Lecture 38: Clinical Translation and Novel Genetic Mechanisms for Atherosclerosis Flashcards
What are the clinical risk factors of atherosclerosis?
- Age and gender (old and male)
- Lipoprotein disorders (LDL, cholesterol, apoB cholesterol proteins)
- HTN
- Diabetes mellitus (not the sugar but the inflammation/insulin resistance)
- Family history of premature CHD
- Smoking
How does age and gender predispose one to atherosclerosis?
Older and men
But death rates for men have gone down because smoking/disease modification has been more successful in men
Also women grow to be of an older age
What are the predictors of lipid risk for atherosclerosis?
- Total and LDL cholesterol is a direct measure
- HDL is inverse
- Triglycerides is direct and independent of LDL
- Lp(a) is inverse = lipoprotein a that is seen in HDL
What is stage I HTN?
140-159/89-99
What is Stage II HTN?
> 160/>100
Why is diabetes a heart disease equivalent?
Because it confers as much risk of future CVD as existing heart disease without diabetes
According to Baigent et al in the Lancet, what is the significance of lowering LDL?
Reducing LDL reduces ALL TYPES of CV events
40mg/dl reduction = 23% reduction of all coronary events
How does one assess risk for CVD?
- Count the number of risk factors
- Use Framingham scoring for persons with >2 risk factors to determine absolute 10-year CHD risk
- estimated risk decides LDL goals
- secondary focus on non-HDL, metabolic syndrome, novel risk factors and imaging
What is the profile of a metabolic syndrome patient?
- abdominal obesity
- high cholesterol (LDL levels)
- high triglycerides
- low HDL
- high BP
- insulin resistance
What are the triglyceride rich lipoproteins?
VLDL
VLDL®
IDL
Significant because elevated TGs are independent CHD risk factor
What is more atherogenenic, small, partly catabolized TG-rich lipoproteins (triglyceride-rich lipoprotein remnants) or new secreted TG-rich remnants?
Remnant lipoporteins are more atherogenic
Intermediate in size between VLDL and LDL
Aka IDL
What is the significance of non-HDL-C?
It is a secondary therapeutic target to those who have high TG levels
What is IDL?
Intermediate density lipoprotein
In between VLDL and LDL in size
Aka lipoprotein remnant
What are novel risk factors for atherosclerosis?
- inflammatory markers screening
- Lp(a), particle density
- subclinical atherosclerosis imaging
What is the significance of inflammatory markers in atherosclerosis?
An emerging risk factors that is being measured for risk of CV disease
Examples: CRP, IL-6
What is the odds ratio of CRP for coronary heart disease according to Danesh et al 2004, NEJM?
1.45 (1.25-1.68)
Is CRP a causal factor for atherosclerosis?
No it is not causal
It is just prognostic
If you reduce CRP, you will not reduce risk of CV disease
According to Zacho et all NEJM 2008
What are the key characteristics of Lp-PLA2?
A possible causal factor leading to atherosclerosis
Thought to be derived from macrophages and upregulated in inflammation
Circulates on LDL and is pro-atherogenic
Hydrolyzes phospholipids to produce lysophopholipids
Could be drug therapy target
Serves the following role:
i. inhibition of NO production and synthesis
ii. induces endothelial dysfunction
iii. inhibits migration and stimulates proliferation of macrophages
Can modulate plaque development
What are the most significant inflammatory markers for atherosclerosis?
- CRP
2. LP-PLA2
What is the significance of ADAMTS7?
Locus for angiographic CAD
Degrades cartilage oligomeric matrix protein (COMP) and has been implicated in inflammatory arthritis and bone growth
Over-expression accelerates VSMC migration in vitro and exacerbates neointimal thickening after carotid injury
Suggests ADAMTS7 may regulate plaque size and can be a target for atherosclerosis
What is the significance of ABO (a locus in 9q)?
Puts shit on RBC to make it ABO type
Now also associated with shit like pancreatic cancer and LDL levels
What do we know about atherosclerosis risk factors?
Most loci completely novel
2/3 of patients have NO RELATIONSHIP with risk factors
Only 10% of heritability accounted for
So we still don’t know a whole lot
