Angiogenic and inflammatory biomarkers for screening and follow-up in patients with pulmonary arterial hypertension.

OBJECTIVE: To identify circulating angiogenic and inflammatory biomarkers with potential in screening for pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc), and in early diagnosis and determination of treatment response in PAH. METHOD: Plasma samples were taken at the time of PAH diagnosis and at treatment follow-up after a median (interquartile range) of 4 months (3-9.8 months) in idiopathic (n = 9) and SSc-associated PAH (n = 11). In patients with SSc-associated PAH, plasma samples had also been gathered a median of 2 years (0.8-3 years) before PAH diagnosis (n = 10). Additional plasma samples were retrieved at two time-points separated by a median of 12 years (10-13 years) from SSc patients who did not develop PAH (n = 10) and from controls (n = 8). Angiogenic and inflammatory biomarkers were analysed by multiplex immunoassays. RESULTS: Plasma levels of placenta growth factor (PlGF), soluble vascular endothelial growth factor receptor-1 (sVEGFR-1), and tumour necrosis factor-α (TNF-α) were higher (p < 0.05) in SSc patients who later developed PAH than in those who did not. Plasma vascular endothelial growth factor (VEGF)-D increased (p < 0.05) in SSc patients as PAH developed. Plasma levels of PlGF, VEGF-A, VEGF-D, sVEGFR-1, interleukin-6, and TNF-α were higher (p < 0.05) in PAH than controls. There were no significant differences in circulating biomarkers between idiopathic and SSc-associated PAH. Plasma sVEGFR-1 decreased (p < 0.05) after initiating PAH-targeted treatments. CONCLUSIONS: Plasma levels of PlGF, sVEGFR-1, TNF-α, and VEGF-D have potential in screening for SSc-associated PAH. Plasma sVEGFR-1 may be a biomarker of treatment response.

The principal pathways involved in the in vivo modulation of hypoxic pulmonary vasoconstriction, pulmonary arterial remodelling and pulmonary hypertension.

Hypoxic pulmonary vasoconstriction (HPV) serves to optimize ventilation-perfusion matching in focal hypoxia and thereby enhances pulmonary gas exchange. During global hypoxia, however, HPV induces general pulmonary vasoconstriction, which may lead to pulmonary hypertension (PH), impaired exercise capacity, right-heart failure and pulmonary oedema at high altitude. In chronic hypoxia, generalized HPV together with hypoxic pulmonary arterial remodelling, contribute to the development of PH. The present article reviews the principal pathways in the in vivo modulation of HPV, hypoxic pulmonary arterial remodelling and PH with primary focus on the endothelin-1, nitric oxide, cyclooxygenase and adenine nucleotide pathways. In summary, endothelin-1 and thromboxane A2 may enhance, whereas nitric oxide and prostacyclin may moderate, HPV as well as hypoxic pulmonary arterial remodelling and PH. The production of prostacyclin seems to be coupled primarily to cyclooxygenase-1 in acute hypoxia, but to cyclooxygenase-2 in chronic hypoxia. The potential role of adenine nucleotides in modulating HPV is unclear, but warrants further study. Additional modulators of the pulmonary vascular responses to hypoxia may include angiotensin II, histamine, serotonin/5-hydroxytryptamine, leukotrienes and epoxyeicosatrienoic acids. Drugs targeting these pathways may reduce acute and/or chronic hypoxic PH. Endothelin receptor antagonists and phosphodiesterase-5 inhibitors may additionally improve exercise capacity in hypoxia. Importantly, the modulation of the pulmonary vascular responses to hypoxia varies between species and individuals, with hypoxic duration and age. The review also define how drugs targeting the endothelin-1, nitric oxide, cyclooxygenase and adenine nucleotide pathways may improve pulmonary haemodynamics, but also impair pulmonary gas exchange by interference with HPV in chronic lung diseases.

sGC stimulation totally reverses hypoxia-induced pulmonary vasoconstriction alone and combined with dual endothelin-receptor blockade in a porcine model.

AIM: Stimulation of soluble guanylate cyclase (sGC) with BAY 41-8543 was hypothesized to attenuate acute hypoxic pulmonary vasoconstriction alone and combined with dual endothelin (ET)-receptor antagonist tezosentan. METHODS: Measurements were taken in 18 anaesthetized pigs with a mean ± SEM weight of 31.1 ± 0.4 kg, in normoxia (FiO(2)~0.21) and hypoxia (FiO(2)~0.10) without (control protocol, n = 6), and with right atrial infusion of BAY 41-8543 at 1, 3, 6, 9 and 12 µg min(-1) per kg (protocol 2, n = 6) or tezosentan at 5 mg kg(-1) followed by BAY 41-8543 at 1, 3 and 6 µg min(-1) per kg (protocol 3, n = 6). RESULTS: Hypoxia (n = 18) increased (P < 0.001) mean pulmonary artery pressure (MPAP) and pulmonary vascular resistance (PVR) by 14.2 ± 0.6 mmHg and 2.8 ± 0.3 WU respectively. During sustained hypoxia without treatment, MPAP and PVR remained stable. BAY 41-8543 (n = 6) dose-dependently decreased (P < 0.001) MPAP and PVR by 15.0 ± 1.2 mmHg and 4.7 ± 0.7 WU respectively. Tezosentan (n = 6) decreased (P < 0.001) MPAP and PVR by 11.8 ± 1.2 mmHg and 2.0 ± 0.2 WU, respectively, whereafter BAY 41-8543 (n = 6) further decreased (P < 0.001) MPAP and PVR by 6.6 ± 0.9 mmHg and 1.9 ± 0.4 WU respectively. Both BAY 41-8543 and tezosentan decreased (P < 0.001) systemic arterial pressure and systemic vascular resistance. Blood-O(2) consumption remained unaltered (P = ns) during all interventions. CONCLUSION: BAY 41-8543 totally reverses the effects of acute hypoxia-induced pulmonary vasoconstriction, and enhances the attenuating effects of tezosentan, without affecting oxygenation. Thus, sGC stimulation, alone or combined with dual ET-receptor blockade, could offer a means to treat pulmonary hypertension related to hypoxia and potentially other causes.

Cyclooxygenase-2 inhibition and thromboxane A(2) receptor antagonism attenuate hypoxic pulmonary vasoconstriction in a porcine model.

AIM: Hypoxic pulmonary vasoconstriction (HPV) causes pulmonary hypertension that may lead to right heart failure. We hypothesized that the COX-2 inhibitor nimesulide and the thromboxane A(2) receptor antagonist daltroban would attenuate HPV. METHODS: Haemodynamic measurements and blood sampling were performed in 18 anaesthetized, mechanically ventilated pigs, with mean ± SEM weights of 31.3 ± 0.6 kg, in normoxia (F(i)O(2)~0.21) and hypoxia (F(i)O(2)~0.10), before and 5, 15 and 45 min after initiation of right atrial infusion of nimesulide (n = 6) or daltroban (n = 6), respectively, and in six control pigs. RESULTS: Compared with normoxia, hypoxia (n = 18) increased mean pulmonary artery pressure by 15.8 ± 0.8 mmHg (P < 0.001), pulmonary vascular resistance (PVR) by 2.7 ± 0.3 WU (P < 0.05) and mean right atrial pressure by 2.3 ± 0.3 mmHg (P < 0.001). In the control pigs, mean pulmonary artery pressure, PVR and mean right atrial pressure remained stable (P = ns) throughout 45 min hypoxia, compared with hypoxia baseline. Nimesulide decreased mean pulmonary artery pressure by 3.7 ± 1.3 mmHg after 45 min (P < 0.013), as well as PVR by 0.8 ± 0.2 WU (P < 0.05), levelling off after 15 min. Daltroban transiently increased (P < 0.001) mean pulmonary artery pressure and mean right atrial pressure by 7.2 ± 1.2 and 2.7 ± 0.4 mmHg, respectively, but they returned to hypoxia baseline (P = ns) within 5 min. Daltroban then decreased mean pulmonary artery pressure to after 45 min be 4.2 ± 1.6 mmHg lower (P < 0.005) than at hypoxia baseline. CONCLUSION: COX-2 inhibition and thromboxane A(2) receptor antagonism attenuate HPV by decreasing mean pulmonary artery pressure by approximately 10-11%, as measured 45 min after initiation of nimesulide or daltroban infusion respectively.

Dual endothelin receptor blockade with tezosentan markedly attenuates hypoxia-induced pulmonary vasoconstriction in a porcine model.

AIM: Our aim was to test the hypothesis that dual endothelin receptor blockade with tezosentan attenuates hypoxia-induced pulmonary vasoconstriction. METHODS: Fourteen anaesthetized, ventilated pigs, with a mean ± SEM weight of 30.5 ± 0.6 kg, were studied, in normoxia (FiO(2) 0.21) and with tezosentan (5 mg kg(-1)) infusion during (n = 7) or before (n = 7) hypoxia (FiO(2) 0.10). RESULTS: Compared to normoxia, hypoxia increased (P < 0.05) pulmonary vascular resistance (PVR) by 3.4 ± 0.7 WU, mean pulmonary artery pressure by 13.7 ± 1.3 mmHg, mean right atrial pressure by 1.9 ± 0.4 mmHg and decreased (P < 0.02) systemic vascular resistance (SVR) by 5.2 ± 2.1 WU. Pulmonary capillary wedge pressure (PCWP), mean aortic blood pressure, heart rate, cardiac output, stroke volume and blood-O(2)-consumption were unaltered (P = ns). Tezosentan infused during hypoxia, normalized PVR, decreased (P < 0.05) maximally mean pulmonary artery pressure by 7.5 ± 0.8 mmHg, SVR by 5.8 ± 0.7 WU, mean aortic blood pressure by 10.8 ± 3.0 mmHg and increased (P < 0.04) stroke volume by 8.5 ± 1.8 mL. Mean right atrial pressure, PCWP, heart rate, cardiac output and blood-O(2) -consumption were unaltered (P = ns). Tezosentan infused before hypoxia additionally attenuated approx. 70% of the initial mean pulmonary artery pressure increase and abolished the PVR increase, without additionally affecting the other parameters. CONCLUSION: Dual endothelin receptor blockade during hypoxia attenuates the 'sustained' acute pulmonary vasoconstrictor response by reducing the mean pulmonary artery pressure increase by approx. 62% and by normalizing PVR. Pre-treatment with tezosentan before hypoxia, additionally attenuates the initial hypoxia-induced mean pulmonary artery pressure rise by approx. 70% and abolishes the PVR increase, during stable circulatory conditions, without affecting oxygenation.