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). 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 on the pulmonary circulation could provide insight into the molecular etiology of PH-LHD in patients with preserved LVEF. 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 reviewed to classify patients as “no PH” (n = 23) or “PH-LHD” (n = 22). 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 = 10) compared to no PH or isolated post-capillary PH (Ipc-PH, n = 12); cAMP and cGMP TPRs were not different among groups. . . . .