• Alessandra Manes, Massimiliano Palazzini, Fabio Dardi, Antonio D'Adamo, Andrea Rinaldi, and Nazzareno Galiè.
• Azienda Ospedaliero-Universitaria S.Orsola-Malpighi, Bologna. alessandra.manes@unibo.it
• G Ital Cardiol (Rome). 2012 Jun 1;13(6):448-60.

AbstractPulmonary arterial hypertension (PAH) is a severe clinical condition defined as mean pulmonary artery pressure ≥25 mmHg and normal pulmonary capillary wedge pressure (≤15 mmHg). In PAH the increase in pulmonary pressure is due to an intrinsic disease of the small pulmonary arteries (resistance vessels) characterized by vascular proliferation and remodeling. The increase in pulmonary vascular resistance with subsequent elevation of the right ventricular afterload leads to right ventricular failure after variable periods of time. Although targeted disease therapies have been developed over the last decade that resulted in improved quality of life and outcome for PAH patients, the prognosis is still severe and there remains no cure for this disease. From a clinical standpoint, PAH includes a group of heterogeneous pathological conditions: in idiopathic, heritable and drug- and toxin-induced PAH, since there are no predisposing clinical conditions, the structural changes in pulmonary circulation are "isolated"; on the other hand, PAH may be associated with some predisposing diseases such as connective tissue disease, HIV infection, portal hypertension, congenital heart disease, schistosomiasis, and chronic hemolytic anemia. PAH can affect individuals of all age groups, and mean age at diagnosis is around 50 years. Epidemiological data show a great preponderance of females in PAH; the high prevalence of females is particularly evident in the so-called "isolated" PAH forms, whereas in PAH associated with other diseases the female:male ratio is strongly influenced by the epidemiological features of the specific predisposing condition. The reason for the higher female prevalence in PAH has never been clarified: some hypotheses involve the role of sexual hormones (estrogens), autoimmunity, or an X-linked locus in disease predisposition. Female gender is not associated with a different clinical presentation. However, the age of onset tends to be earlier in females than in males. As far as prognosis is concerned, male patients are at greater risk of mortality despite similar therapeutic management: this could be linked to the influence of sexual hormones, which may favor disease development but may also have favorable effects on outcome, especially on treatment response (the "estrogen paradox"). The possibility that female sex hormones may influence the development and clinical expression of PAH is underlined by the frequent onset of PAH during pregnancy or shortly after delivery, and by the description of obligate carriers of heritable PAH (BMPR2 mutation carriers) in whom hormone replacement therapy seems to trigger the manifestation of the disease. Nevertheless, a definite pathobiological mechanism to explain the association between female sex hormones and PAH has yet to be identified. The link between pregnancy and PAH is also uncertain. However, the hemodynamic changes that occur during gestation, and mainly during labor and delivery, are poorly tolerated by PAH patients: this is reflected in the timing of clinical deterioration and the increased mortality in the late stages of pregnancy when maximum increase in blood volume and cardiac output occurs. As such, the current clinical recommendation is that pregnancy should strongly be discouraged and if it occurs, early termination is advised. When PAH is not diagnosed until late in pregnancy, close follow-up of the mother is mandatory and elective planned delivery is recommended: care of pregnant women with PAH requires a highly planned, multidisciplinary approach, involving obstetricians, pulmonary hypertension specialists, anesthesiologists and intensivists, preferably in a dedicated PAH referral center. Use of female hormones for birth control and postmenopausal replacement therapy in PAH patients still remains controversial; in fact, although it has been suspected to be a trigger factor for PAH development, a formal association based on case-control studies has not been documented.

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