Function In Pulmonary Hypertension Research Articles

Selective inhibition of Histone deacetylases reverses vascular remodeling and improves right ventricle function in pulmonary hypertension

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Longfonds and CVON Background Pulmonary arterial hypertension (PAH) is a progressive fatal disease characterized by abnormal remodeling of pulmonary vessels, leading to increased vascular resistance and ultimately right ventricle (RV) failure. Disturbed BMPR2/TGFβ signaling is a driver of disease progression. Inhibition of Histone deacetylases (HDACs) using small molecule inhibitors attenuated vascular remodeling, however, they worsened RV function in animal models of PAH. Objectives The aim of this study is to validate if the selective HDAC inhibitor Quisinostat reverses pulmonary vascular remodeling and improves RV function. Methods and results We found that protein levels of HDAC1 are increased in the lungs of PAH patients. Treating microvascular endothelial cells (MVECs) and smooth muscle cells of PAH patients with Quisinostat significantly decreased TGF-β signaling and strongly decreased cell proliferation and the levels of inflammatory cytokines. In the MCT-shunt and Sugen Hypoxia rat models of severe angioproliferative PAH, Quisinostat reversed abnormal vascular remodeling and improved RV function. Furthermore, Quisinostat could be combined safely with the contemporary PAH standard of care. Finally, Quisinostat improved the RV function in rats with RV pressure load induced by pulmonary artery banding, and no systemic or cardiotoxic effects were observed. Conclusions Our data demonstrate that selective inhibition of HDACs reverses pulmonary vascular remodeling and improves RV function. These data support the establishment of a clinical trial with Quisinostat in patients with PAH.

The Echocardiographic Evaluation of the Right Heart: Current and Future Advances.

To discuss physiologic and methodologic advances in the echocardiographic assessment of right heart (RH) function, including the emergence of artificial intelligence (AI) and point-of-care ultrasound. Recent studies have highlighted the prognostic value of right ventricular (RV) longitudinal strain, RV end-systolic dimensions, and right atrial (RA) size and function in pulmonary hypertension and heart failure. While RA pressure is a central marker of right heart diastolic function, the recent emphasis on venous excess imaging (VExUS) has provided granularity to the systemic consequences of RH failure. Several methodological advances are also changing the landscape of RH imaging including post-processing 3D software to delineate the non-longitudinal (radial, anteroposterior, and circumferential) components of RV function, as well as AI segmentation- and non-segmentation-based quantification. Together with recent guidelines and advances in AI technology, the field is shifting from specific RV functional metrics to integrated RH disease-specific phenotypes. A modern echocardiographic evaluation of RH function should focus on the entire cardiopulmonary venous unit-from the venous to the pulmonary arterial system. Together, a multi-parametric approach, guided by physiology and AI algorithms, will help define novel integrated RH profiles for improved disease detection and monitoring.

Real-time Three-dimensional Echocardiography: A Feasible and Accurate Method for Measuring Right Ventricular Function in Pulmonary Hypertension

Right ventricular function is independently associated with poor clinical outcomes in patients with various cardiovascular diseases including pulmonary hypertension (PH). The complex geometry and mode of contractility means the right ventricle (RV) inlet and outlet are not in line; hence, 2-dimensional echocardiography fails to accurately quantify RV volumes and function in such patients. Three-dimensional echocardiography (3DE) allows for reliable and reproducible quantification of RV volumes and function by overcoming these limitations of conventional echocardiography. This review focuses on the 3DE assessment of RV function in patients with PH and discusses the following points: (1) acquiring an RV data set for 3DE imaging, including details of all available 3DE systems and software utilized in daily practice; (2) the reliability and feasibility of RV remodeling measured with 3DE with different modalities in patients with PH; and (3) the prognostic value of 3DE-derived RV function in such patients.

Pentastatin, a matrikine of the Collagen IVa5, is a novel endogenous mediator of pulmonary endothelial dysfunction.

Deposition of basement membrane components, such as collagen IVα5, is associated with altered endothelial cell function in pulmonary hypertension. Collagen IVα5 harbors a functionally active fragment within its C-terminal non-collageneous (NC1) domain, called pentastatin, whose role in pulmonary endothelial cell behavior remains unknown. Here, we demonstrate that pentastatin serves as a mediator of pulmonary endothelial cell dysfunction, contributing to pulmonary hypertension. In vitro, treatment with pentastatin induced transcription of immediate early genes and pro-inflammatory cytokines and led to a functional loss of endothelial barrier integrity in pulmonary arterial endothelial cells. Mechanistically, pentastatin leads to β1-integrin subunit clustering and Rho/ROCK activation. Blockage of the β1-integrin subunit or the Rho/ROCK pathway partially attenuated the pentastatin-induced endothelial barrier disruption. While pentastatin reduced the viability of endothelial cells, smooth muscle cell proliferation was induced. These effects on the pulmonary vascular cells were recapitulated ex vivo in the isolated-perfused lung model, where treatment with pentastatin induced swelling of the endothelium accompanied by occasional endothelial cell apoptosis. This was reflected by increased vascular permeability and elevated pulmonary arterial pressure induced by pentastatin. This study identifies pentastatin as a mediator of endothelial cell dysfunction, which thus might contribute to the pathogenesis of pulmonary vascular disorders such as pulmonary hypertension.

Current clinical use of speckle-tracking strain imaging: insights from a worldwide survey from the European Association of Cardiovascular Imaging (EACVI).

Speckle-tracking echocardiography (STE) strain imaging has been a major advancement in myocardial function quantification. We aimed to explore current worldwide clinical application of STE. Access, feasibility, access, and clinical implementation of STE were investigated with a worldwide open-access online survey of the European Association of Cardiovascular Imaging. Participants (429 respondents and 77 countries) from tertiary centres (46%), private clinics, or public hospitals (54%) using different vendors for data acquisition and analysis were represented. Despite almost universal access (98%) to STE, only 39% of the participants performed and reported STE results frequently (>50%). Incomplete training and time constraints were the main reasons for not using STE more regularly. STE was mainly used to assess the LV (99%) and less frequently the right ventricular (57%) and the left atrial (46%) function. Cardiotoxicity (88%) and cardiac amyloidosis (87%) were the most frequent reasons for the clinical use of LV STE. Left atrial STE was used most frequently for the diagnosis of diastolic dysfunction and right ventricular STE for the assessment of right ventricle (RV) function in pulmonary hypertension (51%). Frequency of STE use, adherence to optimal techniques, and clinical appropriateness of STE differed according to training experience and across vendors. Key suggestions outlined by respondents to increase the clinical use of STE included improved reproducibility (48%) and standardization of strain values across vendors (42%). Although STE is now readily available, it is underutilized in the majority of centres. Structured training, improved reproducibility, and inter-vendor standardization may increase its uptake.

Association Between Right Atrial Strain and Right Ventricular Size and Function in Pulmonary Hypertension

Association Between Right Atrial Strain and Right Ventricular Size and Function in Pulmonary Hypertension

SOX17 is a Critical Factor in Maintaining Endothelial Function in Pulmonary Hypertension by an Exosome-Mediated Autocrine Manner.

Endothelial dysfunction is considered a predominant driver for pulmonary vascular remodeling in pulmonary hypertension (PH). SOX17, a key regulator of vascular homoeostasis, has been found to harbor mutations in PH patients, which are associated with PH susceptibility. Here, this study explores whether SOX17 mediates the autocrine activity of pulmonary artery ECs to maintain endothelial function and vascular homeostasis in PH and its underlying mechanism. It is found that SOX17 expression is downregulated in the endothelium of remodeled pulmonary arteries in IPH patients and SU5416/hypoxia (Su/hypo)-induced PH mice as well as dysfunctional HPAECs. Endothelial knockdown of SOX17 accelerates the progression of Su/hypo-induced PH in mice. SOX17 overexpression in the pulmonary endothelium of mice attenuates Su/hypo-induced PH. SOX17-associated exosomes block the proliferation, apoptosis, and inflammation of HPAECs, preventing pulmonary arterial remodeling and Su/hypo-induced PH. Mechanistic analyses demonstrates that overexpressing SOX17 promotes the exosome-mediated release of miR-224-5p and miR-361-3p, which are internalized by injured HPAECs in an autocrine manner, ultimately repressing the upregulation of NR4A3 and PCSK9 genes and improving endothelial function. These results suggest that SOX17 is a key gene in maintaining endothelial function and vascular homeostasis in PH through regulating exosomal miRNAs in an autocrine manner.

Clinical phenotyping of plasma thrombospondin-2 reveals relationship to right ventricular structure and function in pulmonary hypertension.

Converging evidence from proteogenomic analyses prioritises thrombospondin-2 (TSP2) as a potential biomarker for idiopathic or heritable pulmonary arterial hypertension (PAH). We aimed to assess TSP2 levels in different forms of pulmonary hypertension (PH) and to define its clinical phenotype. Absolute concentrations of TSP2 were quantified in plasma samples from a prospective single-centre cohort study including 196 patients with different forms of PH and 16 disease controls (suspected PH, but normal resting pulmonary haemodynamics). In an unbiased approach, TSP2 levels were related to 152 clinical variables. Concentrations of TSP2 were increased in patients with PH versus disease controls (p<0.001 for group comparison). The discriminatory ability of TSP2 levels to distinguish between patients and controls was superior to that of N-terminal pro-brain natriuretic peptide (p=0.0023 for comparison of areas under the curve). Elevation of TSP2 levels was consistently found in subcategories of PAH, in PH due to lung disease and due to left heart disease. Phenotypically, TSP2 levels were robustly related to echocardiographic markers that indicate the right ventricular (RV) response to chronically increased afterload with increased levels in patients with impaired systolic function and ventriculoarterial uncoupling. Focusing on PAH, increased TSP2 levels were able to distinguish between adaptive and maladaptive RV phenotypes (area under the curve 0.87, 95% CI 0.76-0.98). The study indicates that plasma TSP2 levels inform on the presence of PH and associate with clinically relevant RV phenotypes in the setting of increased afterload, which may provide insight into processes of RV adaptability.

The hemodynamic and prognostic impact of systolic pressure change during right ventricular ejection in patients with HFREF

Abstract Background and purpose The gold-standard method to evaluate right ventricular (RV) function in pulmonary hypertension (PH) relies on invasive pressure-volume loop (PV-loop) measurement of RV-pulmonary artery (PA) coupling defined as the ratio of end-systolic RV elastance to pulmonary arterial elastance (Ees/Ea). The normal RV PV-loop has a triangular shape with a peaking early systolic pressure (early-SP). With progression of PH the PV-loop changes from trapezoid to a rectangular and ultimately to a trapezoid shape. Along with these geometric changes, the ratio between early-SP and end-systolic pressure (ESP) decreases from &amp;gt;1 to &amp;lt;1 with a late systolic peaking of RV pressure. How all these changes relate to RV afterload, RV-PA coupling, non-invasive RV function, and prognosis in PH due to left heart disease is incomplete understood. Methods We analyzed and categorized the conductance catheter-derived single-beat RV PV-loops in 133 patients with HFREF (110 patients: a post-hoc analysis of the Magdeburg CRT Responder Trial, 23 from a local PV-L-derived CRT-optimization trial) according their shape (triangular, rectangular, trapezoid), and determined the early-SP/ESP ratio. Results Using multivariate linear regression analysis (adjusted for afterload parameter PVR, PA-compliance, PCWP, PAmean), only PCWP (beta=−0.17) and PA-compliance (beta=0.61) remained significant determinants of the early-SP/ESP ratio and PV-loop shape. In turn, early-SP/ESP ratio seems to be an important determinant of RV-PA coupling efficiency (Ees/Ea) of the RV to afterload (r=0.8, p&amp;lt;0.001). The association between early-SP/ESP ratio and Ees/Ea ratio was closer than Ees/Ea ratio to the other afterload parameters Ea (r=−0.7), PVR (r=−0.41), and PA-compliance (r=0.62). Furthermore, the early-SP/ESP ratio was significantly associated with parameters of non-invasive RV function such as TAPSE (r=0.67), FAC (r=0.76), RVEF (r=0.7), and the non-invasive RV-PA coupling parameter TAPSE/PASP (r=0.8) (all p&amp;lt;0.001). In cox regression analysis, the early-SP/ESP ratio was a strong indicator for long-term survival (median FU 4.2 years) (OR 0.025, CI 95% 0.007–0.09). Simple categorization of the RV PV-loop shapes into “triangular” (early-SP/ESP ratio &amp;gt;1.1, mean survival 7.7 years), “rectangular” (0.9–1.1, 6.4 years) and “trapezoid” (&amp;lt;0.9, 3.2 years) clearly differentiated long-term survival of HFREF patients (log rank, Chi square 50.1, p&amp;lt;0.001). Conclusion The early-SP/ESP ratio determines the shape of RV-PV-loops and is closely associated with predominately pulsatile PA load, RV-PA coupling capacity, RV function, and long-term prognosis of patients with HFREF. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Boston Scientific

The Variation in the Diastolic Period with Interventricular Septal Displacement and Its Relation to the Right Ventricular Function in Pulmonary Hypertension: A Preliminary Cardiac Magnetic Resonance Study.

Background: Pulmonary hypertension (PH) is known to alter the biventricular shape and temporal phases of the cardiac cycle. The presence of interventricular septal (IVS) displacement has been associated with the severity of PH. There has been limited cardiac magnetic resonance (CMR) data regarding the temporal parameters of the cardiac cycle in PH. This study aimed to quantify the temporal changes in the cardiac cycle derived from CMR in PH patients with and without IVS displacement and sought to understand the mechanism of cardiac dysfunction in the cardiac cycle. Methods: Patients with PH who had CMR and right heart catheterization (RHC) examinations were included retrospectively. Patients were divided into an IVS non-displacement (IVSND) group and an IVS displacement (IVSD) group according to IVS morphology, as observed on short-axis cine CMR images. Additionally, age-matched healthy volunteers were included as the health control (HC). Temporal parameters, IVS displacement, ventricular volume and functional parameters were obtained by CMR, and pulmonary hemodynamics were obtained by RHC. The risk stratification of the PH patients was also graded according to the guidelines. Results: A total of 70 subjects were included, consisting of 33 IVSD patients, 15 IVSND patients, and 22 HC patients. In the IVSND group, only the right ventricle ejection fraction (RVEF) was decreased in the ventricular function, and no temporal change in the cardiac cycle was found. A prolonged isovolumetric relaxation time (IRT) and shortened filling time (FT) in both ventricles, along with biventricular dysfunction, were detected in the IVSD group (p < 0.001). The IRT of the right ventricle (IRTRV) and FT of the right ventricle (FTRV) in the PH patients were associated with pulmonary vascular resistance, right cardiac index, and IVS curvature, and the IRTRV was also associated with the RVEF in a multivariate regression analysis. A total of 90% of the PH patients in the IVSD group were stratified into intermediate- and high-risk categories, and they showed a prolonged IRTRV and a shortened FTRV. The IRTRV was also the predictor of the major cardiovascular events. Conclusions: The temporal changes in the cardiac cycle were related to IVS displacement and mainly impacted the diastolic period of the two ventricles in the PH patients. The IRT and FT changes may provide useful pathophysiological information on the progression of PH.

SPARC, a Novel Regulator of Vascular Cell Function in Pulmonary Hypertension.

Pulmonary hypertension (PH) is a life-threatening disease, characterized by excessive pulmonary vascular remodeling, leading to elevated pulmonary arterial pressure and right heart hypertrophy. PH can be caused by chronic hypoxia, leading to hyper-proliferation of pulmonary arterial smooth muscle cells (PASMCs) and apoptosis-resistant pulmonary microvascular endothelial cells (PMVECs). On reexposure to normoxia, chronic hypoxia-induced PH in mice is reversible. In this study, the authors aim to identify novel candidate genes involved in pulmonary vascular remodeling specifically in the pulmonary vasculature. After microarray analysis, the authors assessed the role of SPARC (secreted protein acidic and rich in cysteine) in PH using lung tissue from idiopathic pulmonary arterial hypertension (IPAH) patients, as well as from chronically hypoxic mice. In vitro studies were conducted in primary human PASMCs and PMVECs. In vivo function of SPARC was proven in chronic hypoxia-induced PH in mice by using an adeno-associated virus-mediated Sparc knockdown approach. C57BL/6J mice were exposed to normoxia, chronic hypoxia, or chronic hypoxia with subsequent reexposure to normoxia for different time points. Microarray analysis of the pulmonary vascular compartment after laser microdissection identified Sparc as one of the genes downregulated at all reoxygenation time points investigated. Intriguingly, SPARC was vice versa upregulated in lungs during development of hypoxia-induced PH in mice as well as in IPAH, although SPARC plasma levels were not elevated in PH. TGF-β1 (transforming growth factor β1) or HIF2A (hypoxia-inducible factor 2A) signaling pathways induced SPARC expression in human PASMCs. In loss of function studies, SPARC silencing enhanced apoptosis and reduced proliferation. In gain of function studies, elevated SPARC levels induced PASMCs, but not PMVECs, proliferation. Coculture and conditioned medium experiments revealed that PMVECs-secreted SPARC acts as a paracrine factor triggering PASMCs proliferation. Contrary to the authors' expectations, in vivo congenital Sparc knockout mice were not protected from hypoxia-induced PH, most probably because of counter-regulatory proproliferative signaling. However, adeno-associated virus-mediated Sparc knockdown in adult mice significantly improved hemodynamic and cardiac function in PH mice. This study provides evidence for the involvement of SPARC in the pathogenesis of human PH and chronic hypoxia-induced PH in mice, most likely by affecting vascular cell function.

Predictors and prognosis of RV function in pulmonary hypertension due to heart failure with reduced ejection fraction

Abstract Background and aims Failure of right ventricular (RV) function worsens outcome in pulmonary hypertension (PH). The adaptation of RV contractility to afterload, the RV-pulmonary artery (PA) coupling, is defined by the ratio of RV end-systolic to PA elastances (Ees/Ea). Using pressure volume loop (PV-L) technique we aimed to identify an Ees/Ea cutoff predictive for overall survival and to assess hemodynamic and morphologic conditions for adapted RV function in secondary PH due to Heart Failure with Reduced Ejection Fraction (HFREF). Methods This post hoc analysis is based on 112 patients of the prospective Magdeburger Resynchronization Responder Trial. All patients underwent right and left heart echocardiography, and a baseline PV-L and RV catheter measurement. A subgroup of patients (n=50) without a pre-implanted cardiac device underwent MRI at baseline. Results The analysis revealed that 0.68 is an optimal Ees/Ea cutoff (area under the curve: 0.697, p&amp;lt;0.001) predictive for overall survival (median follow up = 4.7 years, Ees/Ea ≥0.68 vs. &amp;lt;0.68, log-rank 8.9, p=0.003. In patients with PH (n=76, 68%) Multivariate Cox-regression demonstrated the independent prognostic value of RV-Ees/Ea in PH patients (HR 0.2, p&amp;lt;0.038). Patients without PH (n=36, 32%) and those with PH but RV-Ees/Ea ≥0.68 showed comparable RV-Ees/Ea ratios (0.88 vs. 0.9, p=0.39), RV size/function, and survival. In contrast, secondary PH with RV-PA coupling ratio Ees/Ea &amp;lt;0.68 corresponded extremely close to cut-off values that define RV dilatation/remodeling (RVEDV &amp;gt;160ml, RV-mass/volume-ratio &amp;lt;0.37 g/ml) and dysfunction (RVEF &amp;lt;38%, TAPSE &amp;lt;16mm, FAC &amp;lt;42%, and stroke-volume/end-systolic volume ratio &amp;lt;0.59) and is associated with a dramatically increased short and medium-term all-cause mortality. Independent predictors of prognostically unfavorable RV-PA coupling (Ees/Ea &amp;lt;0.68) in secondary PH were a preexistent dilated RV (end-diastolic volume &amp;gt;171ml, odds ratio, OR 0.96, p=0.021), high pulsatile load (PA compliance &amp;lt;2.3 ml/mmHg, OR 8.6, p=0.003), and advanced systolic left heart failure (left ventricular (LV) ejection fraction &amp;lt;30%, OR 1.23, p=0.028). Conclusions The RV-PA coupling ratio Ees/Ea predicts overall survival in PH due to HFREF and is mainly affected by pulsatile load, RV remodeling and LV dysfunction. Prognostically favorable coupling (RV-Ees/Ea ≥0.68) in PH was associated with preserved RV size/function and mid-term survival, comparable to HFREF without PH. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Boston Scientific

Importance of Cx43 for Right Ventricular Function.

In the heart, connexins form gap junctions, hemichannels, and are also present within mitochondria, with connexin 43 (Cx43) being the most prominent connexin in the ventricles. Whereas the role of Cx43 is well established for the healthy and diseased left ventricle, less is known about the importance of Cx43 for the development of right ventricular (RV) dysfunction. The present article focusses on the importance of Cx43 for the developing heart. Furthermore, we discuss the expression and localization of Cx43 in the diseased RV, i.e., in the tetralogy of Fallot and in pulmonary hypertension, in which the RV is affected, and RV hypertrophy and failure occur. We will also introduce other Cx molecules that are expressed in RV and surrounding tissues and have been reported to be involved in RV pathophysiology. Finally, we highlight therapeutic strategies aiming to improve RV function in pulmonary hypertension that are associated with alterations of Cx43 expression and function.

Abstract 13912: 17-Beta-Estradiol Directly Regulates Microtubule Dynamics: New Insights Into Sex-Differences in Right Ventricular Function in Pulmonary Hypertension

Introduction: Female sex is associated with better right ventricular (RV) function in pulmonary hypertension (PH). The female sex hormone 17-beta-estradiol is postulated to mediate these differences, but the molecular mechanisms underlying these observations are incompletely defined. Interestingly, 17-beta-estradiol induces microtubule depolymerization in cell culture, which may be relevant to RV dysfunction because microtubule remodeling promotes RV dysfunction via dysregulation of junctophilin-2 (MT-JPH2 pathway). We speculate that 17-beta-estradiol modulates the MT-JPH2 pathway and preserves RV function in PH. Methods: Pressure-volume assessments quantified RV function in monocrotaline (MCT) and pulmonary artery-banded (PAB) rats. Immunoblots quantified the tubulin and junctophilin-2 protein content in RV extracts. Echocardiography quantified RV function by RV fractional area change for 379 human PH patients. Sedimentation experiments, fluorescence-based polymerization assessments, and total internal reflection fluorescence (TIRF) microscopy examined the effects of 17-beta-estradiol on microtubules. Results: Female sex results in better RV function and less dysregulation of the MT-JPH2 pathway in both MCT and PAB rats. Moreover, in human PH, female sex was associated with better RV function, which persisted after adjusting for afterload. 17-beta-estradiol inhibited microtubule polymerization in vitro and TIRF microscopy showed 17-beta-estradiol localized to microtubule tips and prevented further microtubule polymerization. Conclusions: Preclinical and human studies show that females are better able to tolerate RV pressure overload. There are blunted microtubule-mediated t-tubule remodeling and preserved RV function in female MCT and PAB rats. In human PH, females have better RV function. These findings may be due to 17-beta-estradiol directly regulating microtubule dynamics as shown by sedimentation and polymerization assays and TIRF microscopy. These results provide additional insights into sex-differences in RV function in PH.

Selective inhibition of Histone deacetylases reverses vascular remodelling and improves right ventricle function in pulmonary hypertension

Abstract Introduction Pulmonary arterial hypertension (PAH) is a progressive fatal disease characterized by abnormal remodelling of pulmonary vessels, leading to increased vascular resistance and right ventricle (RV) failure. This abnormal vascular remodelling is associated with endothelial cell dysfunction, increased proliferation of smooth muscle cells, inflammation, and disturbed transforming growth factor beta (TGF-β) signalling. Histone deacetylases (HDACs) have been shown to promote proliferation and inflammation in vascular cells. Although inhibition of HDACs using small molecule inhibitors attenuated vascular remodeling, these inhibitors worsened RV function in animal models of PAH. Therefore, we aim to validate Quisinostat, a selective inhibitor of HDACs whether it could reverse vascular remodeling in the lungs and improves RV function. Objective To determine the effect of Quisinostat on vascular remodelling and RV function in PAH. Methods and results We found that HDAC1 expression is increased in lungs of PAH patients. Inhibition of HDACs activity by Quisinostat significantly decreased TGF-β signaling and strongly decreased proliferation and inflammation in microvascular endothelial cells (MVECs). In addition, conditioned medium from Quisinostat treated PAH MVECs inhibited the growth of healthy smooth muscle cells. Quisinostat reversed abnormal vascular remodelling in the MCT-shunt and Sugen Hypoxia rat models of severe angioproliferative PAH, and improved RV function. Finally, Quisinostat improved the RV function in rats with RV pressure load induced by pulmonary artery banding. Importantly, Quisinostat exhibited no systemic and cardio toxic effects in vivo. Conclusions Our data demonstrate that selective inhibition of HDACs reverses vascular remodeling in the lungs and improves RV function. These data support the establishment of a clinical trial with Quisinostat in patients with PAH. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Dutch Lung Foundation

Heart Rate Reduction Improves Right Ventricular Function and Fibrosis in Pulmonary Hypertension.

The potential benefit of heart rate reduction (HRR), independent of β-blockade, on right ventricular (RV) function in pulmonary hypertension (PH) remains undecided. We studied HRR effects on RV fibrosis and function in PH and RV pressure-loading models. Adult rats were randomized to 1) sham controls, 2) monocrotaline (MCT)-induced PH, 3) SU5416 + hypoxia (SUHX)-induced PH, or 4) pulmonary artery banding (PAB). Ivabradine (IVA) (10 mg/kg/d) was administered from 2 weeks after PH induction or PAB. Exercise tolerance, echocardiography, and pressure-volume hemodynamics were obtained at a terminal experiment 3 weeks later. RV myocardial samples were analyzed for putative mechanisms of HRR effects through fibrosis, profibrotic molecular signaling, and Ca++ handling. The effects of IVA versus carvedilol on human induced pluripotent stem cell-derived cardiomyocytes beat rate and relaxation properties were evaluated in vitro. Despite unabated severely elevated RV systolic pressures, IVA improved RV systolic and diastolic function, profibrotic signaling, and RV fibrosis in PH/PAB rats. RV systolic-elastance (control, 121 ± 116; MCT, 49 ± 36 vs. MCT+IVA, 120 ± 54; PAB, 70 ± 20 vs. PAB+IVA, 168 ± 76; SUHX, 86 ± 56 vs. SUHX +IVA, 218 ± 111; all P < 0.05), the time constant of RV relaxation, echo indices of RV function, and fibrosis (fibrosis: control, 4.6 ± 1%; MCT, 13.4 ± 6.5 vs. MCT+IVA, 6.7 ± 2.6%; PAB, 11.4 ± 4.5 vs. PAB+IVA, 6.4 ± 5.1%; SUHX, 10 ± 4.6 vs. SUHX+IVA, 3.9 ± 2.2%; all P < 0.001) were improved by IVA versus controls. IVA had a dose-response effect on induced pluripotent stem cell-derived cardiomyocytes beat rate by delaying Ca++ loss from the cytoplasm. In experimental PH or RV pressure loading, HRR improves RV fibrosis, function, and exercise endurance independent of β-blockade. The balance between adverse tachycardia and bradycardia requires further study, but judicious HRR may provide a promising strategy to improve RV function in clinical PH.

Meet the First Authors

Meet the First Authors

Treatment With Treprostinil and Metformin Normalizes Hyperglycemia and Improves Cardiac Function in Pulmonary Hypertension Associated With Heart Failure With Preserved Ejection Fraction.

Pulmonary hypertension (PH) due to left heart disease (group 2), especially in the setting of heart failure with preserved ejection fraction (HFpEF), is the most common cause of PH worldwide; however, at present, there is no proven effective therapy available for its treatment. PH-HFpEF is associated with insulin resistance and features of metabolic syndrome. The stable prostacyclin analog, treprostinil, is an effective and widely used Food and Drug Administration-approved drug for the treatment of pulmonary arterial hypertension. While the effect of treprostinil on metabolic syndrome is unknown, a recent study suggests that the prostacyclin analog beraprost can improve glucose intolerance and insulin sensitivity. We sought to evaluate the effectiveness of treprostinil in the treatment of metabolic syndrome-associated PH-HFpEF. Approach and Results: Treprostinil treatment was given to mice with mild metabolic syndrome-associated PH-HFpEF induced by high-fat diet and to SU5416/obese ZSF1 rats, a model created by the treatment of rats with a more profound metabolic syndrome due to double leptin receptor defect (obese ZSF1) with a vascular endothelial growth factor receptor blocker SU5416. In high-fat diet-exposed mice, chronic treatment with treprostinil reduced hyperglycemia and pulmonary hypertension. In SU5416/Obese ZSF1 rats, treprostinil improved hyperglycemia with similar efficacy to that of metformin (a first-line drug for type 2 diabetes mellitus); the glucose-lowering effect of treprostinil was further potentiated by the combined treatment with metformin. Early treatment with treprostinil in SU5416/Obese ZSF1 rats lowered pulmonary pressures, and a late treatment with treprostinil together with metformin improved pulmonary artery acceleration time to ejection time ratio and tricuspid annular plane systolic excursion with AMPK (AMP-activated protein kinase) activation in skeletal muscle and the right ventricle. Our data suggest a potential use of treprostinil as an early treatment for mild metabolic syndrome-associated PH-HFpEF and that combined treatment with treprostinil and metformin may improve hyperglycemia and cardiac function in a more severe disease.

Clinical Significance of Right Ventricular Function in Pulmonary Hypertension.

Pulmonary hypertension (PH) is a progressive disease characterized by increased pulmonary vascular resistance that leads to right ventricular (RV) failure, a condition that determines its prognosis. This review focuses on the clinical value of the evaluation of RV function in PH. First, the pathophysiology of PH, including hemodynamics, RV function, and their interaction (known as ventriculoarterial coupling), are summarized. Next, non-invasive imaging modalities and the parameters of RV function, mainly assessed by echocardiography, are reviewed. Finally, the clinical impacts of RV function in PH are described. This review will compare the techniques that yield comprehensive information on RV function and their roles in the assessment of PH.

Assessing right atrial function in pulmonary hypertension: window to the soul of the right heart?

Assessing right atrial function in pulmonary hypertension: window to the soul of the right heart?