Q10: What area remains active for investigation in atherosclerosis treatment?
A1: Control of risk factors, symptom control with antianginal agents, and lipid lowering.
A2: Beta-blockers, calcium-channel blockers, and short-acting nitrates.
A3: Lipid-lowering with statins.
A4: IMPROVE-IT trial.
A5: They dramatically lower lipids and improve cardiovascular outcomes.
A6: FOURIER trial.
A7: The safety and efficacy of alirocumab in reducing cardiovascular events in patients with a history of ACS within the last 12 months.
A8: Anti-inflammatory and pleiotropic effects.
A9: JUPITER trial.
A10: Modification of inflammatory risk with novel agents.
Q1: What was the main finding of the IMPROVE-IT trial regarding the addition of ezetimibe to statin therapy?
Q2: What was the focus of the FOURIER trial involving evolocumab?
Q3: What did the ODYSSEY OUTCOMES trial examine in relation to alirocumab?
Q4: How did the JUPITER trial contribute to understanding the effects of statins beyond cholesterol lowering?
Q5: What hypothesis was tested in the JUPITER trial regarding inflammation and statin therapy?
A1: It demonstrated an improvement in the composite primary cardiovascular endpoint when ezetimibe was added to simvastatin.
A2: The clinical efficacy of evolocumab added to statin therapy in reducing cardiovascular events in patients with atherosclerotic cardiovascular disease.
A3: The safety and efficacy of alirocumab in reducing major ischemic cardiovascular events in patients with acute coronary syndrome.
A4: It showed a 44% reduction in cardiovascular events in patients with high inflammation levels, suggesting benefits beyond LDL lowering.
A5: That patients with higher inflammation levels would benefit from statin therapy, even with normal cholesterol levels. In patients with relatively normal levels of cholesterol (LDL cholesterol < 130 mg/dL), patients with higher levels of inflammation as measured by high-sensitivity CRP (>2.0 mg/dL) would benefit from statin therapy.
