Pulmonary arterial hypertension (PAH) is rare and uniformly deadly disease characterized by extensive narrowing of the pulmonary vasculature, leading to progressive increases in pulmonary vascular resistance and ensuing right heart failure.² The underlying pathogenetic mechanisms of PAH are slowly being unraveled, but to a large degree remain poorly understood. Medial hypertrophy, intimal proliferative and fibrotic changes, perivascular inflammatory infiltrates, and thrombotic lesions are noted in the pulmonary arteries.

The nomenclature and classification of pulmonary hypertension was changed in 2009 by the World Health Organization (Table 12-1). Idiopathic PAH is now being used instead of primary pulmonary hypertension. The classification is easy to remember if we think of pulmonary hypertension as a “disease of triggers.” In idiopathic or familial PAH, the trigger is a mutation or polymorphism. In PAH associated with connective tissue disease, congenital disease, HIV, anorexigens, or portal hypertension, the trigger is permissive phenotype. This will also help differentiate PAH from non-PAH etiologies. Non-PAH diseases could be triggered by high left atrial pressure (heart failure and valvular disease), hypoxia (lung disease), or emboli.

A right heart catheterization is mandatory to confirm the diagnosis of PAH (Figure 12-1). Important hemodynamic measurements that should be obtained are pulmonary wedge pressure, cardiac output, and pulmonary vascular resistance. Cardiac output in most cases is calculated by Fick method (using pulmonary artery saturation) because significant tricuspid regurgitation may alter the result of thermodilution method. Intracardiac shunting should be ruled out by saturation of the chambers. The diagnosis of PAH is defined as a mean pulmonary artery pressure ≥25 mm Hg at rest, in the setting of normal pulmonary capillary wedge pressure ≤15 mm Hg.^1,2 PAH remains a diagnosis of exclusion and other factors, like heart failure or emboli, should be evaluated and ruled out.

Pulmonary arterial hypertension is more prevalent in women.² Given PAH worsens during the peripartium period, the association with oral contraceptives (possibly coincidental because of age and gender), and the known prothrombotic effects of estrogens, there is speculation that estrogens play a role in the initiation or progression of PAH. However, animal studies suggest that estrogen also has favorable effects in experimental PAH; there is better outcome in female animals, exacerbation of the disease after ovariectomy, and a strong protective effect of estrogen, a phenomenon known as the estrogen paradox⁴ (Figure 12-2).

The reason for the female predisposition is incompletely understood. PAH is associated with decreased bone morphogenetic protein receptor type 2 (BMPR2) expression.^1,2 Studies in multiple organ systems have shown cross-talk between signaling through the BMPR2 and estrogen pathways.⁵ Increased exogenous estrogen decreases BMPR2 expression in cell culture. BMPR2 gene expression is reduced in females compared to males in live humans and in mice, likely through direct estrogen receptor-α binding to the BMPR2 promoter. This reduced BMPR2 expression may contribute to the increased prevalence of PAH in females.

The effects of estrogens on pulmonary vasculature are well defined: (1) estradiol, via rapid, nongenomic mechanisms, increases prostacyclin release and production of nitric oxide and (2) through estrogen receptor-dependent mechanisms increases endothelial nitric oxide synthase mRNA levels and activity.⁴ Furthermore, ovariectomy augments hypoxia-induced increase in endothelin-1 (ET-1). Low levels of prostacyclin and nitric oxide and increases in endothelin-1 lead to PAH.^1,2

Right ventricular failure is a major cause of morbidity and mortality in patients with PAH. Female rats and swine compared with males, when exposed to chronic hypoxia develop less severe pulmonary hypertension, right ventricular hypertrophy, vascular remodeling, and polycythemia.³ Estradiol may also cause myocardial vasodilatation and help the failing right ventricle. Furthermore, higher circulating estradiol levels are associated with better right-side heart function in postmenopausal women using hormone replacement therapy while higher levels of androgens are associated with greater right ventricular mass and volumes in both sexes.

Further studies are needed to resolve this paradox. To determine the estradiol metabolism, the vascular effects of its active metabolites and the potential benefit of estrogen-based therapies in PAH are required.

Pulmonary arterial hypertension afflicts predominantly women^2,6 and its prevalence among the female population is increasing. In the mid-1980s, the National Institute of Health registry of idiopathic PAH reported a 1.7:1 female-to-male ratio.⁷ Similar US registries reported a 3.3:1 ratio in the period 1982 to 2006, 4.3:1 ratio for 1998 to 2001, and 4.1:1 ratio for 2006 to 2007.^6,8,9 National registries in France, Scotland, and China have reported ratios of 1.9:1, 2.3:1, and 2.4:1, respectively.^10,11,12 The Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL Registry) has been the largest database to date.⁶ It is a 55-US center, observational, prospective registry that includes approximately 3500 patients with new and previously diagnosed PAH. They were enrolled between March 2006 and September 2007 and followed for at least 5 years from time of enrollment. Characteristics of women with PAH are detailed in Table 12-2 and Figures 12-3, 12-4, 12-5, 12-6 and 12-7.^6,13