PBL 4

Question 1

What is the underlying mechanism for the right thigh pain Gladys Legion experienced while shopping in Sam’s Club?

Answer 1

Atherosclerosis → decreased flow → decreased oxygen to the tissues in the legs (increased demand for oxygen when she is shopping in Sam’s Club) → decreased H+ pump through ATP synthase → increased H+ in the tissues → stimulates TRPV1 receptor on C fibers → STT → VPLT → primary sensory cortex → exertional pain

Question 2

What is the underlying mechanism for lactic acid production in PAD?

Answer 2

• decreased peripheral perfusion → bioavailable NO is diminished due to dysfunctional endothelial cells
• If low blood flow, then CO2 will not be carried away as readily (increase H+ ions)
• Muscle will switch to anaerobic glycolysis (lactic acid production and lower pH).
  
  • TRPV1 receptors on C → STT → VPLT → primary sensory cortex → exertional pain

Question 3

What are the five classes of drugs for treatment of dyslipidemias?

Answer 3

• Statins
  
  • Simvastatin, atorvastatin
• Fibrates
  
  • Gemfibrozil and fenofibrate
• Niacin
  
  • Nicotonic Acid
• Bile Acid Sequestrants
  
  • Colestipol
• Sterol Absorption Inhibitor
  
  • Ezetimibe

Question 4

What is the MOA of Statins? Describe their relative effects on LDL, HDL and triglyceride levels!

Answer 4

• MOA: Inhibit HMG-CoA reductase
• Effects:
  
  • significantly reduce cholesterol synthesis
  • Up-regulate LDL receptors on hepatocytes
  • Modest reduction in triglycerides

Question 5

What is the MOA of Fibrates? Describe their relative effects on LDL, HDL and triglyceride levels!

Answer 5

• MOA: Peroxisome proliferator-activated receptor-a (PPAR-a) agonists
  
  • function as ligands for the nuclear transcription receptor (the PPAR-a)
  • fibrates transcriptionally up-regulate LPL (lipoprotein lipase), apo A-I and apo A-II, and down-regulate apo C-III, an inhibitor of lipolysis
• Effects:
  
  • Decrease secretion of VLDL (very-low-density lipoproteins)
  • Increase HDL

Question 6

What is the MOA of Niacin? Describe their relative effects on LDL, HDL and triglyceride levels!

Answer 6

• MOA: Decreases catabolism of apo AI and reduces VLDL secretion
• Effects:
  
  • Increases HDL
  • Decreases lipoprotein (LDL)

Question 7

What is the MOA of Bile Acid Sequestrants? Describe their relative effects on LDL, HDL and triglyceride levels!

Answer 7

• Binds to bile acids in the intestine and forms a nonabsorbable complex that is excreted in feces.
• Partial removal of bile acids from the enterohepatic circulation via this mechanism results in increased conversion of cholesterol to bile acids in the liver.
  
  • causes an increased demand for cholesterol in liver cells, resulting in a compensatory increase in hepatic uptake (and thus systemic clearance) of circulating LDL-cholesterol.
  • Increases cholesterol catabolism
  • Up-regulates LDL receptors
• Effects:
  
  • Decreases LDL

Question 8

What is the MOA of Sterol Absorption Inhibitor? Describe their relative effects on LDL, HDL and triglyceride levels!

Answer 8

• MOA: Blocks sterol transporter NPC1L1 in intestine brush border; Localizes at brush border of small intestine and inhibits absorption of cholesterol, resulting in decreased delivery of intestinal cholesterol to liver.
• Effects
  
  • Inhibits reabsorption of cholesterol excreted in bile
  • Decreases LDL and phytosterols

Question 9

What is the role of statins in reducing cardiovascular risk?

Answer 9

• help the lining of the blood vessels work better (improved endothelial function)
• enhance the stability of atherosclerotic plaques
• reduce the amount of inflammation and damage done to cells through oxidation (oxidative stress)
• keep platelets from clumping together (platelet aggregation), thereby reducing the risk of a blood clot (thrombus)
• reduce risk of mortality, myocardial infarction, and stroke in adults with coronary artery disease
• Reduce LDL up to 67%

Question 10

What is the mechanism of action of aspirin in the treatment of claudication?

Answer 10

• MOA: irreversible COX I and II inhibitor.
• Stops the synthesis of prostaglandin and thromboxane (responsible for platelet activation)
• Baby ASA preferentially inhibits TXA production, leading to an overall vasodilatory effect (PGI2 is vasodilatory and is not inhibited at 81mg dose)

Question 11

What is the pathogenesis of atherosclerosis?

Answer 11

• LDLs in the vasculature → damage to endothelium allows lipids to leak into intima
• Lipids are oxidized and then consumed by macrophages via scavenger receptors, resulting in foam cells.
• Foam cells and LDL accumulate → max release of cytokines
• Inflammation and healing leads to deposition of extracellular matrix and proliferation of smooth muscle → increasing resistance
• Platelet adhesion and accumulation → Fibrous plaque formation → atherosclerosis

Question 12

What are the modifiable risk factors of atherosclerosis?

Answer 12

• Hypertension
• Hypercholesterolemia
• Smoking
• Diabetes

Question 13

What are the non-modifiable risk factors of atherosclerosis?

Answer 13

• Age
• Gender
  
  • increase risk in males and postmenopausal females
• Genetics

Question 14

What is the anatomy, histology, pathology and potential complications of thoracic aortic aneurysms?

Answer 14

• Balloon like dilation of thoracic aorta; due to weakness in aortic wall.
• Seen in tertiary syphilis; endarteritis (inflammation of inner lining of artery) of the vasa vasorum results in luminal narrowing, decreased flow, and atrophy of the vessel wall.
• Major complications: dilation of the aortic valve root, resulting in aortic valve insufficiency (regurgitation). Can also cause compression of mediastinal structures

Question 15

What is the anatomy, histology, pathology and potential complications of abdominal aortic aneurysms?

Answer 15

• Balloon-like dilation of the abdominal aorta; usually arises below the renal arteries but above the aortic bifurcation
• Primarily due to atherosclerosis → increases the diffusion barrier to the media → resulting in atrophy and weakness of the vessel wall
• Presents as a pulsatile abdominal mass that grows
• Major complication is rupture; presents w/ triad of hypotension, pulsatile abdominal mass, and flank pain

Question 16

What are the risk factors for AAA development?

Answer 16

• Atherosclerosis
• HTN
• Age >60 years
• Smokers are 8x more likely to be affected
• History of heart disease or PAD
• Gender → 5x more likely in men than in women.
• Ethnicity → white men
• People who have a family history of aneurysms tend to develop aneurysms at a younger age and are at higher risk of rupture
• Hypercholesterolemia
  
  • Elevated levels of LDLs and total cholesterol are enough to start lesion formation.
• Genetic conditions: Marfan syndrome, Ehlers-Danlos syndrome and Loeys-Dietz syndrome

Question 17

What are the risk factors for AAA rupture?

Answer 17

• Cardiac or renal transplant
• Decreased forced expiratory volume in one second
• Female sex → 2x increase in risk of rupture
• Higher mean blood pressure
• Larger initial AAA diameter (>5cm)
• Current tobacco use (length of time smoking is more significant than amount smoked)

Question 18

What is the pathophysiology of acute aortic dissection?

Answer 18

• Hypertension results in hyaline arteriolosclerosis of the vasa vasorum
  
  • decreased flow causes atrophy of the media.
• blood passes through an intimal tear, separating the intima from the medial layers and creating a false lumen
• Marfan syndrome (mutation on the FBN1 gene on chromosome 15, FBN1 gene encodes matrix protein fibrillin 1 leading to structural weakness of tissues)
• Ehlers-Danlos syndrome (genetic or structural mutation causes abnormal collagen synthesis resulting in reduced tensile strength of connective tissue and tissue fragility) lead to weakness of the connective tissue in the media

Question 19

What is the pathophysiology of Raynaud’s phenomenon?

Answer 19

• Type of peripheral arterial disease characterized by decreased blood flow to skin due to arteriolar vasospasm in response to cold temps or emotional stress
  
  • Thought to be an exaggeration of the normal response to cold temperatures/stress.
• Raynaud’s disease → when it is primary (idiopathic) 90%
• Raynaud’s syndrome → when it is secondary to a disease process such as mixed connective tissue disease, SLE, or CREST syndrome

Question 20

What are the major risk factors for developing peripheral vascular disease?

Answer 20

• Smoking (greatest and most modifiable)
• Poor Diet
• Lifestyle/exercise or lack of
• Diabetes
• Hypertension
• Hyperlipidemia

Question 21

What is the clinical presentation of a typical patient with claudication?

Answer 21

• Intermittent claudication may be the sole manifestation of early symptomatic PVD.
• Level of arterial compromise and location of claudication are closely related:
  
  • Aortoiliac disease manifests as pain in the thigh and buttock vs. femoral-popliteal disease manifests as pain in the calf.
• Symptoms are precipitated by walking a predictable distance and are relieved by rest.
• Claudication may also present as the hip or leg “giving out” (limping) after a certain period of exertion
• The pain of claudication usually does not occur with sitting or standing.
• Distal hair loss
• Hypertrophic nails
• Ulcers

Question 22

What are 3 ways besides claudication that peripheral vascular disease can present clinically?

Answer 22

• Leriche syndrome (aortoiliac obstructive disease)
  
  • fatigue of both lower extremities
  • erectile dysfunction
  • pallor and global atrophy of both lower extremities
• Cool skin, any bruit (iliac, femoral or popliteal), any palpable pulse abnormality
• Walking impairment, presence of nonhealing wounds
• Hair loss or slower than normal hair growth on lower extremities. Decreased toenail growth

Question 23

What is the significance of the ankle brachial index test results in assessing peripheral vascular disease?

Answer 23

• Compares BP measured at the ankle with BP measured at the arm
• Divide the systolic blood pressure at the arteries near the ankle by the systolic blood pressure in the arms
  
  • No blockage → 1.0 to 1.4
  • Blockage → 0.9 or less
    
    • This increases the risk of circulatory problems
    • Possibly causing heart disease or stroke
  • Rigid arteries → more than 1.4
    
    • The patient’s arteries are rigid and don’t compress when the blood pressure cuff is inflated.

Question 24

What are three historical methods that could be applied to identify genes associated or causal to peripheral artery disease?

Answer 24

1. Candidate Gene Approach
2. Linkage analysis (old)
3. Genome-Wide Associated Studies (GWAS)

Question 25

What is Candidate Gene Approach testing?

Answer 25

Typically a case-control approach that searches for a statistical association between a specific genetic variant (ie, a SNP) and a disease of interest

Question 26

What is Linkage Analysis?

Answer 26

• A family-based approach in which the genome is scanned for prespecified DNA markers that are known to be highly variable (ie, microsatellites).
• Regions that are found more commonly in the diseased members of the family are said to be linked to the causative gene, which is then pursued with fine mapping
• AKA = positional cloning

Question 27

What is GWAS?

Answer 27

• A novel approach in which SNPs are genotyped across the entire genome in subjects with and without a given disease (involves thousands of people across the world).
• SNPs that differ in frequency between cases in comparison with controls are “associated” with disease