Role of Phosphodiesterases in Adult-Onset Pulmonary Arterial Hypertension - Phosphodiesterases as Drug Targets - page 280

for PAH may be beneficial in treating the disease. Furthermore, inhibiting PDEs in
the heart and the inflammatory cells that infiltrate the PA may offer new targets to
reduce right ventricular hypertrophy and inhibit inflammation that is associated
with and contributes to the development of PAH. This chapter summarizes the
advances in the area and the future of PDEs in PAH.

Keywords Inflammation Proliferation Pulmonary arterial hypertension

Pulmonary artery Pulmonary artery smooth muscle cells Right ventricular

hypertrophy Vasodilation

1 Pulmonary Arterial Hypertension

The normal pulmonary circulation is a low pressure (mean pulmonary artery
pressure [mPAP] of ~15 mmHg), low resistance (1/8 of the systemic), high flow
circulation, which unlike the systemic circulation is maximally dilated at all times.
The highly compliant structure of the pulmonary arterial tree and the circulating and
locally produced vasoactive mediators that regulate pulmonary vascular tone and
permeability maintain the low-pressure environment and allow the pulmonary
vasculature to accommodate the entire cardiac output (Barnes and Liu 1995 ;
Humbert et al. 2004 ; Morrell et al. 2009 ; Tuder et al. 2009 ). An imbalance of
vasoconstrictor/co-mitogen and vasodilator/antiproliferative mediators in the pul-
monary circulation leads to vasoconstriction, cellular proliferation, and thrombosis,
and thereby increased pulmonary vascular resistance (PVR), which can manifest
as pulmonary hypertension (PH). The World Health Organization (WHO) has
classified PH into five major groups, which include Group 1, pulmonary arterial
hypertension (PAH), Group 2, PH with left heart disease, Group 3, PH associated
with lung diseases and/or hypoxemia, Group 4, PH due to chronic thrombotic and/or
embolic disease, and Group 5, miscellaneous causes of PH. Group 1, termed PAH,
which is the focus of this chapter, is further classified and comprises patients with
similar pathophysiological, histological, and prognostic features (Table 1 ) (Galie
et al. 2009c ; McLaughlin et al. 2009 ; Simonneau et al. 2009 ). PAH is a disease that
is associated with multiple genetic, molecular, and humoral abnormalities that can
lead to right ventricular failure and death.
PAH is defined as a resting mPAP > 25 mmHg or > 30 mmHg with exercise,
pulmonary arterial wedge pressure of 15 mmHg and increased PVR. The preva-
lence of PAH is around 15 per million (although this varies depending on the
underlying condition and between national databases) and affects people of all
races and cultures, usually developing in adults between the ages of 20 and 60
(mean ~ age 48), (Humbert et al. 2006 ; Peacock et al. 2007 ). PAH in adults can be
idiopathic (IPAH, incidence of 2.4 per million), heritable (formally called familial),
or secondary to drug/toxin exposure or to other conditions such as congenital heart
disease, connective tissue disorder, portal hypertension or HIV. Table 1 outlines the
updated clinical classification for PAH (Galie et al. 2009b ; McLaughlin et al. 2009 ;