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Others have found that levels of PDE3 activity are more or less comparable in
normal and failing human myocardium, or at least that the differences are not
statistically significant (Vandeput et al.
2009
; Movsesian et al.
1991
). The reasons
for the different results among these studies are not known.
2 PDE3 Inhibitors in the Treatment of Heart Failure
PDE3 inhibitors are used in the treatment of heart failure resulting from dilated
cardiomyopathy, a disease of several etiologies that is characterized by chamber
enlargement and a reduction in myocardial contractility related to a reduction in
b
-adrenergic receptor-stimulated cAMP generation (Bristow et al.
1986
). By inhi-
biting cAMP hydrolysis in cardiac muscle, PDE3 inhibitors “overcome” the reduc-
tion in intracellular cAMP content and increase myocardial contractility (Baim
et al.
1983
; Sinoway et al.
1983
; Uretsky et al.
1983
; Jaski et al.
1985
). PDE3
inhibition also raises cAMP content in vascular smooth muscle, where the conse-
quence is relaxation of smooth muscle myocytes and vasodilation. The vasodilatory
actions of PDE3 inhibitors contribute to some degree to the hemodynamic
responses to these agents, but the primary response that is sought in clinical
situations is inotropic rather than vasodilatory.
A large number of clinical trials of PDE3 inhibitors in patients with heart failure
have been carried out. Unfortunately, despite short-term inotropic effects, adverse
effects on mortality were common. In a recent meta-analysis covering every
published clinical trial of PDE3 inhibitors, the long-term administration of these
drugs was associated with an ~3%-per-year increase in cardiac mortality that
corresponded to a similar increase in the incidence of sudden death (Amsallem
et al.
2005
) (Fig.
3
). The fact that increases in mortality have also been observed in
patients treated with
b
-adrenergic receptor agonists while reductions in mortality
have been seen in patients treated with
b
-adrenergic receptor antagonists has led to
Placebo
PDE3 inhibition
25%
20%
15%
10%
5%
Fig. 3 Mortality in patients
treated with PDE3 inhibitors
0%
cardiac death
sudden death
