David Kylhammar

Prognosis and response to first-line single and combination therapy in pulmonary arterial hypertension.

Abstract Objectives. To investigate survival, treatment escalation, effects of first-line single- and first-line combination therapy and prognostic markers in idiopathic- (IPAH), hereditary- (HPAH) and connective tissue disease-associated (CTD-PAH) pulmonary arterial hypertension (PAH). Design. Retrospective analysis of medical journals from PAH patients at Skåne University Hospital 2000–2011. Results. 1-, 2- and 3-year survival was 87%, 67%, and 54%, respectively, for the entire population, but worse (p = 0.003) in CTD-PAH than IPAH/HPAH. After 1, 2 and 3 years, 58%, 41% and 24% of patients starting on single therapy were alive on single therapy. 37.5% of patients on first-line single therapy received escalated treatment at first follow-up. First-line combination therapy more greatly decreased pulmonary vascular resistance index (PVRI, p = 0.017) than first-line single therapy. Only first-line combination therapy improved (p = 0.042) cardiac index (CI). Higher mean right atrial pressure (MRAP, p = 0.018), MRAP/CI (p = 0.021) and WHO functional class (p < 0.001) and lower 6-min walking distance (6MWD, p = 0.001) at baseline, and higher PVRI (p = 0.008) and lower 6MWD (p = 0.004) at follow-up were associated with worse outcome. Conclusions. We confirm improved survival with PAH-targeted therapies. Survival is still poor and early treatment escalation frequently needed. First-line combination therapy may more potently improve haemodynamics. MRAP/CI may represent a new prognostic marker in PAH.

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

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.

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

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 A2 receptor antagonist daltroban would attenuate HPV.

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.

Levosimendan attenuates hypoxia-induced pulmonary hypertension in a porcine model.

Background: Levosimendan was hypothesized to attenuate hypoxic pulmonary vasoconstriction (HPV). Methods: Fourteen anaesthetized pigs (30.9 ± 1.0 kg) were studied in normoxia (FiO2∼0.21) and hypoxia (FiO2∼0.10), before and 10–90 minutes after infusion of placebo (n = 7) or levosimendan (n = 7). Results: Compared with normoxia, hypoxia baseline at FiO2∼0.10 (n = 14) increased pulmonary vascular resistance (PVR) by 1.9 ± 0.4 Wood Units (WU) (P < 0.001), mean pulmonary artery pressure (MPAP) by 14.3 ± 0.9 mm Hg (P < 0.001), mean right atrial pressure (MRAP) by 2.1 ± 0.4 mm Hg (P < 0.001), pulmonary capillary wedge pressure (PCWP) by 1.5 ± 0.3 mm Hg (P < 0.001), cardiac output (CO) by 1.3 ± 0.2 L/minute (P < 0.001) and heart rate (HR) by 19.9 ± 5.5 beats·per minute (P < 0.001). Systemic vascular resistance (SVR) decreased by 7.2 ± 1.0 WU (P < 0.001), MAP and stroke volume (SV) remained unaltered (P = ns). Compared with hypoxia baseline, levosimendan decreased MPAP and PVR (P < 0.05), by approximately 9% and 19%, respectively, plateauing between 10 and 90 minutes. SV increased (P < 0.05) by approximately 22%, plateauing after 60 minutes. MRAP, PCWP, HR, CO, MAP, SVR, and blood–O2 consumption remained unaltered (P = ns). Compared with hypoxia baseline, with placebo, MPAP remained stable (P = ns), PVR increased (P < 0.05) and CO decreased (P < 0.05) by approximately 20% and 11% after 60–90 and 30–90 minutes, respectively. SV decreased (P < 0.05) by approximately 8%, plateauing after 60–90 minutes. PCWP and MRAP decreased (P < 0.05) by approximately 12%, plateauing after 10–60 and 10–90 minutes, respectively. MPAP, HR, MAP, SVR, and blood–O2 consumption remained unchanged (P = ns), except at 60 minutes where MAP decreased (P < 0.05) by approximately 4%. Conclusions: Levosimendan attenuated HPV and the cardiodepressive effect of sustained hypoxia.

IMPACT OF AGE AND COMORBIDITY ON RISK STRATIFICATION IN IDIOPATHIC PULMONARY ARTERIAL HYPERTENSION

Recent reports from worldwide pulmonary hypertension registries show a new demographic picture for patients with idiopathic pulmonary arterial hypertension (IPAH), with an increasing prevalence among the elderly. We aimed to investigate the effects of age and comorbidity on risk stratification and outcome of patients with incident IPAH. The study population (n=264) was categorised into four age groups: 18–45, 46–64, 65–74 and ≥75 years. Individual risk profiles were determined according to a risk assessment instrument, based on the European Society of Cardiology and the European Respiratory Society guidelines. The change in risk group from baseline to follow-up (median 5 months) and survival were compared across age groups. In the two youngest age groups, a significant number of patients improved (18–45 years, Z= −4.613, p<0.001; 46–64 years, Z= −2.125, p=0.034), but no significant improvement was found in the older patient groups. 5-year survival was highest in patients aged 18–45 years (88%), while the survival rates were 63%, 56% and 36% for patients in the groups 46–64, 65–74 and ≥75 years, respectively (p<0.001). Ischaemic heart disease and kidney dysfunction independently predicted survival. These findings highlight the importance of age and specific comorbidities as prognostic markers of outcome in addition to established risk assessment algorithms. Change in risk category at follow-up and specific comorbidity predict survival in IPAH across age groups http://ow.ly/EPQ530j765F

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.