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Aims Research on the pathophysiology of right ventricular (RV) failure has, in spite of the associated high mortality and morbidity, lagged behind compared to the left ventricle (LV).Previous work from our lab revealed that the embryonic basic helix-loop-helix transcription factor heart and neural crest derivatives expressed-2 (Hand2) is re-expressed in the adult heart and activates a 'fetal gene program' contributing to pathological cardiac remodeling under conditions of LV pressure overload. As such, ablation of cardiac expression of Hand2 conferred protection to cardiac stress and abrogated the maladaptive effects that were observed upon increased expression levels. In this study, we aimed to understand the contribution of Hand2 to RV remodeling in response to pressure overload induced by pulmonary artery banding (PAB). Methods and results In the present study, Hand2F/F and MCM- Hand2F/F mice were treated with tamoxifen (control and knockout, respectively) and subjected to six weeks of RV pressure overload induced by PAB. Echocardiographic- and MRI-derived hemodynamic parameters as well as molecular remodeling were assessed for all experimental groups and compared to sham-operated controls. Six weeks after PAB, levels of Hand2 expression increased in the control banded animals but, as expected, remained absent in the knockout hearts. Despite the dramatic differences in Hand2 expression, pressure overload resulted in impaired cardiac function independently of the genotype. In fact, Hand2 depletion seems to sensitize the RV to pressure overload as these mice develop more hypertrophy and more severe cardiac dysfunction. Higher expression levels of HAND2 were also observed in RV samples of human hearts from patients with pulmonary hypertension. In turn, the LV of RV-pressure overloaded hearts was also dramatically affected as reflected by changes in shape, decreased LV mass and impaired cardiac function. RNA sequencing revealed a distinct set of genes that are dysregulated in the pressure-overloaded RV, compared to the previously described pressure-overloaded LV. Conclusions Cardiac-specific depletion of Hand2 is associated with severe cardiac dysfunction in conditions of RV pressure overload. While inhibiting Hand2 expression can prevent cardiac dysfunction in conditions of LV pressure overload, the same does not hold true for conditions of RV pressure overload. This study highlights the need to better understand the molecular mechanisms driving pathological remodeling of the RV in contrast to the LV, in order to better diagnose and treat patients with RV or LV failure. Translational perspective RV failure associated with pulmonary hypertension reduces long-term survival rate to 55% within 3 years, suggesting that 3 years after diagnosis almost half of the patients will die. To revert these numbers an adequate RV-specific and, therefore, more efficient treatment is needed. Our work suggests that current therapies and potential mechanisms underlying LV failure may not be suitable for RV failure. While Hand2 deletion is favorable in LV response to stress, it is particularly detrimental in the RV under similar conditions, and thus, highlighting potential severe consequences of not differentiating therapeutic targets or treatment for RV or LV failure.

Background: Treatment of patients with pulmonary arterial hypertension (PAH) is conventionally based on functional plus invasive measurements obtained during right heart catheterization (RHC). Whether risk assessment during repeated measurements could also be performed on the basis of imaging parameters is unclear, as a direct comparison of strategies is lacking. Research Question: How does the predictive value of noninvasive parameters compare with that of invasive hemodynamic measurements 1 year after the diagnosis of idiopathic PAH? Study Design and Methods: One hundred and eighteen patients with idiopathic PAH who underwent RHC and cardiac MRI (CMR) were included in this study (median time between baseline evaluation and first parameter measures, 1.0 [0.8-1.2] years). Forty-four patients died or underwent lung transplantation. Forward Cox regression analyses were done to determine the best predictive functional, hemodynamic, and/or imaging model. Patients were classified as high risk if the event occurred < 5 years after diagnosis (n = 24), whereas patients without event were classified as low risk. Results: A prognostic model based on age, sex, and absolute values at follow-up of functional parameters (6-min walk distance) performed well (Akaike information criterion [AIC], 279; concordance, 0.67). Predictive models with only hemodynamic (right atrial pressure, mixed venous oxygen saturation; AIC, 322; concordance, 0.66) or imaging parameters (right ventricular ejection fraction; AIC, 331; concordance, 0.63) at 1 year of follow-up performed similarly. The predictive value improved when functional data were combined with either hemodynamic data (AIC, 268; concordance, 0.69) or imaging data (AIC, 273; concordance, 0.70). A model composed of functional, hemodynamic, and imaging data performed only marginally better (AIC, 266; concordance, 0.69). Finally, changes between baseline and 1-year follow-up were observed for multiple hemodynamic and CMR parameters; only a change in CMR parameters was of prognostic predictive value. Interpretation: At 1 year of follow-up, risk assessment based on CMR is at least equal to risk assessment based on RHC. In this study, only changes in CMR, but not hemodynamic parameters, were of prognostic predictive value during the first year of follow-up.

Monoamine oxidases (MAOs), a class of enzymes bound to the outer mitochondrial membrane, are important sources of reactive oxygen species. Increased MAO-A activity in endothelial cells and cardiomyocytes contributes to vascular dysfunction and progression of left heart failure. We hypothesized that inhibition of MAO-A can be used to treat pulmonary arterial hypertension (PAH) and right ventricular (RV) failure. MAO-A levels in lung and RV samples from patients with PAH were compared with levels in samples from donors without PAH. Experimental PAH was induced in male Sprague-Dawley rats by using Sugen 5416 and hypoxia (SuHx), and RV failure was induced in male Wistar rats by using pulmonary trunk banding (PTB). Animals were randomized to receive either saline or the MAO-A inhibitor clorgyline at 10 mg/kg. Echocardiography and RV catheterization were performed, and heart and lung tissues were collected for further analysis. We found increased MAO-A expression in the pulmonary vasculature of patients with PAH and in experimental experimental PAH induced by SuHx. Cardiac MAO-A expression and activity was increased in SuHx- and PTB-induced RV failure. Clorgyline treatment reduced RV afterload and pulmonary vascular remodeling in SuHx rats through reduced pulmonary vascular proliferation and oxidative stress. Moreover, clorgyline improved RV stiffness and relaxation and reversed RV hypertrophy in SuHx rats. In PTB rats, clorgyline had no direct clorgyline had no direct effect on the right ventricle effect. Our study reveals the role of MAO-A in the progression of PAH. Collectively, these findings indicated that MAO-A may be involved in pulmonary vascular remodeling and consecutive RV failure.

Right ventricular (RV) function and autonomic dysfunction are important determinants of morbidity and mortality in patients with pulmonary arterial hypertension (PAH). Although successful in animal studies, effects of beta-blocker therapy on RV function in clinical trials were disappointing. To understand this discrepancy, we studied whether beta-blocker therapy changes RV sympathetic activity. Idiopathic PAH (IPAH) patients received beta-blocker therapy (uptitrated to a maximal tolerated dose) and underwent cardiac magnetic resonance imaging, right heart catheterization, and a [ 11 C]-hydroxyephedrine positron emission tomography ([ 11 C]HED PET) scan at baseline to determine, respectively, RV ejection fraction (RVEF), RV pressures, and sympathetic activity. [ 11 C]HED, a norepinephrine analogue, allows determination of sympathetic innervation of the RV. [ 11 C]HED retention index reflects norepinephrine transporter activity. As a consequence of excessive catecholamine levels in the synaptic cleft, this transporter may be downregulated. Therefore, low [ 11 C]HED retention index indicates high sympathetic activity. 13 IPAH patients underwent [ 11 C]HED PET scans at baseline and after bisoprolol treatment. Although heart rate was reduced, systemic modulation of autonomic activity by bisoprolol did not affect local RV sympathetic nerve activity, RV function, or RV wall tension. In PAH patients, RV [ 11 C]HED retention index was lower compared to LV tracer uptake (p

BackgroundPulmonary arterial hypertension (PAH) patients have altered right atrial (RA) function and right ventricular (RV) diastolic stiffness. This study assessed the impact of RV diastolic stiffness on RA–RV interaction.MethodsPAH patients with low or high end-diastolic elastance (Eed) (n=94) were compared with controls (n=31). Treatment response was evaluated in 62 patients. RV and RA longitudinal strain, RA emptying and RV filling were determined and diastole was divided into a passive and active phase. Vena cava backflow was calculated as RA active emptying−RV active filling and RA stroke work as RA active emptying×RV end-diastolic pressure.ResultsWith increased Eed, RA and RV passive strain were reduced while active strain was preserved. In comparison to controls, patients had lower RV passive filling but higher RA active emptying and RA stroke work. RV active filling was lower in patients with high Eed, resulting in higher vena cava backflow. Upon treatment, Eed was reduced in ~50% of the patients with high Eed, which coincided with larger reductions in afterload, RV mass and vena cava backflow and greater improvements in RV active filling and stroke volume in comparison with patients in whom Eed remained high.ConclusionsIn PAH, RA function is associated with changes in RV function. Despite increased RA stroke work, severe RV diastolic stiffness is associated with reduced RV active filling and increased vena cava backflow. In 50% of patients with high baseline Eed, diastolic stiffness remained high, despite treatment. A reduction in Eed coincided with a large reduction in afterload, increased RV active filling and decreased vena cava backflow.

BACKGROUND: To investigate the association between altered sex hormone expression and long-term right ventricular (RV) adaptation and progression of right heart failure in a Dutch cohort of Pulmonary Arterial Hypertension (PAH)-patients across a wide range of ages. METHODS: In this study we included 279 PAH-patients, of which 169 females and 110 males. From 59 patients and 21 controls we collected plasma samples for sex hormone analysis. Right heart catheterization (RHC) and/or cardiac magnetic resonance (CMR) imaging was performed at baseline. For longitudinal data analysis, we selected patients that underwent a RHC and/or CMR maximally 1.5 years prior to an event (death or transplantation, N = 49). RESULTS: Dehydroepiandrosterone-sulfate (DHEA-S) levels were reduced in male and female PAHpatients compared to controls, whereas androstenedione and testosterone were only reduced in female patients. Interestingly, low DHEA-S and high testosterone levels were correlated to worse RV function in male patients only. Subsequently, we analyzed prognosis and RV adaptation in females stratified by age. Females < 45years had best prognosis in comparison to females & GE;55years and males. No differences in RV function at baseline were observed, despite higher pressure-overload in females < 45years. Longitudinal data demonstrated a clear distinction in RV adaptation. Although females < 45years had an event at a later time point, RV function was more impaired at end-stage disease. CONCLUSIONS: Sex hormones are differently associated with RV function in male and female PAHpatients. DHEA-S appeared to be lower in male and female PAH-patients. Females < 45years could persevere pressure-overload for a longer time, but had a more severe RV phenotype at end-stage disease.J Heart Lung Transplant 2022;41:445-457 (c) 2021 The Author(s). Published by Elsevier Inc. on behalf of International Society for Heart and Lung Transplantation. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

Hyperventilation is common in pulmonary arterial hypertension and may be related to autonomic imbalance. Patients underwent exercise testing and hyperoxic breathing before and after bisoprolol treatment. We found that neither beta blocker treatment nor hyperoxic breathing in patients reduced hyperventilation at rest and during exercise, although it reduced heart rate.

Background: Pulmonary arterial hypertension (PAH) has an identifiable genetic cause in 5% of all PAH cases. Due to health benefits conferred by the early detection of PAH and the recent identification of additional PAH-associated genes, we decided to offer (extended) genetic testing to all incident and prevalent idiopathic PAH (iPAH) and pulmonary veno-occlusive disease (PVOD) patients in our clinic. Here, we report the lessons learned from (re-)contacting iPAH/PVOD patients concerning the uptake and analysis of identified PAH-associated genes and patient perspectives of the approach. Methods: Between January 2018 and April 2020, all iPAH/PVOD patients who were not previously genetically tested (contact group) and those who tested negative on prior analysis of BMPR2 and SMAD9 variants (re-contact group) were (re-)contacted for (additional) genetic testing. Results: With our approach, 58% of patients (84 out of 165) opted for genetic counselling, and a pathogenic variant was found in 12% of cases (n = 10) (re-contact group, 11%, and contact group, 13%). Eighty-six percent of participants of the survey study appreciated being (re-)contacted for genetic testing. Mild psychosocial impacts were observed. Conclusions: Our report shows the importance of (re-)contact and interest of patients (as indicated by the uptake, mild psychosocial impact and appreciation) in PAH.

Background Drugs approved for pulmonary arterial hypertension have been considered for patients with heart failure with preserved ejection fraction and combined post- and precapillary pulmonary hypertension (Cpc-PH). We aimed to study changes in cardiac volumes, cardiac load and left ventricular (LV) filling pressures in patients with heart failure with preserved ejection fraction and Cpc-PH in response to pulmonary arterial hypertension-specific treatment. Methods and Results In this prospective study, 23 patients with heart failure with preserved ejection fraction and Cpc-PH underwent right-heart catheterization, including acute provocation testing (fluid loading and inhaled nitric oxide) and cardiac MRI at baseline. Right-heart catheterization and cardiac MRI were repeated after 4 months of treatment. At baseline, acutely increasing preload by fluid loading resulted in a significant increase in pulmonary arterial wedge pressure (PAWP), whereas reducing right ventricular (RV) afterload and increasing LV distensability by acute administration of inhaled nitric oxide had no effect on PAWP. After 4 months of treatment, we observed a significant reduction in RV and LV afterload and increased RV and LV stroke volume, but PAWP significantly increased. Conclusions In patients with heart failure with preserved ejection fraction and Cpc-PH, 4 months of pulmonary arterial hypertension-specific treatment increased RV and LV stroke volume at the expense of increased PAWP. This increase in PAWP was similarly observed acutely after fluid loading.

BACKGROUND: Combined angiotensin II receptor antagonism and neprilysin inhibition by LCZ696 reduces morbidity and mortality in heart failure patients and works by reducing RAAS activity and increasing cGMP levels. This study aims to evaluate the effects of LCZ696 in rats with pulmonary hypertension and right ventricular (RV) failure.METHODS: Pulmonary hypertension was induced in rats (n = 34) by combined exposure to the vascular endothelial growth factor-receptor antagonist SU5416 and hypoxia (SuHx). To distinguish pulmonary vascular from cardiac effects, isolated RV failure was induced by pulmonary trunk banding (PTB) in another group of rats (n = 40). In both models, the development of RV dysfunction was verified before randomization to treatment with LCZ696 (60 mg/kg/day) or vehicle for five weeks.RESULTS: In the SuHx rats, LCZ696 treatment reduced the increase in RV pressure and the development of RV hypertrophy and RV dilatation compared with vehicle treatment. LCZ696 also reduced wall thickness of the smaller pulmonary arteries. In the PTB rats, LCZ696 treatment did not have any effects on RV hypertrophy or function.CONCLUSIONS: Combined angiotensin II receptor antagonism and neprilysin inhibition reduced RV systolic pressure, hypertrophy, and dilatation in rats with pulmonary hypertension. These effects seem secondary to pulmonary vascular changes, including reduced pulmonary vascular remodeling, as similar effects were not seen in rats with isolated RV failure. LCZ696 may have a therapeutic potential in the treatment of pulmonary hypertension.

Background Echocardiography is considered the cornerstone of the diagnostic workup of heart failure with preserved ejection fraction. Thus far, validation of the 2016 American Society of Echocardiography/European Association of Cardiovascular Imaging (ASE/EACVI) echo‐algorithm for evaluation of diastolic (dys)function in a patient suspected of heart failure with preserved ejection fraction has been limited. Methods and Results The diagnostic performance of the 2016 ASE/EACVI algorithm was assessed in 204 patients evaluated for unexplained dyspnea or pulmonary hypertension with echocardiogram and right heart catheterization. Invasively measured pulmonary capillary wedge pressure (PCWP) was used as the gold standard. In addition, the diagnostic performance of H 2 FPEF score and NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) were evaluated. There was a poor correlation between indexed left atrial volume, E/e′ (septal and average) or early mitral inflow (E), and PCWP ( r =0.25–0.30, P values all r =0.17, P 2 FPEF score had a modest correlation with PCWP ( r =0.44, P r =0.24, P Conclusions The 2016 ASE/EACVI algorithm for the assessment of diastolic function has a limited diagnostic accuracy in patients evaluated for unexplained dyspnea and/or pulmonary hypertension, and especially sensitivity to detect diastolic dysfunction was low.

Background The major complication of COVID-19 is hypoxaemic respiratory failure from capillary leak and alveolar oedema. Experimental and early clinical data suggest that the tyrosine-kinase inhibitor imatinib reverses pulmonary capillary leak. Methods This randomised, double-blind, placebo-controlled, clinical trial was done at 13 academic and non-academic teaching hospitals in the Netherlands. Hospitalised patients (aged ≥18 years) with COVID-19, as confirmed by an RT-PCR test for SARS-CoV-2, requiring supplemental oxygen to maintain a peripheral oxygen saturation of greater than 94% were eligible. Patients were excluded if they had severe pre-existing pulmonary disease, had pre-existing heart failure, had undergone active treatment of a haematological or non-haematological malignancy in the previous 12 months, had cytopenia, or were receiving concomitant treatment with medication known to strongly interact with imatinib. Patients were randomly assigned (1:1) to receive either oral imatinib, given as a loading dose of 800 mg on day 0 followed by 400 mg daily on days 1–9, or placebo. Randomisation was done with a computer-based clinical data management platform with variable block sizes (containing two, four, or six patients), stratified by study site. The primary outcome was time to discontinuation of mechanical ventilation and supplemental oxygen for more than 48 consecutive hours, while being alive during a 28-day period. Secondary outcomes included safety, mortality at 28 days, and the need for invasive mechanical ventilation. All efficacy and safety analyses were done in all randomised patients who had received at least one dose of study medication (modified intention-to-treat population). This study is registered with the EU Clinical Trials Register (EudraCT 2020–001236–10). Findings Between March 31, 2020, and Jan 4, 2021, 805 patients were screened, of whom 400 were eligible and randomly assigned to the imatinib group (n=204) or the placebo group (n=196). A total of 385 (96%) patients (median age 64 years [IQR 56–73]) received at least one dose of study medication and were included in the modified intention-to-treat population. Time to discontinuation of ventilation and supplemental oxygen for more than 48 h was not significantly different between the two groups (unadjusted hazard ratio [HR] 0·95 [95% CI 0·76–1·20]). At day 28, 15 (8%) of 197 patients had died in the imatinib group compared with 27 (14%) of 188 patients in the placebo group (unadjusted HR 0·51 [0·27–0·95]). After adjusting for baseline imbalances between the two groups (sex, obesity, diabetes, and cardiovascular disease) the HR for mortality was 0·52 (95% CI 0·26–1·05). The HR for mechanical ventilation in the imatinib group compared with the placebo group was 1·07 (0·63–1·80; p=0·81). The median duration of invasive mechanical ventilation was 7 days (IQR 3–13) in the imatinib group compared with 12 days (6–20) in the placebo group (p=0·0080). 91 (46%) of 197 patients in the imatinib group and 82 (44%) of 188 patients in the placebo group had at least one grade 3 or higher adverse event. The safety evaluation revealed no imatinib-associated adverse events. Interpretation The study failed to meet its primary outcome, as imatinib did not reduce the time to discontinuation of ventilation and supplemental oxygen for more than 48 consecutive hours in patients with COVID-19 requiring supplemental oxygen. The observed effects on survival (although attenuated after adjustment for baseline imbalances) and duration of mechanical ventilation suggest that imatinib might confer clinical benefit in hospitalised patients with COVID-19, but further studies are required to validate these findings.&nbsp

Background: Chronic thromboembolic pulmonary hypertension (CTEPH) and idiopathic pulmonary arterial hypertension (iPAH) are both associated with right ventricular (RV) failure and mortality. However, CTEPH patients are older, more often male and usually have more co-morbidities than iPAH patients, including a history of venous thromboembolism. Therefore, RV adaptation to pressure-overload in CTEPH may be different than in iPAH. Methods: We included all treatment-naive CTEPH and iPAH patients diagnosed in the Amsterdam UMC between 2000 and 2019 if cardiac magnetic resonance imaging (CMR) and a right heart catheterization were performed at time of diagnosis. Load-dependent RV volumes and mass were assessed with CMR. Load-independent RV contractility, afterload and diastolic stiffness in relation to afterload were obtained using single beat pressure-volume loop analysis. Differences in RV characteristics between CTEPH and iPAH were analyzed using multiple linear regression with interaction testing after correcting for confounders. Results: We included 235 patients in this study and performed pressure-volume loop analysis in 136 patients. In addition to being older and more often male, CTEPH patients had a lower pulmonary vascular resistance than iPAH patients at the time of diagnosis. After correcting for these confounders, CTEPH patients had a somewhat higher RV end-diastolic volume index (87 ± 27 ml vs 82 ± 25 ml; p

The search for new biomarkers for right ventricular maladaptation in pulmonary hypertension is exciting. At this moment we are missing some key information that hampers full-scale clinical implementation.https://bit.ly/37xbgwx

Pulmonary arterial hypertension is a heterogeneous group of diseases characterized by vascular cell proliferation leading to pulmonary vascular remodelling and ultimately right heart failure. Previous data indicated that 3′-deoxy-3′-[18F]-fluorothymidine ( 18 FLT) positron emission tomography (PET) scanning was increased in pulmonary arterial hypertension patients, hence providing a possible biomarker for pulmonary arterial hypertension as it reflects vascular cell hyperproliferation in the lung. This study sought to validate 18 FLT-PET in an expanded cohort of pulmonary arterial hypertension patients in comparison to matched healthy controls and unaffected bone morphogenetic protein receptor type 2 mutation carriers. 18 FLT-PET scanning was performed in 21 pulmonary arterial hypertension patients (15 hereditary pulmonary arterial hypertension and 6 idiopathic pulmonary arterial hypertension), 11 unaffected mutation carriers and 9 healthy control subjects. In-depth kinetic analysis indicated that there were no differences in lung 18 FLT k3 phosphorylation among pulmonary arterial hypertension patients, unaffected bone morphogenetic protein receptor type 2 mutation carriers and healthy controls. Lung 18 FLT uptake did not correlate with haemodynamic or clinical parameters in pulmonary arterial hypertension patients. Sequential 18 FLT-PET scanning in three patients demonstrated uneven regional distribution in 18 FLT uptake by 3D parametric mapping of the lung, although this did not follow the clinical course of the patient. We did not detect significantly increased lung 18 FLT uptake in pulmonary arterial hypertension patients, nor in the unaffected bone morphogenetic protein receptor type 2 mutation carriers, as compared to healthy subjects. The conflicting results with our preliminary human 18 FLT report may be explained by a small sample size previously and we observed large variation of lung 18 FLT signals between patients, challenging the application of 18 FLT-PET as a biomarker in the pulmonary arterial hypertension clinic.

Background: Chronic thromboembolic pulmonary hypertension (CTEPH) and idiopathic pulmonary arterial hypertension (iPAH)) are both associated with right ventricular (RV) failure and death. Although both conditions develop in the pre-capillary pulmonary vasculature, patient characteristics are different. CTEPH patients are older, predominantly male and more often have a history of venous thromboembolism. Therefore, the RV might be affected differently in CTEPH compared to iPAH. We aimed to compare RV adaptation in CTEPH and iPAH. Methods: Between 2000 and 2019 all treatment naive iPAH and CTEPH patients diagnosed in the Amsterdam UMC were included if a right heart catheterization and cardiac magnetic resonance imaging (CMR) were performed at the time of diagnosis. RV volumes, mass and function were assessed with CMR. RV contractility, afterload, RV-pulmonary artery (RV-PA) coupling and diastolic stiffness (Eed) were obtained using single beat pressure-volume loop analysis. Differences in RV phenotypes between iPAH and CTEPH were analyzed using multiple linear regression with interaction testing after correcting for confounders. Results: A total of 235 patients were included, 116 with CTEPH and 119 with iPAH. CTEPH patients were older, predominantly male, had a higher systemic blood pressure and a lower pulmonary vascular resistance at the time of diagnosis. After correcting for these confounders, RV function and RV-PA coupling were similar in both groups. However, CTEPH patients had a higher RV end-diastolic volume index (87±27 ml/m2 vs. 82±25 ml/m2), and a lower RV wall thickness (0,6±0,1 g/ml vs. 0,7±0,2 g/ml; figure 1A). The increase in afterload in CTEPH was associated with a disproportionally larger increase in diastolic stiffness compared to iPAH, independent of RV wall thickness (figure 1B). Conclusions: Despite a similar RV function, the RV in CTEPH is more dilated and stiffer than the RV in iPAH, independent of age, sex and afterload.

Introduction: Newly diagnosed idiopathic pulmonary arterial hypertension (PAH) patients increasingly have features of patients with heart failure with preserved ejection fraction (HFpEF). These so-called “atypical” PAH patients can be identified using the H2FPEF-score (Reddy, Circulation 2018). This patient group is often excluded from clinical trials, and it is therefore unclear whether they respond similarly to PAH-specific medication. Aim: To assess baseline characteristics and treatment response of patients diagnosed with PAH stratified by the H2FPEF-score. Methods: A retrospective analysis of 253 treatment naïve PAH-patients who underwent diagnostic right heart catheterization at baseline. Groups were compared with ANOVA, post-hoc pairwise t-tests with Bonferroni correction and multivariate Cox proportional hazards analysis. Results: This cohort included 58 (23%) patients with a low (≤1), 159 (63%) patients with an intermediate (2-5) and 36 (14%) patients with a high (≥6) H2FPEF-score. Patients with a high H2FPEF-score were older and more often male, used more diuretics, had more comorbidities and had more often PAH with severely impaired diffusion capacity compared to patients with a low H2FPEF-score. In addition, patients with a high H2FPEF-score had a significantly lower cardiac index, mixed venous blood gas, oxygen saturation and 6-minute walk distance (6MWD) compared to patients with a low H2FPEF-score. A high H2FPEF-score was associated with worse survival despite correcting for confounders (HR 2.99, 95% CI 1.53-5.84, Fig.1 A). Despite potential survival bias, at 1-year follow-up 6MWD (Fig.1 B) significantly improved in patients with a low and intermediate H2FPEF-score, but did not change in patients with a high H2FPEF-score (interaction p-value< 0.001). Conclusions: A high H2FPEF-score is associated with worse survival in PAH. Also, no improvement in 6MWD was observed in patients with a high H2FPEF-score only.

BACKGROUND: Pulmonary vascular resistance (PVR) and compliance are comparable in proximal and distal chronic thromboembolic pulmonary hypertension (CTEPH). However, proximal CTEPH is associated with inferior right ventricular (RV) adaptation. Early wave reflection in proximal CTEPH may be responsible for altered RV function. The aims of the study are 1) investigate whether reflected pressure returns sooner in proximal than in distal CTEPH, and 2) elucidate whether timing of reflected pressure is related to RV dimensions, ejection fraction (RVEF), hypertrophy and wall stress.METHODS: Right heart catheterization and cardiac MRI were performed in 17 patients with proximal and 17 patients with distal CTEPH. In addition to determination of PVR, compliance and characteristic impedance, wave separation analysis was performed to determine the magnitude and timing of the peak reflected pressure (as % of systole). Findings were related to RV dimensions and time-resolved RV wall stress.RESULTS: Proximal CTEPH was characterized by higher RV volumes, mass and wall stress, and lower RVEF. While PVR, compliance and characteristic impedance were similar, proximal CTEPH was related to an earlier return of reflected pressure than distal CTEPH (proximal 53±8% vs. distal 63±15%, PCONCLUSIONS: Poor RV function in patients with proximal CTEPH is related to an early return of reflected pressure wave. PVR, compliance and characteristic impedance do not explain differences in RV function between proximal and distal CTEPH.

Right ventricular (RV) dysfunction is the most important determinant of survival in patients with pulmonary hypertension (PH). The manifestations of RV dysfunction not only include changes in global RV systolic function but also abnormalities in the pattern of contraction and synchrony. The effects of PH on the right ventricle have been mainly studied in patients with pulmonary arterial hypertension (PAH). However, with the demographic shift towards an aging population, heart failure with preserved ejection fraction (HFpEF) has become an important etiology of PH in recent years. There are significant differences in RV mechanics, function and adaptation between patients with PAH and HFpEF (with or without PH), which are related to different patterns of remodeling and dysfunction. Due to the unique features of the RV chamber, its connection with the main pulmonary artery and the pulmonary circulation, an understanding of the mechanics of RV function and its clinical significance is mandatory for both entities. In this review, we describe the mechanics of the pressure overloaded right ventricle. We review the different mechanical components of RV dysfunction and ventricular dyssynchrony, followed by insights via analysis of pressure-volume loop, energetics and novel blood flow patterns, such as vortex imaging. We conduct an in-depth comparison of prevalence and characteristics of RV dysfunction in HFpEF and PAH, and summarize key outcome studies. Finally, we provide a perspective on needed and expected future work in the field of RV mechanics.

Histone deacetylases (HDACs) are increased in pulmonary arterial hypertension (PAH), and inhibiting HDACs can be a promising treatment for PAH. However, previous studies on experimental PAH revealed controversial results, and adverse effects are common. Quisinostat is a “second generation” HDACs inhibitor, which is highly potent against class I and II HDACs, with prolonged pharmacodynamics response. It has been shown to be well tolerated by phase I trial. Collectively, we hypothesized that quisinostat can be used to treat PAH. Proliferation and inflammation were measured after quisinostat treatment on microvascular endothelial cells (MVECs), which were isolated from lungs of PAH patients. Experimental PAH was induced in male Sprague-Dawley rats by a single injection of SU5416 followed by 4-weeks hypoxia and 2-weeks normoxia. At week 6, rats were randomized to receive either DMSO or quisinostat until week 10. Echocardiography was performed at week 6 and week 10, and right ventricle (RV) catheterization was performed at week 10. In vitro, quisinostat reduced proliferation in PAH MVECs, as well as inflammatory response as shown by decreased TNFα, IL-6, MCP-1 and VCAM-1. In vivo, quisinostat treatment reduced RV systolic pressure, RV afterload and total pulmonary resistance in SuHx rats. Further tissue analysis by histology revealed that quisinostat reduced pulmonary vascular remodeling by reducing intima layer thickness. Meanwhile, quisinostat had no effect on RV function. Quisinostat can partly reverse RV afterload and pulmonary vascular remodeling in established experimental PAH. Therefore, quisinostat may be a promising intervention for PAH.

Background: In recent years, newly diagnosed pulmonary arterial hypertension (PAH) patients have increasing features of patients with heart failure with preserved ejection fraction (HFpEF). A high HFpEF probability, quantified by the H2FPEF-score, may predict treatment response. Objective: To assess whether a high H2FPEF-score predicts treatment response in patients diagnosed with PAH . Methods: A retrospective cohort of 253 idiopathic PAH-patients underwent diagnostic right heart catheterization at baseline and in a subset of patients (n=150) follow-up measurements were available at 1.00 [0.74-1.28] year. Results: This cohort included 55 (22%) patients with a low (≤1), 160 (63%) patients with an intermediate (2-5) and 38 (15%) patients with a high (≥6) H2FPEF-score. Patients with a high H2FPEF-score at time of diagnosis were older, had more comorbidities, a lower DLCO and larger left atrial area compared to patients with a low H2FPEF-score. PAH-specific treatment was comparable among all groups and a similar reduction in PVR at 1-year follow-up was observed. Overall, 6-minute walk test significantly improved after treatment (322±147 to 388±143 m). This improvement was seen in all groups, although only significant in the groups with a low and intermediate H2FPEF-score. No significant correlation was observed between the H2FPEF-score and left atrial area or PCWP. Finally, survival for patients with a high H2FPEF-score was significantly worse than for patients with a low H2FPEF-score. Conclusion: A high H2FPEF-score does not predict hemodynamic or exercise response to vasodilator treatment in PAH, but is nonetheless associated with increased mortality.

Background Although most newly presenting patients with pulmonary hypertension ( PH ) have elevated pulmonary artery wedge pressure, identification of so‐called postcapillary PH can be challenging. A noninvasive tool predicting elevated pulmonary artery wedge pressure in patients with incident PH may help avoid unnecessary invasive diagnostic procedures. Methods and Results A combination of clinical data, ECG, and echocardiographic parameters was used to refine a previously developed left heart failure risk score in a retrospective cohort of pre‐ and postcapillary PH patients. This updated score (renamed the OPTICS risk score) was externally validated in a prospective cohort of patients from 12 Dutch nonreferral centers the OPTICS network. Using the updated OPTICS risk score, the presence of postcapillary PH could be predicted on the basis of body mass index ≥30, diabetes mellitus, atrial fibrillation, dyslipidemia, history of valvular surgery, sum of SV 1 (deflection in V1 in millimeters) and RV 6 (deflection in V6 in millimeters) on ECG, and left atrial dilation. The external validation cohort included 81 postcapillary PH patients and 66 precapillary PH patients. Using a predefined cutoff of >104, the OPTICS score had 100% specificity for postcapillary PH (sensitivity, 22%). In addition, we investigated whether a high probability of heart failure with preserved ejection fraction, assessed by the H 2 FPEF score (obesity, atrial fibrillation, age >60 yrs, ≥2 antihypertensives, E/e' >9, and pulmonary artery systolic pressure by echo >35 mmHg), similarly predicted the presence of elevated pulmonary artery wedge pressure. High probability of heart failure with preserved ejection fraction (H 2 FPEF score ≥6) was less specific for postcapillary PH . Conclusions In a community setting, the OPTICS risk score can predict elevated pulmonary artery wedge pressure in PH patients without clear signs of left‐sided heart disease. The OPTICS risk score may be used to tailor the decision to perform invasive diagnostic testing.

Cardiovascular magnetic resonance imaging is an important modality in pulmonary hypertension for diagnostics, evaluation of treatment response and prognostics. It can replace other modalities at follow-up and serve as an end-point in large clinical trials.https://bit.ly/3hfSKN8

Background: Mutations in bone morphogenetic protein receptor type II (BMPR2) are leading to the development of hereditary pulmonary arterial hypertension (PAH). In non-hereditary forms of PAH, perturbations in the transforming growth factor-&beta, (TGF-&beta, )/BMP-axis are believed to cause deficient BMPR2 signaling by changes in receptor expression, the activity of the receptor and/or downstream signaling. To date, BMPR2 expression and its activity in the lungs of patients with non-hereditary PAH is poorly characterized. In recent decades, different animal models have been used to understand the role of BMPR2 signaling in PAH pathophysiology. Specifically, the monocrotaline (MCT) and Sugen&ndash, Hypoxia (SuHx) models are extensively used in interventional studies to examine if restoring BMPR2 signaling results in PAH disease reversal. While PAH is assumed to develop in patients over months or years, pulmonary hypertension in experimental animal models develops in days or weeks. It is therefore likely that modifications in BMP and TGF-&beta, signaling in these models do not fully recapitulate those in patients. In order to determine the translational potential of the MCT and SuHx models, we analyzed the BMPR2 expression and activity in the lungs of rats with experimentally induced PAH and compared this to the BMPR2 expression and activity in the lungs of PAH patients. Methods: the BMPR2 expression was analyzed by Western blot analysis and immunofluorescence (IF) microscopy to determine the quantity and localization of the receptor in the lung tissue from normal control subjects and patients with hereditary or idiopathic PAH, as well as in the lungs of control rats and rats with MCT or SuHx-induced PAH. The activation of the BMP pathway was analyzed by determining the level and localization of phosphorylated Smad1/5/8 (pSmad 1/5/8), a downstream mediator of canonical BMPR2 signaling. Results: While BMPR2 and pSmad 1/5/8 expression levels were unaltered in whole lung lysates/homogenates from patients with hereditary and idiopathic PAH, IF analysis showed that BMPR2 and pSmad 1/5/8 levels were markedly decreased in the pulmonary vessels of both PAH patient groups. Whole lung BMPR2 expression was variable in the two PAH rat models, while in both experimental models the expression of BMPR2 in the lung vasculature was increased. However, in the human PAH lungs, the expression of pSmad 1/5/8 was downregulated in the lung vasculature of both experimental models. Conclusion: BMPR2 receptor expression and downstream signaling is reduced in the lung vasculature of patients with idiopathic and hereditary PAH, which cannot be appreciated when using human whole lung lysates. Despite increased BMPR2 expression in the lung vasculature, the MCT and SuHx rat models did develop PAH and impaired downstream BMPR2-Smad signaling similar to our findings in the human lung.

Aims: Pulmonary arterial hypertension (PAH) is associated with increased levels of circulating growth factors and corresponding receptors such as platelet derived growth factor, fibroblast growth factor and vascular endothelial growth factor. Nintedanib, a tyrosine kinase inhibitor targeting primarily these receptors, is approved for the treatment of patients with idiopathic pulmonary fibrosis. Our objective was to examine the effect of nintedanib on proliferation of human pulmonary microvascular endothelial cells (MVEC) and assess its effects in rats with advanced experimental pulmonary hypertension (PH). Methods and results: Proliferation was assessed in control and PAH MVEC exposed to nintedanib. PH was induced in rats by subcutaneous injection of Sugen (SU5416) and subsequent exposure to 10% hypoxia for 4 weeks (SuHx model). Four weeks after re-exposure to normoxia, nintedanib was administered once daily for 3 weeks. Effects of the treatment were assessed with echocardiography, right heart catheterization, and histological analysis of the heart and lungs. Changes in extracellular matrix production was assessed in human cardiac fibroblasts stimulated with nintedanib. Decreased proliferation with nintedanib was observed in control MVEC, but not in PAH patient derived MVEC. Nintedanib treatment did not affect right ventricular (RV) systolic pressure or total pulmonary resistance index in SuHx rats and had no effects on pulmonary vascular remodelling. However, despite unaltered pressure overload, the right ventricle showed less dilatation and decreased fibrosis, hypertrophy, and collagen type III with nintedanib treatment. This could be explained by less fibronectin production by cardiac fibroblasts exposed to nintedanib. Conclusion: Nintedanib inhibits proliferation of pulmonary MVECs from controls, but not from PAH patients. While in rats with experimental PH nintedanib has no effects on the pulmonary vascular pathology, it has favourable effects on RV remodelling.

Background: The beneficial effects of parasympathetic stimulation have been reported in left heart failure, but whether it would be beneficial for pulmonary arterial hypertension (PAH) remains to be explored. Here, we investigated the relationship between parasympathetic activity and right ventricular (RV) function in patients with PAH, and the potential therapeutic effects of pyridostigmine (PYR), an oral drug stimulating the parasympathetic activity through acetylcholinesterase inhibition, in experimental pulmonary hypertension (PH). Methods: Heart rate recovery after a maximal cardiopulmonary exercise test was used as a surrogate for parasympathetic activity. RV ejection fraction was assessed in 112 patients with PAH. Expression of nicotinic (α-7 nicotinic acetylcholine receptor) and muscarinic (muscarinic acetylcholine type 2 receptor) receptors, and acetylcholinesterase activity were evaluated in RV (n=11) and lungs (n=7) from patients with PAH undergoing heart/lung transplantation and compared with tissue obtained from controls. In addition, we investigated the effects of PYR (40 mg/kg per day) in experimental PH. PH was induced in male rats by SU5416 (25 mg/kg subcutaneously) injection followed by 4 weeks of hypoxia. In a subgroup, sympathetic/parasympathetic modulation was assessed by power spectral analysis. At week 6, PH status was confirmed by echocardiography, and rats were randomly assigned to vehicle or treatment (both n=12). At the end of the study, echocardiography was repeated, with additional RV pressure-volume measurements, along with lung, RV histological, and protein analyses. Results: Patients with PAH with lower RV ejection fraction ( Conclusions: RV dysfunction is associated with reduced systemic parasympathetic activity in patients with PAH, with an inadequate adaptive response of the cholinergic system in the RV. Enhancing parasympathetic activity by PYR improved survival, RV function, and pulmonary vascular remodeling in experimental PH.

BACKGROUND: Between 16% and 51% of patients with chronic thromboembolic pulmonary hypertension will have residual pulmonary hypertension (PH) after pulmonary endarterectomy (PEA). Whether residual PH is related to remaining (sub-)segmental macrovascular lesions or to microvascular disease is unknown. New imaging techniques can provide detailed information about (sub-)segmental pulmonary arteries and parenchymal perfusion. The aim of this study was to describe the prevalence after PEA of remaining (sub-)segmental vascular lesions on electrocardiogram-gated computed tomography pulmonary angiography (CTPA) and parenchymal hypoperfusion on magnetic resonance imaging (MRI) and to relate these imaging abnormalities to the presence or absence of residual PH after PEA.METHODS: In a prospective cohort of patients with operable chronic thromboembolic pulmonary hypertension, hemodynamics, CTPA, and lung perfusion MRI were performed before and 6 months after PEA. The percentage of (sub-)segmental vascular lesions was calculated on CTPA and parenchymal hypoperfusion on lung perfusion MRI.RESULTS: PEA led to significant improvements in hemodynamics and a reduction of imaging abnormalities. Residual PH was present in 45% of patients after PEA, whereas remaining (sub-)segmental vascular lesions and parenchymal hypoperfusion were present in 20% and 21% of the pulmonary vasculature, respectively. Patients with and without residual PH after PEA had similar percentages of remaining (sub-)segmental vascular lesions (25% +/- 14% vs 17% +/- 15%; p = 0.16) and similar degrees of parenchymal hypoperfusion (20% +/- 7% vs 19% +/- 6%; p = 0.63).CONCLUSIONS: After successful PEA, advanced imaging shows that around 20% of the pulmonary vasculature remains abnormal, independent of the presence of residual PH. This may suggest that microvascular disease, rather than residual macrovascular lesions, plays a prominent role in residual PH after PEA. (C) 2019 International Society for Heart and Lung Transplantation. All rights reserved.

Vena cava backflow is a well-recognised clinical hallmark of right ventricular failure in pulmonary arterial hypertension (PAH). Backflow may result from tricuspid regurgitation during right ventricular systole or from impaired right ventricular diastolic filling during atrial contraction. Our aim was to quantify the forward and backward flow in the vena cava and to establish the main cause in PAH.In 62 PAH patients, cardiac magnetic resonance measurements provided volumetric flows (mL·s−1) in the superior and inferior vena cava; time integration of flow gave volume. The “backward fraction” was defined as the ratio of the backward and forward volumes in the vena cava, expressed as a percentage. Time of maximum vena cava backflow was expressed as a percentage of the cardiac cycle. Right ventricular volumes and aortic stroke volume were determined. Right heart catheterisation gave right ventricular and right atrial pressures. Right ventricular end-diastolic stiffness was determined with the single-beat method.The median (interquartile range) backward fraction was 12% (3–24%) and it was >20% in 21 patients. Maximum backflow occurred at near 90% of the cardiac cycle, coinciding with atrial contraction. The backward fraction was associated with maximal right atrial pressure (Spearman's r=0.77), right ventricular end-diastolic stiffness (r=0.65) and right ventricular end-diastolic pressure (r=0.77), and was negatively associated with stroke volume (r= –0.61) (all pSignificant backward flow in the vena cava was observed in a large group of PAH patients and occurred mostly during atrial contraction as a consequence of impaired right ventricular filling due to right ventricular diastolic stiffness. The backward flow due to tricuspid regurgitation was of significance in only a small minority of patients.

Rationale: Multiple mechanisms have been discovered underlying the pathogenesis of pulmonary arterial hypertension (PAH), including reactive oxygen species (ROS), inflammation and reduced bone morphogenic protein receptor (BMPR)2. MnTBAP can mimic the effects of manganese-superoxide dismutase to reduce ROS. Moreover, MnTBAP can reduce inflammation in endothelial cells via up-regulation of BMPR2. Collectively, we hypothesized that MnTBAP can be used to treat PAH. Methods: Experimental PAH was induced in male Sprague-Dawley rats by a single injection of SU5416 followed by 4-weeks hypoxia and 2-weeks normoxia. At week 6, animals were randomized to receive either saline or MnTBAP until week 10. Echocardiography was performed at week 6 and week 10, and right ventricle (RV) catheterization was performed at week 10. Heart and lung tissues were collected. Results: MnTBAP reduced RV afterload and total pulmonary resistance in SuHx rats. Moreover, MnTBAP improved RV function by increasing stroke volume and TAPSE, as well as reducing RV end diastolic diameter and stiffness. Further tissue analysis by histology revealed that MnTBAP reduced pulmonary vascular remodeling by reducing both intima and media layer thickness. Conclusion: MnTBAP treatment can partly reverse RV afterload and pulmonary vascular remodeling in established experimental PAH. Together with the improved cardiac function, MnTBAP may be a promising intervention for PAH.

While exercise capacity is reduced in all forms of pulmonary hypertension, only in idiopathic pulmonary arterial hypertension (iPAH) this is known to be related to right ventricular (RV) -arterial uncoupling. Here we compare RV-arterial coupling (RVAC) during exercise between patients with chronic thromboembolic pulmonary hypertension (CTEPH) and iPAH. We prospectively included 12 CTEPH and 12 iPAH patients who performed a submaximal invasive cardiopulmonary exercise test between January 2013 and January 2019. RV contractility, defined as end-systolic elestance (Ees), and RV afterload (Ea) were assessed both at rest and during exercise by using single beat pressure-volume loop analysis. RVAC was calculated as Ees/Ea. RV afterload and contractility were similar at rest in iPAH and CTEPH (figure 1). In both groups, Ea significantly increased during exercise, while RV contractility did not change. Resting RVAC was higher in iPAH than in CPTEH (1,6 (0,6) vs. 1,2 (0,3); p CTEPH patients have a worse RV phenotype at rest compared to iPAH patients. Both groups fail to increase contractility during exercise.

PURPOSE OF REVIEW: Right ventricular (RV) function is an important determinant of morbidity and mortality in patients with pulmonary arterial hypertension (PAH). Although substantial progress has been made in understanding the development of RV failure in the last decennia, this has not yet resulted in the development of RV selective therapies. In this review, we will discuss the current status on the treatment of RV failure and potential novel therapeutic strategies that are currently being investigated in clinical trials.RECENT FINDINGS: Increased afterload results in elevated wall tension. Consequences of increased wall tension include autonomic disbalance, metabolic shift and inflammation, negatively affecting RV contractility. Compromised RV systolic function and low cardiac output activate renin-angiotensin aldosterone system, which leads to fluid retention and further increase in RV wall tension. This vicious circle can be interrupted by directly targeting the determinants of RV wall tension; preload and afterload by PAH-medications and diuretics, but is also possibly by restoring neurohormonal and metabolic disbalance, and inhibiting maladaptive inflammation. A variety of RV selective drugs are currently being studied in clinical trials.SUMMARY: Nowadays, afterload reduction is still the cornerstone in treatment of PAH. New treatments targeting important pathobiological determinants of RV failure directly are emerging.

Cardiac fibrosis contributes to the development of heart failure in pulmonary hypertension. We aimed to assess the development of fibrosis and the effects of treatment with the anti-fibrotic agent pirfenidone in pressure overload induced right ventricular (RV) failure. Wistar rat weanlings were randomized to pulmonary trunk banding (PTB) or sham surgery. One week after the procedure, PTB rats were randomized into two groups with either six weeks on standard chow or treatment with pirfenidone mixed in chow (700 mg/kg/day). RV hemodynamic effects were evaluated by echocardiography, cardiac magnetic resonance imaging (MRI), and pressure-volume measurements. Sections from the isolated RV, left ventricle, and septum were sampled systematically; stereological point grids and the nucleator were used to estimate volume of fibrosis and cardiac hypertrophy, respectively. PTB caused RV failure in all rats subjected to the procedure. The volume fraction of fibrosis in the RV increased threefold in PTB rats corresponding to a sixfold increase in total volume of RV fibrosis. Volume fraction of fibrosis and total volume of fibrosis also increased in the septum and in the left ventricle. Pirfenidone reduced body weight but did not improve RV hemodynamics or reduce cardiac fibrosis. RV cardiomyocyte profile area was increased twofold in PTB rats without any effect of pirfenidone. RV pressure overload after PTB induced not only RV but also septal and left ventricular fibrosis assessed by stereology. Treatment with pirfenidone reduced body weight but did not reduce the development of cardiac fibrosis or delay the progression of RV failure.

Visual Abstract, Highlights • Neurohormonal dysfunction (increased sympathetic nervous system and renin angiotensin-aldosterone system) play an important role in pulmonary hypertension progression. • In this proof-of-concept study we demonstrated in 2 pulmonary hypertension rat models that renal denervation therapy improved pulmonary vascular remodeling, lowered right ventricular afterload, and decreased right ventricular stiffness. • Renal denervation effects may be associated with a suppression of the renin-angiotensin-aldosterone system., Summary Neurohormonal overactivation plays an important role in pulmonary hypertension (PH). In this context, renal denervation, which aims to inhibit the neurohormonal systems, may be a promising adjunct therapy in PH. In this proof-of-concept study, we have demonstrated in 2 experimental models of PH that renal denervation delayed disease progression, reduced pulmonary vascular remodeling, lowered right ventricular afterload, and decreased right ventricular diastolic stiffness, most likely by suppression of the renin-angiotensin-aldosterone system.

BIBF1000 is a small molecule tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), and platelet-derived growth factor receptor (PDGFR) and is a powerful inhibitor of fibrogenesis. BIBF1000 is very similar to BIBF1120 (nintedanib), a drug recently approved for the treatment of idiopathic pulmonary fibrosis (IPF). A safety concern pertaining to VEGFR, FGFR, and PDGFR inhibition is the possible interference with right ventricular (RV) responses to an increased afterload, which could adversely affect clinical outcome in patients with IPF who developed pulmonary hypertension. We tested the effect of BIBF1000 on the adaptation of the RV in rats subjected to mechanical pressure overload. BIBF1000 was administered for 35 days in pulmonary artery-banded (PAB) rats. RV adaptation was assessed by echocardiography, pressure volume loop analysis, histology, and determination of atrial natriuretic peptide (ANP) expression. BIBF1000 treatment resulted in growth attenuation but had no effects on RV function after PAB, given absence of changes in cardiac index, end-systolic elastance, connective tissue disposition, and capillary density. We conclude that, in this experimental model of increased afterload, combined VEGFR, FGFR, and PDGFR inhibition does not hamper RV adaptation to pressure overload.

While beta-blockers are considered contraindicated in pulmonary arterial hypertension (PAH), the prognostic significance of sympathetic nervous system over-activity suggests a potential benefit of beta-blocker therapy. The aim of this randomised, placebo-controlled, crossover, single centre study was to determine the effects of bisoprolol on right ventricular ejection fraction (RVEF) in idiopathic PAH (iPAH) patients. Additional efficacy and safety parameters were explored.Patients with optimally treated, stable iPAH (New York Heart Association functional class II/III) were randomised to placebo or bisoprolol. Imaging and functional measurements were performed at baseline, crossover and end of study.18 iPAH patients were included, because inclusion faltered before enrolment of the targeted 25 patients. 17 patients completed 6 months of bisoprolol, 15 tolerated bisoprolol, one patient required intravenous diuretics. Bisoprolol was associated with a lower heart rate (17 beats per minute, p=0.0001) but RVEF remained unchanged. A drop in cardiac index (0.5 L·min−1·m−2, p=0.015) was observed, along with a trend towards a decreased 6-min walking distance (6MWD).Although careful up-titration of bisoprolol was tolerated by most patients and resulted in a decreased heart rate, no benefit of bisoprolol in iPAH was demonstrated. Decreases in cardiac index and 6MWD suggest a deteriorated cardiac function. The results do not favour the use of bisoprolol in iPAH patients.

Patients with pulmonary hypertension (PH) suffer from inspiratory muscle weakness. However, the pathophysiology of inspiratory muscle dysfunction in PH is unknown. We hypothesized that weakness of the diaphragm, the main inspiratory muscle, is an important contributor to inspiratory muscle dysfunction in PH patients. Our objective was to combine ex vivo diaphragm muscle fiber contractility measurements with measures of in vivo inspiratory muscle function in chronic thromboembolic pulmonary hypertension (CTEPH) patients. To assess diaphragm muscle contractility, function was studied in vivo by maximum inspiratory pressure (MIP) and ex vivo in diaphragm biopsies of the same CTEPH patients ( N = 13) obtained during pulmonary endarterectomy. Patients undergoing elective lung surgery served as controls ( N = 15). Muscle fiber cross-sectional area (CSA) was determined in cryosections and contractility in permeabilized muscle fibers. Diaphragm muscle fiber CSA was not significantly different between control and CTEPH patients in both slow-twitch and fast-twitch fibers. Maximal force-generating capacity was significantly lower in slow-twitch muscle fibers of CTEPH patients, whereas no difference was observed in fast-twitch muscle fibers. The maximal force of diaphragm muscle fibers correlated significantly with MIP. The calcium sensitivity of force generation was significantly reduced in fast-twitch muscle fibers of CTEPH patients, resulting in a ∼40% reduction of submaximal force generation. The fast skeletal troponin activator CK-2066260 (5 μM) restored submaximal force generation to levels exceeding those observed in control subjects. In conclusion, diaphragm muscle fiber contractility is hampered in CTEPH patients and contributes to the reduced function of the inspiratory muscles in CTEPH patients.

Pulmonary hypertension is a fatal condition of elevated pulmonary pressures, complicated by right heart failure. Pulmonary hypertension appears in various forms; one of those is pulmonary arterial hypertension (PAH) and is particularly characterised by progressive remodelling and obstruction of the smaller pulmonary vessels. Neurohormonal imbalance in PAH patients is associated with worse prognosis and survival. In this back-to-basics article on neurohormonal modulation in PAH, we provide an overview of the pharmacological and nonpharmacological strategies that have been tested pre-clinically and clinically. The benefit of neurohormonal modulation strategies in PAH patients has been limited by lack of insight into how the neurohormonal system is changed throughout the disease and difficulties in translation from animal models to human trials. We propose that longitudinal and individual assessments of neurohormonal status are required to improve the timing and specificity of neurohormonal modulation strategies. Ongoing developments in imaging techniques such as positron emission tomography may become helpful to determine neurohormonal status in PAH patients in different disease stages and optimise individual treatment responses., Better insight into neurohormonal changes throughout the development of pulmonary arterial hypertension and associated right heart failure is needed to allow efficacious intervention http://bit.ly/2NCV0nO

Objectives of this European Respiratory Society task force were to summarise current studies, to develop strategies for future research and to increase availability and awareness of exercise training for pulmonary hypertension (PH) patients.An evidence-based approach with clinical expertise of the task force members, based on both literature search and face-to-face meetings was conducted. The statement summarises current knowledge and open questions regarding clinical effects of exercise training in PH, training modalities, implementation strategies and pathophysiological mechanisms.In studies (784 PH patients in total, including six randomised controlled trials, three controlled trials, 10 prospective cohort studies and four meta-analyses), exercise training has been shown to improve exercise capacity, muscular function, quality of life and possibly right ventricular function and pulmonary haemodynamics. Nevertheless, further studies are needed to confirm these data, to investigate the impact on risk profiles and to identify the most advantageous training methodology and underlying pathophysiological mechanisms.As exercise training appears to be effective, cost-efficient and safe, but is scarcely reimbursed, support from healthcare institutions, commissioners of healthcare and research funding institutions is greatly needed. There is a strong need to establish specialised rehabilitation programmes for PH patients to enhance patient access to this treatment intervention. ispartof: EUROPEAN RESPIRATORY JOURNAL vol:53 issue:2 ispartof: location:England status: published

The role of right ventricular (RV) fibrosis in pulmonary hypertension (PH) remains a subject of ongoing discussion. Alterations of the collagen network of the extracellular matrix may help prevent ventricular dilatation in the pressure-overloaded RV. At the same time, fibrosis impairs cardiac function, and a growing body of experimental data suggests that fibrosis plays a crucial role in the development of RV failure. In idiopathic pulmonary arterial hypertension and chronic thromboembolic PH, the RV is exposed to a ≈5 times increased afterload, which makes these conditions excellent models for studying the impact of pressure overload on RV structure. With this review, we present clinical evidence of RV fibrosis in idiopathic pulmonary arterial hypertension and chronic thromboembolic PH, explore the correlation between fibrosis and RV function, and discuss the clinical relevance of RV fibrosis in patients with PH. We postulate that RV fibrosis has a dual role in patients with pressure-overloaded RVs of idiopathic pulmonary arterial hypertension and chronic thromboembolic PH: as part of an adaptive response to prevent cardiomyocyte overstretch and to maintain RV shape for optimal function, and as part of a maladaptive response that increases diastolic stiffness, perturbs cardiomyocyte excitation-contraction coupling, and disrupts the coordination of myocardial contraction. Finally, we discuss potential novel therapeutic strategies and describe more sensitive techniques to quantify RV fibrosis, which may be used to clarify the causal relation between RV fibrosis and RV function in future research.

The 2018 European Respiratory Society (ERS) International Congress in Paris, France, highlighted the subject of pulmonary vascular disease (PVD). 2018 was an exciting year for the PVD community as it was the first ERS International Congress since the formation of Assembly 13, which is dedicated to PVD, pulmonary embolism and the right ventricle. This article aims to summarise the high-quality studies presented at the 2018 Congress into four subject areas: the use of risk stratification in pulmonary arterial hypertension, the molecular mechanisms and treatment of pulmonary hypertension (PH), understanding and improving the right ventricle in PH, and finally, advances in the field of acute pulmonary embolus., This article aims to summarise the research presented at #ERSCongress 2018: risk stratification in PAH, the molecular mechanisms and treatment of PH, understanding and improving the RV in PH, and advances in the field of acute pulmonary embolus http://ow.ly/WUcR30nFEcM

BACKGROUND: Several antineoplastic drugs have been proposed as new compounds for pulmonary arterial hypertension treatment but many have cardiotoxic side effects. The chemotherapeutic agent 6-mercaptopurine may have an effect in treatment of pulmonary arterial hypertension but at the same time, its effects on the afterload adaption of the right ventricle is unpredictable due to interaction with multiple downstream signalling pathways in the cardiomyocytes. We investigated the direct cardiac effects of 6-mercaptopurine in rats with isolated right heart failure caused by pulmonary trunk banding (PTB).METHODS: Male Wistar rat weanlings (112±2 g) were randomized to sham operation (sham, n = 10) or PTB. The PTB animals were randomized to placebo (PTB-control, n = 10) and 6-mercaptopurine (7.5 mg/kg/day) groups with treatment start before the PTB procedure (PTB-prevention, n = 10) or two weeks after (PTB-reversal, n = 10). Right ventricular effects were evaluated by echocardiography, cardiac MRI, invasive pressure-volume measurements, and histological and molecular analyses.RESULTS: PTB increased right ventricular afterload and caused right ventricular hypertrophy and failure. 6-mercaptopurine did not improve right ventricular function nor reduce right ventricular remodelling in both prevention and reversal studies compared with placebo-treated rats.CONCLUSION: Treatment with 6-mercaptopurine did not have any beneficial or detrimental effects on right ventricular function or remodelling. Our data suggest that treatment of pulmonary arterial hypertension with 6-mercaptopurine is not harmful to the failing right ventricle.

Background: Reactive oxygen species (ROS) play a crucial role in the pathogenesis of pulmonary arterial hypertension (PAH). Monoamine oxidases (MAO), a class of enzymes located in the outer mitochondrial membrane, are important ROS sources. Increased MAO-A expression in endothelial cells and cardiomyocytes was found to contribute to vascular dysfunction and left heart failure. MAO-A inhibition can improve vascular dysfunction and heart failure. Collectively, given the effects of MAO-A on both vascular and cardiac function, we hypothesized that inhibition of MAO-A can be used to treat PAH. Methods: PAH was induced in male Sprague-Dawley rats by a single injection of SU5416 (25 mg/kg) followed by 4-weeks exposure to hypoxia and 2-weeks of normoxia. At week 8, animals were randomized to receive either intraperitoneal injection of saline or the MAO-A inhibitor clorgyline 10 mg/kg, followed by 2 mg/kg every 3 days until week 10. Echocardiography and RV catheterization was performed at week 10 and heart and lung tissues were collected for further analysis. Results: Compared to the vehicle group, clorgyline treatment reduced right ventricular (RV) systolic pressure and RV afterload. Moreover, clorgyline improved RV function by reducing RV hypertrophy and stiffness. Further tissue analysis by histology revealed that clorgyline reduced pulmonary vascular remodeling by reducing intima layer thickness. Conclusion: Clorgyline partly reversed RV systolic pressure and RV afterload in established experimental PAH. Together with the observed reduced RV remodeling, MAO-A inhibition may be a promising intervention for PAH.

Background: Gender is known to play a role in right ventricular (RV) adaption in pulmonary arterial hypertension (PAH). Sex hormone levels change with aging both in males and females. However effect of aging on RV function within sexes has not been explored. Aim: To study the effect of age on PAH disease severity and RV adaptation in both sexes. Methods: Systolic elastance (Ees), arterial elastance (Ea), diastolic elastance (Eed) and RV-arterial coupling (Ees/Ea) were determined in 88 newly diagnosed, treatment naive, idiopathic and hereditary PAH patients using the single-beat pressure volume analysis. Right ventricular ejection fraction (RVEF) was determined by CMR. Both males and females were divided in an age ≤50 and age > 50 years group, as 50 years is the mean age women reach the menopause. Results: Results are presented in figure 1. Ees (p=0.56), Ea (p=0.40), Ees/Ea (p=0.87) or Eed (p=0.67) were not related to age in women. However, young men presented with a higher afterload (p =0.0006) when compared to men>50 years old. In addition, baseline RVEF was lower in young men compared to men>50 years (21%±11.7 vs. 35%±12.4, p=0.0431). Conclusion: Young males with PAH presented with a high afterload and low RVEF. Further research in a larger cohort is warranted to elucidate whether this is a consequence of a distinct disease phenotype.

Background: Pulmonary vascular cell hyperproliferation is characteristic of pulmonary vascular remodeling in pulmonary arterial hypertension. A noninvasive imaging biomarker is needed to track the pathology and assess the response to novel treatments targeted at resolving the structural changes. Here, we evaluated the application of radioligand 3′-deoxy-3′-[18F]-fluorothymidine ( 18 FLT) using positron emission tomography. Methods and Results: We performed dynamic 18 FLT positron emission tomography in 8 patients with idiopathic pulmonary arterial hypertension (IPAH) and applied in-depth kinetic analysis with a reversible 2-compartment 4k model. Our results show significantly increased lung 18 FLT phosphorylation (k 3 ) in patients with IPAH compared with nonpulmonary arterial hypertension controls (0.086±0.034 versus 0.054±0.009 min −1 ; P 18 FLT signal both between patients with IPAH and within the lungs of each patient, compatible with histopathologic reports of lungs from patients with IPAH. Consistent with 18 FLT positron emission tomographic data, TK1 (thymidine kinase 1) expression was evident in the remodeled vessels in IPAH patient lung. In addition, hyperproliferative pulmonary vascular fibroblasts isolated from patients with IPAH exhibited upregulated expression of TK1 and the thymidine transporter, ENT1 (equilibrative nucleoside transporter 1). In the monocrotaline and SuHx (Sugen hypoxia) rat pulmonary arterial hypertension models, increased lung 18 FLT uptake was strongly associated with peripheral pulmonary vascular muscularization and the proliferation marker, Ki-67 score, together with prominent TK1 expression in remodeled vessels. Importantly, lung 18 FLT uptake was attenuated by 2 antiproliferative treatments: dichloroacetate and the tyrosine kinase inhibitor, imatinib. Conclusions: Dynamic 18 FLT positron emission tomography imaging can be used to report hyperproliferation in pulmonary hypertension and merits further study to evaluate response to treatment in patients with IPAH.