Modulators of hypoxic pulmonary vasoconstriction and pulmonary hypertension. Implications for new treatment strategies.

Pulmonary arterial hypertension (PAH) is a disease of small pulmonary arteries, characterized by excessive vasoconstriction, remodelling of the arterial wall, in-situ thrombotisation and characteristic plexiform lesions. PAH leads to an elevation in right ventricular afterload, which causes right heart failure and ultimately death. As the diagnosis is often set late and the prognosis poor there is a need for new diagnostic approaches and treatment strategies. In a first study, we retrospectively investigated a cohort of patients diagnosed with PAH in Lund from 2000-2010 and demonstrated that the survival of patients still is poor, but comparable to other European countries. We found that initial combination therapy could be more efficient than initial monotherapy in improving the haemodynamic status. Additionally, we identified the 6-minute walking distance, pulmonary vascular resistance index, stroke volume index and mean right atrial pressure/stroke volume index as prognostic markers at treatment follow-up. These variables may therefore potentially be used as future treatment goals. Hypoxia induces pulmonary vasoconstriction. This hypoxic pulmonary vasoconstriction (HPV) matches perfusion with ventilation in focal hypoxia, but in global hypoxia generalized HPV induces pulmonary hypertension (PH). Generalized HPV may additionally worsen PH when primarily of another aetiology. Studies into the mechanisms of HPV can lead to new physiological insights, but also contribute to find new complementary treatments for hypoxia-induced PH. As modulatory pathways may furthermore be common for hypoxia-induced PH and other forms of PH, including PAH, its study can also lead to better comprehension of pathogenetic mechanisms and potential treatments for other forms of PH. We established an in vivo porcine model of HPV and found that endothelin-1 is important for the sustained HPV response and that a cyclooxygenase-2-derived vasoconstrictor, probably thromboxane A2, contributes to potentiate the HPV response. Adenosine diphosphate was not an obligatory potentiating modulator of HPV, but could be a nonmandatory contributor. Additionally, we conclude that the intravenous dual endothelin A and endothelin B receptor antagonist tezosentan, and the ionotropic and pulmonary vasodilatory drug levosimendan, could be new means to modulate hypoxia-induced PH. Finally, in a propspective cohort of patients with systemic sclerosis-associated PAH (SSc-PAH) we identified a panel of circulating angiogenic and inflammatory biomakers that could be used for PAH screening among SSc patients. We additionally found that circulating angiogenic and inflammatory biomarkers were deranged at time of PAH diagnosis and altered after initiation of PH-targeted treatments in a group of patients with idiopathic PAH or SSc-PAH. Plasma levels of some angiogenic and inflammatory biomarkers furthermore correlated with important clinical variables of prognostic impact, such as the 6-minute walking distance, mean right atrial pressure and NT-proBNP levels. These findings could contribute to earlier identificantion and better prognostication of PAH patients and thereby potentially improve their prognosis.