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This article discusses a new algorithm for assessing right ventricular function in patients with pulmonary hypertension. The algorithm simplifies the calculation of right ventricular ejection fraction (RVEF) by using only three points on the right ventricular pressure curve. The algorithm was validated using retrospective data from 99 patients and showed good correlation with conventional methods. It was also able to accurately track changes in RVEF over time in a prospective analysis. While the algorithm may not be as precise as cardiac magnetic resonance imaging, it provides a valuable tool for clinicians to monitor right ventricular function in real-time and make informed decisions in managing patients with pulmonary hypertension. [Extracted from the article]

Aims: Commercially available integrated software for echocardiographic measurement of stroke work (SW) is increasingly used for the right ventricle, despite a lack of validation. We sought to assess the validity of this method [echo‐based myocardial work (MW) module] vs. gold‐standard invasive right ventricular (RV) pressure–volume (PV) loops. Methods and results: From the prospectively recruiting EXERTION study (NCT04663217), we included 42 patients [34 patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH) and 8 patients with absence of cardiopulmonary disease] with RV echocardiography and invasive PV catheterization. Echocardiographic SW was assessed as RV global work index (RVGWI) generated via the integrated pressure–strain MW software. Invasive SW was calculated as the area bounded by the PV loop. An additional parameter derived from the MW module, RV global wasted work (RVGWW), was correlated with PV loop measures. RVGWI significantly correlated with invasive PV loop‐derived RV SW in the overall cohort [rho = 0.546 (P < 0.001)] and the PAH/CTEPH subgroup [rho = 0.568 (P < 0.001)]. Overall, RVGWW correlated with invasive measures of arterial elastance (Ea), the ratio of end‐systolic elastance (Ees)/Ea, and end‐diastolic elastance (Eed) significantly. Conclusions: Integrated echo measurement of pressure–strain loop‐derived SW correlates with PV loop‐based assessment of RV SW. Wasted work correlates with invasive measures of load‐independent RV function. Given the methodological and anatomical challenges of RV work assessment, evolution of this approach by incorporating more elaborated echo analysis data and an RV reference curve might improve its reliability to mirror invasively assessed RV SW. [ABSTRACT FROM AUTHOR]

Background: Parametric imaging has taken a steep rise in recent years and non-cardiac applications are of increasing interest. Therefore, the aim of our study was to assess right (RV) and left ventricular (LV) blood pool T1 and T2 values in patients with chronic thromboembolic pulmonary hypertension (CTEPH) compared to control subjects and their correlation to pulmonary hemodynamic. Methods: 26 patients with CTEPH (mean age 64.8 years ± 12.8 SD; 15 female), who underwent CMR and right heart catheterization (RHC) before and 6-months after balloon pulmonary angioplasty (BPA), were retrospectively included. Ventricular blood pool values were measured, compared to control subjects (mean age 40.5 years ± 12.8 SD; 16 female) and correlated to invasive measures (CI, mPAP, PVR). Results: In both, control subjects and CTEPH patients, RVT1 and RVT2 were significantly reduced compared to LVT1 and LVT2. Compared to control subjects, RVT2 was significantly reduced in CTEPH patients (p = 0.0065) and increased significantly after BPA (p = 0.0048). Moreover, RVT2 was positively correlated with CI and negatively correlated with mPAP and PVR before (r = 0.5155, r = −0.2541, r = −0.4571) and after BPA (r = 0.4769, r = −0.2585, r = −0.4396). Conclusion: Ventricular blood pool T2 mapping might be novel non-invasive CMR imaging marker for assessment of disease severity, prognosis, follow-up and even therapy monitoring in PH. [ABSTRACT FROM AUTHOR]

Background: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. In addition to chronic bronchitis and emphysema, patients often develop at least mild pulmonary hypertension (PH). We previously demonstrated that inhibition of inducible nitric oxide synthase (iNOS) prevents and reverses emphysema and PH in mice. Interestingly, strong iNOS upregulation was found in alveolar epithelial type II cells (AECII) in emphysematous murine lungs, and peroxynitrite, which can be formed from iNOS-derived NO, was shown to induce AECII apoptosis in vitro. However, the specific cell type(s) that drive(s) iNOS-dependent lung regeneration in emphysema/PH has (have) not been identified yet. Aim: we tested whether iNOS knockout in AECII affects established elastase-induced emphysema in mice. Methods: four weeks after a single intratracheal instillation of porcine pancreatic elastase for the induction of emphysema and PH, we induced iNOS knockout in AECII in mice, and gave an additional twelve weeks for the potential recovery. Results: iNOS knockout in AECII did not reduce elastase-induced functional and structural lung changes such as increased lung compliance, decreased mean linear intercept and increased airspace, decreased right ventricular function, increased right ventricular systolic pressure and increased pulmonary vascular muscularization. In vitro, iNOS inhibition did not reduce apoptosis of AECII following exposure to a noxious stimulus. Conclusion: taken together, our data demonstrate that iNOS deletion in AECII is not sufficient for the regeneration of emphysematous murine lungs, and suggest that iNOS expression in pulmonary vascular or stromal cells might be critically important in this regard. [ABSTRACT FROM AUTHOR]

Mitochondrial and immune cell dysfunction contributes to the development of pulmonary arterial hypertension (PAH). We thus aimed to investigate mitochondrial respiration and mitochondrial gene expression patterns in the peripheral blood mononuclear cells (PBMC) of patients with idiopathic and hereditary PAH and their correlation to disease parameters. Mitochondrial respiration determined using high-resolution respirometry was not significantly different in PBMC when comparing an outpatient cohort of PAH patients with healthy controls. However, when directly comparing mitochondrial respiration to the hemodynamic parameters of an inpatient PAH cohort, mitochondrial respiration negatively correlated with pulmonary vascular resistance (PVR) and positively correlated with the cardiac index (CI). Furthermore, microarray analysis shows upregulation of mitochondrial erythroid-specific 5-aminolevulinate synthase 2 (ALAS2), as well as the regulation of genes involved in iron and heme metabolism, in the PBMC of patients with PAH, with ALAS2 upregulation in PAH patients being confirmed on the protein level. Multiple regression analysis with age and gender as confounders showed that both PVR and hemoglobin content negatively correlated with maximal respiration. Therefore, we conclude that mitochondrial function in the PBMC of PAH patients is affected by disease severity. However, further studies to investigate cell-type-specific alterations and functional consequences are necessary. [ABSTRACT FROM AUTHOR]

The article reports that parenteral prostacyclins are recommended for the treatment of severe pulmonary arterial hypertension (PAH) with efficacy related to positive inotropic effects on the right ventricle (RV). It mentions about early in vitro studies drug-induced decrease in afterload arterial elastance accompanied by paradoxical decrease in contractility end-systolic elastance preserving RV–pulmonary arterial coupling.

Phenotypic alterations in resident vascular cells contribute to the vascular remodeling process in diseases such as pulmonary (arterial) hypertension [P(A)H]. How the molecular interplay between transcriptional coactivators, transcription factors (TFs), and chromatin state alterations facilitate the maintenance of persistently activated cellular phenotypes that consequently aggravate vascular remodeling processes in PAH remains poorly explored. RNA sequencing (RNA-seq) in pulmonary artery fibroblasts (FBs) from adult human PAH and control lungs revealed 2460 differentially transcribed genes. Chromatin immunoprecipitation sequencing (ChIP-seq) revealed extensive differential distribution of transcriptionally accessible chromatin signatures, with 4152 active enhancers altered in PAH-FBs. Integrative analysis of RNA-seq and ChIP-seq data revealed that the transcriptional signatures for lung morphogenesis were epigenetically derepressed in PAH-FBs, including coexpression of T-box TF 4 (TBX4), TBX5, and SRY-box TF 9 (SOX9), which are involved in the early stages of lung development. These TFs were expressed in mouse fetuses and then repressed postnatally but were maintained in persistent PH of the newborn and reexpressed in adult PAH. Silencing of TBX4, TBX5, SOX9, or E1A-associated protein P300 (EP300) by RNA interference or small-molecule compounds regressed PAH phenotypes and mesenchymal signatures in arterial FBs and smooth muscle cells. Pharmacological inhibition of the P300/CREB-binding protein complex reduced the remodeling of distal pulmonary vessels, improved hemodynamics, and reversed established PAH in three rodent models in vivo, as well as reduced vascular remodeling in precision-cut tissue slices from human PAH lungs ex vivo. Epigenetic reactivation of TFs associated with lung development therefore underlies PAH pathogenesis, offering therapeutic opportunities. Deactivating developmental reactivation: Pulmonary arterial hypertension (PAH) is a fatal disease, and current treatments do not restore vascular structure. Here, Chelladurai and colleagues integrated RNA sequencing and chromatin immunoprecipitation sequencing data from PAH pulmonary artery fibroblasts, revealing derepression of transcriptional signatures for lung morphogenesis. Silencing of TBX4, TBX5, and SOX9, as well as EP300, a regulator of developmental transcription factor expression, led to regression of mesenchymal signatures, and inhibition of the P300/CREB-binding protein complex using pharmacological compounds reduced vascular remodeling in precision-cut lung tissue slices. In three rat models of PAH, these compounds improved hemodynamics and reduced the muscularization of the distal pulmonary arteries, suggesting that controlling the epigenetic dysregulation of developmental transcription factors may be beneficial in this disease. [ABSTRACT FROM AUTHOR]

Aims We sought to assess the feasibility of constructing right ventricular (RV) pressure–volume (PV) loops solely by echocardiography. Methods and results We performed RV conductance and pressure wire (PW) catheterization with simultaneous echocardiography in 35 patients with pulmonary hypertension. To generate echocardiographic PV loops, a reference RV pressure curve was constructed using pooled PW data from the first 20 patients (initial cohort). Individual pressure curves were then generated by adjusting the reference curve according to RV isovolumic and ejection phase duration and estimated RV systolic pressure. The pressure curves were synchronized with echocardiographic volume curves. We validated the reference curve in the remaining 15 patients (validation cohort). Methods were compared with correlation and Bland–Altman analysis. In the initial cohort, echocardiographic and conductance-derived PV loop parameters were significantly correlated {rho = 0.8053 [end-systolic elastance (Ees)], 0.8261 [Ees/arterial elastance (Ea)], and 0.697 (stroke work); all P  <   0.001}, with low bias [−0.016 mmHg/mL (Ees), 0.1225 (Ees/Ea), and −39.0 mmHg mL (stroke work)] and acceptable limits of agreement. Echocardiographic and PW-derived Ees were also tightly correlated, with low bias (−0.009 mmHg/mL) and small limits of agreement. Echocardiographic and conductance-derived Ees, Ees/Ea, and stroke work were also tightly correlated in the validation cohort (rho = 0.9014, 0.9812, and 0.9491, respectively; all P  <   0.001), with low bias (0.0173 mmHg/mL, 0.0153, and 255.1 mmHg mL, respectively) and acceptable limits. Conclusion The novel echocardiographic method is an acceptable alternative to invasively measured PV loops to assess contractility, RV-arterial coupling, and RV myocardial work. Further validation is warranted. [ABSTRACT FROM AUTHOR]

Aims The pulmonary vascular tone and hypoxia-induced alterations of the pulmonary vasculature may be regulated by the mitochondrial membrane permeability transition pore (mPTP) that controls mitochondrial calcium load and apoptosis. We thus investigated, if the mitochondrial proteins p66shc and cyclophilin D (CypD) that regulate mPTP opening affect the pulmonary vascular tone. Methods and results Mice deficient for p66shc (p66shc−/−), CypD (CypD−/−), or both proteins (p66shc/CypD−/−) exhibited decreased pulmonary vascular resistance (PVR) compared to wild-type mice determined in isolated lungs and in vivo. In contrast, systemic arterial pressure was only lower in CypD−/− mice. As cardiac function and pulmonary vascular remodelling did not differ between genotypes, we determined alterations of vascular contractility in isolated lungs and calcium handling in pulmonary arterial smooth muscle cells (PASMC) as underlying reason for decreased PVR. Potassium chloride (KCl)-induced pulmonary vasoconstriction and KCl-induced cytosolic calcium increase determined by Fura-2 were attenuated in all gene-deficient mice. In contrast, KCl-induced mitochondrial calcium increase determined by the genetically encoded Mito-Car-GECO and calcium retention capacity were increased only in CypD−/− and p66shc/CypD−/− mitochondria indicating that decreased mPTP opening affected KCl-induced intracellular calcium peaks in these cells. All mouse strains showed a similar pulmonary vascular response to chronic hypoxia, while acute hypoxic pulmonary vasoconstriction was decreased in gene-deficient mice indicating that CypD and p66shc regulate vascular contractility but not remodelling. Conclusions We conclude that p66shc specifically regulates the pulmonary vascular tone, while CypD also affects systemic pressure. However, only CypD acts via regulation of mPTP opening and mitochondrial calcium regulation. [ABSTRACT FROM AUTHOR]

The article presents a retrospective analysis of the prevalence of computed tomography (CT) surrogate markers for pulmonary hypertension and their impact on survival in patients with lung cancer. It mentions that individuals with lung cancer frequently have comorbidities, including chronic obstructive pulmonary disease (COPD) and cardiovascular disease.

Chronic obstructive pulmonary disease (COPD) is a major cause of death and a still incurable disease, comprising emphysema and chronic bronchitis. In addition to airflow limitation, patients with COPD can suffer from pulmonary hypertension (PH). Doxycycline, an antibiotic from the tetracycline family, in addition to its pronounced antimicrobial activity, acts as a matrix metalloproteinase (MMP) inhibitor and has anti-inflammatory properties. Furthermore, doxycycline treatment exhibited a beneficial effect in several preclinical cardiovascular disease models. In preclinical research, doxycycline is frequently employed for gene expression modulation in Tet-On/Tet-Off transgenic animal models. Therefore, it is crucial to know whether doxycycline treatment in Tet-On/Tet-Off systems has effects independent of gene expression modulation by such systems. Against this background, we assessed the possible curative effects of long-term doxycycline administration in a mouse model of chronic CS exposure. Animals were exposed to cigarette smoke (CS) for 8 mo and then subsequently treated with doxycycline for additional 3 mo in room air conditions. Doxycycline decreased the expression of MMPs and general pro-inflammatory markers in the lungs from CS-exposed mice. This downregulation was, however, insufficient to ameliorate CS-induced emphysema or PH. Tet-On/Tet-Off induction by doxycycline in such models is a feasible genetic approach to study curative effects at least in established CS-induced emphysema and PH. However, we report several parameters that are influenced by doxycycline and use of a Tet-On/ Tet-Off system when evaluating those parameters should be interpreted with caution. [ABSTRACT FROM AUTHOR]

Right ventricular (RV) function determines outcome in pulmonary arterial hypertension (PAH). RV pressure-volume loops, the gold standard for measuring RV function, are difficult to analyze. Our aim was to investigate whether simple assessments of RV pressure-volume loop morphology and RV systolic pressure differential reflect PAH severity and RV function. We analyzed multibeat RV pressure-volume loops (obtained by conductance catheterization with preload reduction) in 77 patients with PAH and 15 patients without pulmonary hypertension in two centers. Patients were categorized according to their pressure-volume loop shape (triangular, quadratic, trapezoid, or notched). RV systolic pressure differential was defined as end-systolic minus beginning-systolic pressure (ESP - BSP), augmentation index as ESP - BSP/pulse pressure, pulmonary arterial capacitance (PAC) as stroke volume/pulse pressure, and RV-arterial coupling as end-systolic/arterial elastance (Ees/Ea). Trapezoid and notched pressure-volume loops were associated with the highest afterload (Ea), augmentation index, pulmonary vascular resistance (PVR), mean pulmonary arterial pressure, stroke work, B-type natriuretic peptide, and the lowest Ees/Ea and PAC. Multivariate linear regression identified Ea, PVR, and stroke work as the main determinants of ESP - BSP. ESP - BSP also significantly correlated with multibeat Ees/Ea (Spearman’s ρ: -0.518, P < 0.001). A separate retrospective analysis of 113 patients with PAH showed that ESP - BSP obtained by routine right heart catheterization significantly correlated with a noninvasive surrogate of RV-arterial coupling (tricuspid annular plane systolic excursion/pulmonary arterial systolic pressure ratio; ρ: -0.376, P < 0.001). In conclusion, pressure-volume loop shape and RV systolic pressure differential predominately depend on afterload and PAH severity and reflect RV-arterial coupling in PAH. [ABSTRACT FROM AUTHOR]

Venous congestion has emerged as an important cause of renal dysfunction in patients with cardiorenal syndrome. However, only limited progress has been made in differentiating this haemodynamic phenotype of renal dysfunction, because of a significant overlap with pre‐existing renal impairment due to long‐term hypertension, diabetes, and renovascular disease. We propose congestive nephropathy (CN) as this neglected clinical entity. CN is a potentially reversible subtype of renal dysfunction associated with declining renal venous outflow and progressively increasing renal interstitial pressure. Venous congestion may lead to a vicious cycle of hormonal activation, increased intra‐abdominal pressure, excessive renal tubular sodium reabsorption, and volume overload, leading to further right ventricular (RV) stress. Ultimately, renal replacement therapy may be required to relieve diuretic‐resistant congestion. Effective decongestion could preserve or improve renal function. Congestive acute kidney injury may not be associated with cellular damage, and complete renal function restoration may be a confirmatory diagnostic criterion. In contrast, a persistently low renal perfusion pressure might induce renal dysfunction and histopathological lesions with time. Thus, urinary markers may differ. CN is mostly seen in biventricular heart failure but may also occur secondary to pulmonary arterial hypertension and elevated intra‐abdominal pressure. An increase in central venous pressure to >6 mmHg is associated with a steep decrease in glomerular filtration rate. However, the central venous pressure range that can provide an optimal balance of RV and renal function remains to be determined. We propose criteria to identify cardiorenal syndrome subgroups likely to benefit from decongestive or pulmonary hypertension‐specific therapies and suggest areas for future research. [ABSTRACT FROM AUTHOR]

Adaptation of right ventricular (RV) function to increased afterload—known as RV–arterial coupling—is a key determinant of prognosis in pulmonary hypertension. However, measurement of RV–arterial coupling is a complex, invasive process involving analysis of the RV pressure–volume relationship during preload reduction over multiple cardiac cycles. Simplified methods have therefore been proposed, including echocardiographic and cardiac MRI approaches. This review describes the available methods for assessment of RV function and RV–arterial coupling and the effects of pharmacotherapy on these variables. Overall, pharmacotherapies for pulmonary hypertension have shown beneficial effects on various measures of RV function, but it is often unclear if these are direct RV effects or indirect results of afterload reduction. Studies of the effects of pharmacotherapies on RV–arterial coupling are limited and mostly restricted to experimental models. Simplified methods to assess RV–arterial coupling should be validated and incorporated into routine clinical follow‐up and future clinical trials. LINKED ARTICLES: This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.1/issuetoc [ABSTRACT FROM AUTHOR]

Epigenetic mechanisms, including DNA methylation and histone post‐translational modifications (PTMs), have been known to regulate chromatin structure and lineage‐specific gene expression during cardiovascular development and disease. However, alterations in the landscape of histone PTMs and their contribution to the pathogenesis of incurable cardiovascular diseases such as pulmonary hypertension (PH) and associated right heart failure (RHF) remain largely unexplored. This review focusses on the studies in PH and RHF that investigated the gene families that write (histone acetyltransferases), read (bromodomain‐containing proteins) or erase (histone deacetylases [HDACs] and sirtuins [SIRT]) acetyl moieties from the ε‐amino group of lysine residues of histones and non‐histone proteins. Analysis of cells and tissues isolated from the in vivo preclinical models of PH and human pulmonary arterial hypertension not only confirmed significant alterations in the expression levels of multiple HDACs, SIRT1, SIRT3 and BRD4 proteins but also demonstrated their strong association to proliferative, inflammatory and fibrotic phenotypes linked to the pathological vascular remodelling process. Due to the reversible nature of post‐translational protein acetylation, the therapeutic efficacy of numerous small‐molecule inhibitors (vorinostat, valproic acid, sodium butyrate, mocetinostat, entinostat, tubastatin A, apabetalone, JQ1 and resveratrol) have been evaluated in different preclinical models of cardiovascular disease, which revealed the promising therapeutic benefits of targeting histone acetylation pathways in the attenuation of cardiac hypertrophy, fibrosis, left heart dysfunction, PH and RHF. This review also emphasizes the need for deeper molecular insights into the contribution of epigenetic changes to PH pathogenesis and therapeutic evaluation of isoform‐specific modulation in ex vivo and in vivo models of PH and RHF. LINKED ARTICLES: This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.1/issuetoc [ABSTRACT FROM AUTHOR]

Background and Purpose: Chronic obstructive pulmonary disease, encompassing chronic airway obstruction and lung emphysema, is a major worldwide health problem and a severe socio-economic burden. Evidence previously provided by our group has shown that inhibition of inducible NOS (iNOS) prevents development of mild emphysema in a mouse model of chronic tobacco smoke exposure and can even trigger lung regeneration. Moreover, we could demonstrate that pulmonary hypertension is not only abolished in cigarette smoke-exposed iNOS-/- mice but also precedes emphysema development. Possible regenerative effects of pharmacological iNOS inhibition in more severe models of emphysema not dependent on tobacco smoke, however, are hitherto unknown.Experimental Approach: We have established a mouse model using a single dose of porcine pancreatic elastase or saline, intratracheally instilled in C57BL/6J mice. Emphysema, as well as pulmonary hypertension development was determined by both structural and functional measurements.Key Results: Our data revealed that (i) emphysema is fully established after 21 days, with the same degree of emphysema after 21 and 28 days post instillation, (ii) emphysema is stable for at least 12 weeks and (iii) pulmonary hypertension is evident, in contrast to smoke models, only after emphysema development. Oral treatment with the iNOS inhibitor N(6)-(1-iminoethyl)-l-lysine (L-NIL) was started after emphysema establishment and continued for 12 weeks. This resulted in significant lung regeneration, evident in the improvement of emphysema and reversal of pulmonary hypertension.Conclusion and Implications: Our data indicate that iNOS is a potential new therapeutic target to treat severe emphysema and associated pulmonary hypertension.Linked Articles: This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.1/issuetoc. [ABSTRACT FROM AUTHOR]

In pulmonary arterial hypertension (PAH), progressive structural remodeling accounts for the pulmonary vasculopathy including the obliteration of the lung vasculature that causes an increase in vascular resistance and mean blood pressure in the pulmonary arteries ultimately leading to right heart failure--mediated death. Deciphering themolecular details of aberrant signaling of pulmonary vascular cells in PAH is fundamental for the development of new therapeutic strategies.We aimed to identify kinases as new potential drug targets that are dysregulated in PAH by means of a peptide-based kinase activity assay.We performed a tyrosine kinase--dependent phosphorylation assay using 144 selected microarrayed substrate peptides. The differential signature of phosphopeptides was used to predict alterations in tyrosine kinase activities in human pulmonary arterial smoothmuscle cells (HPASMCs) frompatientswithidiopathic PAH (IPAH) compared with healthy control cells. Thereby, we observed an overactivation and an increased expression of Jak2 (Janus kinase 2) in HPASMCs from patients with IPAH as compared with controls. In vitro,IL-6--induced proliferation and migration of HPASMCs from healthy individuals as well as from patients with IPAHwere reduced in a dose-dependentmanner by theU.S. Food and Drug Administration--approved Jak1 and Jak2 inhibitor ruxolitinib. In vivo, ruxolitinib therapy in two experimental models of pulmonary arterial hypertension dose-dependently attenuated the elevation in pulmonary arterial pressure, partially reduced right ventricular hypertrophy, and almost completely restored cardiac index without signs of adverse events on cardiac function. Therefore, we propose that ruxolitinib may present a novel therapeutic option for patients with PAH by reducing pulmonary vascular remodeling through effectively blocking Jak2--Stat3 (signal transducer of activators of transcription)--mediated signaling pathways. [ABSTRACT FROM AUTHOR]

Rationale: Long noncoding RNAs (lncRNAs) are emerging as important regulators of diverse biological functions. Their role in pulmonary arterial hypertension (PAH) remains to be explored.Objectives: To elucidate the role of TYKRIL (tyrosine kinase receptor-inducing lncRNA) as a regulator of p53/ PDGFRβ (platelet-derived growth factor receptor β) signaling pathway and to investigate its role in PAH.Methods: Pericytes and pulmonary arterial smooth muscle cells exposed to hypoxia and derived from patients with idiopathic PAH were analyzed with RNA sequencing. TYKRIL knockdown was performed in above-mentioned human primary cells and in precision-cut lung slices derived from patients with PAH.Measurements and Main Results: Using RNA sequencing data, TYKRIL was identified to be consistently upregulated in pericytes and pulmonary arterial smooth muscles cells exposed to hypoxia and derived from patients with idiopathic PAH. TYKRIL knockdown reversed the proproliferative (n = 3) and antiapoptotic (n = 3) phenotype induced under hypoxic and idiopathic PAH conditions. Owing to the poor species conservation of TYKRIL, ex vivo studies were performed in precision-cut lung slices from patients with PAH. Knockdown of TYKRIL in precision-cut lung slices decreased the vascular remodeling (n = 5). The number of proliferating cell nuclear antigen-positive cells in the vessels was decreased and the number of terminal deoxynucleotide transferase-mediated dUTP nick end label-positive cells in the vessels was increased in the LNA (locked nucleic acid)-treated group compared with control. Expression of PDGFRβ, a key player in PAH, was found to strongly correlate with TYKRIL expression in the patient samples (n = 12), and TYKRIL knockdown decreased PDGFRβ expression (n = 3). From the transcription factor-screening array, it was observed that TYKRIL knockdown increased the p53 activity, a known repressor of PDGFRβ. RNA immunoprecipitation using various p53 mutants demonstrated that TYKRIL binds to the N-terminal of p53 (an important region for p300 interaction with p53). The proximity ligation assay revealed that TYKRIL interferes with the p53-p300 interaction (n = 3) and regulates p53 nuclear translocation.Conclusions: TYKRIL plays an important role in PAH by regulating the p53/PDGFRβ axis. [ABSTRACT FROM AUTHOR]

The article discusses Sex Differences in Right Ventricular-Pulmonary Arterial Coupling in Pulmonary Arterial Hypertension. Topics include ventricle initially compensates for the PAH-induced increase in afterload through hypertrophy and increased contractile function, maintaining RV–pulmonary arterial (PA) coupling and cardiac magnetic resonance imaging study, female patients with PAH exhibited better RV ejection fraction than their male counterparts.

Pharmacological modulation of class I histone deacetylases (HDAC) has been evaluated as a therapeutic strategy for pulmonary hypertension (PH) in experimental models of PH. However, information of their expression, regulation and transcriptional targets in human PH and the therapeutic potential of isoform-selective enzyme modulation are lacking. Comprehensive analysis of expression and regulation of class I HDACs (HDAC1, HDAC2, HDAC3 and HDAC8) was performed in cardiopulmonary tissues and adventitial fibroblasts isolated from pulmonary arteries (PAAF) of idiopathic pulmonary arterial hypertension (IPAH) patients and healthy donors. Cellular functions and transcriptional targets of HDAC enzymes were investigated. Therapeutic effects of pan-HDAC (Vorinostat), class-selective (VPA) and isoform-selective (CAY10398, Romidepsin, PCI34051) HDAC inhibitors were evaluated ex vivo (IPAH-PAAF, IPAH-PASMC) and in vivo (rat chronic hypoxia-induced PH and zebrafish angiogenesis). Our screening identifies dysregulation of class I HDAC isoforms in IPAH. Particularly, HDAC1 and HDAC8 were consistently increased in IPAH-PAs and IPAH-PAAFs, whereas HDAC2 and HDAC8 showed predominant localization with ACTA2-expressing cells in extensively remodeled IPAH-PAs. Hypoxia not only significantly modulated protein levels of deacetylase (HDAC8), but also significantly caused dynamic changes in the global histone lysine acetylation levels (H3K4ac, H3K9/K14ac and H3K27ac). Importantly, isoform-specific RNA-interference revealed that HDAC isoforms regulate distinct subset of transcriptome in IPAH-PAAFs. Reduced transcript levels of KLF2 in IPAH-PAAFs was augmented by HDAC8 siRNA and HDAC inhibitors, which also attenuated IPAH-associated hyperproliferation and apoptosis-resistance ex vivo, and mitigated chronic hypoxia-induced established PH in vivo, at variable degree. Class I HDAC isoforms are significantly dysregulated in human PAH. Isoform-selective HDAC inhibition is a viable approach to circumvent off-target effects. [ABSTRACT FROM AUTHOR]

Background and Purpose: Recruitment and involvement of bone-/blood-derived circulating fibrocytes (CF) in the promotion of fibrotic tissue remodelling processes have been shown. However, their direct contribution to pathological changes is not clear. The present study investigates the causal role of CF in the pathogenesis of pulmonary hypertension (PH).Experimental Approach: For selective ablation of CF, we applied the suicidal gene strategy with herpes simplex virus thymidine kinase (HSV-TK) and ganciclovir. The transgenic mice were generated, having HSV-TK-GFP transgene under the collagen 1 promoter. To selectively target CF, HSV-TK-GFP+ bone marrow transplanted into irradiated wild type mice. These chimera mice were subjected to hypoxia for PH induction and ganciclovir for CF ablation.Key Results: In vivo CF ablation reduced right ventricular hypertrophy and vascular remodelling with reduced total collagen content. We quantified the CF recruited in the perivascular area and arterial wall of small pulmonary arteries. There was significant recruitment of CF in the lung in response to hypoxia. The characterization of CF showed the expression of CD45 and collagen1 (GFP) along with α-smooth muscle actin (αSMA).Conclusion and Implications: Our data demonstrated that CF ablation has a potential impact on right ventricular hypertrophy and vascular remodelling in the setting of experimental pulmonary hypertension induced by hypoxia. The beneficial effects may be related to the direct contribution of fibrocytes or its paracrine effect on other resident cell types. Thus, clinical manipulation of CF may represent a novel therapeutic approach to ameliorate the disease state in pulmonary hypertension. [ABSTRACT FROM AUTHOR]

Aim: This study assessed the utility of SPARC-like protein 1 (SPARCL1) as a biomarker of maladaptive right ventricular (RV) function in patients with pulmonary hypertension (PH). Methods: In this prospective study, we examined SPARCL1 levels in 105 patients with adaptive (n = 34) and maladaptive RV (n = 32) pressure overload caused by PH, dilated cardiomyopathy (DCM, n = 18) with LVEF < 35% and preserved RV function and controls without LV or RV abnormalities (n = 21). Results: The median SPARCL1 concentration in patients with maladaptive RV function was higher than in those with adaptive RV function (p < 0.01), DCM (p < 0.001) or controls (p < 0.001). Patients with adaptive RV function had higher SPARCL1 concentrations than controls (p < 0.05), whereas there was no difference between adaptive RV and DCM. SPARCL1 showed good predictive power for maladaptive RV (AUC 0.77, p < 0.001) with an optimal cut-off value of 9.66 ng/ml. The TAPSE/PASP ratio was the only independent predictor of SPARCL1 ≥ 9.66 ng/ml in multivariable logistic regression analysis. Conclusion: SPARCL1 shows potential as novel biomarker of RV pathological remodelling and is associated with RV maladaptation and ventriculoarterial uncoupling in PH. [ABSTRACT FROM AUTHOR]

Alterations of right atrial (RA) function have emerged as determinants of outcome in pulmonary hypertension (PH). We aimed to clarify the pathophysiological associations of impaired RA conduit function with right ventricular (RV) function in PH. In 51 patients with PH (48 with pulmonary arterial hypertension), RA conduit function was assessed as echocardiographic peak early diastolic strain rate (PEDSR). PEDSR and cardiac magnetic resonance parameters were measured within 24 h of right heart catheterization and generation of pressure-volume loops to assess RV diastolic (RV end-diastolic pressure [EDP] and relaxation [Tau]) and systolic function. Spearman rho correlation and linear regression analysis were used to determine the association of PEDSR with RV function. The impact of PEDSR on time to clinical worsening was assessed using Kaplan-Meier and Cox regression analyses. Median (interquartile range) PEDSR was - 0.56 s - 1 (- 1.08 to - 0.37). Impaired PEDSR was significantly correlated with RV diastolic stiffness [EDP (rho = 0.570; p < 0.001) and Tau (rho = 0.500; p < 0.001)] but not with RV contractility or coupling. In multivariate linear regression including parameters of RV lusitropic and inotropic function, EDP remained independently associated with impaired PEDSR. During a median follow-up of 9 months, 23 patients deteriorated. After multivariate adjustment, PEDSR remained associated with clinical worsening (hazard ratio: 2.85; 95% confidence interval: 1.20-6.78). Altered RV lusitropy is associated with impaired RA conduit phase. PEDSR emerged as a promising, non-invasive, bedside-ready parameter to evaluate RV diastolic function and to predict prognosis in PH. [ABSTRACT FROM AUTHOR]

This article reviews the scientific reasons that support the intriguing vision of pulmonary hypertension (PH) as a disease with a cancer-like nature and to understand whether this point of view may have fruitful consequences for the overall management of PH. This review compares cancer and PH in view of Hanahan and Weinberg's principles (i.e., hallmarks of cancer) with an emphasis on hyperproliferative, metabolic, and immune/inflammatory aspects of the disease. In addition, this review provides a perspective on the role of transcription factors and chromatin and epigenetic aberrations, besides genetics, as "common driving mechanisms" of PH hallmarks and the foreseeable use of transcription factor/epigenome targeting as multitarget approach against the hallmarks of PH. Thus, recognition of the widespread applicability and analogy of these concepts will increasingly affect the development of new means of PH treatment. [ABSTRACT FROM AUTHOR]

The functional relevance of right atrial (RA) function in pulmonary hypertension (PH) remains incompletely understood. The purpose of this study was to explore the correlation of cardiac magnetic resonance (CMR) feature tracking-derived RA phasic function with invasively measured pressure-volume (P-V) loop-derived right ventricular (RV) end-diastolic elastance (Eed) and RV-arterial coupling [ratio of end-systolic elastance to arterial elastance (Ees/Ea)]. In 54 patients with severe PH, CMR was performed within 24 h of diagnostic right heart catheterization and P-V measurements. RA phasic function was assessed by CMR imaging of RA reservoir, passive, and active strain. The association of RA phasic function with indexes of RV function was evaluated by Spearman's rank correlation and linear regression analyses. Median [interquartile range] RA reservoir strain, passive strain, and active strain were 19.5% [11.0-24.5], 7.0% [4.0-12.0], and 13.0% [7.0-18.5], respectively. Ees/Ea was 0.73 [0.48-1.08], and Eed was 0.14 mmHg/mL [0.05-0.22]. RV diastolic impairment [RV end-diastolic pressure (EDP) and Eed] was correlated with RA phasic function, but Ea and Ees were not. In addition, RA phasic function was correlated with inferior vena cava diameter. In multivariate linear regression analysis, adjusting for key P-V loop indexes, Eed and EDP remained significantly associated with RA phasic function. We conclude that RA phasic function is altered in relation to impaired diastolic function of the chronically overloaded right ventricle and contributes to backward venous flow and systemic congestion. These results call for more attention to RA function in the management of patients with PH. NEW & NOTEWORTHY There is growing awareness of the importance of the right atrial (RA)-right ventricular (RV) axis in pulmonary hypertension (PH). Our results uncover alterations in RA phasic function that are related to depressed RV lusitropic function and contribute to backward venous return and systemic congestion in chronic RV overload. Assessment of RA function should be part of the management and follow-up of patients with PH. [ABSTRACT FROM AUTHOR]

Renal congestion is becoming recognized as a potential contributor to cardiorenal syndromes. Adequate control of congestion with simultaneous preservation of renal function has been proposed as a central goal of the management of heart failure. We report our care of a 48-year-old woman suffering from right heart failure and massive fluid overload due to severe pulmonary hypertension secondary to a combination of left-heart disease and status after recurrent pulmonary embolisms. Alterations in Doppler-derived intrarenal venous flow patterns and a novel renal venous stasis index were used to evaluate improvement in renal venous congestion during recompensation. Due to refractory congestion despite optimal medical treatment and continuous veno-venous hemodialysis, a peritoneal dialysis catheter was placed to relieve the massive ascites. The paracentesis of ascites led to a significant loss of weight, normalization of hydration status with subsequent termination of continuous veno-venous hemodialysis, and a significant improvement in clinical and echocardiographic parameters. Renal Doppler ultrasonography showed continuous improvement in intrarenal venous flow patterns and the renal venous stasis index indicative of effective decongestion up to a normal intrarenal venous flow pattern and renal venous stasis index. Furthermore, residual renal function increased during follow-up. This case demonstrates the feasibility of renal Doppler ultrasonography as a simple, non-invasive, and integrative measure of renal congestion. The renal venous stasis index and intrarenal venous flow patterns may be useful to evaluate the treatment response and to guide therapy in patients with right heart failure. [ABSTRACT FROM AUTHOR]

This study sought to compare cardiac magnetic resonance (CMR) imaging-derived right ventricular (RV) strain and invasively measured pressure-volume loop-derived RV contractility, stiffness, and afterload and RV-arterial coupling in pulmonary hypertension (PH). In chronic RV pressure overload, RV-arterial uncoupling is considered the driving cause of RV maladaptation and eventual RV failure. The pathophysiological and clinical value of CMR-derived RV strain relative to that of invasive pressure-volume loop-derived measurements in PH remains incompletely understood. In 38 patients with PH, global RV CMR strain was measured within 24 h of diagnostic right heart catheterization and conductance (pressure-volume) catheterization. Associations were evaluated by correlation, multivariate logistic binary regression, and receiver operating characteristic analyses. Long-axis RV longitudinal and radial strain and short-axis RV radial and circumferential strain were −18.0 ± 7.0%, 28.9% [interquartile range (IQR): 17.4% to 46.6%]; 15.6 ± 6.2%; and −9.8 ± 3.5%, respectively. RV-arterial coupling (end-systolic [Eds]/arterial elastance [Ea]) was 0.76 (IQR: 0.47 to 1.07). Peak RV strain correlated with Ees/Ea, afterload (Ea), RV diastolic dysfunction (Tau), and stiffness (end-diastolic elastance [Eed]) but not with contractility (Ees). In multivariate analysis, long-axis RV radial strain was associated with RV-arterial uncoupling (Ees/Ea: <0.805; odds ratio [OR]: 5.50; 95% confidence interval [CI]: 1.50 to 20.18), whereas long-axis RV longitudinal strain was associated with increased RV diastolic stiffness (Eed: ≥0.124 mm Hg/ml; OR: 1.23; 95% CI: 1.10 to 1.51). The long-axis RV longitudinal strain-to-RV end-diastolic volume/body surface area ratio strongly predicted RV diastolic stiffness (area under receiver operating characteristic curve: 0.908). In chronic RV overload, CMR-determined RV strain is associated with RV-arterial uncoupling and RV end-diastolic stiffness and represents a promising noninvasive alternative to current invasive methods for assessment of RV-arterial coupling and end-diastolic stiffness in patients with PH. (Right Ventricular Haemodynamic Evaluation and Response to Treatment [Rightheart I]; NCT03403868) [ABSTRACT FROM AUTHOR]

Current therapies for pulmonary arterial hypertension (PAH) provide symptomatic relief and improve prognosis but fall short of improving long-term survival. There is emerging evidence for a role of inflammatory mediators, primarily IL-6, in the pathogenesis of PAH. However, the mechanisms by which IL-6 potentially affects PAH are unknown. In this issue of the JCI, Tamura, Phan, and colleagues identified ectopic upregulation of the membrane-bound IL-6 receptor (IL6R), indicating classical IL-6 signaling in the smooth muscle layer of remodeled vessels in human and experimental PAH. They performed a series of in vitro and in vivo experiments that provide deeper insights into the mechanisms of classical IL-6 signaling and propose interventions directed against IL6R as a potential therapeutic strategy for PAH. [ABSTRACT FROM AUTHOR]

The article presents a study showing association of lung cancer with pulmonary hypertension. Topics discussed include role of microenvironmental inflammation based on tumor cell–immune cell cross-talk; use of computed tomography for the treatment of lung cancer; and evaluating histopathological evidence of lung vascular remodeling in patients with lung cancer.

Background. Increased pulmonary vascular resistance in patients with pulmonary hypertension (PH) leads to an increased afterload of right heart and cardiac remodeling which could provide the substrate or trigger for arrhythmias. Supraventricular arrhythmias were associated with clinical deterioration but were not associated with sudden cardiac death (SCD). SCD has been reported to account for approximately 30% of deaths in patients with pulmonary arterial hypertension (PAH). Objective. The role of nonsustained ventricular tachycardia (nsVT) and its prognostic relevance in patients with PH remains unclear. This study evaluated the prognostic relevance of nsVT in patients with PAH and chronic thromboembolic pulmonary hypertension (CTEPH). Methods. Retrospectively, patients with PAH and CTEPH who underwent Holter ECG monitoring and available data of survival were investigated. Results. Seventy-eight (PAH: 55, CTEPH: 23) patients were evaluated. Holter ECG revealed nsVT in 12 patients. Twenty-one patients died during follow-up. In patients with nsVT, tricuspid annular plane systolic excursion was lower (p=0.001), and systolic pulmonary arterial pressure was higher (p=0.163). Mean survival of patients without/with nsVT was 155.2 ± 8.5/146.4 ± 21.4 months (p=0.690). The association between arrhythmias and survival was not confounded by age (p=0.681), gender (p=0.752), 6-MW distance (p=0.196), or arterial hypertension (p=0.238). Conclusions. In patients with PH, nsVT occurs more often than previously reported, and patients with PH group 1 seem to be more at risk. [ABSTRACT FROM AUTHOR]

Background: Circulating angiopoietin-1 (Ang-1) has been linked to pulmonary hypertension (PH) in experimental studies. However, the clinical relevance of Ang-1 as a biomarker in PH remains unknown. We aimed to investigate the prognostic and clinical significance of Ang-1 in PH using data from the prospectively recruiting Giessen PH Registry. Methods: Patients with suspected PH (without previous specific pulmonary arterial hypertension [PAH] therapy) who underwent initial right heart catheterization (RHC) in our national referral center between July 2003 and May 2012 and who agreed to optional biomarker analysis were included if they were diagnosed with idiopathic PAH, connective tissue disease-associated PAH (CTD-PAH), PH due to left heart disease (PH-LHD), or chronic thromboembolic PH (CTEPH), or if PH was excluded by RHC (non-PH controls). The association of Ang-1 levels with disease severity (6-minute walk distance and pulmonary hemodynamics) was assessed using linear regression, and the impact of Ang-1 levels on transplant-free survival (primary endpoint) and clinical worsening was assessed using Kaplan—Meier curves, receiver operating characteristic (ROC) analyses, and Cox regression. Results: 151 patients (39, 39, 32, and 41 with idiopathic PAH, CTD-PAH, PH-LHD, and CTEPH, respectively) and 41 non-PH controls were included. Ang-1 levels showed no significant difference between groups (p = 0.8), and no significant associations with disease severity in PH subgroups (p ≥ 0.07). In Kaplan—Meier analyses, Ang-1 levels (stratified by quartile) had no significant impact on transplant-free survival (p ≥ 0.27) or clinical worsening (p ≥ 0.51) in PH subgroups. Regression models found no significant association between Ang-1 levels and outcomes (p ≥ 0.31). ROC analyses found no significant cut-off that would maximize sensitivity and specificity. Conclusions: Despite a strong pathophysiological association in experimental studies, this first comprehensive analysis of Ang-1 in PH subgroups suggests that Ang-1 is not a predictive and clinically relevant biomarker in PH. [ABSTRACT FROM AUTHOR]