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Pulmonary arterial hypertension 

Pulmonary arterial hypertension
Pulmonary arterial hypertension

Dr Christopher Valerio

and Dr Gerry Coghlan

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date: 25 July 2021

In many respects the field of PAH remains in its adolescence. The work of Ernst von Romberg in the nineteenth century established the existence of a disease affecting the pulmonary arteries, and then in the middle of the twentieth century Paul Wood detailed the haemodynamic consequences. In the 1970s there was a recognition that PPH was a condition that needed to be understood. The first international meeting dedicated to PPH was held in 1973. Particular interest existed at that time because of an outbreak of pulmonary hypertension associated with use of the anorexigen, aminorex fumarate. It would be 25 years before the next meeting in Evian. Subsequent world symposia in Venice (2003) and Dana Point (2008) each provide a progress summary of the developments in the field of pulmonary hypertension. The classification and diagnostic criteria have also been reviewed at each world symposium (see Tables 18.1 and th Table 18.2).

By 1980 associations had been demonstrated with recurrent thrombo-embolism, portal hypertension, scleroderma, and systemic lupus erythematosis. Since then new diseases have been described with an increased incidence of PAH, for example HIV, and revisiting well-known diseases has uncovered hallmark pathological changes of PAH, for example schistosomiasis. Recently, our understanding of the genetic basis of PAH has led to the term ‘heritable’ PAH being preferred over familial. Culprits for drug-induced PAH now include fenfluramine, dexfenfluramine, and toxic rapeseed oil, with substances such as amphetamines and L-tryptophan likely candidates. We expect that left heart disease is still the likeliest explanation for pulmonary hypertension, detected by echocardiography. Hypoxia driven pulmonary hypertension is also far more common than PAH and attention has returned to these two more common clinical phenomena. However, attempts to apply lessons learned from PAH have met with limited success, whereas our management of PAH has perhaps benefitted from avoiding mistakes made in these fields. Chronic thrombo-embolic pulmonary hypertension (CTEPH) has become an increasingly important diagnosis to make, as outcomes following thrombo-endarterectomy are unmatched by medical therapy.

Our understanding of PAH has moved on from histopathological and physiological changes to a more detailed analysis of molecular mechanisms. The categorization of different associations of PAH with similar pathological features has promoted concerted research efforts. Occasionally, it has been the differences rather than the similarities, which have driven things forward. Many developments have been derived from work in general vascular biology, for example the discovery of endothelin-19. Subsequent analysis of the pathways in the lungs has led to this molecule being regarded as a key player in PAH. Arguably, the clearest evidence for the role of endothelin-1 in PAH is the efficacy of the endothelin receptor antagonists.

By far the most dramatic change in the field of PAH has been the development of specific therapies in the last twenty years. Only a small minority of patients with a vasodilator response can expect any benefit from calcium channel blockade and for other patients treatment was, in effect, palliative up to 1990. Heart failure management with diuretics and digoxin has been augmented with anticoagulation to prevent intravascular thrombosis and oxygen for patients with hypoxaemia. First, intravenous prostacyclin analogues (epoprostenol), then endothelin receptor antagonists (bosentan) and phosphodiesterase-5 inhibitors (sildenafil) have demonstrated efficacy. Demonstrating improvements in survival has proved more challenging due to the short duration of trials, but a meta-analysis of randomized, controlled trials has confirmed the benefit exists. A secondary effect of trials in PAH is the importance of the six-minute walk distance as the principal measure of disease progression.

Within this chapter we have tried to include those papers which have, by themselves, provoked a shift in our understanding of PAH (and one relating to CTEPH) and have moved the field forward. Many of the developments in our understanding have come from work in cardiovascular biology and risen to prominence in piecemeal fashion. As is always the case with research, the uncertainty of experimentation means that many studies in PAH do not stand alone. They are reliant on previous trials or lacked power to show a conclusive result. This has been a continuing problem in PAH trials as ethical considerations restrict the use of mortality end points and the number of cases remain relatively small. However, we have been able to select the most worthy papers in pulmonary hypertension; they demonstrate the ingenuity and originality of the researchers, feature coherent scientific arguments firmly supported by appropriate data, and still stand up as examples of how to conduct research in a rare, but important disease.

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