Endothelium, Plaque Rupture, and Vascular Injury Flashcards
Normal endothelium is ______, ______, and ______.
anti-inflammatory, anti-thrombotic, and vasodilatory
While there are different mechanisms of ischemia depending on the vascular bed, all of them involve ______.
Endothelial dysfunction
What is endothelium?
A tissue consisting of a single layer of cells that lines the blood and lymph vessels, heart, and some other cavities.
Is endothelium the same between arteries, capillaries, veins, and lymphatics?
No, there are differences.
What are the 3 layers of normal artery wall?
Tunica intima, tunica media, tunica adventitia
What is in normal tunica intima?
Endothelium and thin layer of connective tissue
What is in normal tunica media?
Smooth muscle cells and connective tissue
What is normal tunica adventitia?
Loose connective tissue. Gives structure.
What happens in pathologic tunica media?
There is dysfunctional smooth muscle and excess connective tissue.
How does artery composition depend on level of artery?
Large arteries - more elastin (more recoil) Smaller arteries - more collagen Arterioles - more smooth muscle (because arterioles control vascular resistance)
What are 5 characteristics of normal endothelial cells?
- Impermeable to large molecules 2. Anti-inflammatory 3. Resist leukocyte adhesion 4. Promote vasodilation 5. Resist thrombosis
What are 5 characteristics of abnormal/activated endothelial cells?
- Increased permeability 2. Increased inflammatory cytokines 3. Increased leukocyte adhesion molecules 4. Decreased vasodilatory molecules 5. Decreased antithrombotic molecules
What are 3 characteristics of normal smooth muscle cells?
- Normal contractile function 2. Maintain extracellular matrix 3. Contained in medial layer
What are 3 characteristics of abnormal/activated smooth muscle cells?
- Increased inflammatory cytokines 2. Increased extracellular matrix synthesis 3. Increased migration and proliferation into subintima (behaves like cancer)
What was the first gas to be discovered as a signaling molecule in the body?
NO (nitric oxide)
Where is nitric oxide made and what enzyme makes it?
Endothelial cell, nitric oxide synthase
What is the does nitric oxide synthase convert into NO?
L-arginine
What are the cofactors used for converting L-Arginine into NO?
BH4, NADPH, Calmodulin
What does eNOS stand for?
Endothelial nitric oxide synthase
Where is eNOS expressed?
Luminal side of endothelium
What are 5 stimuli that eNOS responds to?
- Acetylcholine 2. Serotonin 3. Thrombin 4. Bradykinin 5. Shear Stress
Once NO is made in endothelium, where can it diffuse to?
Diffuses into smooth muscle in tunica media
What does NO do in the vascular smooth muscle cell?
cGMP-mediated vasodilation GTP -> cGMP
In disease states with decreased NO and presence of oxidative stress, what can happen via cascade and activation of genes?
In these states, signaling cascades can trigger inflammatory genes to be expressed which up regulates mRNA for creation of inflammatory proteins.
Some of the up-regulated inflammatory proteins from decreased NO and presence of oxidative stress allow for circulating monocytes to attach. What are these 3 proteins?
Selectins, cell adhesion molecules, and cytokines
What are selectins?
Selectins are proteins on the luminal side of endothelial cells that allow attachment of circulating monocytes (margination) so that they can enter the vessel wall.
What are foam cells?
They are macrophages that have engulfed LDL lipoproteins.
How do monocytes trigger formation of atherosclerotic plaque once entering the sub-endothelial space?
- Monocytes enter sub endothelial space and turn into macrophages 2. Macrophages engulf LDL and turn into foam cells 3. Foam cells are active in secreting cytokines which changes the phenotype of smooth muscle cells which causes them to start acting malignant, trigger apoptosis, trigger fibrosis, and trigger ongoing inflammation.
Foam cells actively secrete cytokines. What 4 things are triggered?
- Smooth muscle activation/migration/malignancy 2. Apoptosis 3. Fibrosis 4. Ongoing inflammation
What are the 3 general stages of atherosclerotic plaque progression?
- Fatty streak 2. Plaque progression 3. Plaque disruption
What is the fatty streak stage of atherosclerotic plaque? (4 things)
Endothelial dysfunction, lipoprotein entry and modification, leukocyte recruitment, foam cell formation
What is the plaque progression stage of atherosclerotic plaque? (2 things)
Smooth muscle cell migration, altered matrix synthesis and degradation
What is the plaque disruption stage of atherosclerotic plaque? (2 things)
Disrupted plaque integrity, thrombus formation
T lymphocytes can trigger foam cells to create Matrix Metalloproteinase. What does MMP do?
MMP degrades the fibrous cap in atherosclerotic plaque which makes the plaques unstable
Activated (abnormal) smooth muscle cells can express ____ and ____ which form the fibrous cap.
Collagen and elastin. These make the ECM that forms the fibrous cap.
What is the danger of plaque rupture?
The lipid core of plaques is composed of highly thrombotic components. When plaques rupture, clot formations happen.
What are 5 characteristics of a stable plaque?
- Rich in fibrous tissue 2. Calcified 3. Less lipid content 4. Less inflammation 5. Less apoptosis
____ plaques are less likely than ____ plaques to rupture and cause thrombotic events.
Stable, vulnerable
What are 5 characteristics of vulnerable plaques?
- Less fibrous tissue 2. Less calcified 3. More lipid content (more LDL, foam cells) 4. More inflammation 5. More apoptosis
What are two different outcomes of a ruptured plaque? both with serious consequences
- Acute MI 2. Healed rupture causes severely narrowed lumen and fibrous tunica intima
How does normal endothelium regulate thrombosis? Name 3 examples and what they do
The endothelium regulates thrombosis through surface molecules and secreted molecules. These include: Heparin sulfate (expressed on endothelium surface) which inhibits thrombin. NO (secreted by endothelium) which inhibits platelet activation Prostacyclin (secreted by endothelium) which inhibits platelet activation
The degree of _____ dysfunction is further progressed by _____ (unique to patients).
endothelial dysfunction, risk factors
What are 5 different mechanisms of ischemia?
- Narrowing of vessel by fibrous plaque 2. Plaque ulceration or rupture 3. Intraplaque hemorrhage 4. Peripheral emboli 5. Weakening of vessel wall
What is the mechanism of ischemia for Embolic Stroke?
Peripheral emboli
What is the mechanism of ischemia for Thrombotic Stroke?
Plaque ulceration or rupture, intraplaque hemorrhage
What is the mechanism of ischemia for Myocardial Ischemia?
Narrowing of vessel by fibrous plaque
What is the mechanism of ischemia for Unstable Angina?
Plaque ulceration or rupture, intraplaque hemorrhage
What is the mechanism of ischemia for Myocardial Infarction?
Plaque ulceration or rupture, intraplaque hemorrhage
What is the mechanism of ischemia for Atheroembolic Renal Disease?
Peripheral emboli
What is the mechanism of ischemia for Renal Artery Stenosis?
Narrowing of vessel by fibrous plaque
What is the mechanism of ischemia for Aneurysms?
Weakening of vessel wall
What is the mechanism of ischemia for Limb Claudication?
Narrowing of vessel by fibrous plaque
What is the mechanism of ischemia for Limb Ischemia?
Narrowing of vessel by fibrous plaque, peripheral emboli
What is the mechanism of ischemia for Raynaud’s Phenomenon?
Vasospasm in the presence of cold
What is a common site of atheroembolization for stroke events?
Carotid bifurcation lesion The source lesion does not need to be obstructive. Bits can break off and travel to cause stroke
What artery can be blocked by embolus (typically from carotid bifurcation lesion) to cause temporary or permanent blindness in one eye?
Ophthalmic artery
What is a common site of thromboembolization for stroke events?
Left atrial appendage (setting of atrial fibrillation)
Why is it important to recognize the difference between thromboembolization and atheroembolization?
The treatment is different. For thromboembolization (e.g. left atrial appendage thromboembolization from atrial fibrillation), you can use anti-coagulants. For atheroembolization, you need to treat the atherosclerosis.
While _____ and _____ are both manifestations of CAD, vascular pathology is different.
Myocardial infarction, chronic stable angina
What is the vascular pathology of myocardial infarction? and why is this a dangerous killer?
Ruptured plaque, in-situ thrombosis, not necessarily obstructive prior to rupture. This is particularly dangerous because patients can have plaques that are asymptomatic but when they rupture it causes MI and possibly leading to death.
What is the vascular pathology of angina?
Stable, obstructive plaques (>70% diameter reduction). Fixed obstruction leads to lack of O2 delivery which results in angina.
Are myocardial infarctions all of the same severity?
NO
What is the flow of events of a Myocardial Infarction that can be stabilized and treated?
Plaque rupture -> non-occlusive thrombosis -> some flow but intermittent occlusion or embolization -> stabilize with anticoagulation/vasodilators
What is the flow of events for a Myocardial Infarction that cannot be stabilized?
Plaque rupture -> occlusive thrombus -> no flow -> clinical emergency -> recanalize
What is a sequela(e)?
A sequela is a pathological condition resulting from a disease, injury, therapy, or other trauma
What is the most benign outcome of a coronary thrombus from ruptured coronary plaque? What kind of patients are more likely to have these benign events?
The most benign outcome is when the thrombus is small and non-flowlimiting. In these cases, there are no ECG changes and the case is resolved with healing and plaque enlargement. The plaque enlargment results in a more severe stenosis of the site.
Patients that are more likely to have these benign events probably have their risk factors well managed (not smoking, treating hypertension, controls diabetes, aspirin to limit thrombosis, etc)
What 2 diagnosis can you arrive at with a partially occlusive thrombus? What finding allows you to differentiate between the 2 diagnosis?
Partially occlusive thrombus causes unstable angina or non-ST-segment elevation MI. On ECG, these BOTH have ST segment depression and/or T wave inversion.
Unstable angina shows negative for serum biomarkers (troponin).
Non-ST-segment elevation MI shows positive for serum biomarkers (troponin).
TRUE or FALSE: Partially occlusive thrombus events (unstable angina or non-st-segment elevation MI) are not urgent.
FALSE! These are urgent events. You typically aim to do angiogram and revascularization within 24 hours.
What is the most severe outcome of ruptured coronary plaque causing coronary thrombus? How is it diagnosed?
Occlusive thrombus causing ST-segment elevation MI.
Manifests as unrelenting chest discomfort. On ECG, ST elevation occurs and Q waves appear later. Positive serum biomarkers (troponin)
What is the proper response to an ST-segment elevation MI?
These are emergencies! You need to try to get the artery unobstructed within 90 minutes. Typically done with angioplasty (mechanical) or thrombolytic (pharmaceutical).
_____ and _____ are manifestations of peripheral arterial disease but their underlying endothelial pathology differs.
Claudication, acute limb ischemia
What is the vascular pathology of claudication?
Similar/same as angina.
Obstructive, stable plaque. (>70% diameter reduction)
What is the vascular pathology of acute limb ischemia?
Acute event obstructs blood flow without prior development of collaterals. Could be atheroembolization or thromboembolization. Rarely in-situ thrombosis.
Are stable or unstable plaques more biologically active?
Unstable
What kind of plaque (stable or unstable) cause angina and claudication (exertional ischemia)?
Stable plaques
What kind of plaques are less likely to cause thrombotic and embolic events?
Stable plaques
What kind of plaque (stable or unstable) causes MI and stroke?
Unstable
TRUE or FALSE: Venous thrombosis and arterial thrombosis have different vascular pathology.
TRUE
What are two issues caused by venous thromboembolic disease?
Deep Venous Thrombosis, Pulmonary Embolism
What 6 factors are characteristic of venous thrombosis (in comparison to arterial thrombosis)?
- Fibrin rich
- More RBC
- Areas of Stasis
- Genetic predisposition
- Environmental predisposition (plane for 20 hours, or just had knee surgery and immobile in bed)
- Treated with anticoagulation
What 5 factors are characteristic of arterial thrombosis (in contrast to venous thrombosis)?
- Platelet rich
- Plaque rupture
- Areas of high flow
- Atherosclerosis, trauma, Anti Phospholipid Antibody Syndrome (acquired)
- Focus more on antiplatelet therapy
What’s the difference between Primary and Secondary Raynaud’s Phenomenon?
Primary is more common in younger people and is not associated with other disorder/disease/tissue loss.
What are vasospastic disorders?
These are disorders where endothelium is dysfunctional but not necessarily with thrombosis or atherosclerosis.
What is an example of a vasospastic disorder?
Raynaud’s Phenomenon
What is Raynaud’s Phenomenon?
It is a disorder where there is excessively decreased blood flow to fingers, toes, and occasionally other areas during times of high stress or cold temperature.
