Search

Background Idiopathic pulmonary arterial hypertension (iPAH) is a rare and chronic disease associated with poor outcomes. Previously considered a disease restricted to the pulmonary circulation, PAH is now being recognized as a systemic disorder that is associated with metabolic dysfunction. The aim of this study is to analyze the metabolic reprogramming in the lung and peripheral blood mononuclear cell (PBMCs) of iPAH patients and explore their potential roles in PAH pathophysiology. Methods Five independent datasets, containing transcriptomic data of human PBMCs (GSE22356 and GSE33463) and lung (GSE48149 GSE113439 and GSE117261) samples, from 139 iPAH patients and 96 healthy controls, were downloaded at the GEO database. In each dataset, the samples were normalized and a pair-wise comparison between control and iPAH samples was performed using limma package, for the R programming language. Genes with a p-value lower than 0.05 were considered differentially expressed between the two groups. A subset of metabolism related genes was selected, and their expression was compared across the datasets. Results Among the 13 genes with differential expression identified, only 10 had a coherent expression across all datasets (Figure 1). Firstly, we report an association with insulin resistance through impairment of PI3K signaling in iPAH patients, by expressing lower levels of the heterodimer PIK3CD and regulatory PIK3IP1 and PIKR1 subunits in PBMCs, and by expressing higher levels of its downstream targets in the lung (TBC1D4). However, more extensive metabolic dysfunction was observed. A significant glycolytic shift in the lung and PBMCs was present, as a consequence of deregulation in genes involved in aerobic glycolysis and decreased fatty acid oxidation, namely increased expression of PD1K and lower levels of expression of LDHB. The findings of decreased SLC25A1 protein in both PBMCs and lung suggest impairment of the tricarboxylic acid (TCA) cycle flux in PAH. Additionally, SLC1A5 highlights the involvement of glutamine metabolism and glutaminolysis derangements in PAH. Conversely, SREBP1 is involved in sterol biosynthesis and lower levels in PMBCs results in impaired resolution of inflammatory responses. Finally, although the role of autophagy in iPAH is complex, higher levels of expression of ATG13 in PBMCs and lower levels in the lung confirm autophagy deregulation in iPAH. Interestingly, all the metabolic pathways identified (Figure 2) are hallmarks of the metabolic reprogramming seen in cancer cells, a finding already suggested by the clonal proliferation of pulmonary artery smooth muscle cells described in plexiform lesions. Conclusion Our results provide novel insights into the metabolic regulation in iPAH. Molecularly, these cells exhibit many features common to cancer cells, suggesting the opportunity to exploit therapeutic strategies used in cancer to treat iPAH. Funding Acknowledgement Type of funding sources: None.

Introduction Chronic thromboembolic pulmonary hypertension (CPTEH) is the result of thromboemboli leading not only to mechanical obstruction but also pulmonary vascular remodelling and progressive increase in right heart afterload. Prognostic assessment in CPTEH is complex and multifactorial. Purpose We used two-dimensional strain echocardiography (2D-STE) to quantify right atrial (RA) mechanics and its correlation with invasive hemodynamics, load-dependent biomarkers and well-known prognostic markers in patients with CTEPH. Methods A total of 44 patients (24 females, mean age 61±15.6 years) with CTEPH were recruited. 2D-STE was used to measure right atrial reservoir strain (RASr) (Figure 1) which was then compared to conventional ultrasound measurements, right heart catheterisation (RHC) measurements, the percentage of obstruction in ventilation-perfusion pulmonary single-photon emission computed tomography (V/Q SPECT), B-type natriuretic peptide (BNP) values and 6-minute walk test (6MWT) performance. All patients underwent transthoracic echocardiographic evaluation with a maximal time distance of three months to RHC. Results There was a significant positive correlation of RASr with RV longitudinal function determined by tricuspid annular plane systolic excursion (TAPSE) (r=0.488, p=0.003), tricuspid annular peak systolic velocity (S') (r=0.490, p=0.002), right ventricular outflow tract velocity time integral (RVOT VTI) (r=0.457, p=0.005), as well as with 6MWT (r=0.491, p=0.004). There was a significant negative correlation of RASr with mean pulmonary artery pressure (r=−0.513, p=0.002), pulmonary vascular resistance (r=−0.439, p=0.011) and right atrial pressure (RAP) (r=−0.513, p=0.002). RASr was also correlated with Log-transformed BNP values (r=−0.552, p Conclusion 2D-STE-derived RA mechanics demonstrated to be a useful, non-invasive, surrogate measurement of RHC parameters. It also predicted important clinical/laboratory prognostic measurements, such as BNP and 6MWT performance. The absence of correlation between 2D-STE values and the percentage of vessel obstruction determined by SPECT may suggest that RV maladaptive response to the obstruction, rather than the degree of obstruction, dictates right heart failure in CTEPH. Right atrial strain components Funding Acknowledgement Type of funding source: None

Background Two-dimensional speckle tracking (2D-ST) echocardiography for the measurement of circumferential ascending thoracic aortic strain (CAAS) in the context of aortic stenosis (AS) is not elucidated. Purpose This study assesses the thoracic ascending aortic deformation using 2D-ST echocardiography in AS patients. Population and methods Forty-five consecutive patients with an aortic valvular area (AVA) ≤0.85 cm2/m2 were included. Regarding aortic deformation, the global peak CAAS was the parameter used, and an average of six segments of arterial wall deformation was calculated. The corrected CAAS was calculated as the global CAAS/pulse pressure (PP). Aortic stiffness ( β 2) index was assessed according to ln( P s/ P d)/CAAS. The sample was stratified according to the stroke volume index (SVI) as: Group A (low flow, SVI ≤35 mL/m2; n = 19) and Group B (normal flow, SVI >35 mL/m2; n = 26). Results The mean age was 76.8 ± 10.3 years, 53.3% were male, the mean indexed AVA was 0.43 ± 0.15 cm2/m2, and the mean CAAS was 6.3 ± 3.0%. The CAAS was predicted by SVI ( β = 0.31, P < 0.01) and by valvulo-arterial impedance ( Z va). The corrected CAAS was correlated with the M-mode guided aortic stiffness index (β1) ( r = −0.39, P < 0.01), and was predicted by SVI, Z va, and systemic arterial compliance ( β = 0.15, P < 0.01). The β 2 index was significantly higher for the low-flow patients (16.1 ± 4.8 vs. 9.8 ± 5.3, P < 0.01), and was predicted by SVI ( β −0.58, P < 0.01) and PP ( β = 0.17, P < 0.01). Global CAAS was more accurate to predict low flow than Z va, systolic function and systemic vascular resistance. Conclusion In patients with moderate-to-severe aortic stenosis, SVI and LV afterload-related variables were the most important determinants of 2S-ST global CAAS.

Background and objectives: Although iron is a pivotal player in several critical enzymes, limited data is available on the prevalence of iron deficiency in pulmonary hypertension (PH). We sought to assess the prevalence of iron deficiency in a population with PH. Methods: We performed a clinical, hemodynamic and echocardiographic characterization of all PH patients currently being followed in PH clinic between 2008 and 2012. We have assessed the prevalence of iron deficiency in this population by the evaluation of ferritin and transferrin saturation at baseline, nadir values and latest assessment on outpatient clinic. We also compared the different groups of PH. A total of 114 patients (68.4% female, mean age 44±18.3 years) were included. Results: Most patients were from group 1 PH (40.6%) whereas chronic thromboembolic PH comprised 23.8% patients, followed by congenital heart disease-associated PH in 22,8% (18.3% with Eisenmenger's Syndrome). At baseline, most patients were in NYHA 3 (44%) and NYHA 4 (28.4%). Mean brain natriuretic peptide was 355 pg/mL, mean pulmonary artery pressure was 51 mmHg, mean capillary wedge pressure was 9 mmHg and cardiac output was 3.0 L/min. Approximately one-third of patients were receiving warfarin and 14% patients required continuous oxygen. We have found that all the three groups showed transferrin saturation values lower than the reference values. The difference between the groups was statistically significant (DADOS p=0,009). The lowest values were found in group 1, with a mean value of 12%. Serial ferritin values were normal or elevated and no difference between groups was found. After follow-up, there was a favorable outcome when assessing the final transferrin saturation with respect to the minimum value (p