Background: An elevated serum level of interleukin-6 (IL-6) in pulmonary arterial hypertension (PAH) patients results in a greater symptom burden and increased mortality; however, the mechanisms underlying these observations remain unclear. Because both pre-clinical and clinical data associate elevated IL-6 levels with impaired cardiac function, we hypothesized that the adverse effects of IL-6 in PAH result, in part, from right ventricular (RV) dysfunction. Methods: We analyzed the relationship between IL-6 and RV function in 40 patients with PAH identified in our institutional PAH registry. Serum IL-6 levels was quantified by enzyme-linked immunoassay. Results: PAH patients had higher IL-6 levels than age- and gender-matched controls. Circulating IL-6 levels correlated inversely with echocardiography-based measures of RV function and RV–pulmonary artery (RV-PA) coupling. When dividing PAH patients by median IL-6 level, patients with higher IL-6 had significantly worse RV function (fractional area change [FAC] 23 ± 12% vs 38 ± 11%, tricuspid annular plane systolic excursion [TAPSE] 1.3 ± 0.3 cm vs 2.1 ± 0.5 cm), impaired RV-PA coupling (0.6 ± 0.5%/mm Hg vs 0.9 ± 0.5%/mm Hg), higher right atrial pressure (13 ± 7 mm Hg vs 9 ± 5 mm Hg), reduced cardiac index (2.0 ± 0.5 liters/min/m 2 vs 2.8 ± 1.0 liters/min/m 2 ) and lower stroke volume (48 ± 20 ml vs 70 ± 28 ml). In contrast, the relationships between IL-6 and mean pulmonary artery pressure (mPAP), pulmonary vascular resistance (PVR) and pulmonary arterial compliance (PAC) were not significant. Finally, IL-6 was independently associated with RV function and RV-PA coupling after adjusting for static (PVR) and pulsatile (PAC) after-load on the RV. Conclusions: Serum IL-6 levels are independently associated with RV function and RV-PA coupling in PAH. Patients with higher IL-6 levels have more severe RV dysfunction and diminished RV-PA coupling despite a comparable severity of pulmonary vascular disease.
Bibliographical noteFunding Information:
T.T. received a modest honorarium from Gilead Sciences and Actelion for advisory board participation. The remaining authors have no conflicts of interest to disclose. This study was supported by the National Institutes of Health (NIH RO1 HL113003 and ROI HL071115, and NIH F32 HL129554 to S.A.), the Canada Foundation for Innovation (229252 and 33012 to S.A.), a Tier 1 Canada Research Chair in Mitochondrial Dynamics and Translational Medicine (950-229252), the William J Henderson Foundation and the American Heart Association (Scientist Development Grant 15SDG25560048 to T.T.).
- RV-PA coupling
- pulmonary hypertension