Pulmonary arterial hypertension (PAH) must be classified into primary pulmonary hypertension and PAH related to other diseases such as collagen vascular diseases, HIV infection or portal hypertension. PAH must also be differentiated from other entities, in particular pulmonary hypertension secondary to thromboembolic diseases, requiring specific approaches. All PAH results in similar histological remodelling of pulmonary arteries, with thickening of the intima, proliferation of the media and plexogenic lesions. Today the physiopathology of these lesions is much better understood and has resulted in new therapies involving substances such as prostacyclins, endothelin receptor antagonists or phosphodiesterase inhibitors, aimed not only at dilating arteries but also at preventing their remodelling. Thromboendarterectomy, septostomy and transplantation remain the only option where medical treatment has failed.
Pulmonary arterial hypertension (PAH) has often been misdiagnosed in the past, due to the poor specificity of symptoms early in the disease until the appearance of right heart failure. Although primary pulmonary hypertension (PPH) remains a rare disease, in recent times PAH related to other diseases has been better recognised. These forms are related to systemic connective tissue diseases, thromboembolic disease, congenital heart disease, portal hypertension or HIV infection, or are secondary to the use of drugs as anorexigens. They all result in an indistinguishable histological picture [1, 2].
Improved understanding of the pathogenesis of PPH has produced new treatments, not only for PPH but for PAH related to other diseases. Genetic predisposition has been found in familial PPH, a disease transmitted as an autosomal trait with a low penetrance of 10–20%. A heterozygous germ line mutation in bone morphogenetic protein (BMP) receptor II, a member of the TGF beta family, has been identified in 60% of familial PPH and in 25% of sporadic cases. These alterations may result in altered vascular growth and remodelling. In addition, there is strong evidence that alterations of endothelial function cause or contribute to vasculopathy: unbalance in the production of vasoactive substances and mitogens, including excessive production of endothelin-1 (ET-1); and diminished production of prostacyclin and nitric oxide (NO). Additionally, altered smooth muscle K-channel activity has been demonstrated in PPH, resulting in membrane polarisation and increased intracellular calcium concentrations which probably contribute to vasoconstriction and smooth muscle cell proliferation. It has also been suggested that inflammation may contribute to production of cytokines, providing a further stimulus for growth. As will be discussed later, serotonin and a serotonin transporter gene have recently been implicated in this process as well. Although the sequence of events still needs to be elucidated, these observations provide a strong rationale for the newer, targeted approaches to therapy with agents which affect not merely vasomotor but also vascular growth and remodelling.
To determine the therapeutic options, a precise diagnosis of pre- or postcapillary pulmonary hypertension is required, as well as testing of the reversibility of PAH by initial catheterisation. After this, non-invasive evaluation using echo Doppler, combined with a walking test (easier to perform than cardiopulmonary exercise testing), suffice in most situations to follow up the therapeutic effect. In view of the many new forms of treatment and various ongoing clinical trials, it is suggested that patients with pulmonary hypertension be managed in cooperation with an experienced centre. In Switzerland, the Swiss Working Group for Pulmonary Hypertension (SAPH) constitutes a collective of experts in this field.
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Pulmonary hypertension
