Dweik, Raed A.

Background The current classification of pulmonary hypertension (PH), based largely on expert opinion, has limitations in prognostication and guiding therapies. We hypothesize that novel PH clusters that predict survival will reveal mechanistic phenotypes associated with biomarkers of vascular health across all PH groups. Methods We first identify novel PH clinical clusters by performing unsupervised clustering analysis on the CC‐PH (Cleveland Clinic PH) registry (N=1529). We develop classification models to predict the new PH clusters and then apply them to the multicenter PVDOMICS (Pulmonary Vascular Diseases Phenomics) cohort (N=853) for validation. We compare transplantation‐free survival across the new PH clusters. We quantify metabolites of the arginine‐nitric oxide pathway and D‐dimer levels and calculate global arginine bioavailability (arginine/[ornithine+citrulline]) to assess endothelial function and activation in the new clusters and link these biomarkers to clinical outcomes. Results Clustering analysis identify 3 clear clusters in CC ‐ PH that are validated in PVDOMICS and outperform conventional classifications in predicting transplantation‐free survival. The phenotype associated with the worst survival is characterized by reduced lung diffusion capacity, decreased arginine bioavailability and nitrate levels, and elevated D‐dimer levels, consistent with loss of pulmonary microcirculation and endothelial dysfunction. Conclusions We identify new informative PH phenotypes associated with mortality and defined by biomarkers of endothelial function and activation. Loss of endothelial health and pronounced pulmonary vascular rarefication contribute more substantially to mortality across the spectrum of PH than right heart function. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02980887.

Background and Aims Portopulmonary hypertension (POPH) was previously associated with a single‐nucleotide polymorphism (SNP) rs7175922 in aromatase (cytochrome P450 family 19 subfamily A member 1 [CYP19A1]). We sought to determine whether genetic variants and metabolites in the estrogen signaling pathway are associated with POPH. Approach and Results We performed a multicenter case‐control study. POPH patients had mean pulmonary artery pressure >25 mm Hg, pulmonary vascular resistance >240 dyn‐sec/cm−5, and pulmonary artery wedge pressure ≤15 mm Hg without another cause of pulmonary hypertension. Controls had advanced liver disease, right ventricular (RV) systolic pressure <40 mm Hg, and normal RV function by echocardiography. We genotyped three SNPs in CYP19A1 and CYP1B1 using TaqMan and imputed SNPs in estrogen receptor 1 using genome‐wide markers. Estrogen metabolites were measured in blood and urine samples. There were 37 patients with POPH and 290 controls. Mean age was 57 years, and 36% were female. The risk allele A in rs7175922 (CYP19A1) was significantly associated with higher levels of estradiol (P = 0.02) and an increased risk of POPH (odds ratio [OR], 2.36; 95% confidence interval [CI], 1.12‐4.91; P = 0.02) whereas other SNPs were not. Lower urinary 2‐hydroxyestrogen/16‐α‐hydroxyestrone (OR per 1‐ln decrease = 2.04; 95% CI, 1.16‐3.57; P = 0.01), lower plasma levels of dehydroepiandrosterone‐sulfate (OR per 1‐ln decrease = 2.38; 95% CI, 1.56‐3.85; P < 0.001), and higher plasma levels of 16‐α‐hydroxyestradiol (OR per 1‐ln increase = 2.16; 95% CI, 1.61‐2.98; P < 0.001) were associated with POPH. Conclusions Genetic variation in aromatase and changes in estrogen metabolites were associated with POPH.

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by severe remodeling of the pulmonary artery resulting in increased pulmonary artery pressure and right ventricular hypertrophy and, ultimately, failure. Bone marrow–derived progenitor cells play a critical role in vascular homeostasis and have been shown to be involved in the pathogenesis of PAH. A proliferation of c‐Kit+ hematopoietic progenitors and mast cells has been noted in the remodeled vessels in PAH. Imatinib, a tyrosine kinase inhibitor that targets c‐Kit, has been shown to be beneficial for patients with PAH. Here we hypothesize that the clinical benefit of imatinib in PAH could be related to c‐Kit inhibition of progenitor cell mobilization and maturation into mast cells. As a corollary to the phase 3 study using imatinib in PAH, blood samples were collected from 12 patients prior to starting study drug (baseline) and while on treatment at weeks 4 and 24. Eight were randomized to imatinib and 4 to placebo. Circulating c‐Kit+ and CD34+ CD133+ hematopoietic progenitors as well as biomarkers of mast cell numbers and activation were measured. Circulating CD34+ CD133+ and c‐Kit+ progenitor cells as well as c‐Kit+/CD34+ CD133+ decreased with imatinib therapy (all P < 0.05). In addition, total tryptase, a marker of mast cell load, dropped with imatinib therapy (P = 0.02) and was related to pulmonary vascular resistance (R = 0.7, P = 0.02). The findings support c‐Kit inhibition as a potential mechanism of action of imatinib in PAH and suggest that tryptase is a potential biomarker of response to therapy.

Abstract The Division of Lung Diseases of the National Heart, Lung, and Blood Institute, with the Office of Rare Diseases Research, held a workshop to identify priority areas and strategic goals to enhance and accelerate research that will result in improved understanding of the lung vasculature, translational research needs, and ultimately the care of patients with pulmonary vascular diseases. Multidisciplinary experts with diverse experience in laboratory, translational, and clinical studies identified seven priority areas and discussed limitations in our current knowledge, technologies, and approaches. The focus for future research efforts include the following: (1) better characterizing vascular genotype–phenotype relationships and incorporating systems biology approaches when appropriate; (2) advancing our understanding of pulmonary vascular metabolic regulatory signaling in health and disease; (3) expanding our knowledge of the biologic relationships between the lung circulation and circulating elements, systemic vascular function, and right heart function and disease; (4) improving translational research for identifying disease-modifying therapies for the pulmonary hypertensive diseases; (5) establishing an appropriate and effective platform for advancing translational findings into clinical studies testing; and (6) developing the specific technologies and tools that will be enabling for these goals, such as question-guided imaging techniques and lung vascular investigator training programs. Recommendations from this workshop will be used within the Lung Vascular Biology and Disease Extramural Research Program for planning and strategic implementation purposes.