BPK 305 - Lecture 19

Arteriosclerosis

hardening of the arteries due to arterial wall thickening and loss of elasticity

Atherosclerosis

hardening due to intimal lesions

Characteristics of atheromas

- soft yellow, cholesterol rich core

- white fibrous cap

- protrude into vessel lumen

Where are plaques common?

- large to small arteries

- coronary and carotid

- aorta

- particularity where there are bifurcation points

Cardiovascular effects of plaques

1. Decrease effective vessel radius

2. Rupture

3. Increased risk of embolism

Plaques in the coronary arteries

- impede local vasodilation reflex

- vasodilator reserve is reduced

- tolerance to exercise is reduced

What can the reduced vasodilator reserve cause?

Angina or myocardial infarction

Plaque rupture

- exposes collagen and other thrombogenic substances

- local thrombus

- partial or complete vessel occlusion

How do plaques increase risk of embolism

debris becomes lodged downstream

Thromboembolism

the thrombus or debris from ruptured plaque (embolus) lodges in and blocks a vessel downstream of the ruptured plaque

Classic risk factors for atherosclerosis

- hypercholesterolemia

- dyslipidaemia

Dyslipidaemia

- incorrect lipid balance

- altered ratio of LDL and HDL

LDL

Transports cholesterol from the liver to tissues

HDL

Transports cholesterol from tisses to the liver

LDL structure

Apoprotein B

HDL structure

Apoprotein A

How do we know lipids are involved in atherosclerosis?

1. Epidemiological studies

2. Genetic disorders

3. Transgenic mice

4. Pharmacological interventions

Genetic disorders that increased risk of CV disease

- tangier

- familial hypercholesterolemia

Tangier disease

- congenital mutation in ABC protein

- ABC enables cholesterol to exit tissue and bind to Apoa1 of HDL

- decreases HDL in blood and increases CV disease risk

ABC

ATP binding cassette

Familial Hypercholesterolemia

- mutation in tissue LDL receptor. APOB and PCSK9

- increased LDL concentration

- increased CV disease risk

How do transgenic mice show that lipids are involved?

- overexpression of ApoB

- increased development of atherosclerosis and CHD

- increased CVD risk

Pharmacological interventions for atherosclerosis

- statins

- alirocumab

- inclisiran

Statins

- lipid lowering drug

- reduce cholesterol synthesis by blocking HMG-coA reductase in the liver

- secondary anti inflammatory effect

- decreased CVD risk

Alirocumab

- PCSK9 inhibitor

- PCSK9 decreases LDL receptors in the liver

- LDL levels decrease

Inclisiran

siRNA knockdown of PCSK9

Prophylactic prevention treatment of atherosclerosis

The side effects are too bad so not recommended

Decreasing dietary cholesterol in CVD treatment

Dietary cholesterol has nothing to do with blood cholesterol it is lipid intake

Classic atherosclerosis risk factors

- obesity

- diabetes 2x

- smoking 2x

- sedentary

- hypertension 1.6x

- gender

- hyperlipidemia

What do multiple atherosclerosis risk factors do?

Multiplicative

Why is atherosclerosis more likely in men?

Less circulating estrogen

1/2 the people who die from atherosclerosis

Don't have classical risk factors

Emerging diagnostic indicators

1. CRP

2. Bacteria/viruses

3. Hyperhomocystinemia

4. Lipoprotein A

5. Blood iron concentration

6. Platelet aggregation

7. Erectile dysfunction

8. Periodontal disease

CRP and atherosclerosis

- released from the liver in responses to cytokines

- indicator of inflammation and infection

Bacteria/viruses and atherosclerosis

- implicated in atherosclerosis, chronic inflammation, leukocytes, and lipid accumulation

- bacteria and viruses found in plaques

Hyperhomocysteinemia and atherosclerosis

- increased homocysteine associated with CHD and increased oxidative stress

- folic acid reduces homocysteines but has an uncertain therapeutic efficacy

Lipoprotein A and atherosclerosis

Genetic variant of LDL associated with increases coronary and cerebrospinal disease

Blood iron concentration and atherosclerosis

- pro oxidative

- premenopausal women are protected

Platelet aggregation and atherosclerosis

increases susceptibility to aggregation

Erectile dysfunction and atherosclerosis

- warning sign for impaired vascular health

- high CRP promotes

Periodontal disease and atherosclerosis

20% higher risk of CHD due to inflammatory disease