Contemporary insights into the pathogenesis, diagnosis and therapy of pulmonary arterial hypertension.

ABSTRACT

Current data challenge the concept that pulmonary arterial hypertension (PAH) is purely a disorder of impaired vasomotor tone. Instead, we recognise today that the phenotype of PAH represents the complex and disordered regulation of expression of key signalling molecules and abnormal molecular trafficking. Discovery of mutations of the ubiquitous receptors of the transforming growth factor beta (TGF-ß) superfamily in many patients with PAH has been instrumental in unravelling the pathobiology of this otherwise fatal disorder. Much still needs to be learnt before we are able to substantially alter the natural history of PAH. Until such time, therapies that fundamentally attempt to restore vasomotor tone continue to be developed and tested. Current clinical research in the therapeutic arena is focused on defining the best permutation of the three major groups of drugs - prostacyclin analogues, phosphodiesterase type-five inhibitors and the endothelin receptor antagonists. However, if we are to make any significant impact on the otherwise dismal outcome of PAH, we have to recognise that even more important than the challenge of new therapies, is the challenge in diagnosing the condition early in the course of its relentless progression to right heart failure and eventual death.