Ectopic Cardio Vascular Disease 1 - intro. Don't ask why this is here. Flashcards
(41 cards)
What is CVD?
Cardiovascular disease refers not just to ‘heart disease’, but also to all diseases of the heart and circulation, including coronary heart disease (angina and heart attacks) and strokes.
These are linked by their potential cause being atherosclerosis, the production of a fatty plaque (atheroma) inside the blood vessels.
Describe the global epidemiology of CVD.
In a population of over 7.3bn, 57m deaths occur per annum. Of these, AIDS is responsible for 2.9m, TB for 1.7m and malaria for 1.2m. CVD on the other hand causes 17.3m deaths per year, around 30% of all deaths.
There is an inverse correlation between wealth and CVD incidence due to improvements in lifestyle and diet.
CVD kills men 2-3x more often than women, but the effect is age dependent. CVD is far more common in young men than women. But as age increases this trend decreases to the point of inversion, at the approximate age of menopause, whose hormonal changes are linked to CVD.
At what age does CVD develop?
Early forms of atherosclerosis are very frequently present in 20-30 year olds, and 17% of US teenagers were found to have small atherosclerotic plaques in their arteries (Tuzcu et al, 2001). Even children younger than 13 showed significant fatty streaks.
Astoundingly, studies on premature babies even showed that such fatty streaks can develop in utero, a phenomenon that correlates with the cholesterol levels in the mother.
However, these early forms of atherosclerosis are reversible through lifestyle change.
What are the non-modifiable risk factors of CVD?
• Gender
• Age
o > 50 years
o Post-menopause
• History of disease
o Personal
o Family
What are the modifiable risk factors of CVD?
• Smoking • High blood pressure • Diabetes mellitus • Central Obesity • Sedentary lifestyle • High sodium intake • High alcohol intake • Psychological stress • High levels of Homocysteine • High cholesterol levels o Elevated LDL o Decrease HDL
What are the layers of an artery?
The intima, media and adventitia, or alternately the tunica intima, tunica media and tunica externa.
Describe the intima.
The innermost layer, called the intima, is a monolayer of endothelial cells with a base of collagen and proteoglycans through which a sheet of elastic fibres – the internal elastic lamina – runs.
Describe the media.
The media is a layer of smooth muscle cells (SMCs) that enable some control of vascular diameter through vasodilation and constriction.
This is bordered on the inner side by the internal elastic lamina and on the outer side by the external elastic lamina.
Describe the adventitia.
The outer layer, the adventitia, is a thick layer of connective tissue interspersed with SMCs, fibroblasts, nerves and small blood vessels (vasa recta) that supply the artery itself. This layer provides strength and elasticity to the blood vessel.
What are the roles of the endothelium?
- Regulation of vasomotor tone (the tension in the smooth muscle of the media)
- Prevents spontaneous thrombosis
- Modulates immune function through expression of adhesion molecules
- Lipid transport
- Cell transport (both active and passive)
- Vascular remodelling through cellular growth
What is viable endothelium?
Viable endothelium is the name given to the intended quiescent, protective phenotype. However, damage to the endothelium can lead to endothelial dysfunction.
What are the primary causes of damage to the endothelium?
• Turbulent blood flow
• Free Radicals/Toxins
• Oxidised LDLs
o Product of Hypercholesterolemia
• Glycated proteins
o A consequence of diabetes
• Bacterial or viral infection
o Causes Systemic inflammation
The endothelium can be damaged just by the normal continuous exposure to the high pressure of the artery lumen, and damage has also been linked to dietary imbalance, smoking and even poor dental hygiene.
What effect does shear stress have on the endothelium?
This is linked to increased endothelial stability as it activates the mechanical receptors in the cells, causing them to increase production of NO and leads to inhibition of the angiotensin 2 receptor which reduces blood pressure.
This is particularly true of unidirectional laminar flow and pulsatile shear stress.
What effect does disturbed blood flow have on the endothelium?
Regions of disturbed flow, such as artery bifurcations, branch points and regions of high curvature in the artery reduce the shear stress and have high risk of atherogenesis.
This acts through upregulation of inflammatory pathways and atherogenic factors, including ROS, NF-κB, VCAM-1 and MCP-1.
What is the first form of atherosclerosis?
Atheromata develop first as fatty streaks in the intima, a stage which, due to its reversibility, is increasingly an area of study in order to design therapies that stabilise or reduce the size of the streaks.
The size/presence of fatty streaks is a metric which can now be externally monitored by ultrasound or, in a very recent development, PET-CT scans.
What often occurs in tandem with fatty streak formation?
This often occurs in tandem with adaptive thickening of the smooth muscle, though neither is the cause of the other – their coincidence is due to a shared tendency to form in response to varying hemodynamic forces.
Adaptive thickening occurs in defined places, a process that begins at birth.
What are type II lesions?
Stary et al, 1995, describe six lesion types which represent a common sequence of events in the development of an atheroma. Type II lesions are when the fatty streaks attract monocytes that ingest enough of the lipid to become foam cells.
What are type III and IV lesions?
Stages III and IV (preatheroma and atheroma) are largely characterised by the increased deposition of extracellular lipid. Type V, the fibroatheroma, is caused by fibrous thickening due to thrombotic deposits and calcification which gradually occlude the artery.
What are type V lesions?
In type VI complicated lesions, fissures have been produced which allow for clotting of blood within the gaps which recruits blood cells into an external thrombus.
Modern classifications identify intermediate classes both above and below type VI
What is the Response-to-Injury Hypothesis?
This is the modern explanation for the processes histologically identified. In this model, the damage to the endothelium (endothelial activation) by the accumulation of lipids leads to inflammation.
This inflammation leads to expression of adhesion molecules on the endothelium and subsequent monocyte recruitment.
What occurs after monocyte recruitment in the Response-to-Injury Hypothesis?
The monocytes then migrate into the intima to the edge of the fat deposits and differentiate into macrophages, after which they ingest lipids to form foam cells.
The lipid deposition and foam cell generation stimulates the reparative response in which smooth muscle cells proliferate and migrate into the intima and over the fat deposit to produce an extracellular matrix – the fibrous cap that is observed. This is what leads to calcification, plaque fissure and thrombus formation – i.e. the formation of a complex lesion.
When does an atheroma begin producing symptoms?
Until the fibrous cap develops the atheroma is clinically silent, as the lumen size is not affected due to compensatory widening and the fat deposit growing outwards.
However, the fibrous cap does lead to narrowing of the lumen, restricting blood flow and causing angina. Detachment of the thrombus is what leads to myocardial infarction/stroke.
How are lipids internalised in healthy endothelia?
LDLs move into the intima due to interaction with the LDL receptors present, and are typically disgorged of their cargo and released back into the bloodstream as HDLs, having provided the artery with the lipids that cells require.
The LDLs are kept in a reduced state within the endothelium due to the anti-oxidant capacity of the cells.
What occurs during lipid internalisation in activated endothelium?
When the endothelium is dysfunctional it is unable to maintain its antioxidant capacity, leading to production of oxidised LDLs within the endothelium.
These ox-LDLs exacerbate endothelium damage, promoting further deposition of LDLs to become oxidised, creating a positive feedback loop of death.
