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The definition of pulmonary hypertension (PH) has been revised recently, with the mean pulmonary artery pressure (mPAP) threshold (assessed by right heart catheterization) reduced from ⩾25 mm Hg to >20 mm Hg. This change reflects the mPAP upper limit of normal and a lower limit that is independently associated with adverse outcomes. To improve the specificity of diagnosing pathogenic increases in mPAP, however, a diagnosis of precapillary PH now also includes pulmonary vascular resistance >2.0 Wood units (WU) (lowered from >3.0 WU). These changes are positioned to capture approximately 55% more patients with PH. Because all clinical trials showing a benefit of pulmonary vasodilator therapy in precapillary PH used the classical hemodynamic definition, the approach to the diagnosis and management of patients with mild PH (i.e., mPAP 21-24 mm Hg and pulmonary vascular resistance 2-3 WU) requires particular consideration. Here, we use a question/answer format to discuss key areas in the management of mild PH, including practical information tailored to clinicians without training in PH.

Background: In pulmonary hypertension subgroups, elevated pulmonary vascular resistance (PVR) of 3·0 Wood units or more is associated with poor prognosis. However, the spectrum of PVR risk in pulmonary hypertension is not known. To address this area of uncertainty, we aimed to analyse the relationship between PVR and adverse clinical outcomes in pulmonary hypertension., Methods: We did a retrospective cohort study of all patients undergoing right heart catheterisation (RHC) in the US Veterans Affairs health-care system (Oct 1, 2007-Sep 30, 2016). Patients were included in the analyses if data from a complete RHC and at least 1 year of follow-up were available. Both inpatients and outpatients were included, but individuals with missing mean pulmonary artery pressure (mPAP), pulmonary artery wedge pressure, or cardiac output were excluded. The primary outcome measure was time to all-cause mortality assessed by the Veteran Affairs vital status file. Cox proportional hazards models were used to assess the association between PVR and outcomes, and the mortality hazard ratio was validated in a RHC cohort from Vanderbilt University Medical Center (Sept 24, 1998-June 1, 2016)., Findings: The primary cohort (N=40 082; 38 751 [96·7%] male; median age 66·5 years [IQR 61·1-73·5]; median follow-up 1153 days [IQR 570-1971]), included patients with a history of heart failure (23 201 [57·9%]) and chronic obstructive pulmonary disease (13 348 [33·3%]). We focused on patients at risk for pulmonary hypertension based on a mPAP of at least 19 mm Hg (32 725 [81·6%] of 40 082). When modelled as a continuous variable, the all-cause mortality hazard for PVR was increased at around 2·2 Wood units compared with PVR of 1·0 Wood unit. Among patients with a mPAP of at least 19 mm Hg and pulmonary artery wedge pressure of 15 mm Hg or less, the adjusted hazard ratio (HR) for mortality was 1·71 (95% CI 1·59-1·84; p<0·0001) and for heart failure hospitalisation was 1·27 (1·13-1·43; p=0·0001), when comparing PVR of 2·2 Wood units or more to less than 2·2 Wood units. The validation cohort (N=3699, 1860 [50·3%] male, median age 60·4 years [49·5-69·2]; median follow-up 1752 days [IQR 1281-2999]) included 2870 patients [77·6%] with mPAP of at least 19 mm Hg (1418 [49·4%] male). The adjusted mortality HR for patients in the mPAP of 19 mm Hg or more group and with PVR of 2·2 Wood units or more and pulmonary artery wedge pressure of 15 mm or less Hg (1221 [42·5%] of 2870) was 1·81 (95% CI 1·33-2·47; p=0·0002)., Interpretation: These data widen the continuum of clinical risk for mortality and heart failure in patients referred for RHC with elevated pulmonary artery pressure to include PVR of around 2.2 Wood units and higher. Testing the generalisability of these findings in at-risk populations with fewer cardiopulmonary comorbidities is warranted., Funding: None., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Pulmonary arterial hypertension (PAH) is a highly morbid disease characterized by elevated pulmonary vascular resistance (PVR) and pathogenic right ventricular remodeling. Endothelial expression of the prometastatic protein NEDD9 is increased in fibrotic PAH arterioles, and NEDD9 inhibition decreases PVR in experimental PAH. We hypothesized that circulating NEDD9 is increased in PAH and informs the clinical profile of patients., Methods: Clinical data and plasma samples were analyzed retrospectively for 242 patients from 5 referral centers (2010-2017): PAH (n = 139; female 82%, 58 [48-67] years), non-PAH pulmonary hypertension (PH) (n = 54; female 56%, 63.4 ± 12.2 years), and dyspnea non-PH controls (n = 36; female 75%, 54.2 ± 14.0 years)., Results: Compared with controls, NEDD9 was increased in PAH by 1.82-fold (p < 0.0001). Elevated NEDD9 correlated with PVR in idiopathic PAH (ρ = 0.42, p < 0.0001, n = 54), connective tissue disease (CTD)-PAH (ρ = 0.53, p < 0.0001, n = 53), and congenital heart disease-PAH (ρ = 0.68, p < 0.0001, n = 10). In CTD-PAH, NEDD9 correlated with 6-minute walk distance (ρ = -0.35, p = 0.028, n = 39). In contrast to the PAH biomarker N-terminal pro-brain natriuretic peptide (n = 38), NEDD9 correlated inversely with exercise pulmonary artery wedge pressure and more strongly with right ventricular ejection fraction (ρ = -0.41, p = 0.006, n = 45) in a mixed population. The adjusted hazard ratio for lung transplant-free survival was 1.12 (95% confidence interval [CI], 1.02-1.22, p = 0.01) and 1.75 (95% CI, 1.12-2.73, p = 0.01) per 1 ng/ml and 5 ng/ml increase in plasma NEDD9, respectively, by Cox proportional hazard model., Conclusions: In PAH, plasma NEDD9 is increased and associates with key prognostic variables. Prospective studies that include hard end points are warranted to validate NEDD9 as a novel PAH biomarker., (Published by Elsevier Inc.)

Objectives: Pulmonary vascular dysfunction is associated with adverse prognosis in patients with the acute respiratory distress syndrome; however, the prognostic impact of pulmonary arterial compliance in acute respiratory distress syndrome is not established., Design, Setting, Patients: We performed a retrospective analysis of 363 subjects with acute respiratory distress syndrome who had complete baseline right heart catheterization data from the Fluid and Catheter Treatment Trial to test whether pulmonary arterial compliance at baseline and over the course of treatment predicted mortality., Main Results: Baseline pulmonary arterial compliance (hazard ratio, 1.18 per interquartile range of 1/pulmonary arterial compliance; 95% CI, 1.02-1.37; p = 0.03) and pulmonary vascular resistance (hazard ratio, 1.28 per interquartile range; 95% CI, 1.07-1.53; p = 0.006) both modestly predicted 60-day mortality. Baseline pulmonary arterial compliance remained predictive of mortality when pulmonary vascular resistance was in the normal range (p = 0.02). Between day 0 and day 3, pulmonary arterial compliance increased in acute respiratory distress syndrome survivors and remained unchanged in nonsurvivors, whereas pulmonary vascular resistance did not change in either group. The resistance-compliance product (resistance-compliance time) increased in survivors compared with nonsurvivors, suggesting improvements in right ventricular load., Conclusions: Baseline measures of pulmonary arterial compliance and pulmonary vascular resistance predict mortality in acute respiratory distress syndrome, and pulmonary arterial compliance remains predictive even when pulmonary vascular resistance is normal. Pulmonary arterial compliance and right ventricular load improve over time in acute respiratory distress syndrome survivors. Future studies should assess the impact of right ventricular protective acute respiratory distress syndrome treatment on right ventricular afterload and outcome.

Pulmonary hypertension includes heterogeneous diagnoses with distinct hemodynamic pathophysiologic features. Identifying elevated pulmonary vascular resistance (PVR) is critical for appropriate treatment. We reviewed data from patients seen at referral pulmonary hypertension clinics who had undergone echocardiography and right-side cardiac catheterization within 1 year. We derived equations to estimate PVR using the ratio of estimated pulmonary artery (PA) systolic pressure (PASPDoppler) to right ventricular outflow tract velocity time integral (VTI). We validated these equations in a separate sample and compared them with a published model based on the ratio of the transtricuspid flow velocity to right ventricular outflow tract VTI (model 1, Abbas et al 2003). The derived models were as follows: PVR = 1.2 × (PASP/right ventricular outflow tract VTI) (model 2) and PVR = (PASP/right ventricular outflow tract VTI) + 3 if notch present (model 3). The cohort included 217 patients with mean PA pressure of 45.3 ± 11.9 mm Hg, PVR of 7.3 ± 5.0 WU, and PA wedge pressure of 14.8 ± 8.1 mm Hg. Just >1/3 had a PA wedge pressure >15 mm Hg (35.5%) and 82.0% had PVR >3 WU. Model 1 systematically underestimated catheterization estimated PVR, especially for those with high PVR. The derived models demonstrated no systematic bias. Model 3 correlated best with PVR (r = 0.80 vs r = 0.73 and r = 0.77 for models 1 and 2, respectively). Model 3 had superior discriminatory power for PVR >3 WU (area under the curve 0.946) and PVR >5 WU (area under the curve 0.924), although all models discriminated well. Model 3-estimated PVR >3 was 98.3% sensitive and 61.1% specific for PVR >3 WU (positive predictive value 93%; negative predictive value 88%). In conclusion, we present an equation to estimate the PVR, using the ratio of PASPDoppler to right ventricular outflow tract VTI and a constant designating presence of right ventricular outflow tract VTI midsystolic notching, which provides superior agreement with catheterization estimates of PVR across a wide range of values., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Vascular remodeling of distal pulmonary arterioles that promotes abnormal pulmonary vascular reactivity is a central mechanism in the pathogenesis of pulmonary arterial hypertension (PAH). In selected patients, invasive pulmonary vasoreactivity testing performed in the cardiac catheterization laboratory with inhaled nitric oxide, epoprostenol, or adenosine is useful for PAH diagnosis, risk stratification, and assessing patient appropriateness for PAH-specific treatment(s). Limited accessibility to inhaled nitric oxide and a suboptimal test sensitivity profile reported for adenosine has contributed to the selection of epoprostenol for pulmonary vasoreactivity testing in some pulmonary hypertension referral centers. However, standardized procedural protocols for administrating epoprostenol for this purpose are largely unavailable to the practicing clinical community. The current work aims to bridge this gap by providing a stepwise procedure for the safe administration of clinically indicated intravenous epoprostenol during pulmonary vasoreactivity testing.

For decades, pulmonary hypertension (PH) used to be defined by a mean pulmonary artery pressure (mPAP) ≥25 mm Hg; however, this criterion was not based on data that were systematically collected. With the availability of contemporary datasets however, it was evident that the upper limit of normal mPAP was ∼20 mm Hg, which is also the level of mPAP above which adverse outcomes increase. In addition, it is now evident that the specificity of mPAP >20 mm Hg to denote precapillary pulmonary vascular disease could be enhanced by adding pulmonary vascular resistance (PVR) to the precapillary PH definition. Finally, after characterizing large groups of normal individuals, akin to observations for mPAP, it was recently demonstrated that a PVR of ∼2.0 Wood units (WU) is the upper limit of normal, and the lower level associated with all-cause mortality in at-risk patients. The current hemodynamic criteria for PH are positioned to capture more patients compared to the classical definition, with particular implications for earlier diagnosis. Importantly, pulmonary vasodilator therapies have not been tested adequately in patients with mPAP <25 mm Hg or PVR between 2 to 3 WU and, thus, should not be administered in these patients. Mild PH is an active focus of clinical trial design; at present, these patients should be referred to expert PH centers earlier for individualized therapeutic planning. The revised definition of precapillary PH uses a PVR threshold of >2 WU. This value is evidence-based, and exceeding this threshold is associated with adverse clinical outcomes. This revision places focus on early diagnosis, close monitoring, and consideration for certain treatments. Further studies are needed that test the efficacy and safety of pulmonary arterial hypertension-specific therapy in precapillary PH patients with PVR 2 to 3 WU. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension (PH) is an independent risk factor for adverse clinical outcome, particularly in left heart disease (LHD) patients. Recent advances have clarified the mean pulmonary artery pressure (mPAP) range that is above normal and is associated with clinical events, including mortality. This progress has for the first time resulted in a new clinical definition of PH that is evidenced-based, is inclusive of mPAP >20 mm Hg, and emphasizes early diagnosis. Additionally, pulmonary vascular resistance (PVR) 2.2 to 3.0 WU, considered previously to be normal, appears to associate with elevated clinical risk. A revised approach to classifying PH patients as pre-capillary, isolated post-capillary, or combined pre-/post-capillary PH now guides point-of-care diagnosis, risk stratification, and treatment. Exercise hemodynamic or confrontational fluid challenge studies may also aid decision-making for patients with PH-LHD or otherwise unexplained dyspnea. This collective progress in pulmonary vascular and heart failure medicine reinforces the critical importance of accurate hemodynamic assessment. [ABSTRACT FROM AUTHOR]

Background: At the recent 6th World Symposium on Pulmonary Hypertension (PH), the definition of PH was redefined to include lower pulmonary artery pressures in the setting of elevated pulmonary vascular resistance (PVR). However, the relevance of this change to subjects with PH due to left-heart disease as well as the preoperative assessment of heart transplant (HT) recipients is unknown.Methods: The United Network for Organ Sharing database was queried to identify adult recipients who underwent primary HT from 1996 to 2015. Recipients were subdivided into those with mean pulmonary artery pressure (mPAP) < 25 mm Hg and ≥ 25 mm Hg. Exploratory univariable analysis was undertaken to identify candidate risk factors associated with 30-day and 1-year survival (conditional on 30-day survival) in recipients with mPAP < 25 mm Hg, and subsequently, parsimonious multivariable Cox proportional hazards models were constructed to assess the independent association with PVR.Results: Over the study period, 32,465 patients underwent HT, including 12,257 (38%) with mPAP < 25 mm Hg. The median age was 55 years (interquartile range, 47-62) and the median PVR was 1.5 Wood units (WU) (interquartile range, 1-2.2) in recipients with mPAP < 25 mm Hg. After controlling for confounders, PVR was independently associated with increased risk for 30-day mortality (hazard ratio, 1.16; 95% CI, 1.05-1.27; P < .01), but not conditional 1-year mortality (hazard ratio, 1.03; 95% CI, 0.94-1.12; P = .55). PVR ≥ 3 WU was associated with an absolute 1.9% increase in 30-day mortality in those with mPAP < 25 mm Hg, a similar risk to recipients with PVR ≥ 3 WU and mPAP ≥ 25 mm Hg.Conclusions: Elevated PVR remains associated with a significant increase in the hazard for 30-day mortality after cardiac transplantation, even in the setting of lower pulmonary artery pressures. These data support the validity of the new definition of pulmonary hypertension. [ABSTRACT FROM AUTHOR]