Lecture 38: Clinical Translation and Novel Genetic Mechanisms for Atherosclerosis

Question 1

What are the clinical risk factors of atherosclerosis?

Answer 1

1. Age and gender (old and male)
2. Lipoprotein disorders (LDL, cholesterol, apoB cholesterol proteins)
3. HTN
4. Diabetes mellitus (not the sugar but the inflammation/insulin resistance)
5. Family history of premature CHD
6. Smoking

Question 2

How does age and gender predispose one to atherosclerosis?

Answer 2

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

Question 3

What are the predictors of lipid risk for atherosclerosis?

Answer 3

1. Total and LDL cholesterol is a direct measure
2. HDL is inverse
3. Triglycerides is direct and independent of LDL
4. Lp(a) is inverse = lipoprotein a that is seen in HDL

Question 4

What is stage I HTN?

Answer 4

140-159/89-99

Question 5

What is Stage II HTN?

Answer 5

> 160/>100

Question 6

Why is diabetes a heart disease equivalent?

Answer 6

Because it confers as much risk of future CVD as existing heart disease without diabetes

Question 7

According to Baigent et al in the Lancet, what is the significance of lowering LDL?

Answer 7

Reducing LDL reduces ALL TYPES of CV events

40mg/dl reduction = 23% reduction of all coronary events

Question 8

How does one assess risk for CVD?

Answer 8

1. Count the number of risk factors
2. Use Framingham scoring for persons with >2 risk factors to determine absolute 10-year CHD risk
3. estimated risk decides LDL goals
4. secondary focus on non-HDL, metabolic syndrome, novel risk factors and imaging

Question 9

What is the profile of a metabolic syndrome patient?

Answer 9

1. abdominal obesity
2. high cholesterol (LDL levels)
3. high triglycerides
4. low HDL
5. high BP
6. insulin resistance

Question 10

What are the triglyceride rich lipoproteins?

Answer 10

VLDL
VLDL®
IDL
Significant because elevated TGs are independent CHD risk factor

Question 11

What is more atherogenenic, small, partly catabolized TG-rich lipoproteins (triglyceride-rich lipoprotein remnants) or new secreted TG-rich remnants?

Answer 11

Remnant lipoporteins are more atherogenic
Intermediate in size between VLDL and LDL
Aka IDL

Question 12

What is the significance of non-HDL-C?

Answer 12

It is a secondary therapeutic target to those who have high TG levels

Question 13

What is IDL?

Answer 13

Intermediate density lipoprotein
In between VLDL and LDL in size
Aka lipoprotein remnant

Question 14

What are novel risk factors for atherosclerosis?

Answer 14

1. inflammatory markers screening
2. Lp(a), particle density
3. subclinical atherosclerosis imaging

Question 15

What is the significance of inflammatory markers in atherosclerosis?

Answer 15

An emerging risk factors that is being measured for risk of CV disease
Examples: CRP, IL-6

Question 16

What is the odds ratio of CRP for coronary heart disease according to Danesh et al 2004, NEJM?

Answer 16

1.45 (1.25-1.68)

Question 17

Is CRP a causal factor for atherosclerosis?

Answer 17

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

Question 18

What are the key characteristics of Lp-PLA2?

Answer 18

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

Question 19

What are the most significant inflammatory markers for atherosclerosis?

Answer 19

1. CRP

2. LP-PLA2

Question 20

What is the significance of ADAMTS7?

Answer 20

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

Question 21

What is the significance of ABO (a locus in 9q)?

Answer 21

Puts shit on RBC to make it ABO type

Now also associated with shit like pancreatic cancer and LDL levels

Question 22

What do we know about atherosclerosis risk factors?

Answer 22

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