• Group 4: Pulmonary hypertension associated with chronic pulmonary artery obstruction. Some causes include chronic blood clots (pulmonary emboli) [2].

• Group 5: Pulmonary hypertension with unclear and/or multifactorial mechanisms. Some causes include inflammatory conditions such as sarcoidosis, metabolic disorders such as glycogen storage disease, blood disorders such as sickle cell disease and chronic kidney disease [2].

By far the most common type of PH is that caused by left-sided heart disease which may account for 34% of all cases of PH [3]. In addition to medical conditions other identified risk factors for PH include age, gender (being more common in women), a family history of the condition, lifestyle factors (e.g. smoking, being overweight) and exposure to hazardous substances (e.g. asbestos).

Mechanisms underlying PH

Much of what is known about the pathophysiology of PH comes from studies on PAH, which is thought to make up around 14% of all cases of PH [3]. While the mechanisms underlying the different types of PH may differ slightly, some common mechanisms include vasoconstriction, microthrombotic events, pulmonary vascular remodelling and inflammation.

• Vasoconstriction: Represents an early step in the pathogenesis of PH. It is thought that vasoconstriction is primarily mediated by an imbalance of vasoactive factors, i.e. an excess of vasoconstrictors and a concomitant deficiency of vasodilating mediators [4]. Some key vasoactive players likely include prostacyclins, endothelin-1 and nitric oxide, all of which are known to be dysregulated in PH [4].

• Microthrombotic events:  Play an important role in the progression of PH and occur with increasing frequency in the more advanced stages of the disease [4]. Specifically, decreased levels of thrombomodulin and increased levels of plasminogen activator inhibitor, fibrinogen and von Willebrand antigen have been noted in patients with PH [5,6]. More research is needed to determine their true relevance as some of these proteins are acute-phase reactants and increase in response to inflammation [4].

• Pulmonary vascular remodelling: Another key event in the progression of PH. Vascular remodelling primarily involves the excessive proliferation and migration of pulmonary artery smooth muscle cells [4] A particularly notable molecule in vascular remodelling is bone morphogenetic protein receptor type II (BPM2)[4]. As many as 75% of patients with heritable PAH  possess mutations in the BPM2 gene [7]. Dysfunctional BPM2 signalling may contribute to remodelling through an imbalance between proliferation and apoptosis [4].

• Inflammation: Helps drive vascular remodelling in PH. Numerous cellular factors including T‐ and B‐lymphocytes, dendritic cells, mast cells and macrophages have been observed in lung tissue samples from PH sufferers [8]. Additionally, many cytokines including the proinflammatory cytokines IL-6 and TGF-β have been shown to be dysregulated in PH patients [9].

Additional research is clearly needed to help identify more causative factors and shed more light on the pathophysiological mechanisms underlying the development of PH. This would enable the development of more tailored PH prevention strategies and novel treatment approaches with the potential to alter disease trajectory and improve patient outcomes.

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