Pulmonary hypertension (PH) occurs when the pulmonary vasculature is itself diseased or becomes affected secondarily by comorbid conditions, commonly left heart or lung disease. The high prevalence of chronic cardiopulmonary conditions among patients served by Veterans Health Administration (VHA) suggests this population may be particularly susceptible to PH. We sought to identify clinical features and outcomes in veterans diagnosed with PH. We utilized the VHA Corporate Data Warehouse to identify veterans diagnosed between January 1, 2003 and September 30, 2015, assess relevant patient characteristics and their survival time. The effects of PH subtype and baseline factors on outcome were estimated by Cox modeling. There were 110,564 veterans diagnosed with PH during the study period. These veterans were predominantly male, had median age 70.2, and had a high burden of comorbid conditions. PH was frequently due to left heart and/or lung disease. Average survival after PH diagnosis was 3.88 years. Compared with other types, PH due to left heart disease, lung disease or both had shorter survival. This large retrospective study of veterans demonstrates the significance of PH due to left heart and/or lung disease which was common and had high risk of death. Multi-comorbidity was common and added to risk. These findings underscore the need for risk assessment tools for subjects with non-Group 1 PH and novel management strategies to improve their outcome. This study details the largest retrospective cohort assembled for evaluation of secondary PH and allows hypothesis-generating inquiries into these common conditions that are rarely prospectively studied.

Pulmonary hypertension (PH) comprises a diverse group of disorders that share a common pathway of pulmonary vascular remodeling leading to right ventricular failure. Development of anti-remodeling strategies is an emerging frontier in PH therapeutics that requires a greater understanding of the interactions between vascular wall cells and their extracellular matrices. The ubiquitous matrix glycan, hyaluronan (HA), is markedly elevated in lungs from patients and experimental models with PH. Herein, we identified HA synthase-2 (HAS2) in the pulmonary artery smooth muscle cell (PASMC) layer as a predominant locus of HA dysregulation. HA upregulation involves depletion of NUDT21, a master regulator of alternative polyadenylation, resulting in 3’UTR shortening and hyper-expression of HAS2. The ensuing increase of HAS2 and hyper-synthesis of HA promoted bioenergetic dysfunction of PASMC characterized by impaired mitochondrial oxidative capacity and a glycolytic shift. The resulting HA accumulation stimulated pro-remodeling phenotypes such as cell proliferation, migration, apoptosis-resistance, and stimulated pulmonary artery contractility. Transgenic mice, mimicking HAS2 hyper-synthesis in smooth muscle cells, developed spontaneous PH, whereas targeted deletion of HAS2 prevented experimental PH. Pharmacological blockade of HAS2 restored normal bioenergetics in PASMC, ameliorated cell remodeling phenotypes, and reversed experimental PH in vivo. In summary, our results uncover a novel mechanism of HA hyper-synthesis and downstream effects on pulmonary vascular cell metabolism and remodeling.

Background: Sepsis is one of the leading causes of hospital mortality, and diabetes is a risk factor for the development of infections. Although strong evidence has shown an association between metformin and reduced risk of infections, the risk of developing infections with newer classes of oral anti-diabetic drugs (OADs) has been less certain. Our study aims to examine the association between outpatient OAD use and hospital admissions for infections. Methods: The study cohort included 1.39 million adults with diabetes utilizing the Veterans Health Affairs Corporate Data Warehouse. Multivariate logistic regression was used to estimate the effect of each drug class on hospital admission for infection while adjusting for covariates. Results: After adjusting for covariates, those who took metformin during the study period had 3.3% lower odds of hospital admission for infection compared to those who were never on metformin (OR 0.97, 95% CI 0.95-0.98). OADs that were associated with a statistically significant increased odds of being admitted included meglitinides (OR 1.22, 95% CI 1.07-1.38), SGLT2 inhibitors (OR 1.16, 95% CI 1.08-1.24), alpha-glucosidase inhibitors (OR 1.09, 95% CI 1.04-1.15), and DPP4 inhibitors (OR 1.04, 95% CI 1.01-1.06). Conclusions: Metformin was associated with lower odds of hospital admission for infection while meglitinides, SGLT2 inhibitors, alpha-glucosidase inhibitors, and DPP4 inhibitors were associated with higher odds of admission for infection.

Evaluation for right ventricular (RV) dysfunction is an important part of risk assessment in care of patients with pulmonary hypertension (PH) as it is associated with morbidity and mortality. Echocardiography provides a widely available and acceptable method to assess RV function. RV global longitudinal strain (RVGLS), a measure of longitudinal shortening of RV deep muscle fibers obtained by two-dimensional echocardiography, was previously shown to predict short-term mortality in patients with PH. The purpose of the current study was to assess the performance of RVGLS in predicting 1-year outcomes in PH. We retrospectively identified 83 subjects with precapillary PH and then enrolled 50 consecutive prevalent pulmonary arterial hypertension (PAH) subjects into a prospective validation cohort. Death as well as combined morbidity and mortality events at 1 year were assessed as outcomes. In the retrospective cohort, 84% of patients had PAH and the overall 1-year mortality rate was 16%. Less negative RVGLS was marginally better than tricuspid annular plane systolic excursion (TAPSE) as a predictor for death. However, in the prospective cohort, 1-year mortality was only 2%, and RVGLS was not predictive of death or a combined morbidity and mortality outcome. This study supports that RV strain and TAPSE have similar 1-year outcome predictions but highlights that low TAPSE or less negative RV strain measures are often false-positive in a cohort with low baseline mortality risk. While RV failure is considered the final common pathway for disease progression in PAH, echocardiographic measures of RV function may be less informative of risk in serial follow-up of treated PAH patients.

Pulmonary hypertension (PH) is a complex condition that arises due to pulmonary vascular disease, heart disease, lung disease, chronic thromboembolism, or several rare causes. Regardless of underlying cause, PH increases mortality, yet there are no directed treatments for the most common forms of PH due to left heart or lung disease. Because metabolic factors have been implicated in the pathogenesis of PH, we used a large administrative cohort to assess diabetes and weight, potentially modifiable risk factors, on PH outcome. We analyzed 110,495 veterans diagnosed with PH from January 1, 2003 to September 30, 2015 in the Veterans Health Affairs system. Veterans with PH survived an average of 3.88 [IQR 3.85, 3.92] years after PH diagnosis. Diabetes occurred in 36% and increased risk of death by 31% (95% confidence interval 28% to 33%, multivariate adjusted). Higher body mass index was associated with lower mortality in a J-shaped pattern with highest risk in underweight and normal weight veterans. Improved survival in obesity has been referred to as the obesity paradox in heart failure and other diseases. These data show that lower weight and diabetes are strong risk factors for mortality in PH. Our results underscore the importance of systemic conditions on outcome in PH.

Pulmonary arterial hypertension (PAH) is associated with metabolic derangements including insulin resistance, although their effects on the cardiopulmonary disease are unclear. We hypothesized that insulin resistance promotes pulmonary hypertension (PH) development and mutations in type 2 bone morphogenetic protein receptor (BMPR2) cause cellular insulin resistance. Using a BMPR2 transgenic murine model of PAH and two models of inducible diabetes mellitus, we explored the impact of hyperglycemia and/or hyperinsulinemia on development and severity of PH. We assessed insulin signaling and insulin-mediated glucose uptake in human endothelial cells with and without mutations in BMPR2. PH developed in control mice fed aWestern diet and PH in BMPR2 mutant mice was increased by Western diet. Pulmonary artery pressure correlated strongly with fasting plasma insulin but not glucose. Reactive oxygen species were increased in lungs of insulin-resistant animals. BMPR2 mutation impaired insulin-mediated endothelial glucose uptake via reduced glucose transporter translocation despite intact insulin signaling. Experimental hyperinsulinemia is strongly associated with PH in both control and BMPR2-mutant mice, though to a greater degree in those with BMPR2 mutation. Human pulmonary endothelial cells with BMPR2 mutation have evidence of reduced glucose uptake due to impaired glucose transporter translocation. These experiments support a role for hyperinsulinemia in pulmonary vascular disease.

Pulmonary hypertension affects about one in four patients with advanced chronic kidney disease and significantly increases the risk of death. Kidney transplantation is the recommended management option for patients with progressive or end‐stage kidney disease. However, the resource‐limited nature of kidney transplantation and its intensive peri‐operative and posttransplantation management motivates careful consideration of potential candidates’ medical conditions to optimally utilize available graft organs. Since pulmonary hypertension is known to increase peri‐operative morbidity and mortality among patients living with chronic kidney disease, we performed a retrospective cohort study to assess the impact of pretransplantation pulmonary hypertension on posttransplantation outcome. All patients who underwent single‐organ kidney transplantation at our center in calendar years 2010 and 2011 were identified and the presence of pulmonary hypertension was determined from pretransplantation echocardiography. Outcome was assessed at 5 years following kidney transplantation. Of 350 patients who were included, 117 (33%) had evidence of pulmonary hypertension. The risk of death, graft dysfunction, or graft failure at 5 years after kidney transplantation was higher among those with pulmonary hypertension, primarily owing to an increased risk of graft dysfunction. Importantly, in this institutional cohort of kidney transplant recipients, pretransplant pulmonary hypertension was not associated with a difference in posttransplant survival at 5 years. While institutional and regional differences in outcome can be expected, this report suggests that carefully selected patients with pulmonary hypertension receive similar long‐term benefits from kidney transplantation.