Positive Vasoreactivity Testing in Pulmonary Arterial Hypertension: Therapeutic Consequences, Treatment Patterns, and Outcomes in the Modern Management Era.

BACKGROUND: Among patients with pulmonary arterial hypertension (PAH), acute vasoreactivity testing during right heart catheterization may identify acute vasoresponders, for whom treatment with high-dose calcium channel blockers (CCBs) is recommended. However, long-term outcomes in the current era remain largely unknown. We sought to evaluate the implications of acute vasoreactivity response for long-term response to CCBs and other outcomes. METHODS: Patients diagnosed with PAH between January 1999 and December 2018 at 15 pulmonary hypertension centers were included and analyzed retrospectively. In accordance with current guidelines, acute vasoreactivity response was defined by a decrease of mean pulmonary artery pressure by ≥10 mm Hg to reach <40 mm Hg, without a decrease in cardiac output. Long-term response to CCBs was defined as alive with unchanged initial CCB therapy with or without other initial PAH therapy and World Health Organization functional class I/II and/or low European Society of Cardiology/European Respiratory Society risk status at 12 months after initiation of CCBs. Patients were followed for up to 5 years; clinical measures, outcome, and subsequent treatment patterns were captured. RESULTS: Of 3702 patients undergoing right heart catheterization for PAH diagnosis, 2051 had idiopathic, heritable, or drug-induced PAH, of whom 1904 (92.8%) underwent acute vasoreactivity testing. A total of 162 patients fulfilled acute vasoreactivity response criteria and received an initial CCB alone (n=123) or in combination with another PAH therapy (n=39). The median follow-up time was 60.0 months (interquartile range, 30.8-60.0), during which overall survival was 86.7%. At 12 months, 53.2% remained on CCB monotherapy, 14.7% on initial CCB plus another initial PAH therapy, and the remaining patients had the CCB withdrawn and/or PAH therapy added. CCB long-term response was found in 54.3% of patients. Five-year survival was 98.5% in long-term responders versus 73.0% in nonresponders. In addition to established vasodilator responder criteria, pulmonary artery compliance at acute vasoreactivity testing, low risk status and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels at early follow-up correlated with long-term response and predicted survival. CONCLUSIONS: Our data display heterogeneity within the group of vasoresponders, with a large subset failing to show a sustained satisfactory clinical response to CCBs. This highlights the necessity for comprehensive reassessment during early follow-up. The use of pulmonary artery compliance in addition to current measures may better identify those likely to have a good long-term response.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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-ß1 (transforming growth factor ß1) 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. CONCLUSIONS: 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.

Multicenter Standardization of Phase-Resolved Functional Lung MRI in Patients With Suspected Chronic Thromboembolic Pulmonary Hypertension.

BACKGROUND: Detection of pulmonary perfusion defects is the recommended approach for diagnosing chronic thromboembolic pulmonary hypertension (CTEPH). This is currently achieved in a clinical setting using scintigraphy. Phase-resolved functional lung (PREFUL) magnetic resonance imaging (MRI) is an alternative technique for evaluating regional ventilation and perfusion without the use of ionizing radiation or contrast media. PURPOSE: To assess the feasibility and image quality of PREFUL-MRI in a multicenter setting in suspected CTEPH. STUDY TYPE: This is a prospective cohort sub-study. POPULATION: Forty-five patients (64 ± 16 years old) with suspected CTEPH from nine study centers. FIELD STRENGTH/SEQUENCE: 1.5 T and 3 T/2D spoiled gradient echo/bSSFP/T2 HASTE/3D MR angiography (TWIST). ASSESSMENT: Lung signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were compared between study centers with different MRI machines. The contrast between normally and poorly perfused lung areas was examined on PREFUL images. The perfusion defect percentage calculated using PREFUL-MRI (QDPPREFUL ) was compared to QDP from the established dynamic contrast-enhanced MRI technique (QDPDCE ). Furthermore, QDPPREFUL was compared between a patient subgroup with confirmed CTEPH or chronic thromboembolic disease (CTED) to other clinical subgroups. STATISTICAL TESTS: t-Test, one-way analysis of variance (ANOVA), Pearson's correlation. Significance level was 5%. RESULTS: Significant differences in lung SNR and CNR were present between study centers. However, PREFUL perfusion images showed a significant contrast between normally and poorly perfused lung areas (mean delta of normalized perfusion -4.2% SD 3.3) with no differences between study sites (ANOVA: P = 0.065). QDPPREFUL was significantly correlated with QDPDCE (r = 0.66), and was significantly higher in 18 patients with confirmed CTEPH or CTED (57.9 ± 12.2%) compared to subgroups with other causes of PH or with excluded PH (in total 27 patients with mean ± SD QDPPREFUL = 33.9 ± 17.2%). DATA CONCLUSION: PREFUL-MRI could be considered as a non-invasive method for imaging regional lung perfusion in multicenter studies. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 1.

First Genotype-Phenotype Study in TBX4 Syndrome: Gain-of-Function Mutations Causative for Lung Disease.

Rationale: Despite the increased recognition of TBX4 (T-BOX transcription factor 4)-associated pulmonary arterial hypertension (PAH), genotype-phenotype associations are lacking and may provide important insights. Objectives: To compile and functionally characterize all TBX4 variants reported to date and undertake a comprehensive genotype-phenotype analysis. Methods: We assembled a multicenter cohort of 137 patients harboring monoallelic TBX4 variants and assessed the pathogenicity of missense variation (n = 42) using a novel luciferase reporter assay containing T-BOX binding motifs. We sought genotype-phenotype correlations and undertook a comparative analysis with patients with PAH with BMPR2 (Bone Morphogenetic Protein Receptor type 2) causal variants (n = 162) or no identified variants in PAH-associated genes (n = 741) genotyped via the National Institute for Health Research BioResource-Rare Diseases. Measurements and Main Results: Functional assessment of TBX4 missense variants led to the novel finding of gain-of-function effects associated with older age at diagnosis of lung disease compared with loss-of-function effects (P = 0.038). Variants located in the T-BOX and nuclear localization domains were associated with earlier presentation (P = 0.005) and increased incidence of interstitial lung disease (P = 0.003). Event-free survival (death or transplantation) was shorter in the T-BOX group (P = 0.022), although age had a significant effect in the hazard model (P = 0.0461). Carriers of TBX4 variants were diagnosed at a younger age (P < 0.001) and had worse baseline lung function (FEV1, FVC) (P = 0.009) than the BMPR2 and no identified causal variant groups. Conclusions: We demonstrated that TBX4 syndrome is not strictly the result of haploinsufficiency but can also be caused by gain of function. The pleiotropic effects of TBX4 in lung disease may be in part explained by the differential effect of pathogenic mutations located in critical protein domains.

[New definition and classification of pulmonary hypertension]. / Die neue Definition und Klassifikation der pulmonalen Hypertonie.

In the recent ESC/ERS guidelines on the diagnosis and management of pulmonary hypertension (PH) several important changes have been made in respect of the definition and classification of PH.The mPAP cut-off for defining PH was lowered. PH is now defined by an mPAP > 20 mmHg assessed by right heart catheterization. Moreover, the PVR threshold for defining precapillary PH was lowered. Precapillary PH is now defined by a PVR > 2 WU and a pulmonary arterial wedge pressure (PAWP) ≤ 15 mmHg. Furthermore, the increasing evidence for the clinical relevance of pulmonary exercise hemodynamics led to the reintroduction of exercise pulmonary hypertension (EPH) 1. EPH is characterized by a mPAP/CO-slope > 3 mmHg/L/min during exercise testing. In the classification of PH five groups are distinguished: Pulmonary arterial hypertension (group 1), PH associated with left heart disease (group 2), PH associated with lung diseases and/or hypoxia (Group 3), PH associated with pulmonary artery obstructions (group 4) and PH with unclear and/or multi-factorial mechanisms (group 5).In the following guideline-translation we focus on novel aspects regarding the definition and classification of PH and to provide additional background information.

[Diagnostic Algorithm and Screening of Pulmonary Hypertension]. / Diagnose Algorithmus der pulmonalen Hypertonie und Screening-Verfahren.

The new guidelines for the diagnosis and treatment of pulmonary hypertension include a new diagnostic algorithm and provide specific recommendations for the required diagnostic procedures, including screening methods. These recommendations are commented on by national experts under the auspices of the DACH. These comments provide additional decision support and background information, serving as a further guide for the complex diagnosis of pulmonary hypertension.

Temporal trends in pulmonary arterial hypertension: results from the COMPERA registry.

BACKGROUND: Since 2015, the European pulmonary hypertension guidelines recommend the use of combination therapy in most patients with pulmonary arterial hypertension (PAH). However, it is unclear to what extent this treatment strategy is adopted in clinical practice and if it is associated with improved long-term survival. METHODS: We analysed data from COMPERA, a large European pulmonary hypertension registry, to assess temporal trends in the use of combination therapy and survival of patients with newly diagnosed PAH between 2010 and 2019. For survival analyses, we looked at annualised data and at cumulated data comparing the periods 2010-2014 and 2015-2019. RESULTS: A total of 2531 patients were included. The use of early combination therapy (within 3 months after diagnosis) increased from 10.0% in patients diagnosed with PAH in 2010 to 25.0% in patients diagnosed with PAH in 2019. The proportion of patients receiving combination therapy 1 year after diagnosis increased from 27.7% to 46.3%. When comparing the 2010-2014 and 2015-2019 periods, 1-year survival estimates were similar (89.0% (95% CI 87.2-90.9%) and 90.8% (95% CI 89.3-92.4%), respectively), whereas there was a slight but nonsignificant improvement in 3-year survival estimates (67.8% (95% CI 65.0-70.8%) and 70.5% (95% CI 67.8-73.4%), respectively). CONCLUSIONS: The use of combination therapy increased from 2010 to 2019, but most patients still received monotherapy. Survival rates at 1 year after diagnosis did not change over time. Future studies need to determine if the observed trend suggesting improved 3-year survival rates can be confirmed.

COMPERA 2.0: a refined four-stratum risk assessment model for pulmonary arterial hypertension.

BACKGROUND: Risk stratification plays an essential role in the management of patients with pulmonary arterial hypertension (PAH). The current European guidelines propose a three-stratum model to categorise risk as low, intermediate or high, based on the expected 1-year mortality. However, with this model, most patients are categorised as intermediate risk. We investigated a modified approach based on four risk categories, with intermediate risk subdivided into intermediate-low and intermediate-high risk. METHODS: We analysed data from the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA), a European pulmonary hypertension registry, and calculated risk at diagnosis and first follow-up based on World Health Organization functional class, 6-min walk distance (6MWD) and serum levels of brain natriuretic peptide (BNP) or N-terminal pro-BNP (NT-proBNP), using refined cut-off values. Survival was assessed using Kaplan-Meier analyses, log-rank testing and Cox proportional hazards models. RESULTS: Data from 1655 patients with PAH were analysed. Using the three-stratum model, most patients were classified as intermediate risk (76.0% at baseline and 63.9% at first follow-up). The refined four-stratum risk model yielded a more nuanced separation and predicted long-term survival, especially at follow-up assessment. Changes in risk from baseline to follow-up were observed in 31.1% of the patients with the three-stratum model and in 49.2% with the four-stratum model. These changes, including those between the intermediate-low and intermediate-high strata, were associated with changes in long-term mortality risk. CONCLUSIONS: Modified risk stratification using a four-stratum model based on refined cut-off levels for functional class, 6MWD and BNP/NT-proBNP was more sensitive to prognostically relevant changes in risk than the original three-stratum model.

Gene panel diagnostics reveals new pathogenic variants in pulmonary arterial hypertension.

BACKGROUND: A genetic predisposition can lead to the rare disease pulmonary arterial hypertension (PAH). Most mutations have been identified in the gene BMPR2 in heritable PAH. However, as of today 15 further PAH genes have been described. The exact prevalence across these genes particularly in other PAH forms remains uncertain. We present the distribution of mutations across PAH genes identified at the largest German referral centre for genetic diagnostics in PAH over a course of > 3 years. METHODS: Our PAH-specific gene diagnostics panel was used to sequence 325 consecutive PAH patients from March 2017 to October 2020. For the first year the panel contained thirteen PAH genes: ACVRL1, BMPR1B, BMPR2, CAV1, EIF2AK4, ENG, GDF2, KCNA5, KCNK3, KLF2, SMAD4, SMAD9 and TBX4. These were extended by the three genes ATP13A3, AQP1 and SOX17 from March 2018 onwards following the genes' discovery. RESULTS: A total of 79 mutations were identified in 74 patients (23%). Of the variants 51 (65%) were located in the gene BMPR2 while the other 28 variants were found in ten further PAH genes. We identified disease-causing variants in the genes AQP1, KCNK3 and SOX17 in families with at least two PAH patients. Mutations were not only detected in patients with heritable and idiopathic but also with associated PAH. CONCLUSIONS: Genetic defects were identified in 23% of the patients in a total of 11 PAH genes. This illustrates the benefit of the specific gene panel containing all known PAH genes.

Right ventricular pressure-volume loop shape and systolic pressure change in pulmonary hypertension.

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.

CILP1 as a biomarker for right ventricular maladaptation in pulmonary hypertension.

The aim of our study was to analyse the protein expression of cartilage intermediate layer protein (CILP)1 in a mouse model of right ventricular (RV) pressure overload and to evaluate CILP1 as a biomarker of cardiac remodelling and maladaptive RV function in patients with pulmonary hypertension (PH).Pulmonary artery banding was performed in 14 mice; another nine mice underwent sham surgery. CILP1 protein expression was analysed in all hearts using Western blotting and immunostaining. CILP1 serum concentrations were measured in 161 patients (97 with adaptive and maladaptive RV pressure overload caused by PH; 25 with left ventricular (LV) hypertrophy; 20 with dilative cardiomyopathy (DCM); 19 controls without LV or RV abnormalities)In mice, the amount of RV CILP1 was markedly higher after banding than after sham. Control patients had lower CILP1 serum levels than all other groups (p<0.001). CILP1 concentrations were higher in PH patients with maladaptive RV function than those with adaptive RV function (p<0.001), LV pressure overload (p<0.001) and DCM (p=0.003). CILP1 showed good predictive power for maladaptive RV in receiver operating characteristic analysis (area under the curve (AUC) 0.79). There was no significant difference between the AUCs of CILP1 and N-terminal pro-brain natriuretic peptide (NT-proBNP) (AUC 0.82). High CILP1 (cut-off value for maladaptive RV of ≥4373 pg·mL-1) was associated with lower tricuspid annular plane excursion/pulmonary artery systolic pressure ratios (p<0.001) and higher NT-proBNP levels (p<0.001).CILP1 is a novel biomarker of RV and LV pathological remodelling that is associated with RV maladaptation and ventriculoarterial uncoupling in patients with PH.

Temporarily switching from oral to intravenous selexipag in patients with pulmonary arterial hypertension: safety, tolerability, and pharmacokinetic results from an open-label, phase III study.

BACKGROUND: The oral IP receptor agonist selexipag is approved for the long-term treatment of pulmonary arterial hypertension (PAH). Treatment interruptions should be avoided due to the progressive nature of the disease. An intravenous (IV) formulation of selexipag was developed to provide a treatment option for short-term interruptions to oral selexipag. In this prospective, multicenter, open-label study, the safety, tolerability, and pharmacokinetics of temporarily switching between oral and IV selexipag were investigated (NCT03187678, ClinicalTrials.gov). METHODS: PAH patients receiving stable oral selexipag doses were enrolled. Following three consecutive IV selexipag infusions patients resumed oral selexipag. Corresponding IV and oral doses were selected to achieve comparable exposure to the active metabolite of selexipag. Safety outcomes were monitored throughout, and pharmacokinetic samples were obtained after oral and IV administration. RESULTS: All 20 patients completed the study. Fifteen patients had adverse events (AEs), most were mild, and none resulted in discontinuation. Headache was the most common AE throughout the study (four patients). Three serious AEs occurred in two patients with underlying comorbidities when oral dosing had resumed. There were no changes in WHO functional class for any patient and no clinically symptomatic changes in blood pressure were observed. Comparable exposure to the active metabolite of selexipag was demonstrated following corresponding oral and IV selexipag doses. CONCLUSIONS: Temporarily switching between corresponding doses of oral and IV selexipag was well-tolerated with no unexpected safety findings and comparable exposure to the active metabolite. Treatment with IV selexipag is a feasible option to bridge temporary oral selexipag treatment interruptions.

Characterization of GDF2 Mutations and Levels of BMP9 and BMP10 in Pulmonary Arterial Hypertension.

Rationale: Recently, rare heterozygous mutations in GDF2 were identified in patients with pulmonary arterial hypertension (PAH). GDF2 encodes the circulating BMP (bone morphogenetic protein) type 9, which is a ligand for the BMP2 receptor.Objectives: Here we determined the functional impact of GDF2 mutations and characterized plasma BMP9 and BMP10 levels in patients with idiopathic PAH.Methods: Missense BMP9 mutant proteins were expressed in vitro and the impact on BMP9 protein processing and secretion, endothelial signaling, and functional activity was assessed. Plasma BMP9 and BMP10 levels and activity were assayed in patients with PAH with GDF2 variants and in control subjects. Levels were also measured in a larger cohort of control subjects (n = 120) and patients with idiopathic PAH (n = 260).Measurements and Main Results: We identified a novel rare variation at the GDF2 and BMP10 loci, including copy number variation. In vitro, BMP9 missense proteins demonstrated impaired cellular processing and secretion. Patients with PAH who carried these mutations exhibited reduced plasma levels of BMP9 and reduced BMP activity. Unexpectedly, plasma BMP10 levels were also markedly reduced in these individuals. Although overall BMP9 and BMP10 levels did not differ between patients with PAH and control subjects, BMP10 levels were lower in PAH females. A subset of patients with PAH had markedly reduced plasma levels of BMP9 and BMP10 in the absence of GDF2 mutations.Conclusions: Our findings demonstrate that GDF2 mutations result in BMP9 loss of function and are likely causal. These mutations lead to reduced circulating levels of both BMP9 and BMP10. These findings support therapeutic strategies to enhance BMP9 or BMP10 signaling in PAH.

Right ventricular function correlates of right atrial strain in pulmonary hypertension: a combined cardiac magnetic resonance and conductance catheter study.

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.

A comprehensive echocardiographic method for risk stratification in pulmonary arterial hypertension.

QUESTION ADDRESSED: Echocardiography is not currently considered as providing sufficient prognostic information to serve as an integral part of treatment goals in pulmonary arterial hypertension (PAH). We tested the hypothesis that incorporation of multiple parameters reflecting right heart function would improve the prognostic value of this imaging modality. METHODS AND MAIN RESULTS: We pooled individual patient data from a total of 517 patients (mean age 52±15 years, 64.8% females) included in seven observational studies conducted at five European and United States academic centres. Patients were subdivided into three groups representing progressive degrees of right ventricular dysfunction based on a combination of echocardiographic measurements, as follows. Group 1 (low risk): normal tricuspid annular plane systolic excursion (TAPSE) and nonsignificant tricuspid regurgitation (TR) (n=129); group 2 (intermediate risk): normal TAPSE and significant TR or impaired TAPSE and nondilated inferior vena cava (IVC) (n=256); group 3 (high risk): impaired TAPSE and dilated IVC (n=132). The 5-year cumulative survival rate was 82% in group 1, 63% in group 2 and 43% in group 3. Low-risk patients had better survival rates than intermediate-risk patients (log-rank Chi-squared 12.25; p<0.001) and intermediate-risk patients had better survival rates than high-risk patients (log-rank Chi-squared 26.25; p<0.001). Inclusion of other parameters such as right atrial area and pericardial effusion did not provide added prognostic value. ANSWER TO THE QUESTION: The proposed echocardiographic approach integrating the evaluation of TAPSE, TR grade and IVC is effective in stratifying the risk for all-cause mortality in PAH patients, outperforming the prognostic parameters suggested by current guidelines.

SPARCL1 as a biomarker of maladaptive right ventricular remodelling in pulmonary hypertension.

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.

Impaired right ventricular lusitropy is associated with ventilatory inefficiency in pulmonary arterial hypertension.

Cardiopulmonary exercise testing (CPET) is an important tool for assessing functional capacity and prognosis in pulmonary arterial hypertension (PAH). However, the associations of CPET parameters with the adaptation of right ventricular (RV) function to afterload remain incompletely understood.In this study, 37 patients with PAH (idiopathic in 31 cases) underwent single-beat pressure-volume loop measurements of RV end-systolic elastance (Ees), arterial elastance (Ea) and diastolic elastance (Eed). Pulmonary arterial stiffness was assessed by magnetic resonance imaging. The results were correlated to CPET variables. The predictive relevance of RV function parameters for clinically relevant ventilatory inefficiency, defined as minute ventilation/carbon dioxide production (V' E/V' CO2 ) slope >48, was evaluated using logistic regression analysis.The median (interquartile range) of the V' E/V' CO2 slope was 42 (32-52) and the V' E/V' CO2 nadir was 40 (31-44). The mean±sd of peak end-tidal carbon dioxide tension (P ETCO2 ) was 23±8 mmHg. Ea, Eed and parameters reflecting pulmonary arterial stiffness (capacitance and distensibility) correlated with the V' E/V' CO2 slope, V' E/V' CO2 nadir, P ETCO2 and peak oxygen pulse. RV Ees and RV-arterial coupling as assessed by the Ees/Ea ratio showed no correlations with CPET parameters. Ea (univariate OR 7.28, 95% CI 1.20-44.04) and Eed (univariate OR 2.21, 95% CI 0.93-5.26) were significantly associated with ventilatory inefficiency (p<0.10).Our data suggest that impaired RV lusitropy and increased afterload are associated with ventilatory inefficiency in PAH.

Riociguat for treatment of pulmonary hypertension in COPD: a translational study.

Chronic obstructive pulmonary disease (COPD), which comprises the phenotypes of chronic bronchitis and emphysema, is often associated with pulmonary hypertension (PH). However, currently, no approved therapy exists for PH-COPD. Signalling of the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) axis plays an important role in PH and COPD.We investigated the treatment effect of riociguat, which promotes the NO-cGMP pathway, in the mouse model of smoke-induced PH and emphysema in a curative approach, and retrospectively analysed the effect of riociguat treatment on PH in single patients with PH-COPD.In mice with established PH and emphysema (after 8 months of cigarette smoke exposure), riociguat treatment for another 3 months fully reversed PH. Moreover, histological hallmarks of emphysema were decreased. Microarray analysis revealed involvement of different signalling pathways, e.g. related to matrix metalloproteinases (MMPs). MMP activity was decreased in vivo by riociguat. In PH-COPD patients treated with riociguat (n=7), the pulmonary vascular resistance, airway resistance and circulating MMP levels decreased, while oxygenation at rest was not significantly changed.Riociguat may be beneficial for treatment of PH-COPD. Further long-term prospective studies are necessary to investigate the tolerability, efficacy on functional parameters and effect specifically on pulmonary emphysema in COPD patients.

Alterations in Doppler-derived renal venous stasis index during recompensation of right heart failure and fluid overload in a patient with pulmonary hypertension.

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.

Association of galectin-3 with changes in left ventricular function in recent-onset dilated cardiomyopathy.

Background: The course of newly diagnosed dilated cardiomyopathy (DCM) varies from persistent reduction of left ventricular ejection fraction (LVEF) to recovery or even worsening. The aim of the present study was to examine the prognostic value of selected biomarkers with regard to changes in LVEF. Methods: Main inclusion criterion was LVEF ≤45% with exclusion of coronary artery or valvular heart disease. The primary endpoint was LVEF ≤35% in the follow-up echocardiogram. Galectin-3, N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and C-reactive protein (CRP) were related to the endpoint. Results: Data from 80 DCM patients (55 male, mean age 53 years) were analyzed. Median LVEF was 25% (IQR 25-30). The endpoint was met for 24 patients (30%). These had higher baseline levels of galectin-3 (median 20.3 ng/mL [IQR 14.3-26.9] vs. 14.7 ng/mL [IQR 10.9-17.7], p = 0.007) and NT-proBNP (3089 pg/mL [IQR 1731-6694] vs. 1498 pg/mL [IQR 775-3890]; p = 0.004) in univariate Cox regression analysis. ROC analysis revealed that CRP (median 0.4 mg/dL [IQR 0.2-1.2]) was also related to the endpoint (p = 0.043). Conclusion: Higher levels of galectin-3, NT-proBNP, and CRP were associated with LVEF ≤35% in our cohort. An approach utilizing a combination of biomarkers for patient management should be assessed in further studies.