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In pulmonary hypertension, the right ventricle adapts to the increasing vascular load by enhancing contractility ("coupling") to maintain flow. Ventriculoarterial coupling implies that stroke volume changes little while preserving ventricular efficiency. Ultimately, a phase develops where ventricular dilation occurs in an attempt to limit the reduction in stroke volume, with uncoupling and increased wall stress as a consequence. With pressure-volume analysis, we separately describe the changing properties of the pulmonary vascular system and the right ventricle, as well as their coupling, as important concepts for understanding the changes that occur in pulmonary hypertension. On the basis of the unique properties of the pulmonary circulation, we show how all relevant physiological parameters can be derived using an integrative approach. Because coupling is maintained by hypertrophy until the end stage of the disease, when progressive dilation begins, right ventricular volume is the essential parameter to measure in follow-up of patients with pulmonary hypertension. [ABSTRACT FROM AUTHOR]

The article cites a study of exercise testing to estimate survival in pulmonary hypertension (PH). The study aims to compare prognostic value of different exercise parameters in PH and to assess whether cardiopulmonary exercise test (CPET) adds prognostic value to the information from the 6-minute walk distance (6MWD). The result of the study showed that only multivariate Cox regression with a forward selection procedure showed that only peak pulse improved the univariate 6MWD prediction model. It concludes that CPET parameters predicts survival in PH patients and add marginally to the prognostic value of the 6MWD.

Background: Electrical impedance tomography (EIT) is a non-invasive imaging technique which can be used to measure the blood volume changes in the pulmonary vascular bed during the cardiac cycle. Study Objectives: This study was performed to evaluate the differences in the EIT signal of the pulmonary vascular bed between healthy subjects and patients with idiopathic pulmonary arterial hypertension (IPAH), who are known to have a remodelled pulmonary vascular bed. Patients and Methods: Twenty-one patients (17 females, 4 males) with IPAH and 30 healthy controls (5 females, 25 males) were measured. EIT measurements were performed in duplicate, on the same day as right heart catheterization to obtain haemodynamic data. The maximal impedance change during systole (Δ Zsys) was used as a measure of the pulmonary volume pulse and expressed in arbitrary units (AU). Total lung capacity, spirometric values and diffusion capacity for carbon monoxide were measured as well. Results: Mean Δ Zsys was 215 ± 58 × 10–2 AU (95% CI 193 × 10–2 to 236 × 10–2) in the healthy subjects and 78 ± 27 × 10–2 AU (95% CI 66 × 10–2 to 91 × 10–2) in the IPAH patient group (p < 0.0001). No significant correlation was found between Δ Zsys and any of the haemodynamic or lung function data. Conclusion: The impedance pulsation of the pulmonary vascular bed is reduced in IPAH in comparison with controls, indicating a reduced volume pulse. This might represent the reduced cross section area, as well as the reduced compliance and number of the pulmonary vessels in these patients. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Examines the structural and functional cardiac changes in chronic obstructive pulmonary disease (COPD) patients with mild hypoxemia. Magnetic resonance imaging of right and left ventricular structure; Role of concentric right ventricular hypertrophy as the earliest sign of right ventricle pressure overload in patients with COPD; Systolic function of the right and left ventricles.

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

Examines the changes in main pulmonary artery flow and right ventricular mass and volumes in patients with pulmonary hypertension during epoprostenol therapy. Evaluation of 11 patients before the start of therapy and every four months thereafter; Magnetic resonance imaging; Indication that epoprostenol lowers pulmonary vascular resistance, leading to an increase in pulmonary artery flow.

Autofluorescence bronchoscopy (AFB) has been shown to be sensitive to detect preneoplastic lesions in central airways. Apart from bronchial mucosa thickness, tissue autofluorescence is also related to the biochemical properties of the target cells. Genetic studies have shown molecular abnormalities to be present in histologically normal mucosal specimens. Forty-six high-risk individuals, free of micro-invasive cancer at the initiation of the study, were included in this analysis and have been subjected to repeat bronchoscopic examinations every 4–6 months. They had previous curatively treated lung cancer (n=18), ENT tumor (n=11) or were at risk to acquire lung cancer primaries (n=17). Baseline AFB is scored for each suspicious lesion, thus the total score represents the number of AFB suspicious lesions present in each individual at risk. Baseline AFB score was correlated to outcome, i.e. the development of squamous-cell cancer (SCC) in each individual. So far, 11/46 (24%) of the individuals acquired SCC. Follow up has been 12–80 months. All five individuals with ≥3 lesions (100%, 12–36 months), five of the ten (50%, 12–48 months) individuals who had two lesions and one among the 12 (8%, 36 months) individuals with one suspicious AFB lesion, developed SCC. Up till now (12–80 months), the remaining 19 individuals without any suspicious AFB lesion have not acquired SCC. The average AFB score for the group of individuals which developed SCC was significantly different (P<0.001) from the remaining individuals who did not acquire SCC (2.64±1.1 vs. 0.6±0.7 S.D.). The number of suspicious lesions at baseline AFB is a good predictor for the development of SCC in the individuals at risk in our study population. This finding is compatible with field carcinogenesis and warrants a more upfront use of AFB in a lung cancer screening to sift the different risk-cohorts in a population mainly at risk for developing metachronous lung cancer. [Copyright &y& Elsevier]

Background: Electrical impedance tomography (EIT) is a noninvasive imaging technique using impedance to visualize and measure blood volume changes. Study objective: To examine the validity of EIT in the measurement of hypoxic pulmonary vasoconstriction (HPV) and hyperoxic pulmonary vasodilation in healthy volunteers and COPD patients. Participants: Group 1 consisted of seven healthy volunteers (mean age, 46 years; age range, 36 to 53 years). Group 2 comprised six clinically stable COPD patients (mean age, 65 years; age range, 50 to 74 years). Interventions: EIT measurements were performed in healthy subjects while they were breathing room air, 14% oxygen (ie, hypoxia), and 100% oxygen (ie, hyperoxia) through a mouthpiece. Maximal impedance change during systole (ΔZsys) was used as a measure of pulmonary perfusion-related impedance changes. Stroke volume (SV) was measured by means of MRI. In the COPD group, EIT and SV also were determined, but only in room air and under hyperoxic conditions. Results: The data were statistically compared to data for the room air baseline condition. In the volunteers, the mean (± SD) ΔZsys for the group was 352 ± 53 arbitrary units (AU) while breathing room air, 309 ± 75 AU in hypoxia (p < 0.05), and 341 ± 69 AU in hyperoxia (not significant INS]). The mean MRI-measured SV was 83 ± 21 mL while breathing room air, 90 ± 29) mL in hypoxia (NS), and 94 ± 19 mL in hyperoxia (p < 0.05). In the COPD patients, the mean ΔZsys for this group was 222 ± 84 AU while breathing room air and 255 ± 83 AU in hyperoxia (p < 0.05). In this group, the SV was 59 ± 16 mL while breathing room air and 61 ± 13 mL in hyperoxia (NS). Thus, the volunteer EIT response to hypoxia is not caused by decreased SV, because SV did not show a significant decrease. Similarly, in COPD patients the EIT response to hyperoxia is not caused by increased SV, because SV showed only... [ABSTRACT FROM AUTHOR]

Bronchoscopic treatment (BT) has a curative potential for patients with intraluminal microinvasive radiographically occult lung cancer (ROLC). We report the long-term follow-up in a group of 32 patients, ineligible for surgery, in whom ROLC was diagnosed and treated with BT. Tumors were strictly &les;1 cm in size, intraluminally located in the central airways, with no bronchial wall invasion or extraluminal tumor growth on high resolution CT (HRCT), with visible distal margin under conventional and autofluorescence bronchoscopy (AFB). BT was given with curative intent and consecutive patients were treated with photodynamic therapy (five patients), Nd-YAG laser therapy (one patient), electrocautery (24 patients) and argon plasma coagulation (two patients). Follow-up evaluation at 3–4 months interval included HRCT scans, both conventional and AFB, including biopsies and brush cytology for histological evaluation. The average follow-up period was 5 years (range: 2–10 years). In three patients local recurrence was again successfully treated with electrocautery. Sixteen patients died during follow-up. Eight of the nine patients who died due to lung cancer had a previous resection of a more advanced stage lung cancer up to 5 years before BT of the ROLC. The remaining seven patients cause of death was not related to lung cancer. Sixteen patients are still alive without any tumor recurrence. These data showed that BT is an effective treatment modality for high-risk patients with ROLC, who are not eligible for surgical resection. [Copyright &y& Elsevier]

Study objectives: To evaluate the palliative benefit of stent insertion in a group of patients with central airways obstruction due to terminal cancer. Design: Retrospective analysis of the symptomatic score of patients immediately after stent insertion, and questionnaires completed by the general practitioner (GP) after the patients died at home. Setting: Academic hospital, tertiary referral center for interventional bronchoscopy. Patients and methods: Fourteen patients with imminent suffocation due to major obstruction of the central airways, caused by end-stage esophageal cancer (n = 5) and non-small cell lung cancer (n = 9), were referred for stent insertion. All prostheses were placed within 24 h after hospital admittance. Patients were then asked whether their symptoms had improved. After the patients died, a questionnaire was sent to each patient's GP. Results: All patients expressed immediate benefit after stenting. The average length of survival after stent insertion was 11 weeks (range, 0.5 to 34 weeks). Two patients died within I week in our hospital after stent placement. In the remaining 12 patients, the GP considered stent insertion in 7 patients to be worthwhile, no judgment was made in 4 patients, and stent insertion in 1 patient was regarded as futile. Conclusion: Despite terminal disease and the fact that, in our country, patients may legally refuse any treatment and formally ask for euthanasia, the palliative benefit of stent placement should always be considered. All patients had immediate symptomatic relief afterwards. Retrospectively, the GPs responsible for terminal care at home still considered stent insertion worthwhile in 58% (7 of 12 patients) of cases. Stent placement should always be considered as part of the treatment of terminal cancer patients with imminent suffocation. [ABSTRACT FROM AUTHOR]

The clinical phenotype of patients with idiopathic pulmonary arterial hypertension (IPAH) has changed. Whether subgroups of patients with IPAH have different vascular phenotypes is a subject of debate. What are the histologic patterns and their clinical correlates in patients with a diagnosis of IPAH or hereditary pulmonary arterial hypertension? In this this cross-sectional registry study, lung histology of 50 patients with IPAH was assessed qualitatively by two experienced pathologists. In addition, quantitative analysis by means of histopathologic morphometry using immunohistochemistry was performed. Histopathologic characteristics were correlated with clinical and hemodynamic parameters. In this cohort of 50 patients with IPAH, a plexiform vasculopathy was observed in 26 of 50 patients (52%), whereas 24 of 50 patients (48%) showed a nonplexiform vasculopathy. The nonplexiform vasculopathy was characterized by prominent pulmonary microvascular (arterioles and venules) remodeling and vascular rarefaction. Although hemodynamic parameters were comparable in plexiform vs nonplexiform vasculopathy, patients with nonplexiform vasculopathy were older, more often were male, more often had a history of cigarette smoking, and had lower diffusing capacity of the lungs for carbon monoxide at diagnosis. No mutations in established pulmonary arterial hypertension genes were found in the nonplexiform group. This study revealed different vascular phenotypes within the current spectrum of patients with a diagnosis of IPAH, separated by clinical characteristics (age, sex, history of cigarette smoking, and diffusing capacity of the lungs for carbon monoxide at diagnosis). Potential differences in underlying pathobiological mechanisms between patients with plexiform and nonplexiform microvascular disease should be taken into account in future research strategies unravelling the pathophysiologic features of pulmonary hypertension and developing biology-targeted treatment approaches. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Initial combination therapy with ambrisentan and tadalafil reduced the risk of clinical failure events for treatment-naïve participants with pulmonary arterial hypertension (PAH) as compared to monotherapy. Previous studies in PAH have demonstrated greater treatment benefits in more symptomatic participants.Methods: AMBITION was an event-driven, double-blind study in which participants were randomized 2:1:1 to once-daily initial combination therapy with ambrisentan 10 mg plus tadalafil 40 mg, ambrisentan 10 mg plus placebo, or tadalafil 40 mg plus placebo. In this pre-specified subgroup analysis, we compared the efficacy data between those with functional class (FC) II vs. FC III symptoms at baseline.Results: This analysis included 500 participants in the previously defined primary analysis set (n = 155 FC II, n = 345 FC III). Comparing combination therapy to pooled monotherapy, the risk of clinical failure events was reduced by 79% (hazard ratio, 0.21 [95% confidence interval: 0.071, 0.63]) for FC II patients and 42% (hazard ratio, 0.58 [95% confidence interval: 0.39, 0.86]) for FC III patients. In a post-hoc analysis, the risk of first hospitalization for worsening PAH was also reduced by combination therapy, particularly for FC II patients (0 combination vs. 11 [14%] pooled monotherapy). Adverse events were frequent but comparable between the subgroups.Conclusions: Treatment benefit from initial combination therapy appeared at least as great for FC II as for FC III participants. Hospitalizations for worsening PAH were not observed in FC II participants assigned to combination. The present data support an initial combination strategy for newly diagnosed patients even when symptoms are less severe. Funded by Gilead Sciences, Inc. and GlaxoSmithKline; AMBITION ClinicalTrials.gov number, NCT01178073. [ABSTRACT FROM AUTHOR]

This article presents a study on the role played by interventricular mechanical asynchrony in the impaired left ventricular. In this study, fifty-nine patients with idiopathic hypertension were measured by using magnetic resonance imaging system. To study right ventricular (RV) and left ventricular (LV) systolic contraction time, seven patients were measured by means of measuring myocardial of the RV and LV. With the help of harmonic phase strain analysis, the time from electrocardiogram R-wave trigger to peak shortening was computed as a parameter for systolic contraction duration.

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

Objectives Pulmonary arterial hypertension (PAH) occurs in various connective tissue diseases (CTDs). We sought to assess contemporary treatment patterns and survival of patients with various forms of CTD-PAH. Methods We analysed data from COMPERA, a European pulmonary hypertension registry, to describe treatment strategies and survival in patients with newly diagnosed PAH associated with SSc, SLE, MCTD, UCTD and other types of CTD. All-cause mortality was analysed according to the underlying CTD. For patients with SSc-PAH, we also assessed survival according to initial therapy with endothelin receptor antagonists (ERAs), phosphodiesterase type 5 inhibitors (PDE5is) or a combination of these two drug classes. Results This analysis included 607 patients with CTD-PAH. Survival estimates at 1, 3 and 5 years for SSc-PAH (n  = 390) were 85%, 59% and 42%; for SLE-PAH (n  = 34) they were 97%, 77% and 61%; for MCTD-PAH (n  = 33) they were 97%, 70% and 59%; for UCTD-PAH (n  = 60) they were 88%, 67% and 52%; and for other CTD-PAH (n  = 90) they were 92%, 69% and 55%, respectively. After multivariable adjustment, the survival of patients with SSc-PAH was significantly worse compared with the other conditions (P  = 0.001). In these patients, the survival estimates were significantly better with initial ERA–PDE5i combination therapy than with initial ERA or PDE5i monotherapy (P  = 0.016 and P  = 0.012, respectively). Conclusions Mortality remains high in patients with CTD-PAH, especially for patients with SSc-PAH. However, for patients with SSc-PAH, our results suggest that long-term survival may be improved with initial ERA–PDE5i combination therapy compared with initial monotherapy. [ABSTRACT FROM AUTHOR]

Long-term changes in exercise capacity and cardiopulmonary hemodynamics after pulmonary endarterectomy (PEA) for chronic thromboembolic pulmonary hypertension (CTEPH) have been poorly described. We analyzed the data from 2 prospective surgical CTEPH cohorts in Hammersmith Hospital, London, and Amsterdam UMC. A structured multimodal follow-up was adopted, consisting of right heart catheterization, cardiac magnetic resonance imaging, and cardiopulmonary exercise testing before and after PEA. Preoperative predictors of residual pulmonary hypertension (PH; mean pulmonary artery pressure >20 mm Hg and pulmonary vascular resistance ≥2 WU) and long-term exercise intolerance (VO 2 max <80%) at 18 months were analyzed. A total of 118 patients (61 from London and 57 from Amsterdam) were included in the analysis. Both cohorts displayed a significant improvement of pulmonary hemodynamics, right ventricular (RV) function, and exercise capacity 6 months after PEA. Between 6 and 18 months after PEA, there were no further improvements in hemodynamics and RV function, but the proportion of patients with impaired exercise capacity was high and slightly increased over time (52%-59% from 6 to 18 months). Long-term exercise intolerance was common and associated with preoperative diffusion capacity for carbon monoxide (DLCO), preoperative mixed venous oxygen saturation, and postoperative PH and right ventricular ejection fraction (RVEF). Clinically significant RV deterioration (RVEF decline >3%; 5 [9%] of 57 patients) and recurrent PH (5 [14%] of 36 patients) rarely occurred beyond 6 months after PEA. Age and preoperative DLCO were predictors of residual PH post-PEA. Restoration in exercise tolerance, cardiopulmonary hemodynamics, and RV function occurs within 6 months. No substantial changes occurred between 6 and 18 months after PEA in the Amsterdam cohort. Nevertheless, long-term exercise intolerance is common and associated with postoperative RV function. [Display omitted] [ABSTRACT FROM AUTHOR]

Introduction: The aim of this sub-study was to evaluate the relationship between echocardiography (echo) and cardiac magnetic resonance imaging (cMRI) variables and to utilize echo to assess the effect of macitentan on right ventricle (RV) structure and function. Methods: REPAIR (NCT02310672) was a prospective, multicenter, single-arm, open-label, 52-week, phase 4 study in pulmonary arterial hypertension (PAH) patients, which investigated the effect of macitentan 10 mg as monotherapy, or in combination with a phosphodiesterase 5 inhibitor, on RV structure, function, and hemodynamics using cMRI and right heart catheterization. In this sub-study, patients were also assessed by echo at screening and at weeks 26 and/or 52. Post hoc correlation analyses between echo and cMRI variables were performed using Pearson's correlation coefficient, Spearman's correlation coefficient, and Bland–Altman analyses. Results: The Echo sub-study included 45 patients. Improvements in echo-assessed RV stroke volume (RVSV), left ventricular SV (LVSV), LV end-diastolic volume (LVEDV), RV fractional area change (RVFAC), tricuspid annular plane systolic excursion (TAPSE), and in 2D global longitudinal RV strain (2D GLRVS) were observed at weeks 26 and 52 compared to baseline. There was a strong correlation between echo (LVSV, 2D GLRVS, and LVEDV) and cMRI variables, with a moderate correlation for RVSV. Bland–Altman analyses showed a good agreement for LVSV measured by echo versus cMRI, whereas an overestimation in echo-assessed RVSV was observed compared to cMRI (bias of − 15 mL). Hemodynamic and functional variables, as well as safety, were comparable between the Echo sub-study and REPAIR. Conclusions: A good relationship between relevant echo and cMRI parameters was shown. Improvements in RV structure and function with macitentan treatment was observed by echo, consistent with results observed by cMRI in the primary analysis of the REPAIR study. Echo is a valuable complementary method to cMRI, with the potential to non-invasively monitor treatment response at follow-up. Trial registration number: REPAIR NCT02310672. [ABSTRACT FROM AUTHOR]

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. 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. 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 <.01), and a lower RV relative wall thickness (0.6 ± 0,1 g/ml vs 0.7 ± 0,2 g/ml; p <.01). The correlation coefficient of RV diastolic stiffness to afterload was higher in CTEPH compared to iPAH (p <.05; independent of age and gender). Despite differences in patient characteristics, disease etiology and physiology, RV functional parameters in CTEPH and iPAH are mostly similar. The right ventricle in CTEPH is marginally more dilated, stiffer and less hypertrophic than in iPAH. [ABSTRACT FROM AUTHOR]

The correlation between hemodynamics and degree of pulmonary vascular obstruction (PVO) is known to be poor in chronic thromboembolic pulmonary hypertension (CTEPH), which makes the selection of patients eligible for pulmonary endarterectomy (PEA) challenging. It can be postulated that patients with similar PVO but different hemodynamic severity have different postoperative hemodynamics and exercise capacity. Therefore, we aimed to assess the effects of PEA on hemodynamics and exercise physiology in mild and severe CTEPH patients. We retrospectively studied 18 CTEPH patients with a mild hemodynamic profile (mean pulmonary arterial pressure [mPAP] between 25 and 30 mmHg at rest) and CTEPH patients with a more severe hemodynamic profile (mPAP > 30 mmHg), matched by age, gender, and PVO. Cardiopulmonary exercise testing parameters were evaluated at baseline and 18 months following PEA. At baseline, exercise capacity, defined as oxygen uptake, was less severely impaired in the mild CTEPH group compared to the severe CTEPH group. After PEA, in the mild CTEPH group, ventilatory efficiency and oxygen pulse improved significantly (p < 0.05), however, the change in ventilatory efficiency and oxygen pulse was smaller compared to the severe CTEPH group. Only in the severe CTEPH group exercise capacity improved significantly (p < 0.001). Hence, in the present study, postoperative hemodynamic outcome and the CPET‐determined recovery of exercise capacity in mild CTEPH patients did not differ from a matched group of severe CTEPH patients. [ABSTRACT FROM AUTHOR]

The 2022 European Society of Cardiology/European Respiratory Society pulmonary hypertension (PH) guidelines incorporate cardiac magnetic resonance (CMR) imaging metrics in the risk stratification of patients with pulmonary arterial hypertension (PAH). Thresholds to identify patients at estimated 1-year mortality risks of < 5%, 5% to 20%, and > 20% are introduced. However, these cutoff values are mostly single center-based and require external validation. What are the discriminative prognostic properties of the current CMR risk thresholds stratifying patients with PAH? We analyzed data from incident, treatment-naïve patients with PAH from the Amsterdam University Medical Centres, Vrije Universiteit, The Netherlands. The discriminative properties of the proposed CMR three risk strata were tested at baseline and first reassessment, using the following PH guideline variables: right ventricular ejection fraction, indexed right ventricular end-systolic volume, and indexed left ventricular stroke volume. A total of 258 patients with PAH diagnosed between 2001 and 2022 fulfilled the study criteria and were included in this study. Of these, 172 had follow-up CMR imaging after 3 months to 1.5 years. According to the CMR three risk strata, most patients were classified at intermediate risk (n = 115 [45%]) upon diagnosis. Only 29 (11%) of patients with PAH were classified at low risk, and 114 (44%) were classified at high risk. Poor survival discrimination was seen between risk groups. Appropriate survival discrimination was seen at first reassessment. Risk stratifying patients with PAH with the recent proposed CMR cutoffs from the European Society of Cardiology/European Respiratory Society 2022 PH guidelines requires adjustment because post-processing consensus is lacking and general applicability is limited. Risk assessment at follow-up yielded better survival discrimination, emphasizing the importance of the individual treatment response. [ABSTRACT FROM AUTHOR]

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

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. [ABSTRACT FROM AUTHOR]

The article focuses on a study which looks into the relationship between pulmonary vascular resistance (PVR) and right ventricular ejection fraction (RVEF) in patients with pulmonary hypertension (PH). The study has discovered changes in the right ventricular function and hypertensive pulmonary circulation during the pulmonary hypertension's targeted therapies. It has compared the combination therapy with epoprostenol and bosentan and epoprostenol monotherapy. However, it has also identified that the preservation of PVR is not guaranteed by a small PVR reduction.

In this article, the author discusses a study on the occurrence of a shrinking heart in patient with chronic obstructive pulmonary disease (COPD), published in a 2010 issue of the "New England Journal of Medicine." The author describes the cardiac silhouette on the radiograph performed on patients with emphysema. The linear relation between emphysema and stroke is tackled. Also noted are the consequences of the research findings.

Survival in patients with pulmonary arterial hypertension (PAH) is closely related to right ventricular (RV) function. Although pulmonary load is an important determinant of RV systolic function in PAH, there remains a significant variability in RV adaptation to pulmonary hypertension. In this report, the authors discuss the emerging concepts of right heart pathobiology in PAH. More specifically, the discussion focuses on the following questions. 1) How is right heart failure syndrome best defined? 2) What are the underlying molecular mechanisms of the failing right ventricle in PAH? 3) How are RV contractility and function and their prognostic implications best assessed? 4) What is the role of targeted RV therapy? Throughout the report, the authors highlight differences between right and left heart failure and outline key areas of future investigation. [ABSTRACT FROM AUTHOR]

Introduction:Exercise variables determined in patients with pulmonary arterial hypertension (PAH) at the time of diagnosis, predict survival. It is unknown whether upon treatment, subsequent changes in these exercise variables reflect improvements in survival. The aim of this study was to determine changes in exercise variables in PAH patients and to relate these changes to survival. Methods:Baseline cardiopulmonary exercise test (CPET) variables and six-minute-walk-distance (6MWD) were available from 65 idiopathic PAH patients (50 females; mean age 45±2yrs). The same variables were determined after treatment (13months) in a sub group of 43 patients. To estimate the association between changes in exercise variables and changes in cardiac function, right-ventricle ejection fraction (RVEF) was measured by cardiac MRI at baseline and after treatment in 34 patients. Mean follow-up time after the second CPET was 53 (range: 4-111) months. Kaplan-Meier analysis was used to relate survival to baseline and treatment-associated changes in exercise variables. Results:Survivors showed a significantly greater change in maximal oxygen uptake than non-survivors and this change in aerobic capacity was significantly related to changes in RVEF. From baseline until the end of the study period, two patients underwent a lung transplantation and 19 patients died. Survival analysis showed that baseline 6MWD (p<0.0001), maximal heart rate (p<0.0001) and the slope relating ventilation with carbon dioxide production (p≤0.05) were significant predictors of survival, whereas baseline oxygen uptake and oxygen pulse held no predictive value. Treatment associated changes in 6MWD (p<0.01), maximal heart rate (p<0.05), oxygen uptake (p<0.001) and oxygen pulse predicted survival (p<0.05), whereas changes in the slope relating ventilation with carbon dioxide production did not. Conclusion:Exercise variables with prognostic significance when determined at baseline, retain their prognostic relevance after treatment. However, when changes in exercise variables upon treatment are considered, a different set of variables provides prognostic information. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) is a disease of the pulmonary vasculature characterized by vasoconstriction and vascular remodeling leading to a progressive increase in pulmonary vascular resistance (PVR). It is becoming increasingly recognized that it is the response of the right ventricle (RV) to the increased afterload resulting from this increase in PVR that is the most important determinant of patient outcome. A range of hemodynamic, structural, and functional measures associated with the RV have been found to have prognostic importance in PAH and, therefore, have potential value as parameters for the evaluation and follow-up of patients. If such measures are to be used clinically, there is a need for simple, reproducible, accurate, easy-to-use, and noninvasive methods to assess them. Cardiac magnetic resonance imaging (CMRI) is regarded as the “gold standard” method for assessment of the RV, the complex structure of which makes accurate assessment by 2-dimensional methods, such as echocardiography, challenging. However, the majority of data concerning the use of CMRI in PAH have come from studies evaluating a variety of different measures and using different techniques and protocols, and there is a clear need for the development of standardized methodology if CMRI is to be established in the routine assessment of patients with PAH. Should such standards be developed, it seems likely that CMRI will become an important method for the noninvasive assessment and monitoring of patients with PAH. [Copyright &y& Elsevier]

The idiopathic pulmonary arterial hypertension (iPAH) phenotype is changing from a predominantly young female patient to an older, frequently obese patient of either sex. Many newly diagnosed iPAH-patients have risk factors for left ventricular diastolic dysfunction (LVDD), possibly affecting management and treatment. To determine whether the H 2 FPEF-score identifies a subgroup of iPAH-patients with blunted response to PAH-targeted treatment. We performed a retrospective analysis of 253 treatment-naïve iPAH-patients (1989-2019) with a confirmed diagnosis after right heart catheterization by a multidisciplinary team. Follow-up RHC measurements were available in 150 iPAH-patients. iPAH-patients were stratified by the H 2 FPEF-score; a score ≥5 identified a higher possibility of (concealed) LVDD. The presence of a high H 2 FPEF-score in incident iPAH-patients rose 30% in thirty years. Patients with a H 2 FPEF-score ≥5 were older, more often male and/or obese, and had more comorbidities than patients with a H 2 FPEF-score ≤1. A high H 2 FPEF-score was associated with worse survival and poor functional capacity. Right ventricular function was equally depressed among iPAH-groups. Imaging and invasive hemodynamic measurements suggested concealed LVDD in iPAH patients with a high H 2 FPEF-score. At follow-up, hemodynamic and functional responses were similar in iPAH-patients with a high or low H 2 FPEF-score. While a high H 2 FPEF-score in iPAH is associated with a worse prognosis and signs of LVDD, hemodynamic and functional responses to PAH treatment are not predicted by the H 2 FPEF-score. [ABSTRACT FROM AUTHOR]

Background: Pulmonary arterial hypertension (PAH) increases right ventricular (RV) workload and decreases myocardial oxygen reserve, eventually leading to poor cardiac output. This study created and assessed a novel model of RV work output based on RV hemodynamics and oxygen supply, allowing new insight into causal mechanisms of RV dysfunction. Methods: The RV function model was built upon an earlier, left ventricular model and further adjusted for more accurate clinical use. The model assumes that RV total power output (1) is the sum of isovolumic and stroke power and (2) is linearly related to its right coronary artery oxygen supply. Thus, when right coronary artery flow is limited or isovolumic power is elevated, less energy is available for producing cardiac output. The original and adjusted models were validated via data from patients with idiopathic PAH (n = 14) and large animals (n = 6) that underwent acute pulmonary banding with or without hypoxia. Results: Both models demonstrated strong, significant correlations between RV oxygen consumption rate and RV total power output for PAH patients (original model, R2 = 0.66; adjusted model, R2 = 0.78) and sheep (original, R2 = 0.85; adjusted, R2 = 0.86). Furthermore, the models demonstrate a significant inverse relationship between required oxygen consumption and RV efficiency (stroke power/total power) (p < 0.001). Lastly, higher NYHA class was indicative of lower RV efficiency and higher oxygen consumption (p = 0.013). Conclusion: Right ventricular total power output can be accurately estimated directly from pulmonary hemodynamics and right coronary perfusion during PAH. This model highlights the increased vulnerability of PAH patients with compromised right coronary flow coupled with high afterload. [ABSTRACT FROM AUTHOR]

Background: Prognosis in pulmonary arterial hypertension (PAH) is closely related to indexes of right ventricular function. A better understanding of their relationship may provide important implications for risk stratification in PAH.Research Question: Can clinical network graphs inform risk stratification in PAH?Study Design and Methods: The study cohort consisted of 231 patients with PAH followed up for a median of 7.1 years. An undirected, correlation network was used to visualize the relationship between clinical features in PAH. This network was enriched for right heart parameters and included N-terminal pro-hormone B-type natriuretic peptide (NT-proBNP), comprehensive echocardiographic parameters, and hemodynamics, as well as 6-min walk distance (6MWD), vital signs, laboratory data, and diffusing capacity for carbon monoxide (Dlco). Connectivity was assessed by using eigenvector and betweenness centrality to reflect global and regional connectivity, respectively. Cox proportional hazards regression was used to model event-free survival for the combined end point of death or lung transplantation.Results: A network of closely intertwined features centered around NT-proBNP with 6MWD emerging as a secondary hub were identified. Less connected nodes included Dlco, systolic BP, albumin, and sodium. Over the follow-up period, death or transplantation occurred in 92 patients (39.8%). A strong prognostic model was achieved with a Harrell's C-index of 0.81 (0.77-0.85) when combining central right heart features (NT-proBNP and right ventricular end-systolic remodeling index) with 6MWD and less connected nodes (Dlco, systolic BP, albumin, sodium, sex, connective tissue disease etiology, and prostanoid therapy). When added to the baseline risk model, serial change in NT-proBNP significantly improved outcome prediction at 5 years (increase in C-statistic of 0.071 ± 0.024; P = .003).Interpretation: NT-proBNP emerged as a central hub in the intertwined PAH network. Connectivity analysis provides explainability for feature selection and combination in outcome models. [ABSTRACT FROM AUTHOR]

Irrespective of its cause, pulmonary hypertension (PH) leads to an increase in pulmonary vascular resistance (PVR). Failing adaption of the right ventricle (RV) to the increased afterload is the main cause of death in PH patients and therefore monitoring RV function during treatment is essential. However, consensus on the optimal method for serial assessment of RV function is lacking and therefore the major clinical trials on PH-specific therapies have not provided clear answers with respect to the response of the RV to treatment. This short review will give an overview of the most important load-dependent and load-independent parameters for assessing RV response to therapy in PH patients. [ABSTRACT FROM AUTHOR]

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

• In daily practice, concomitant signs of CTEPH on CTPA scans performed for suspected acute PE were insufficiently reported. • After dedicated instruction, CTEPH-non-expert readers were able to differentiate the majority of CTEPH patients from those with acute PE. • Overall judgment outperformed a strategy focussing on 6 predefined radiological predictors only. • Closer CTPA reading may therefore help in achieving an earlier CTEPH diagnosis. Expert reading often reveals radiological signs of chronic thromboembolic pulmonary hypertension (CTEPH) or chronic PE on computed tomography pulmonary angiography (CTPA) performed at the time of acute pulmonary embolism (PE) presentation preceding CTEPH. Little is known about the accuracy and reproducibility of CTPA reading by radiologists in training in this setting. To evaluate 1) whether signs of CTEPH or chronic PE are routinely reported on CTPA for suspected PE; and 2) whether CTEPH-non-expert readers achieve comparable predictive accuracy to CTEPH-expert radiologists after dedicated instruction. Original reports of CTPAs demonstrating acute PE in 50 patients whom ultimately developed CTEPH, and those of 50 PE who did not, were screened for documented signs of CTEPH. All scans were re-assessed by three CTEPH-expert readers and two CTEPH-non-expert readers (blinded and independently) for predefined signs and overall presence of CTEPH. Signs of chronic PE were mentioned in the original reports of 14/50 cases (28%), while CTEPH-expert radiologists had recognized 44/50 (88%). Using a standardized definition (≥3 predefined radiological signs), moderate-to-good agreement was reached between CTEPH-non-expert readers and the experts' consensus (k-statistics 0.46; 0.61) at slightly lower sensitivities. The CTEPH-non-expert readers had moderate agreement on the presence of CTEPH (κ-statistic 0.38), but both correctly identified most cases (80% and 88%, respectively). Concomitant signs of CTEPH were poorly documented in daily practice, while most CTEPH patients were identified by CTEPH-non-expert readers after dedicated instruction. These findings underline the feasibility of achieving earlier CTEPH diagnosis by assessing CTPAs more attentively. [ABSTRACT FROM AUTHOR]

The study aimed to assess whether the 12-lead ECG-derived ventricular gradient, a vectorial representation of ventricular action potential duration heterogeneity directed toward the area of shortest action potential duration, can improve ECG diagnosis of chronic right ventricular (RV) pressure load. ECGs from 72 pulmonary arterial hypertension patients recorded <30 days before onset of therapy were compared with ECGs from matched healthy control subjects (n = 144). Conventional ECG criteria for increased RV pressure load were compared with the ventricular gradient. In 38 patients a cardiac magnetic resonance (CMR) study had been performed within 24 h of the ECG. By multivariable analysis, combined use of conventional ECG parameters (rsr' or rsR' in VI, RJS > 1 with R > 0.5 mV in VI, and QRS axis >90°) had a sensitivity of 89% and a specificity of 93% for presence of chronic RV pressure load. However, the ventricular gradient not only had a higher diagnostic accuracy for chronic RV pressure load by receiver operating characteristic analysis [areas under the curve (AUC) = 0.993, SE 0.004 as. AUC = 0.945, SE 0.021, P < 0.05], but also discriminated between mild-to-moderate and severe RV pressure load. CMR identified an inverse relation between the ventricular gradient and RV mass, and a trend toward a similar relation with RV volume. In conclusion, chronically increased RV pressure load is electrocardiographically reflected by an altered ventricular gradient associated with RV remodeling-related changes in ventricular action potential duration heterogeneity. The use of the ventricular gradient allows ECO detection of even mildly increased RV pressure load. [ABSTRACT FROM AUTHOR]

Background: For patients with early-stage lung cancer (ESLC) and severe comorbidities, the cost-effectiveness of early intervention may be reduced by screening and treatment-related morbidity and mortality in addition to the risk for non-cancer-related deaths. Objectives: The use of bronchoscopic treatment (BT) for centrally located ESLC as minimally invasive technique has raised questions whether this approach will be more cost-effective than standard surgical resection in the above-mentioned cohort of patients. Methods: The cost-effectiveness of BT of 32 medically inoperable patients with intraluminal tumor has been compared to a matched control group of surgically treated stage IA cancer patients. Results: Median follow-up after BT for ESLC has been 5 years (range 2-10) versus 6.7 years (range 2-10) for the surgical group. Five patients (16%) developed subsequent primaries/ local recurrences after BT versus 4 (12.5%) in the surgical group. The respective percentages of actual survival during follow-up have been 50 and 41%, non-lung-cancer-related death 22 and 31% and lung-cancer-related death 28% in both groups, respectively. So far, the average costs per individual for early management by BT have been €6,547 versus €22,638 by surgery, and total expenses have been €209,492 and €724,403, respectively. Conclusions: Despite the worse initial health status of patients treated with BT, actual survival rates and costs for early intervention underscore the superior cost-effectiveness of BT as early intervention in properly selected individuals with ESLC in the central airways. [ABSTRACT FROM AUTHOR]

Background and objective: Patients with coronavirus disease 2019 (COVID‐19) pneumonia present with typical findings on chest computed tomography (CT), but the underlying histopathological patterns are unknown. Through direct regional correlation of imaging findings to histopathological patterns, this study aimed to explain typical COVID‐19 CT patterns at tissue level. Methods: Eight autopsy cases were prospectively selected of patients with PCR‐proven COVID‐19 pneumonia with varying clinical manifestations and causes of death. All had been subjected to chest CT imaging 24–72 h prior to death. Twenty‐seven lung areas with typical COVID‐19 patterns and two radiologically unaffected pulmonary areas were correlated to histopathological findings in the same lung regions. Results: Two dominant radiological patterns were observed: ground‐glass opacity (GGO) (n = 11) and consolidation (n = 16). In seven of 11 sampled areas of GGO, diffuse alveolar damage (DAD) was observed. In four areas of GGO, the histological pattern was vascular damage and thrombosis, with (n = 2) or without DAD (n = 2). DAD was also observed in five of 16 samples derived from areas of radiological consolidation. Seven areas of consolidation were based on a combination of DAD, vascular damage and thrombosis. In four areas of consolidation, bronchopneumonia was found. Unexpectedly, in samples from radiologically unaffected lung parenchyma, evidence was found of vascular damage and thrombosis. Conclusion: In COVID‐19, radiological findings of GGO and consolidation are mostly explained by DAD or a combination of DAD and vascular damage plus thrombosis. However, the different typical CT patterns in COVID‐19 are not related to specific histopathological patterns. Microvascular damage and thrombosis are even encountered in the radiologically normal lung. [ABSTRACT FROM AUTHOR]

Background: Pulmonary hypertension (PH) in COPD is a poorly investigated clinical condition.Research Question: Which factors determine the outcome of PH in COPD?Study Design and Methods: We analyzed the characteristics and outcome of patients enrolled in the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) with moderate or severe PH in COPD as defined during the 6th PH World Symposium who received medical therapy for PH and compared them with patients with idiopathic pulmonary arterial hypertension (IPAH).Results: The population included incident patients with moderate PH in COPD (n = 68), with severe PH in COPD (n = 307), and with IPAH (n = 489). Patients with PH in COPD were older, predominantly male, and treated mainly with phosphodiesterase-5 inhibitors. Despite similar hemodynamic impairment, patients with PH in COPD achieved a worse 6-min walking distance (6MWD) and showed a more advanced World Health Organization functional class (WHO FC). Transplant-free survival rates at 1, 3, and 5 years were higher in the IPAH group than in the PH in COPD group (IPAH: 94%, 75%, and 55% vs PH in COPD: 86%, 55%, and 38%; P = .004). Risk factors for poor outcomes in PH in COPD were male sex, low 6MWD, and high pulmonary vascular resistance (PVR). In patients with severe PH in COPD, improvements in 6MWD by ≥ 30 m or improvements in WHO FC after initiation of medical therapy were associated with better outcomes.Interpretation: Patients with PH in COPD were functionally more impaired and had a poorer outcome than patients with IPAH. Predictors of death in the PH in COPD group were sex, 6MWD, and PVR. Our data raise the hypothesis that some patients with severe PH in COPD may benefit from PH treatment. Randomized controlled studies are necessary to explore this hypothesis further.Trial Registry: ClinicalTrials.gov; No.: NCT01347216; URL: www.clinicaltrials.gov. [ABSTRACT FROM AUTHOR]

Background: During the COVID-19 pandemic, most of the health care systems suspended their non-urgent activities. This included the cancellation of consultations for patients with rare diseases, such as severe pulmonary hypertension (PH), resulting in potential medication shortage and loss of follow-up. Thus, the aim of the study was to evaluate PH patient health status evolution, access to health care and mental health experience during the early phase of the pandemic.Methods: We conducted an online patient survey, available in 16 languages, between 22/05/2020 and 28/06/2020. The survey included questions corresponding to demographic, COVID-19 and PH related information.Results: 1073 patients (or relatives, 27%) from 52 countries all over the world participated in the survey. Seventy-seven percent (77%) of responders reported a diagnosis of pulmonary arterial hypertension and 15% of chronic thromboembolic PH. The COVID-19 related events were few: only 1% of all responders reported a diagnosis of COVID-19. However, 8% of patients reported health deterioration possibly related to PH, and 4% hospitalization for PH. Besides, 11% of the patients reported difficulties to access their PH expert centre, and 3% interruption of treatment due to shortage of medication. Anxiety or depression was reported by 67% of the participants.Conclusion: Although COVID-19 incidence in PH patients was low, PH related problems occurred frequently as the pandemic progressed, including difficulties to have access to specialized care. The importance of primary health care was emphasized. Further studies are needed to evaluate the long-term consequences of COVID-related PH care disruption. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: The pathophysiology of chronic thromboembolic pulmonary hypertension (CTEPH) is not fully understood. Poor-quality anticoagulation may contribute to a higher risk of CTEPH after acute pulmonary embolism (PE), partly explaining the transition from acute PE to CTEPH. We assessed the association between the time in therapeutic range (TTR) of vitamin-K antagonist (VKA) treatment and incidence of CTEPH after a PE diagnosis. Methods: Case-control study in which the time spent in, under and above therapeutic range was calculated in 44 PE patients who were subsequently diagnosed with CTEPH (cases). Controls comprised 150 consecutive PE patients in whom echocardiograms two years later did not show pulmonary hypertension. All patients were treated with VKA for at least 6 months after the PE diagnosis. Time in (TTR), under and above range were calculated. Mean differences between cases and controls were estimated by linear regression. Results: Mean TTR during the initial 6-month treatment period was 72% in cases versus 78% in controls (mean difference -6%, 95%CI -12 to -0.1), mainly explained by more time above the therapeutic range in the cases. Mean difference of time under range was 0% (95%CI -6 to 7) and 2% (95CI% -3 to 7) during the first 3 and 6 months, respectively. In a multivariable model, adjusted odds ratios (ORs) for CTEPH were around unity considering different thresholds for 'poor anticoagulation', i.e. TTR <50%, <60% and <70%. Conclusion: Subtherapeutic initial anticoagulation was not more prevalent among PE patients diagnosed with CTEPH than in those who did not develop CTEPH. [ABSTRACT FROM AUTHOR]

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. 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. 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). 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. [ABSTRACT FROM AUTHOR]

Assessing right ventricular (RV) functional reserve is important for determining clinical status and prognosis in patients with pulmonary hypertension (PH). In this study, we aimed to establish RV oxygen (O2) delivery as a determinant for RV functional reserve during exercise in swine with chronic PH. Chronic PH was induced by pulmonary vein banding (PVB), with sham operation serving as control. RV function and RV O2 delivery were measured over time in chronically instrumented swine, up to 12 wk after PVB at rest and during exercise. At rest, RV afterload (pulmonary artery pressure and arterial elastance) and contractility (Ees and dP/dtmax) were higher in PH compared with control with preserved cardiac index and RV O2 delivery. However, RV functional reserve, as measured by the exercise-induced relative change (Δ) in cardiac index, dP/dtmax, and end-systolic elastance (Ees), was decreased in PH, and RV pulmonary arterial coupling was lower both at rest and during exercise in PH. Furthermore, the increase in RV O2 delivery was attenuated in PH during exercise principally due to a lower systolic coronary blood flow in combination with an attenuated increase in aorta pressure while arterial O2 content was not significantly altered in PH. Moreover, RV O2 delivery reserve correlated with RV functional reserve, Δcardiac index (r2 = 0.85), ΔdP/dtmax (r2 = 0.49), and ΔEes (r2 = 0.70), all P < 0.05. The inability to sufficiently increase RV O2 supply to meet the increased O2 demand during exercise is principally due to the reduced RV perfusion relative to healthy control values and likely contributes to impaired RV contractile function and thereby to the limited exercise capacity that is commonly observed in patients with PH. NEW & NOTEWORTHY Impaired right ventricular (RV) O2 delivery reserve is associated with reduced RV functional reserve during exercise in a swine model of pulmonary hypertension (PH) induced by pulmonary vein banding. Our data suggest that RV function and exercise capacity might be improved by improving RV O2 delivery. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background Heritable pulmonary veno-occlusive disease (PVOD) is linked to mutations in the eukaryotic initiation factor 2 alpha kinase 4 (EIF2AK4 ) gene, leading to a loss of general control nonderepressible 2 ( GCN2). The role of GCN2 expression in pulmonary vascular remodeling remains obscure. We sought to identify specific histologic and biologic features in heritable PVOD. Methods Clinical data and lung histology of 24 PVOD patients (12 EIF2AK4 mutation carriers, 12 non-carriers) were submitted to systematic histologic analysis and semiautomated morphometry. GCN2 expression was quantified by Western blotting in 24 PVOD patients, 44 patients with pulmonary arterial hypertension (PAH; 23 bone morphogenetic protein receptor type II [ BMPR2 ] mutation carriers, 21 non-carriers), and 3 experimental pulmonary hypertension models. Results PVOD patients showed a significant decrease of pulmonary arterial patency ( p < 0.0001) compared with healthy controls. Histology of EIF2AK4 mutation carriers was distinctive from non-carriers regarding (1) arterial remodeling, with significantly more severe intimal fibrosis ( p = 0.001), less severe medial hypertrophy ( p = 0.001), and (2) stronger muscular hyperplasia of interlobular septal veins ( p = 0.002). GCN2 expression was abolished in heritable PVOD ( p < 0.0001), but also importantly decreased in sporadic PVOD ( p = 0.03) as well as in heritable ( p = 0.002) and idiopathic PAH ( p = 0.003); moreover, GCN2 was abolished in 2 experimental pulmonary hypertension models and importantly decreased in 1 model ( p < 0.0001 for all models). Conclusions Pulmonary arterial remodeling in PVOD is present to an important extent. A significant decrease of GCN2 expression is a common denominator of all tested groups of PVOD and PAH, including their respective experimental models. Our results underline specific morphologic and biologic similarities between PAH and PVOD and let us consider both conditions rather in one large spectrum of disease than as two distinct and clear-cut entities. [ABSTRACT FROM AUTHOR]

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 (<41%) had a significantly reduced heart rate recovery in comparison with patients with higher RV ejection fraction. In PAH RV samples, α-7 nicotinic acetylcholine receptor was increased and acetylcholinesterase activity was reduced versus controls. No difference in muscarinic acetylcholine type 2 receptor expression was observed. Chronic PYR treatment in PH rats normalized the cardiovascular autonomic function, demonstrated by an increase in parasympathetic activity and baroreflex sensitivity. PYR improved survival, increased RV contractility, and reduced RV stiffness, RV hypertrophy, RV fibrosis, RV inflammation, and RV α-7 nicotinic acetylcholine receptor and muscarinic acetylcholine type 2 receptor expression, as well. Furthermore, PYR reduced pulmonary vascular resistance, RV afterload, and pulmonary vascular remodeling, which was associated with reduced local and systemic inflammation.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. [ABSTRACT FROM AUTHOR]

The function of the right ventricle (RV) determines the prognosis of patients with pulmonary hypertension. While much progress has been made in the treatment of pulmonary hypertension, therapies for the RV are less well established. In this review of treatment strategies for the RV, first we focus on ways to reduce wall stress since this is the main determinant of changes to the ventricle. Secondly, we discuss treatment strategies targeting the detrimental consequences of increased RV wall stress. To reduce wall stress, afterload reduction is the essential. Additionally, preload to the ventricle can be reduced by diuretics, by atrial septostomy, and potentially by mechanical ventricular support. Secondary to ventricular wall stress, left-to-right asynchrony, altered myocardial energy metabolism, and neurohumoral activation will occur. These may be targeted by optimising RV contraction with pacing, by iron supplement, by angiogenesis and improving mitochondrial function, and by neurohumoral modulation, respectively. We conclude that several treatment strategies for the right heart are available; however, evidence is still limited and further research is needed before clinical application can be recommended. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension ( PH) resulting from left heart failure is an increasingly recognized clinical entity. To distinguish isolated postcapillary PH from combined post- and precapillary PH, the use of a diastolic pressure gradient ( DPG = diastolic Pulmonary Artery Pressure − Pulmonary Arterial Wedge Pressure, dPAP − PAWP) has been advocated over the transpulmonary pressure gradient ( TPG = mean Pulmonary Artery Pressure − PAWP, mPAP − PAWP) since DPG was suggested to be independent of cardiac output ( CO) and only slightly related to PAWP, while TPG depends on both. We quantitatively derived and compared the DPG and TPG. Using right heart catheterization data ( n = 1054), we determined systolic pulmonary artery pressure ( sPAP), dPAP and mPAP, PAWP, and CO. From this data, we derived TPG and DPG and tested their dependence on PAWP and CO. We found that dPAP and sPAP are proportional with mPAP over a wide range of PAWP (1-31 mmHg), with dPAP = 0.62m PAP and sPAP = 1.61m PAP. As a consequence, TPG and DPG are equally dependent on PAWP: TPG = mPAP − PAWP, and DPG = 0.62m PAP − PAWP. Furthermore, we showed that both TPG and DPG depend on CO. The absolute increase in DPG with CO is 62% of the TPG increase with CO, but the relative dependence is the same. Both TPG and DPG depend on PAWP and CO. Thus, in principle, there are no major advantages for using DPG to distinguish postcapillary pulmonary hypertension from combined post- and precapillary pulmonary hypertension. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]