TREND Study Findings

1
TREND Study Findings

• At baseline, before randomization, the degree of
  acetylcholine-induced vasoconstriction in the
  target artery segment was similar in placebo and
  quinapril groups
• After 6 months, the placebo group had no change
  in responses, whereas the quinapril group showed
  significantly less constrictor response (1.6 and
  2.3) compared with prerandomization (6.1 and
  14.3 plt0.014)
• In the quinapril group, responses expressed as
  net change from baseline (primary end point)
  improved by 4.5 /- 3.0 and 12.1 /- 3.0 at
  each acetylcholine dose, whereas the placebo
  group responses did not change (plt0.002)

Mancini,G., et. al., Angiotensin-Converting
Enzyme Inhibition with Quinapril Improves
Endothelial Vasomotor Dysfunction in Patients
with Coronary Artery Disease, Circulation, vol.
94, no. 3, August 1, 1996, pp. 258- 265.
2
TREND Study Findings

• With respect to smokers vs. nonsmokers, ACE
  inhibition was effective in both groups
• The improvement in the smokers is accentuated
  mainly by the tendency toward net deterioration
  in endothelial function that occurred over the
  6-month period in the smokers in the placebo group

Mancini, G.B., Role of Angiotensin-Converting
Enzyme Inhibition in Reversal of Endothelial
Dysfunction in Coronary Artery Disease, The
American Journal of Medicine, vol. 105 (1A), July
6, 1998, pp.40S-47S.
3
TREND Study Findings

• Pitt et. al., examined the effect of quinapril on
  endothelial function stratified on the basis of
  LDL level
• Quinapril was equally effective in inducing a net
  improvement in the constrictor response,
  irrespective of the LDL level
• The placebo patients with LDLgt130 showed a
  tendency toward deterioration
• At the high dose of acetylcholine infusion, the
  difference between placebo and quinapril achieved
  statistical significance
• The impact of ACE inhibition may be modulated by
  the underlying absolute risk profile of the
  patient

Mancini, G.B., Role of Angiotensin-Converting
Enzyme Inhibition in Reversal of Endothelial
Dysfunction in Coronary Artery Disease, The
American Journal of Medicine, vol. 105 (1A), July
6, 1998, pp.40S-47S.
4
Improvement in Tissue Oxygen Consumption With
ACE-I

• Mitochondrial respiration in cardiac myocytes is
  subject to regulation by locally formed kinins
  via an NO-mediated mechanism according to a
  recent study in mongrel dogs
• Oxygen consumption in myocardium was inhibited by
  ACE-I, acting via this mechanism
• NO appears to be a competitive inhibitor of O2
  for its binding site on cytochrome C oxidase, the
  terminal complex of the mitochondrial electron
  transport chain

Zhang, X., et. al., ACE Inhibitors Promote
Nitric Oxide Accumulation to Modulate Myocardial
Oxygen Consumption, Circulation, vol. 95, no. 1,
January 7, 1997, pp. 176-182.
5
NO in Sepsis
Cooke, J., Dzau, V., Nitric Oxide Synthase Role
in the Genesis of Vascular Disease, Ann. Rev.
Medicine, 1997, vol. 48 489-509.

• iNOS produces very large quantities of NO for
  prolonged periods and is up-regulated as part of
  the immune response
• The marked reduction in vascular resistance that
  is associated with septicemia is now known to be
  a result of NO derived from activated macrophages
  and smooth muscle cells - the subsequent
  production of NO by these activated cells greatly
  exceeds that of the endothelium, accounting in
  part for the hypotension observed in septic shock
• In animal models of septic shock, administration
  of NOS antagonists reverses the blood pressure
  drop and increases survival
• The therapeutic dose range is narrow
  administration of higher doses of the antagonists
  increases the mortality in these animals,
  presumably as a result of the blockade of
  endothelial NOS with consequent vasocostriction,
  tissue ischemia, necrosis

6
NO Systolic CHF
Birks, E., et. al., The Role of Nitric Oxide and
Cytokines in Heart Failure, Coronary Artery
Disease, 8389-402.

• Cytokines may play an important role in both
  sepsis and CHF either directly or via induction
  of inducible NOS
• Several studies have found elevated levels of
  tumor necrosis factor-alpha associated with
  severe CHF TNF-a may trigger NO synthesis via
  iNOS
• Most studies indicate that a decrease in
  endothelial NOS is accompanied by an increase in
  inducible NOS
• The mechanism for decreased inotropy in systolic
  CHF may be related to this switch to iNOS
  predominance
• Shultz et. al. Showed that the contractile
  function of isolated perfused rat hearts
  decreases after a combination of recombinant
  IL-1b and TNF-a with a time course consistent
  with inducible NOS induction - this decrease was
  blocked by a NOS inhibitor

7
NO Diastolic CHF
Friedrich, S., et. al., Intracardiac
Angiotensin-Converting Enzyme Inhibition Improves
Diastolic Function in Patients With Left
Ventricular Hypertrophy Due To Aortic Stenosis,
Circulation, Dec., 1994 90(6)2761-71 Paulus,
W., et. al., Acute Effects of Nitric Oxide on
Left Ventricular Relaxation and Diastolic
Distensibility in Humans Assessment By
Bicoronary Sodium Nitroprusside Infusion,
Ciculation, May, 1994 89(5)2070-8.

• Evidence supports the concept that NO affects
  diastolic function by hastening ventricular
  relaxation and enhancing LV chamber relaxation
• Infusion of nitroprusside via intracoronary route
  demonstrated reduced LV pressure development, an
  LV relaxation-hastening effect, and improved LV
  diastolic distensibility in patients who were
  being investigated for chest pain who were found
  to be free of obstructive coronary disease
• Intracardiac ACE-I was shown to improve diastolic
  function parameters when infused into the
  coronaries of patients with concentric LVH due to
  aortic stenosis. Inhibition of the tissue RAS
  and consequent increased NO production via
  bradykinin was hypothesized to be the mechanism.

8
NO Cardiac Transplant Cardiomyopathy

• After heart transplantation, myocardial
  dysfunction is often a clinical problem
• Lewis, et. al. studied inducible NO synthase mRNA
  expression in myocardial biopsies after heart
  transplantation and found that it was associated
  with systolic and diastolic dysfunction in these
  patients
• There is evidence for a dual role of increased
  iNOS expression in allograft rejection - Russell
  et. al., noted that increased iNOS expression
  early after transplantation, predominantly in
  graft-infiltrating inflammatory cells, promoted
  acute parenchymal rejection, whereas increased
  iNOS expression much later appeared to protect
  against graft failure due to arteriosclerosis in
  chronic rejection models

Birks, E., et. al., The Role of Nitric Oxide and
Cytokines in Heart Failure, Coronary Artery
Disease, 8389-402 Liao, J., Nitric Oxide and
Cardiovascular Disease, Card.iology Rounds
(Brigham Womens Hospital), vol. 2, issue 5
(5/98).
9
Summary

• Impairment of endothelial vasodilator function is
  a major contributor to cardiovascular disease
• Accumulating evidence indicates that strategies
  for restoring endothelial function via ACE
  inhibition Statins can have important
  therapeutic effects
• Future research directions re. NO CV disease
• ACE trials, e.g. QUIET (Quinapril Ischemic Event
  Trial), HOPE (Heart Outcomes Prevention
  Evaluation)
• pharmacolgic approaches, e.g. L-arginine
• effects of antioxidants, e.g., carvedilol, vit. E
  C
• gene transfer techniques

Pepine, C., Improved Endothelial Function With
Angiotensin-Converting Enzyme Inhibitors,
American Journal of Cardiology, 1997 79(5A)
29-32 Mancini,G., et. al., Angiotensin-Convertin
g Enzyme Inhibition with Quinapril Improves
Endothelial Vasomotor Dysfunction in Patients
with Coronary Artery Disease, Circulation, vol.
94, no. 3, August 1, 1996, pp. 258- 265 Channon,
K., et. al., In Vivo Gene Transfer of Nitric
Oxide Synthase Enhances Vasomotor Function in
Carotid Arteries From Normal and Cholesterol-Fed
Rabbits, Circulation, Nov. 3, 1998, vol. 98, no.
18, pp. 1905-1911 Boger, R., et. al., Restoring
Vascular Nitric Oxide Formation By L-Arginine
Improves the Symptoms of Intermittent Claudiction
in Patients with Peripheral Arterial Occlusive
Disease, JACC, vol.32,no.5, Nov. 1, 19981336-44.
10
References

• Birks, E., et. al., The Role of Nitric Oxide and
  Cytokines in Heart Failure, Coronary Artery
  Disease, 8389-402.
• Boger, R., et. al., Restoring Vascular Nitric
  Oxide Formation By L-Arginine Improves the
  Symptoms of Intermittent Claudiction in Patients
  with Peripheral Arterial Occlusive Disease,
  JACC, vol.32,no.5, Nov. 1, 19981336-44.
• Channon, K., et. al., In Vivo Gene Transfer of
  Nitric Oxide Synthase Enhances Vasomotor Function
  in Carotid Arteries From Normal and
  Cholesterol-Fed Rabbits, Circulation, Nov. 3,
  1998, vol. 98, no. 18, pp. 1905-1911.
• Cooke, J., Dzau, V., Nitric Oxide Synthase Role
  in the Genesis of Vascular Disease, Ann. Rev.
  Medicine, 1997, vol. 48 489-509.
• Friedrich, S., et. al., Intracardiac
  Angiotensin-Converting Enzyme Inhibition Improves
  Diastolic Function in Patients With Left
  Ventricular Hypertrophy Due To Aortic Stenosis,
  Circulation, Dec., 1994 90(6)2761-71.
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  Enzyme Inhibition with Quinapril Improves
  Endothelial Vasomotor Dysfunction in Patients
  with Coronary Artery Disease, Circulation, vol.
  94, no. 3, August 1, 1996, pp. 258- 265.
• Paulus, W., et. al., Acute Effects of Nitric
  Oxide on Left Ventricular Relaxation and
  Diastolic Distensibility in Humans Assessment By
  Bicoronary Sodium Nitroprusside Infusion,
  Ciculation, May, 1994 89(5)2070-8.
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