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181 cholesterol independent therapeutic effects of hdl


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181 cholesterol independent therapeutic effects of hdl

  1. 1. Editorial Slides VP Watch, February 26, 2003, Volume 3, Issue 8 Cholesterol Independent Therapeutic Effects of HDL Morteza Naghavi, MD
  2. 2. –The inverse correlation between high-density lipoproteins (HDL) and cardiovascular atherosclerotic disease is “well known”. –However, the underlying mechanisms of actions for beneficial effects of HDL remain to be completely elucidated.
  3. 3. –Although HDL acts mainly by reversing the cholesterol transport and inhibiting the oxidation of low- density lipoproteins, several lines of evidence suggest that HDL can also act directly in cholesterol- independent ways including inhibition of endothelial cell adhesion molecule expression1 and facilitating release of prostacyclin2 from endothelial cells.
  4. 4. –Besides being a strong independent predictor of the occurrence of primary coronary events, a low plasma HDL cholesterol level is also associated with unfavorable prognosis in patients who have recovered from a myocardial infarction. 5
  5. 5. –Whether this association reflects accelerated atherogenesis or a direct detrimental effect of a low HDL level on postischemic myocardial function is unknown. –A low HDL level adversely influences postinfarct left ventricular function in patients with a first myocardial infarction, independent of the severity of coronary atherosclerosis6.
  6. 6. –As featured in VP Watch of this week, Calabresi et al3 investigated the possible direct cardio protective effect of HDL administered 10 minutes before ischemia on the isolated rat heart which underwent 20-minute low-flow ischemia followed by a 30-minute reperfusion.
  7. 7. The analyzed the following parameters: – postischemic functional recovery, – creatine kinase release in the coronary effluent, – expression and content of tumor necrosis factor-α in the myocardium and – coronary effluent and prostaglandin release. In addition, the effect of the recombinant TNF- α-blocking protein etanercept on the functional recovery was also studied.
  8. 8. Control This figure shows the changes in cardiac function recovery in rat hearts perfused with saline (circles),This figure shows the changes in cardiac function recovery in rat hearts perfused with saline (circles), HDLs at 0.5 mg/ml (triangles) and 1.0 mg/ml (inverted triangles).HDLs at 0.5 mg/ml (triangles) and 1.0 mg/ml (inverted triangles). LVDP indicates left ventricular developed pressure; CPP, coronary perfusion pressure..LVDP indicates left ventricular developed pressure; CPP, coronary perfusion pressure.. HDL showed a dose-dependent beneficialHDL showed a dose-dependent beneficial effect on cardiac functioneffect on cardiac function Increase in HDL dose
  9. 9. Etanercept caused a dose-dependent improvement in functional recovery. The lipid-free apoA-I did not reproduce the effects of HDL. Reconstituted HDL containing apoA-I and phosphatidylcholine. However, had the same effect as native HDL.
  10. 10. HDL increased prostaglandin release in the coronary effluent in a dose-dependent manner
  11. 11. – In an accompanying editorial in Circulation Research, Dipak Das4 discussed all the known possible scenarios that contribute to the effect of HDL on cardio-protection from ischemia/reperfusion injury.
  12. 12. Conclusion: • HDL exerts multiple beneficial effects on parameters involved in ischemia/reperfusion mediated cardiac injury. • This may have major therapeutic implications in the near future.
  13. 13. Question: • What could be the underlying mechanism(s) for direct cardio- protective effect of HDL on myocardium? –Anti-inflammatory? –Anti-oxidant? –Anti-Apoptotic? –Cholesterol reverse transfer?
  14. 14. Question: • Is the anti-inflammatory effect of HDL specific to ischemia- reperfusion injury of myocardial cells or it can exerts similar effects on other types of cells and tissues as well?
  15. 15. Question: • As far as reducing adverse cardiovascular events, do you think the cardio-protective effect of HDL may turn out to be more important than its anti- atherosclerotic effect?
  16. 16. Question: • Since HDL has some degree of protective effect against stroke, is it safe to assume that anti- atherosclerotic effect of HDL in coronary heart disease may be equal to its anti-stroke effect?