Endothelin-1 May Be a Potential Biomarker for Monitoring Changes in Nitric Oxide Metabolism in Pulmonary Hypertension

Pulmonary hypertension (PH) is characterized by endothelial cell dysfunction and dysregulation of endogenous nitric oxide (NO) synthesis. NO bioavailability is further decreased due to dysregulation of the oral microbiome and reduction of dietary nitrate (NO3-) to nitrite (NO2-). PH biomarkers such as NT-proBNP have been associated with disease severity, prognosis and response to therapy. Emerging biomarkers like Endothelin-1 (ET-1) reflect NO signaling and cellular dysregulation. We evaluated the effect of a single dose of nitrate on NT-proBNP, ET-1, NO3- and NO2- levels in PH patients versus controls.

Patients with prior right heart catheterization were administered 1000mg of sodium nitrate orally. Plasma NT-proBNP, ET-1, NO3- and NO2- were measured at baseline, 2, 6, and 24 hours following nitrate drug administration. Response of patients with PH (mPAP ≥ 25mmHg, TPG ≥ 12mmHg) was compared to controls (mean PAP < 25 mm Hg, PCWP ≤ 15 mm Hg).

Nine patients were evaluated (control: n=4, age 53 ± 14 years, 100% female, EF 55 ± 0%, mPAP 19 ± 4 mmHg, PCWP 11 ± 3 mmHg, TPG 9 ± 4 mmHg, PVR 1.5 ± 0.6 WU; PH: n=5, age of 59 ± 9 years, 80% female, EF 58 ± 8%, mPAP 41 ± 8 mmHg, PCWP 26 ± 7 mmHg, TPG 14 ± 3 mmHg, PVR 2.9 ± 0.7 WU). Following oral nitrate dose, mean plasma NO3- and NO2- levels increased in both groups. NO3- levels were significantly greater in the control vs PH group at 2 hrs (803 ± 404 µm vs 571 ± 202 µm) and 6 hrs (634 ± 254 µm vs 482 ± 183 µm) (overall P < 0.05). NO2- levels were not significantly different (overall P = 0.17). ET-1 levels were significantly elevated in PH patients versus controls at baseline (3.0 ± 1.5 pg/mL vs 1.9 ± 0.3 pg/mL) and across all time points (overall P< 0.001). ET-1 showed a significant decline over time following oral nitrate dose in both PH (3.0 ± 1.5 pg/mL at 0 hrs to 2.8 ± 1.0 pg/mL at 24 hrs) and control (1.9 ± 0.3 pg/mL at 0 hrs to 1.6 ± 0.4 pg/mL at 24 hrs) (p<0.001; Figure 1). In contrast, NT-proBNP levels were similar in PH vs control; 810 ± 579 pg/mL vs 678 ± 836 pg/mL at baseline and 718.0 ± 415.6 pg/mL vs 290 ± 164.0 pg/mL at 24hrs (p=0.08). There was no significant change in NT-proBNP levels over time (p=0.60; Figure 2). ET-1 was significantly elevated in PH patients compared to controls and showed a significant decline over time after 1 dose of oral nitrate with associated increases in serum NO3- and NO2- levels. These changes were not observed with NT-proBNP. ET-1 may be an effective biomarker in monitoring changes in NO metabolism in PH, and may be more acutely responsive than NT-proBNP.