Cardio 14 – Atherosclerosis
Anil Chopra
INTRO
1&2. Know the changes in the walls of the arteries that lead to atherosclerosis & how atherosclerosis leads to clinical manifestations.
Risk Factors of Atherosclerosis:
Modifiable: Non Modifiable
-Smoking- Age
-High blood pressure- Sex
-High cholesterol- Genetics
-Diabetes
-Lack of exercise
-Central obesity
Stenosis – loss of luminal diameter. This results in a reduction of blood flow and can lead to…
Ischaemia– insufficient blood supply to meet metabolic demands of the tissues causing hypoxic cellular dysfunction e.g. angina pectoris in heart or intermittent claudication in legs.
Atherosclerotic Plaque – area of fat deposition and tissue breakdown (necrosis) in arterial walls. This can lead to…
Plaque rupture – when the fibrous cap of tissue which separates the plaque from the blood is broken down or…
Plaque erosion – when the endothelial lining is broken down without fully rupturing the cap. This can result in…
Plaque Growth – platelets are recruited resulting in blood coagulation.
Occlusive thrombosis – total block of blood vessel resulting in cessation of blood flow.
Embolism – dislodgement of solid material. This can then cause occlusion at different sites – an embolus.
Transient Occlusion – short spell of ischaemia which resolves itself spontaneously e.g. “transient ischaemic attack” in hear or “amaurosis fugax”.
Infarction – death of tissue due to prolonged ischaemia e.g. “myocardial infarction” in heart or CVA (cerebrovascular accident – stroke).
Aneurysm – ballooning of artery wall due to advanced atherosclerosis. It puts pressure of the surrounding tissues.
Glagow Phenomenon – early expansion of arterial walls before the lumen actually gets smaller.
VASCULAR ENDOTHELIUM
- The importance of vascular endothelium for the health of blood vessels.
Vascular Endothelium
-Separates blood from other tissues
-Is incredibly extensive (surface area over 1000m2 weight over 100g)
-Is one cell thick (1-2μm wide and 10-20μm long).
-Synthesises antithrombotic factors (thrombomodulin, antithrombin, tPA)
-Synthesises procoagulant factors (von Willebrand factor, factor V, thromboxane)
-Synthesises growth factors
-Synthesises vasoconstrictors and vasodilators.
-Synthesises inflammatory mediators
-Synthesises enzymes for metabolism
-Is involved with leukocyte trafficking.
- The role of endothelium in regulating permeability and leukocyte recruitment.
-The endothelium regulates the permeability of the arterial walls and an increased permeability results in plasma proteins leaking into the space between the endothelium and the internal lamina (tunica Media) subendothelial space (contains collagen and glycoproteins).
-Endothelium is responsible for leukocyte recruitment.
-In atherosclerosis, instead of leukocytes adhering to post capillary venule endothelium, they adhere to subendothelial spaces of large arteries.
- Know the role of the flow in regulating nitric oxide and endothelial function.
In Laminar flow:
- Nitric oxide production is promoted by the O2 in the blood reacting with L-arginine to produce Nitric oxide under the action of eNOS (endothelial Nitric Oxide Synthase). This results in cGMP production which results in relaxation of smooth muscle & vasodilation.
- Endothelium survives
- Leukocyte cohesion inhibited
- Expansion of inflammatory genes inhibited.
In Turbulent flow:
- There is less O2 to react with L-arginine so less NO is produced.
- This promotes leukocyte adhesion and endothelial cell apoptosis.
Certain risk factors such as smoking and diabetes cause release of suproxide which reacts with the nitric oxide and uses it up:
O2-+ NO ONOO-
Suproxide + Nitric oxide peroxynitrite (this also
encourages tissue injury)
- The role of vascular endothelium in atherosclerosis.
1)Endothelial dysfunction: increased permeability to lipoproteins and encouraged leukocyte adhesion.
2)Fatty streak formation
3)Progression to advanced complicated lesions: fibrous cap covers a mixture of leukocytes, lipids and debris.
(1)(2)(3)
LIPIDS MACROPHAGES AND SMOOTH MUSCLE CELLS
- How lipoproteins that are deposited in the arterial wall stimulate macrophage functions.
Monocytes differentiate into macrophages once they migrate into the sub-endothelial space.
There, low density lipoproteins (LDL’s) which have also leaked into the subendothelial space become oxidatively modified by free-radicals.
These are phagocytosed by macrophages and stimulate chronic inflammation.
Brown and Goldstein proposed that a second LDL receptor in atherosclerotic regions which is not under negative feedback controls called “scavenger receptors” gets rid of modified LDL’s on macrophages.
- The protective and deleterious functions of macrophages resulting in chronic inflammation.
Macrophages
Generate the free radicals that oxidise the lipoproteins
Then phagocytose the modified oxidise LDL’s
Become foam cells
Secrete cytokine mediators that recruit more monocytes (e.g. TNF, IL-1)
Secrete chemoattractants (IL-8, MLL1) and growth factors for vascular smooth muscle
Secrete proteinases that degrade fibrous cap.
Secrete tissue factor that promotes coagulation
Die by apoptosis so contribute to plaque
Have oxidative enzymes that modify native LDL such as superoxide (iNOS) inducible Nitric Oxide Synthase, myeloper oxidase.
Growth Factors include:
- Platelet derived growth factors
- Fibroblast growth factor
- Transforming growth factor beta
- Vascular endothelial growth factor
3 & 4. The way in which vascular smooth muscle cells VSMC remodel the structure of the artery and protect plaque integrity & macrophage in plaque instability.
-Under the influence of free-radical stress, smooth muscles switch from contractile phenotype to “synthetic” phenotype. They then migrate to the extracellular matrix.
-They also cause proteolysis of the extra-cellular matrix, so the collagen is degraded.
-The necrotic core of the plaque is large and lipid-rich.
-The fiborous cap of the core is thin
-The smooth muscle and collagen content is low due to smooth muscle apoptosis.
-Macrophages also express tissue factor which initiates coagulation cascade.