Endothelial Dysfunction Hypercholesterolemia

1
Endothelial Dysfunction - Hypercholesterolemia
Zeiher, A., et. al., Modulation of Coronary
Vasomotor Tone in Humans Progressive Endothelial
Dysfunction with Early Stages of Coronary
Atherosclerosis, Circulation, 1991 83 391-401
Pepine, C., et. al., Vascular Health as as
Therapeutic Target in Cardiovascular Disease,
Vascular Biology Working Group, University of
Florida, 1998.

• A progressive impairment in endothelium-mediated
  modulation of coronary vasomotor tone exists with
  different stages of early atherosclerosis in
  humans
• Patients with angiographically normal coronary
  arteries but with hypercholesterolemia and
  elevated plasma concentrations of LDL demonstrate
  a selective endothelial dysfunction with
  vasoconstriction in response to acetylcholine but
  preserved vasodilation in response to sympathetic
  stimulation and increased coronary blood flow
• Angiographically normal coronary artery segments
  in patients with atherosclerosis elsewhere in the
  coronary system lose the ability to dilate in
  response to acetylcholine and sympathetic
  stimulation, whereas their ability to dilate flow
  dependently is still intact
• Atherosclerotic vessels demonstrate a complete
  lack of vasoactive function

2
Endothelial Dysfunction - Hypercholesterolemia

• Endothelium-dependent vasodilation is reduced in
  hypercholesterolemic human epicardial coronary
  and resistance vessels
• There is a progressive impairment in
  endothelium-mediated modulation of coronary
  vasomotor tone with different stages of early
  atherosclerosis in humans
• These abnormalities likely contribute to angina
  during exertion or emotional stress
• Indeed, human coronary arteries exhibiting an
  abnormal response to acetylcholine also
  vasoconstrict with mental stress, exertion, or in
  response to the cold pressor test, according to
  previous studies

Pepine, C., et. al., Vascular Health as as
Therapeutic Target in Cardiovascular Disease,
Vascular Biology Working Group, University of
Florida, 1998.
3
Cholesterol-Lowering Endothelial Function

• Randomized, double-blind study to evaluate
  HMGCoA-R rx.
• 23 patients undergoing PTCA assigned to
  lovastatin 40 mg/day vs placebo
• Intracoronary infusion of acetylcholine at 12
  days and 51/2 months
• Significant improvement in response to
  acetylcholine was noted in the lovastatin group
  at 51/2 months (LDL reduced from 148/-7 to
  110/-8)

Treasure, C., et. al., Beneficial Effects of
Cholesterol-Lowering Therapy on the Coronary
Endothelium in Patients with Coronary Artery
Disease, NEJM, vol. 332, no. 8, February 23,
1995, pp. 481-487.
4
eNOS Ischemic Stroke

• Few therapeutic options are available for
  preventing or treating ischemic stroke
  prophylactic treatment strategies are limited
  mainly to agents that block platelet aggregation
  or the coagulation cascade
• Clinical trials have demonstrated the
  effectiveness of anti-platelet agents in reducing
  the incidence of ischemic stroke, but it is not
  clear whether they impact on cerebral infarct
  size
• In mice, increased NO production achieved by
  infusing L-arginine, the substrate for NO
  synthesis, decreases cerebral ischemia and limits
  cerebral infarct size

Liao, J., Nitric Oxide and Cardiovascular
Disease, Card.iology Rounds (Brigham Womens
Hospital), vol. 2, issue 5 (5/98).
5
eNOS Ischemic Stroke
Liao, J., Nitric Oxide and Cardiovascular
Disease, Card.iology Rounds (Brigham Womens
Hospital), vol. 2, issue 5 (5/98).

• In an experimental model using eNOS-deficient
  mice, following middle cerebral artery occlusion,
  larger strokes are noted as compared with
  wild-type mice who are similarly treated
• Recent studies have demonstrated that treatment
  with statins upregulates eNOS mRNA expression and
  enzyme activity even in mice who are
  normocholesterolemic
• This upregulation of eNOS by statins was
  independent of serum cholesterol levels and
  caused both increased cerebral blood flow and
  smaller cerebral infarcts following experimental
  middle cerebral artery occlusion