Pulmonary hypertension complicating left heart disease (PH-LHD) is associated with increased morbidity and mortality, especially in patients who develop combined pre- and post-capillary PH (Cpc-PH). Molecular mechanisms underlying PH-LHD are incompletely understood, particularly for individuals with preserved left ventricular ejection fraction (LVEF). We hypothesized that transpulmonary concentrations of biomarkers representing signaling pathways with known effects in the pulmonary circulation could provide insight into the molecular etiology of PH-LHD.
Methods and results
Blood samples were collected from the pulmonary artery (PA) and wedge positions of outpatients with normal LVEF referred for right heart catheterization. Hemodynamic tracings were manually reviewed to classify patients as no PH (mean PA pressure <25mmHg, n=22) or PH-LHD (mean PA pressure ≥25mmHg and wedge pressure >15mmHg, n=20); patients with PH-LHD were further divided into Cpc-PH (diastolic pressure gradient ≥7mmHg or pulmonary vascular resistance >3 Wood units) and isolated pre-capillary PH (Ipc-PH). A biomarker’s transpulmonary ratio (TPR) was calculated as the quotient of wedge and PA concentrations.
The TPR of endothelin 1 (ET-1) was elevated in Cpc-PH (n=7) compared to Ipc-PH (n=13) or no PH The TPRs of cAMP and cGMP were not different among groups. The difference in ET-1 TPR was due to higher wedge ET-1 in Cpc-PH (3.3±0.8 pg/mL) compared to No PH (1.6±0.9 pg/mL, p<0.001) or Ipc-PH (1.9±0.8 pg/mL, p<0.05). Pulmonary vascular resistance (PVR) strongly correlated with wedge ET-1 exclusively in Cpc-PH patients (r=0.79, p<0.05).
In patients with preserved LVEF, ET-1 TPR is higher in those with Cpc-PH compared to those without PH or with Ipc-PH. The correlation between PVR and wedge ET-1, observed only in the Cpc-PH group, also suggests increased pulmonary vascular responsiveness to ET-1 in these patients. These findings implicate elevated pulmonary ET-1 as a marker of, and potential contributor to, development of Cpc-PH in this population.