Treatment-related biomarkers in pulmonary hypertension patients on oral therapies.

BACKGROUND: Multiple classes of oral therapy are available for the treatment of pulmonary arterial hypertension (PAH), but there is little to guide clinicians in choosing a specific regimen or therapeutic class. We aimed to investigate whether treatment-relevant blood biomarkers can predict therapy response in prevalent PAH patients. METHODS: This prospective cohort study longitudinally assessed biomarkers along the endothelin-1 (ET-1) and nitric oxide (cGMP, ADMA, SDMA, nitrite, and S-nitrosohemoglobin) pathways along with the cGMP/NT-proBNP ratio over 12 months in patients with WHO Group 1 PAH on oral PAH-specific therapies. The relationship between biomarkers and 6MWD at the same and future visits was examined using mixed linear regression models adjusted for age. As cGMP can be elevated when NT-proBNP is elevated, we also tested the relationship between 6MWD and the cGMP/NT-pro BNP ratio. Patients with PAH with concomitant heart or lung disease or chronic thromboembolic pulmonary hypertension (CTEPH) were included in a sensitivity analysis. RESULTS: The study cohort included 58 patients with PAH treated with either an endothelin receptor antagonist (27.6%), phosphodiesterase-5 inhibitor (25.9%) or a combination of the two (43.1%). Among biomarkers along the current therapeutic pathways, ET-1 and the cGMP/NT-proBNP ratio associated with same visit 6MWD (p = 0.02 and p = 0.03 respectively), and ET-1 predicted future 6MWD (p = 0.02). ET-1 (p = 0.01) and cGMP/NT-proBNP ratio (p = 0.04) also predicted future 6MWD in the larger cohort (n = 108) of PAH patients with concomitant left heart disease (n = 17), lung disease (n = 20), or CTEPH (n = 13). Finally, in the larger cohort, SDMA associated with 6MWD at the same visit (p = 0.01) in all subgroups and ADMA associated with 6MWD in PAH patients with concomitant lung disease (p = 0.03) and PAH patients on ERA therapy (p = 0.01). CONCLUSIONS: ET-1, cGMP/NTproBNP ratio, and dimethylarginines ADMA and SDMA are mediators along pathways targeted by oral PAH therapies that associate with or predict 6MWD.

Experience in Transitioning From Parenteral Prostacyclins to Selexipag in Pulmonary Arterial Hypertension.

Parenteral prostacyclin therapies remain first-line therapy for patients with pulmonary arterial hypertension (PAH) with class IV symptoms. In selected patients who have been clinically stabilized, switching to selexipag, a chemically distinct prostacyclin receptor agonist, may alleviate risks associated with long-term parenteral therapy. We report our experience with transition of patients from parenteral prostacyclin therapy to selexipag. From January 2016 to July 2017, patients with PAH at the Duke University Pulmonary Vascular Disease Center with functional class II symptoms on stable parenteral prostacyclin therapy were offered the opportunity to transition to selexipag. A standardized protocol was developed to guide titration of therapies. Patients underwent pre- and post-transition assessments of hemodynamics, echocardiography, laboratory biomarkers, and functional status. We studied 14 patients with PAH (11 women; median age 53 years) in total. Overall, 13 patients tolerated the switch to selexipag and remained on the drug at study completion, and 1 patient passed away due to progressive liver failure. Surrogate markers including NT-proBNP, 6MWD, RV function, and TAPSE, and right heart catheterization hemodynamics were similar before and after transition. The transition from parenteral prostanoid therapy to oral selexipag was overall well-tolerated in patients with stable PAH and functional class II symptoms. Finally, doses of selexipag up to 3200 µg twice daily were well-tolerated in patients who had been treated with prior parenteral prostacyclins.

Genetically based susceptibility to herbivory influences the ectomycorrhizal fungal communities of a foundation tree species.

Although recent research indicates that herbivores interact with plant-associated microbes in complex ways, few studies have examined these interactions using a community approach. For example, the impact of herbivory on the community structure of ectomycorrhizal fungi (EMF) is not well known. The influence of host plant genetics on EMF community composition is also poorly understood. We used a study system in which susceptibility to herbivory has a genetic basis and a 20-yr insect removal experiment to examine the influence of chronic herbivory and plant genetics on the EMF community structure of Pinus edulis. We compared EMF communities of herbivore resistant trees, herbivore susceptible trees and herbivore susceptible trees from which herbivores were experimentally removed at two dates 10 yr apart. In both years sampled, resistant and susceptible trees differed significantly in EMF community composition. After 10 yr and 20 yr of herbivore removal, the EMF communities of removal trees were similar to those of susceptible trees, but different from resistant trees. The EMF community composition was more strongly influenced by innate genetic differences in plant traits associated with resistance and susceptibility to herbivory than by indirect effects of herbivory on host plant relationships with ectomycorrhizal fungi.

Mortality gradients within and among dominant plant populations as barometers of ecosystem change during extreme drought.

Understanding patterns of plant population mortality during extreme weather events is important to conservation planners because the frequency of such events is expected to increase, creating the need to integrate climatic uncertainty into management. Dominant plants provide habitat and ecosystem structure, so changes in their distribution can be expected to have cascading effects on entire communities. Observing areas that respond quickly to climate fluctuations provides foresight into future ecological changes and will help prioritize conservation efforts. We investigated patterns of mortality in six dominant plant species during a drought in the southwestern United States. We quantified population mortality for each species across its regional distribution and tested hypotheses to identify ecological stress gradients for each species. Our results revealed three major patterns: (1) dominant species from diverse habitat types (i.e., riparian, chaparral, and low- to high-elevation forests) exhibited significant mortality, indicating that the effects of drought were widespread; (2) average mortality differed among dominant species (one-seed juniper[Juniperus monosperma (Engelm.) Sarg.] 3.3%; manzanita[Arctostaphylos pungens Kunth], 14.6%; quaking aspen[Populus tremuloides Michx.], 15.4%; ponderosa pine[Pinus ponderosa P. & C. Lawson], 15.9%; Fremont cottonwood[Populus fremontii S. Wats.], 20.7%; and pinyon pine[Pinus edulis Engelm.], 41.4%); (3) all dominant species showed localized patterns of very high mortality (24-100%) consistent with water stress gradients. Land managers should plan for climatic uncertainty by promoting tree recruitment in rare habitat types, alleviating unnatural levels of competition on dominant plants, and conserving sites across water stress gradients. High-stress sites, such as those we examined, have conservation value as barometers of change and because they may harbor genotypes that are adapted to climatic extremes.