Biology Reference
In-Depth Information
Table 1 Outline of the
updated clinical
classification of pulmonary
arterial hypertension
(PAH), modified from
(Galie et al.
2009c
;
McLaughlin et al.
2009
;
Simonneau et al.
2009
)
Clinical classification of pulmonary arterial hypertension (Group 1)
1.1 Idiopathic
1.2 Heritable
1.2.1 BMPR2
1.2.2 ALK-1, endoglin
1.2.3 Unknown
1.3 Induced by drugs and toxins
1.4 Associated with:
1.4.1 Connective tissue disease
1.4.2 HIV
1.4.3 Portal hypertension
1.4.4 Congenital heart disease
1.4.5 Schistosomiasis
1.4.6 Chronic hemolytic anemia
1.5 Persistent pulmonary hypertension of the newborn
Simonneau et al.
2009
). Younger women are more than twice as likely to develop
IPAH (life expectancy
3 years if untreated), which has an unknown etiology;
therefore, one focus of current research is to determine the link between gender and
PAH (D'Alonzo et al.
1991
; Humbert et al.
2006
; Peacock et al.
2007
).
Heritable PAH, in around 70% of cases, has been shown to be the result of
mutations in the bone morphogenetic protein receptor 2 (BMPR2) gene; more
recently, mutations in receptor members of the transforming growth factor-
b
(TGF-
b
), activin-like kinase-type 1 and endoglin families, have been implicated
in a subset of patients (Chaouat et al.
2004
; Lane et al.
2000
; Machado et al.
2001
;
Trembath
2001
). Mutations in BMPR2 include frameshifts, partial deletions,
insertions, missense, and splice-site mutations, and although many reduce BMPR2
expression and lead to dysfunctional SMAD signaling and an increase in TGF-
b
signaling, the full impact of these mutations still needs to be determined (Machado
et al.
2009
). Interestingly, animal models of PAH are also associated with a
reduction in the expression of BMPR2 mRNA, protein and BMP signaling, sug-
gesting that the alteration in BMP/TGF-
b
pathways may also underlie other forms
of PAH (Long et al.
2009
).
Despite different mechanisms of PAH, much of the remodeling in the lung is
similar and the prognosis is poor for all forms; therefore, novel therapeutic
approaches are much needed. Current treatments for PAH (Group 1) include anti-
coagulants, diuretics, digoxin, supplemental oxygen, calcium-channel blockers,
prostanoids, endothelin-receptor antagonists, and phosphodiesterse-5 inhibitors,
the focus of this chapter (Galie et al.
2009b
; McLaughlin et al.
2009
; Simonneau
et al.
2009
). Future successful treatments of PAH will likely require a better
understanding of the physiology, pathophysiology, and triggers of the disease.
The adventitial, medial, and intimal thickening that leads to the remodeling of
the pulmonary artery (PA) and the development of PAH are the result of the
complex interaction between activation of fibroblasts and smooth muscle cells,
endothelial dysfunction, and infiltration of
<
inflammatory mediators such as
