Pulmonary Hypertension due to left heart disease is the most common type of Pulmonary Hypertension. Morbidity and mortality significantly increase once Pulmonary Hypertension is present. Treatment is aimed toward optimizing the underlying condition. Targeted therapy has been evaluated in small studies with mixed results. The goal of this systematic review is to identify the possible benefit and safety of Phosphodiesterase 5 inhibitors in Pulmonary Hypertension due to left heart disease with elevated pulmonary vascular resistance, diagnosed by right heart catheterization. Electronic searches using MEDLINE/PREMEDLINE, EMBASE, and The Cochrane Library were searched on 21 October 2018. Randomized clinical trials comparing Phosphodiesterase 5 inhibitors versus placebo in patients with proven Pulmonary Hypertension by right heart catheterization secondary to left heart disease (both heart failure with reduced ejection fraction and with preserved ejection fraction) and reported pulmonary vascular resistance were included. We identified 436 potentially relevant studies. After reviewing the titles and abstracts to exclude irrelevant articles, five randomized clinical trials were considered for the study. Sildenafil was well tolerated among all studies. Sildenafil was found to improve hemodynamics, exercise capacity, and quality of life in patients with elevated pulmonary vascular resistance. Phosphodiesterase 5 inhibitors therapy in patients with proven Pulmonary Hypertension due to left heart disease and elevated pulmonary vascular resistance by right heart catheterization may improve the quality of life, exercise capacity, and pulmonary hemodynamics. Further prospective randomized controlled studies are needed to confirm.

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RATIONAL To date, no single biomarker has been identified that correlates with severity of pulmonary arterial hypertension (PAH). The oxidant-antioxidant balance is altered in lungs of patients with PAH, with superoxide contributing to a pro-oxidative environment.(1) The REVEAL registry risk score is a validated tool for predicting one-year survival in patient with PAH.(2) We hypothesized that whole blood superoxide levels are elevated in patients with a higher REVEAL risk score and subsequently more severe PAH. METHODS This study was conducted at the University of Nebraska Medical Center in Omaha, NE. Subjects with previously diagnosed PAH by right heart catheterization (mean pulmonary arterial pressure > 25mmHg, pulmonary arterial occlusion pressure ≤ 15, and pulmonary vascular resistance > 3 Wood Units) were identified and consented. Whole blood (2 mL) was collected in EDTA tubes. Immediately after the blood draw, 200 ul of blood was incubated for 1 hour at 37 o C with a superoxide-sensitive electron paramagnetic resonance (EPR) spectroscopy spin probe, 1-hydroxy-3-methoxycarbonyl-2,2,5,5tetramethylpyrrolidine (CMH). Following incubation with CMH, 100 uL of blood was flash frozen in liquid nitrogen and the sample was then inserted into a Bruker eScan EPR Spectrometer. EPR spectra from each blood sample were obtained, with the amplitude of each spectrum being directly proportional to the levels of free radicals (i.e. superoxide) in the sample. Data for the REVEAL risk score (WHO group 1 subgroup, renal insufficiency, age, NYHA functional class, systolic blood pressure, heart rate, six-minute walk test [6MWT] distance, brain-natriuretic peptide, pericardial effusion, diffusion capacity, mean right atrial pressure, pulmonary vascular resistance) was collected retrospectively from the patient's electronic medical record. RESULTS In our cohort of 40 subjects with PAH, there was no correlation when comparing peripheral, whole blood superoxide levels to REVEAL registry risk score. There was a very modest correlation when comparing superoxide to six-minute walk distance (Figure 1). CONCLUSION Peripheral, whole blood superoxide does not correlate with severity of disease in our cohort of group one, PAH patients. Six-minute walk distance may correlate with superoxide levels in a larger cohort.

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