Endothelial dysfunction

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Endothelial dysfunction

• Razeen Davids
• University of Stellenbosch Tygerberg Hospital

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The normal endothelium
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Control of vascular tone
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Smooth muscle cell function
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Dysfunctional endothelium
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Nitric oxide (NO)

• Key vasodilator
• From L-arginine via action of eNOS
• Anti-platelet, anti-inflammatory
• Prevents oxidation of LDL
• Activated by shear stress
• Inhibited by ADMA, GGPP, L-NAME, oxidative stress

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The dysfunctional endothelium

• Initial reports in 1980, 1986, 1990
• Many vascular beds
• Hypertension, diabetes, CAD, CHF, chronic kidney
  disease
• Precedes cardiovascular disease
• Metabolic syndrome, insulin resistance, smokers,
  sedentary lifestyle, hyperhomocysteinaemia

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Pathophysiology
Cardiovascular risk factors
Angiotensin II, oxygen radicals, lipids,
homocysteine
Endothelial dysfunction
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How to assess ED

• Endothelium-dependent vasodilation
• Acetyl choline or post-ischaemic FMD
• Coronary or forearm arteries
• Intima-media thickness
• Microalbuminuria
• Plasma markers
• ADMA, CRP, adhesion molecules
• Clinical diagnosis

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Prognostic implications of ED
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Insulin resistance

• ED occurs early in insulin resistance
• Also in IR relatives of diabetics
• Mechanism
• ?free fatty acids
• ? inflammatory adipokines
• ? oxidative stress
• ? oxidised LDL
• ? HDL
• hypertension, hyperglycaemia, hyperuricaemia

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AJM 2004117109-117
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Correcting ED

• BP reduction per se not effective
• Blockade of the RAS
• Lowering cholesterol
• PPAR-? agonists
• Antioxidants
• Reducing homocysteine levels
• Aspirin
• Exercise and weight loss
• Reducing hyperglycaemia

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Benefits of statins

• Many studies since 1994 showed benefit
• Six months six weeks one day
• Mediated via NO, blocked by L-NMMA
• Prevent inhibition of eNOS by LDL or caveolin-1,
  stabilised eNOS mRNA
• Increased PA and less PAI-1
• Reduce levels of inflammatory factors and
  adhesion molecules
• Inhibits SMC migration and proliferation
• Reduce oxidation of lipoproteins and uptake of
  oxidised LDL
• Reduces endothelin-1 and AT1 receptor expression
• Affects regulatory proteins via FPP and GGPP

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Thiazolidinediones and ED

• Activate PPAR-? which enhances insulin-mediated
  glucose uptake
• Reverses IR and many components of the metabolic
  syndrome
• Reduces progression to diabetes
• Improves endothelial function
• Anti-inflammatory effects

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Ongoing research

• DREAM and NAVIGATOR studies
• Function relevance of endothelial progenitor
  cells