guazzi.qxp 4/7/08 11:26 am Page 29
Phosphodiesterase-5 Inhibition in Chronic Heart Failure – An Emerging Therapeutic Opportunity
microvessel over-reactivity to vasoconstrictor stimuli has been the endothelial effect of sildenafil 50mg on top of the angiotensin-converting
rationale for a number of studies.
16–19
enzyme (ACE) inhibitor ramipril was also demonstrated in patients with
heart failure by Hryniewicz et al.
25
Interestingly, according to observations
Similar to what has been described for idiopathic pulmonary obtained in a canine model of cardiac failure, sildenafil produced
hypertension, studies performed by Guazzi et al.
16
and by Lewis et al.
17
haemodynamic effects reminiscent of those produced by B-type
in patients with chronic HF and secondary pulmonary hypertension natriuretic peptides
26
and exerted a cumulative influence on pulmonary
have shown that oral acute sildenafil 50mg lowers the pulmonary blood pressure elevation. Considering that resistance to the natriuretic
vascular pressure and resistance without significantly affecting the peptide in HF is in part related to increased PDE
5
activity, a combined
systemic arterial and wedge pulmonary pressures. The response of approach and an additional therapeutic role for PDE
5
inhibition may be
cardiac output is variable and in part related to the severity of the prospectively investigated.
disease. The resistance-lowering effect of sildenafil in the pulmonary
circulation at rest is also evident during exercise. Recently, the same Cardiac Remodelling
authors have reported that the PDE
5
inhibitor maintains the PDE
5
has been shown to prevent the development of cardiac
same efficacy during long-term prescription.
18,19
hypertrophy, ischaemia-reperfusion injury and excessive adrenergic
stimulation; PDE
5
inhibition can prevent these protective activities.
Sildenafil reverses hypertrophy
27,28
through a cGMP-mediated effect in
The potential favourable therapeutic
hypertrophic and failing hearts by sustained exposition to pressure
properties of phosphodiesterase-5
overload. In a rat model of isoproterenol-induced cardiac hypertrophy, an
inverse correlation was consistently evident between cGMP heart content
inhibition on pulmonary vascular
and severity of hypertrophy.
29
However, cGMP catabolism regulates
remodelling and lung microvessel
cardiac adrenergic stimulation.
30
Sildenafil also exhibits a direct protective
property against myocite apoptosis,
28
an effect also observed in a model
over-reactivity to vasoconstrictor
of cardiac dysfunction secondary to doxorubicin cardiotoxicity.
31
Benefits
stimuli has been the rationale for a of sildenafil on experimental post-myocardial infarction (MI) ventricular
number of studies.
remodelling have recently been reported by several authors.
32,33
In
particular, recent findings by Salloum et al. obtained in a murine model
document that sildenafil modulates reactive post-MI hypertrophy and
An additional finding by Guazzi et al.
16
is that sildenafil improves the attenuates late adverse remodelling through myocite savage and reduced
lung diffusion capacity for carbon monoxide (DLCO) by more than 10% apoptotic cell death.
33
There is also recent evidence that PDE
5
is highly
in patients with CHF through a selective increase of the DM component expressed in the hypertrophied human right ventricle and that acute PDE
5
(alveolar capillary membrane conductance) of DLCO without affecting inhibition improves contractility.
34
the pulmonary capillary volume of blood (Vc) available for gas exchange
(the other component of DLCO). This is significant because not only
does it prove the ability of PDE
Considering that resistance to the
5
inhibition to influence one of the lung
functional shortcomings in CHF, but also because it suggests that a
natriuretic peptide in heart failure
defective NO/cGMP pathway is involved in the shortcoming.
is in part related to increased
Systemic Haemodynamics and Endothelial Function
phosphodiesterase-5 (PDE
5
) activity, a
Impaired vasomotion and endothelial dysfunction are hallmarks of HF that
combined approach and an additional
increase systemic vascular resistance (SVR). Hirata et al.
20
investigated the
acute effects of oral sildenafil 50mg on SVR, large artery stiffness and wave therapeutic role for PDE
5
inhibition
reflection as major determinants of left ventricular ejection impedance.
may be prospectively investigated.
They found a parallel decrease of these variables with an improvement in
cardiac performance. A similar effect on aortic pressure augmentation
index has been observed in patients with hypertensive heart disease.
21
Due In the human heart, PDE
5
is basically involved in the contractile response
to these effects on large-conduit systemic arteries, sildenafil has been to β-adrenergic receptor stimulation
35
and sildenafil blunts the inotropic
suggested to have an indication also in the management of systemic response. Acute sildenafil also reduces the cardiac norepinephrine
hypertension, especially of the isolated systolic form. Oliver et al.
22
spillover, which seemingly results from an inhibition of the sympathetic
demonstrated that prolonged (three-month) administration of sildenafil outflow to the heart.
36
50mg three times a day to patients with high blood pressure induced a
modulation of the arterial wave reflection and lowered systolic and diastolic Exercise Performance and Gas Exchange Analysis
ambulatory pressure by an average of 8 and 6mmHg, respectively. Studies have consistently found that peak oxygen consumption (VO
2
) is
improved by sildenafil in heart failure,
16,17
and several mechanisms may
A number of studies suggest that sildenafil may also improve endothelial be involved in this effect: the increased NO availability may promote
dysfunction due to HF.
23,24
In a report in which sildenafil was tested in the alveolar capillary membrane gas conductance improvement;
16
the
patients with stable HF at doses of 12.5, 25 and 50mg, flow-mediated cGMP-mediated lowering effect of pulmonary arterial pressure and
dilatation in the forearm circulation increased in a dose-dependent effect, vascular resistance decreases the right ventricular afterload and
and the lowest effective dose was shown to be 25mg. An additional improves right ventricular output and lung perfusion; and a better right
EUROPEAN CARDIOLOGY 29
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