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Cardiac fibrosis contributes to the development of heart failure, and is the response of cardiac fibroblasts (CFs) to pressure or volume overload. Limiting factors in CFs research are the poor availability of human cells and the tendency of CFs to transdifferentiate into myofibroblasts when cultured in vitro. The possibility to generate CFs from induced pluripotent stem cells (iPSC), providing a nearly unlimited cell source, opens new possibilities. However, the behaviour of iPSC-CFs under mechanical stimulation has not been studied yet. Our study aimed to assess the behaviour of iPSC-CFs under mechanical stretch and pro-fibrotic conditions. First, we confirm that iPSC-CFs are comparable to primary CFs at gene, protein and functional level. Furthermore, iPSC-derived CFs adopt a pro-fibrotic response to transforming growth factor beta (TGF-β). In addition, mechanical stretch inhibits TGF-β-induced fibroblast activation in iPSC-CFs. Thus, the responsiveness to cytokines and mechanical stimulation of iPSC-CFs demonstrates they possess key characteristics of primary CFs and may be useful for disease modelling. [ABSTRACT FROM AUTHOR]

Objectives: Closer reading of computed tomography pulmonary angiography (CTPA) scans of patients presenting with acute pulmonary embolism (PE) may identify those at high risk of developing chronic thromboembolic pulmonary hypertension (CTEPH). We aimed to validate the predictive value of six radiological predictors that were previously proposed. Methods: Three hundred forty-one patients with acute PE were prospectively followed for development of CTEPH in six European hospitals. Index CTPAs were analysed post hoc by expert chest radiologists blinded to the final diagnosis. The accuracy of the predictors using a predefined threshold for 'high risk' (≥ 3 predictors) and the expert overall judgment on the presence of CTEPH were assessed. Results: CTEPH was confirmed in nine patients (2.6%) during 2-year follow-up. Any sign of chronic thrombi was already present in 74/341 patients (22%) on the index CTPA, which was associated with CTEPH (OR 7.8, 95%CI 1.9–32); 37 patients (11%) had ≥ 3 of 6 radiological predictors, of whom 4 (11%) were diagnosed with CTEPH (sensitivity 44%, 95%CI 14–79; specificity 90%, 95%CI 86–93). Expert judgment raised suspicion of CTEPH in 27 patients, which was confirmed in 8 (30%; sensitivity 89%, 95%CI 52–100; specificity 94%, 95%CI 91–97). Conclusions: The presence of ≥ 3 of 6 predefined radiological predictors was highly specific for a future CTEPH diagnosis, comparable to overall expert judgment, while the latter was associated with higher sensitivity. Dedicated CTPA reading for signs of CTEPH may therefore help in early detection of CTEPH after PE, although in our cohort this strategy would not have detected all cases. Key Points: • Three expert chest radiologists re-assessed CTPA scans performed at the moment of acute pulmonary embolism diagnosis and observed a high prevalence of chronic thrombi and signs of pulmonary hypertension. • On these index scans, the presence of ≥ 3 of 6 predefined radiological predictors was highly specific for a future diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH), comparable to overall expert judgment. • Dedicated CTPA reading for signs of CTEPH may help in early detection of CTEPH after acute pulmonary embolism. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) is a devastating disease, characterized by obstructive pulmonary vascular remodelling ultimately leading to right ventricular (RV) failure and death. Disturbed transforming growth factor-β (TGF-β)/bone morphogenetic protein (BMP) signalling, endothelial cell dysfunction, increased proliferation of smooth muscle cells and fibroblasts, and inflammation contribute to this abnormal remodelling. Peptidyl-prolyl isomerase Pin1 has been identified as a critical driver of proliferation and inflammation in vascular cells, but its role in the disturbed TGF-β/BMP signalling, endothelial cell dysfunction, and vascular remodelling in PAH is unknown. Here, we report that Pin1 expression is increased in cultured pulmonary microvascular endothelial cells (MVECs) and lung tissue of PAH patients. Pin1 inhibitor, juglone significantly decreased TGF-β signalling, increased BMP signalling, normalized their hyper-proliferative, and inflammatory phenotype. Juglone treatment reversed vascular remodelling through reducing TGF-β signalling in monocrotaline + shunt-PAH rat model. Juglone treatment decreased Fulton index, but did not affect or harm cardiac function and remodelling in rats with RV pressure load induced by pulmonary artery banding. Our study demonstrates that inhibition of Pin1 reversed the PAH phenotype in PAH MVECs in vitro and in PAH rats in vivo, potentially through modulation of TGF-β/BMP signalling pathways. Selective inhibition of Pin1 could be a novel therapeutic option for the treatment of PAH. [ABSTRACT FROM AUTHOR]

Background: In patients with pulmonary arterial hypertension, the 6-Minute Walk Test (6MWT) is recommended for risk stratification and follow-up by all guidelines. However, the prognostic value of the 6MWT has been discussed controversially. We sought to compare and validate all published 6MWT cut-off points.Methods: From the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA)—registry we identified 2391 patients with pulmonary arterial hypertension who had at least one documented 6MWT measurement. A Medline search identified a total of 21 different threshold values for either single-point or change of 6MWT. All values were tested individually for prognostication of 1-year, 2-year and 3-year all-cause mortality.Results: The highest positive likelihood ratio was a cut-off value < 165 ms, whereas the best negative likelihood ratio was found to be a threshold of 440 ms. Furthermore, improvement in 6MWT had considerably less predictive value on mortality and survival than deterioration. Moreover, absolute single-point values outperformed change values for both improvement and worsening.Conclusion: Our data confirmed the prognostic relevance of the 6MWT and support the cut-off values stated in most recent guidelines. Furthermore, these results explain why changes in 6MWT did not correlate consistently with prognosis in previous studies. [ABSTRACT FROM AUTHOR]

Cardiac magnetic resonance imaging of the pressure overloaded right ventricle (RV) of precapillary pulmonary hypertension (PH) patients, exhibits late gadolinium enhancement at the interventricular insertion regions, a phenomenon which has been linked to focal fibrosis. Native T1-mapping is an alternative technique to characterize myocardium and has the advantage of not requiring the use of contrast agents. The aim of this study was to characterize the myocardium of idiopathic pulmonary arterial hypertension (IPAH), systemic scleroderma related PH (PAH-Ssc) and chronic thromboembolic PH (CTEPH) patients using native T1-mapping and to see whether native T1-values were related to disease severity. Furthermore, we compared native T1-values between the different precapillary PH categories. Native T1-mapping was performed in 46 IPAH, 14 PAH-SSc and 10 CTEPH patients and 10 control subjects. Native T1-values were assessed using regions of interest at the RV and LV free wall, interventricular septum and interventricular insertion regions. In PH patients, native T1-values of the interventricular insertion regions were significantly higher than the native T1-values of the RV free wall, LV free wall and interventricular septum. Native T1-values at the insertion regions were significantly related to disease severity. Native T1-values were not different between IPAH, PAH-Ssc and CTEPH patients. Native T1-values of the interventricular insertion regions are significantly increased in precapillary PH and are related to disease severity. Native T1-mapping can be developed as an alternative technique for the characterization of the interventricular insertion regions and has the advantage of not requiring the use of contrast agents. [ABSTRACT FROM AUTHOR]

The most common feature of pulmonary hypertension (PH) on computed tomography pulmonary angiography (CTPA) is an increased diameter-ratio of the pulmonary artery to the ascending aorta (PA/AA). The aim of this study was to investigate whether combining PA/AA measurements with ventricular measurements improves the predictive value of CTPA for precapillary PH. Three predicting models were analysed using baseline CTPA scans of 51 treatment naïve precapillary PH patients and 25 non-PH controls: model 1: PA/AA only; model 2: PA/AA combined with the ratio of the right ventricular and left ventricular diameter measured on the axial view (RV/LV); model 3: PA/AA combined with the RV/LV-ratio measured on a four chamber view (RV/LV). Prediction models were compared using multivariable binary logistic regression, ROC analyses and decision curve analyses (DCA). Multivariable binary logistic regression showed an improvement of the predictive value of model 2 (−2LL = 26.48) and 3 (−2LL = 21.03) compared to model 1 (−2LL = 21.03). ROC analyses showed significantly higher AUCs of model 2 and 3 compared to model 1 ( p = 0.011 and p = 0.007, respectively). DCA showed an increased clinical benefit of model 2 and 3 compared to model 1. The predictive value of model 2 and 3 were almost equal. We found an optimal cut-off value for the RV/LV-ratio for predicting precapillary PH of RV/LV ≥ 1.20. The predictive value of CTPA for precapillary PH improves when ventricular and pulmonary artery measurements are combined. A PA/AA ≥ 1 or a RV/LV ≥ 1.20 needs further diagnostic evaluation to rule out or confirm the diagnosis. [ABSTRACT FROM AUTHOR]

To assess the contribution of right ventricular (RV) trabeculae and papillary muscles (TPM) to RV mass and volumes in controls and patients with pulmonary arterial hypertension (PAH). Furthermore, to evaluate whether TPM shows a similar response as the RV free wall (RVFW) to changes in pulmonary artery pressure (PAP) during follow-up. 50 patients underwent cardiac magnetic resonance (CMR) and right heart catheterization at baseline and after one-year follow-up. Furthermore 20 controls underwent CMR. RV masses were assessed with and without TPM. TPM constituted a larger proportion of total RV mass and RV end-diastolic volume (RVEDV) in PAH than in controls (Mass: 35 ± 7 vs. 25 ± 5 %; p < 0.001; RVEDV: 17 ± 6 vs. 12 ± 6 %; p = 0.003). TPM mass was related to the RVFW mass in patients (baseline: R = 0.65; p < 0.001; follow-up: R = 0.80; p < 0.001) and controls (R = 0.76; p < 0.001). In PAH and controls, exclusion of TPM from the assessment resulted in altered RV mass, volumes and function than when included (all p < 0.01). Changes in RV TPM mass (β = 0.44; p = 0.004) but not the changes in RVFW mass ( p = 0.095) were independently related to changes in PAP during follow-up. RV TPM showed a larger contribution to total RV mass in PAH (~35 %) compared to controls (~25 %). Inclusion of TPM in the analyses significantly influenced the magnitude of the RV volumes and mass. Furthermore, TPM mass was stronger related to changes in PAP than RVFW mass. Our results implicate that TPM are important contributors to RV adaptation during pressure overload and cannot be neglected from the RV assessment. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) is a rare, severe disease resulting from progressive obliteration of small-caliber pulmonary arteries by proliferating vascular cells. PAH can occur without recognized etiology (idiopathic PAH), be associated with a systemic disease or occur as a heritable form, with BMPR2 mutated in approximately 80% of familial and 15% of idiopathic PAH cases. We conducted a genome-wide association study (GWAS) based on 2 independent case-control studies for idiopathic and familial PAH (without BMPR2 mutations), including a total of 625 cases and 1,525 healthy individuals. We detected a significant association at the CBLN2 locus mapping to 18q22.3, with the risk allele conferring an odds ratio for PAH of 1.97 (1.59-2.45; P = 7.47 × 10−10). CBLN2 is expressed in the lung, and its expression is higher in explanted lungs from individuals with PAH and in endothelial cells cultured from explanted PAH lungs. [ABSTRACT FROM AUTHOR]

Background: Fibrosis is associated with various cardiac pathologies and dysfunction. Current quantification methods are time-consuming and laborious. We describe a semi-automated quantification technique for myocardial fibrosis and validated this using traditional methods. Methods: Pulmonary Hypertension (PH) was induced in adult Wistar rats by subcutaneous monocrotaline (MCT) injection(40 mg/kg). Cryosections of myocardial tissue (5 μm) of PH rats ( n = 9) and controls ( n = 9) were stained using Picrosirius red and scanned with a digital microscopic MIRAX slide scanner. From these sections 21 images were taken randomly of each heart. Using ImageJ software a macro for automated image analysis of the amount of fibrosis was developed. For comparison, fibrosis was quantified using traditional polarisation microscopy. Both methods were correlated and validated against stereology as the gold standard. Furthermore, the method was tested in paraffin-embedded human tissues. Results: Automated analysis showed a significant increase of fibrosis in PH hearts vs. control. Automated analysis correlated with traditional polarisation and stereology analysis ( r = 0.92 and r = 0.95 respectively). In human heart, lungs, kidney, and liver, a similar correlation with stereology ( r = 0.91) was observed. Time required for automated analysis was 22% and 33% of the time needed for stereology and polarisation analysis respectively. Conclusion: Automated quantification of fibrosis is feasible, objective, and time-efficient. [ABSTRACT FROM AUTHOR]

Recently, it was shown that proportional relationships exist between systolic, diastolic and mean pulmonary artery pressure ( P, P and P) and that they are maintained under various conditions in both health and disease. An arterial-ventricular interaction model was used to study the contribution of model parameters to the ratios P/ P, and P/ P. The heart was modeled by a time-varying elastance function, and the arterial system by a three-element windkessel model consisting of peripheral resistance, R, arterial compliance C, and pulmonary artery characteristic impedance Z. Baseline model parameters were estimated in control subjects and compared to values estimated in patients with pulmonary hypertension. Results indicate that experimentally derived ratios P/ P and P/ P could be accurately reproduced using our model (1.59 and 0.61 vs. 1.55 and 0.64, respectively). Sensitivity analysis showed that the (empirical) constancy of P/ P and P/ P was primarily based on the inverse hyperbolic relation between total vascular resistance ( R; calculated as R + Z) and C, (i.e. constant R C product). Of the cardiac parameters, only heart rate affected the pressure ratios, but the contribution was small. Therefore, we conclude that proportional relations between systolic, diastolic and mean pulmonary artery pressure result from the constancy of R C thus from pulmonary arterial properties, with only little influence of heart rate. [ABSTRACT FROM AUTHOR]

Simulations are useful to study the heart’s ability to generate flow and the interaction between contractility and loading conditions. The left ventricular pressure–volume (PV) relation has been shown to be nonlinear, but it is unknown whether a linear model is accurate enough for simulations. Six models were fitted to the PV-data measured in five sheep and the estimated parameters were used to simulate PV-loops. Simulated and measured PV-loops were compared with the Akaike information criterion (AIC) and the Hamming distance, a measure for geometric shape similarity. The compared models were: a time-varying elastance model with fixed volume intercept (LinFix); a time-varying elastance model with varying volume intercept (LinFree); a Langewouter’s pressure-dependent elasticity model (Langew); a sigmoidal model (Sigm); a time-varying elastance model with a systolic flow-dependent resistance (Shroff) and a model with a linear systolic and an exponential diastolic relation (Burkh). Overall, the best model is LinFree (lowest AIC), closely followed by Langew. The remaining models rank: Sigm, Shroff, LinFix and Burkh. If only the shape of the PV-loops is important, all models perform nearly identically (Hamming distance between 20 and 23%). For realistic simulation of the instantaneous PV-relation a linear model suffices. [ABSTRACT FROM AUTHOR]

Electrical impedance tomography (EIT) is a non-invasive imaging technique for detecting blood volume changes that can visualize pulmonary perfusion. The two studies reported here tested the hypothesis that the size of the pulmonary microvascular bed, rather than stroke volume (SV), determines the EIT signal. In the first study, the impedance changes relating to the maximal pulmonary pulsatile blood volume during systole (ΔZsys) were measured in ten healthy subjects, ten patients diagnosed with chronic obstructive pulmonary disease, who were considered to have a reduced pulmonary vascular bed, and ten heart failure patients with an assumed low cardiac output but with a normal lung parenchyma. Mean ΔZsys (SD) in these groups was 261 (34)×10-5, 196 (39)×10-5 (P<0.001) and 233 (61)×10-5 arbitrary units (AU) (P=NS), respectively. In the second study, including seven healthy volunteers, ΔZsys was measured at rest and during exercise on a recumbent bicycle while SV was measured by means of magnetic resonance imaging. The ΔZsys at rest was 352 (53)×10-5 and 345 (112)×10-5 AU during exercise (P=NS), whereas SV increased from 83 (21) to 105 (34) ml (P<0.05). The EIT signal likely reflects the size of the pulmonary microvascular bed, since neither a low cardiac output nor a change in SV of the heart appear to influence EIT. [ABSTRACT FROM AUTHOR]

n accurate differential diagnosis is crucial in pulmonary hypertension/pulmonary arterial hypertension (PH/PAH), because the treatment options in the different PH/PAH groups and subgroups differ substantially. [ABSTRACT FROM AUTHOR]

The long-term outcomes of operated and nonoperated patients with chronic thromboembolic pulmonary hypertension were reported in a large, prospective, multicentre, European and Canadian registry. The long-term prognosis of operated patients was superior to that of nonoperated patients, indicating that surgery should be the first-choice treatment in this patient cohort. [ABSTRACT FROM AUTHOR]