Pulmonary arterial hypertension (PAH) is a deadly disease with no cure. Alternate conversion of angiotensin II (AngII) to angiotensin-(1-7) (Ang-(1-7)) by angiotensin-converting enzyme 2 (ACE2) resulting in Mas receptor (Mas1) activation improves rodent models of PAH. Effects of recombinant human (rh) ACE2 in human PAH are unknown. Our objective was to determine the effects of rhACE2 in PAH.We defined the molecular effects of Mas1 activation using porcine pulmonary arteries, measured AngII/Ang-(1-7) levels in human PAH and conducted a phase IIa, open-label pilot study of a single infusion of rhACE2 (GSK2586881, 0.2 or 0.4 mg·kg intravenously).Superoxide dismutase 2 (SOD2) and inflammatory gene expression were identified as markers of Mas1 activation. After confirming reduced plasma ACE2 activity in human PAH, five patients were enrolled in the trial. GSK2586881 was well tolerated with significant improvement in cardiac output and pulmonary vascular resistance. GSK2586881 infusion was associated with reduced plasma markers of inflammation within 2-4 h and increased SOD2 plasma protein at 2 weeks.PAH is characterised by reduced ACE2 activity. Augmentation of ACE2 in a pilot study was well tolerated, associated with improved pulmonary haemodynamics and reduced markers of oxidant and inflammatory mediators. Targeting this pathway may be beneficial in human PAH.

R ight ventricular (RV) failure is the predominant cause of death in pulmonary arterial hypertension (PAH), but no RV-specific therapies exist because the underlying mechanisms are poorly understood. Abnormalities of glucose homeostasis and insulin resistance are well described in PAH, 1-4 but less is known about lipid metabolism despite the interrelated nature of glucose and lipid homeostasis. Abnormalities in fatty acid metabolism have been described in experimental models of PAH, 5,6 but systemic and myocardial fatty acid metabolism have not been studied in human PAH. Clinical Perspective on p 1944Given the heart's preference for fatty acids (FAs) as an energy source, 7 understanding FA metabolism may be particularly relevant to understanding RV adaptation to elevated afterload in PAH. We recently showed that RV failure is associated with myocardial steatosis and accumulation of the lipotoxic and proapoptotic mediator ceramide in human heritable PAH because of mutation in bone morphogenetic protein receptor type II (BMPR2). 8 Others and we have also shown indirect evidence of abnormal fatty acid oxidation (FAO) in experimental models of PAH. [9][10][11] The generalizability of these abnormalities in FA metabolism to idiopathic PAH and whether they are a systemic feature in human PAH are unknown.We hypothesized that reduced FA metabolism is ubiquitous in PAH and associated with lipotoxic cardiac steatosis in the RV. We tested this hypothesis by studying blood, RV Background-The mechanisms of right ventricular (RV) failure in pulmonary arterial hypertension (PAH) are poorly understood. Abnormalities in fatty acid (FA) metabolism have been described in experimental models of PAH, but systemic and myocardial FA metabolism has not been studied in human PAH. Methods and Results-We used human blood, RV tissue, and noninvasive imaging to characterize multiple steps in the FA metabolic pathway in PAH subjects and controls. Circulating free FAs and long-chain acylcarnitines were elevated in PAH patients versus controls. Human RV long-chain FAs were increased and long-chain acylcarnitines were markedly reduced in PAH versus controls. With the use of proton magnetic resonance spectroscopy, in vivo myocardial triglyceride content was elevated in human PAH versus controls ( Sample Collection and AnalysisFasting peripheral blood samples were obtained at the time of clinic visits or at the Vanderbilt General Clinical Research Center. Plasma samples were collected into ethylenediaminetetraacetic acid plasma tubes. Ethylenediaminetetraacetic acid tubes were centrifuged within 45 minutes at 4000 rpm and the plasma fraction immediately aliquoted as 20-µL aliquots and stored at -80ºC. Plasma acylcarnitine samples were analyzed as described previously. 13 The Hormone Assay Core of the Mouse Metabolic Phenotypic Center at Vanderbilt University quantified plasma-free fatty acids by using standard enzymatic reactions. RV Gene Expression ArrayRNA isolation and Microarray techniques have been described previously. 8 All array results...

BACKGROUND Animal and human data suggest insulin resistance is common in pulmonary arterial hypertension (PAH). Although routine assessment of insulin resistance is difficult, hemoglobin A1c (HbA1c) is a sensitive test to detect diabetes mellitus (DM) and those at high risk for diabetes. We aimed to define the prevalence of elevated HbA1c in PAH patients and to correlate HbA1c with functional assessment. METHODS HbA1c was measured in 41 PAH patients without a diagnosis of DM, along with demographic, functional, and hemodynamic data. Using published criteria, HbA1c ≤ 5.9% defined normal, 6.0–6.4% glucose intolerance, and ≥ 6.5% diabetes. RESULTS Twenty-three patients (56%) had HbA1c ≥ 6.0%, 6 patients (15%) had unrecognized DM (HbA1c ≥ 6.5%). Age and body mass index were similar in patients with HbA1c ≥ 6.0% versus HbA1c < 6.0%. There was a trend towards lower mean six-minute walk distance in patients with elevated HbA1c (331.0 ± 126.6 meters versus 413.6 ± 74.9 meters, p=0.07). Six-month event-free survival was not significantly different in patients with elevated HbA1c. CONCLUSIONS Unrecognized glucose intolerance as assessed by HbA1c is common in PAH. Further studies are needed to discern if glucose or insulin dysregulation mediates PAH pathogenesis or is secondary to advanced PAH.

Background Determining the cause for pulmonary hypertension (PH) is difficult in many patients. Pulmonary arterial hypertension (PAH) is differentiated from pulmonary venous hypertension (PVH) by a wedge pressure (PWP) >15 mmHg in PVH. Patients undergoing RHC for evaluation of PH may be dehydrated and have reduced intravascular volume, potentially leading to a falsely low measurement of PWP and an erroneous diagnosis of PAH. We hypothesized that a fluid challenge during RHC would identify occult pulmonary venous hypertension (OPVH). Methods and Results We reviewed the results of patients undergoing fluid challenge in our PH database from 2004-2011. Baseline hemodynamics were obtained and repeated following infusion of 0.5 liters of normal saline over 5-10 minutes. Patients were categorized as OPVH if PWP increased to >15 mm Hg after fluid challenge. Baseline hemodynamics in 207 patients met criteria for PAH. Following fluid challenge, 46 patients (22.2%) developed a PWP >15 mm Hg and were re-classified as OPVH. OPVH patients had a greater increase in PWP compared to PAH patients, p<0.001, and their demographics and comorbid illnesses were similar to PVH patients. There were no adverse events related to fluid challenge. Conclusions Fluid challenge at the time of RHC is easily performed, safe, and identifies a large group of patients diagnosed initially with PAH, but for whom OPVH contributes to PH. These results have implications for therapeutic trials in PAH and support the routine use of fluid challenge during RHC in patients with risk factors for PVH.