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This article discusses the importance of early diagnosis and treatment initiation for pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH), two rare but serious conditions that can lead to right heart failure and death. Despite efforts to improve outcomes, there has been a significant diagnostic delay in PAH and CTEPH. The article proposes a structured evaluation of unclear dyspnea, outlining a three-step approach that includes baseline evaluation, targeted evaluation, and referral to a specialist center. The authors emphasize the need for collaboration between primary care physicians and expert centers to optimize prompt referrals and improve patient care. [Extracted from the article]

Aims: Patients with heart failure (HF) exhibit poor prognosis, which is further deteriorated by pulmonary hypertension (PH), with negative impact on morbidity and mortality. As PH due to left HF (LHF‐PH) is among the most common causes of PH, there is an urge according to the 2021 European Society of Cardiology HF guidelines to find new biomarkers that aid in prognostication of this patient cohort. Given the role of tumour necrosis factor‐alpha (TNF‐α) in HF progression, we aimed to investigate the prognostic value of plasma proteins related to TNF‐α in patients with LHF‐PH, in relation to haemodynamic changes following heart transplantation (HT). Methods and results: Twenty TNF‐α‐related plasma proteins were analysed using proximity extension assay in healthy controls (n = 20) and patients with LHF‐PH (n = 67), before and 1 year after HT (n = 19). Plasma levels were compared between the groups, and the prognostic values were determined using Kaplan–Meier and Cox regression analyses. Plasma levels of lymphotoxin‐beta receptor (LTBR), TNF receptor superfamily member 6B (TNFRSF6B), and TNF‐related apoptosis‐inducing ligand receptors 1 and 2 (TRAIL‐R1 and TRAIL‐R2, respectively) were higher in LHF‐PH pre‐HT vs. controls (P < 0.0001), as well as higher in pre‐HT vs. post‐HT (P < 0.001). The elevated pre‐HT levels of LTBR, TNFRSF6B, TRAIL‐R1, and TRAIL‐R2 decreased towards the levels of healthy controls after HT. Higher preoperative levels of LTBR, TNFRSF6B, TRAIL‐R1, and TRAIL‐R2 in LHF‐PH were associated with worse survival rates (P < 0.002). In multivariate Cox regression models, each adjusted for age and sex, LTBR, TNFRSF6B, TRAIL‐R1, and TRAIL‐R2 predicted mortality (P < 0.002) [hazard ratio (95% confidence interval): 1.12 (1.04–1.19), 1.01 (1.004–1.02), 1.28 (1.14–1.42), and 1.03 (1.02–1.04), respectively]. Conclusions: Elevated pre‐HT plasma levels of the TNF‐α‐related proteins LTBR, TNFRSF6B, TRAIL‐R1, and TRAIL‐R2 in LHF‐PH decreased 1 year after HT, displaying a normalization pattern towards the levels of the healthy controls. These proteins were also prognostic, where higher levels were associated with worse survival rates in LHF‐PH, providing new insight in their potential role as prognostic biomarkers. Larger studies are warranted to validate our findings and to investigate their possible pathobiological mechanisms in LHF‐PH. [ABSTRACT FROM AUTHOR]

Aims: Heart failure (HF) is a frequent condition in the elderly, further complicated by associated pulmonary hypertension (PH), with impact on morbidity and mortality. Plasma proteins associated with cardiovascular disease, related to inflammation, neurohormonal changes, and myocyte stress, pathways recognized in the pathophysiology of HF, may provide information on disease severity and prognosis. We aimed to investigate such cardiovascular proteins and their relationship to haemodynamics before and 1 year after heart transplantation (HT), as well as their prognostic value in advanced HF with PH. Methods and results: In 20 healthy controls and 67 patients with HF and PH, before and 1 year after HT, N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) and 18 cardiovascular proteins were analysed with proximity extension assay. Right heart catheterization was used to measure the haemodynamics of the HF patients pre‐operatively and at 1 year follow‐up after HT. Prognosis was estimated using Kaplan–Meier and Cox regression analyses. Out of 18 plasma proteins, 11 proteins including adrenomedullin peptides and precursor levels (ADM) and protein suppression of tumourigenicity 2 receptor were elevated before HT compared with healthy controls and had decreased 1 year after HT. The decrease in plasma levels 1 year after HT was towards the healthy controls' levels. The decrease in ADM levels before vs. after HT correlated with decreased mean right atrial pressure (rs = 0.61; P = 0.0077), decreased NT‐proBNP (rs = 0.75; P = 0.00025), and decreased stroke volume index (rs = −0.52; P = 0.022). High levels of pre‐operative plasma ADM were associated with worse event‐free survival (HT or death), as well as survival compared with low ADM levels (log‐rank P value = 0.023 and 0.0225, respectively). Univariable Cox regression analysis demonstrated that ADM levels were associated with survival, hazard ratio (HR) 1.007 (95% confidence interval (CI): 1.00–1.015, P = 0.049), and the association remained after adjusting for NT‐proBNP, HR 1.01 (95% CI: 1.00–1.021, P = 0.041). Conclusions: Elevated plasma levels of ADM may be a marker of pressure/volume overload in HF patients with PH, as well as long‐term prognosis after HT. In line with previous studies, our findings additionally confirm that ADM may be a marker of venous congestion in HF. Further studies are encouraged to establish a deeper understanding of the properties of ADM and its relationship with HF and PH, in order to potentially facilitate clinical management of HF and associated PH. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) is a rare vasculopathy, with high morbidity and mortality. The sensitivity of the current european society of cardiology/european respiratory society (ESC/ERS) risk assessment strategy may be improved by the addition of biomarkers related to PAH pathophysiology. Such plasma-borne biomarkers may also reduce time to diagnosis, if used as diagnostic tools in patients with unclear dyspnea, and in guiding treatment decisions. Plasma levels of proteins related to tumor necrosis factor (TNF), inflammation, and immunomodulation were analyzed with proximity extension assays in patients with PAH (n = 48), chronic thromboembolic pulmonary hypertension (PH; CTEPH, n = 20), PH due to left heart failure (HF) with preserved (HFpEF-PH, n = 33), or reduced (HFrEF-PH, n = 36) ejection fraction, HF without PH (n = 15), and healthy controls (n = 20). TNF-related apoptosis-inducing ligand (TRAIL) were lower in PAH versus the other disease groups and controls (p < 0.0082). In receiver operating characteristics analysis, TRAIL levels identified PAH from the other disease groups with a sensitivity of 0.81 and a specificity of 0.53 [area under the curve: 0.70; (95% confidence interval, CI: 0.61-0.79; p < 0.0001)]. In both single (p < 0.05) and multivariable Cox regression models Annexin A1 (ANXA1) [hazard ratio, HR: 1.0367; (95% CI: 1.0059-1.0684; p = 0.044)] and carcinoembryonic antigen-related cell adhesion molecule 8 [HR: 1.0603; (95% CI: 1.0004-1.1237; p = 0.0483)] were significant predictors of survival, adjusted for age, female sex and ESC/ERS-initial risk score. Low plasma TRAIL predicted PAH among patients with dyspnea and differentiated PAH from those with CTEPH, HF with and without PH; and healthy controls. Higher plasma ANXA1 was associated with worse survival in PAH. Larger multicenter studies are encouraged to validate our findings. [ABSTRACT FROM AUTHOR]

Aims Estimation of prognosis in pulmonary arterial hypertension (PAH) has been influenced by that various risk stratification models use different numbers of prognostic parameters, as well as the lack of a comprehensive and time-saving risk assessment calculator. We therefore evaluated the various European Society of Cardiology (ESC)-/European Respiratory Society (ERS)-based three- and four-strata risk stratification models and established a comprehensive internet-based calculator to facilitate risk assessment. Methods and results Between 1 January 2000 and 26 July 2021, 773 clinical assessments on 169 incident PAH patients were evaluated at diagnosis and follow-ups. Risk scores were calculated using the original Swedish Pulmonary Arterial Hypertension Registry (SPAHR)/Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) three-strata model, the updated SPAHR three-strata model with divided intermediate risk, and the simplified three-parameter COMPERA 2.0 four-strata model. The original SPAHR/COMPERA and the updated SPAHR models were tested for both 3–6 and 7–11 available parameters, respectively. Prognostic accuracy [area under the receiver operating characteristic (ROC) curve (AUC)] and Uno's cumulative/time-dependent C-statistics (uAUC) were calculated for 1-, 3-, and 5-year mortality. At baseline, both the original SPAHR/COMPERA and the updated SPAHR models, using up to six parameters, provided the highest accuracy (uAUC = 0.73 for both models) in predicting 1-, 3-, and 5-year mortality. At follow-ups, the updated SPAHR model with divided intermediate risk (7–11 parameters) provided the highest accuracy for 1-, 3-, and 5-year mortality (uAUC = 0.90), followed by the original SPAHR/COMPERA model (7–11 parameters) (uAUC = 0.88) and the COMPERA 2.0 model (uAUC = 0.85). Conclusions The present study facilitates risk assessment in PAH by introducing a comprehensive internet-based risk score calculator (https://www.svefph.se/risk-stratification). At baseline, utilizing the original or the updated SPAHR models using up to six parameters was favourable, the latter model additionally offering sub-characterization of the intermediate risk group. Our findings support the 2022 ESC/ERS pulmonary hypertension guidelines' strategy for risk stratification suggesting the utilization of a three-strata model at baseline and a simplified four-strata model at follow-ups. Our findings furthermore support the utility of the updated SPAHR model with divided intermediate risk, when a more comprehensive assessment is needed at follow-ups, complementing the three-parameter COMPERA 2.0 model. Larger multi-centre studies are encouraged to validate the utility of the updated SPAHR model. Take home message By introducing an internet-based risk score calculator (https://www.svefph.se/risk-stratification), risk assessment is facilitated. Our results support the 2022 ESC/ERS pulmonary hypertension guidelines' risk stratification strategy, additionally suggesting the updated SPAHR three-strata model with divided intermediate risk, as a promising complement to the new simplified three-parameter COMPERA 2.0 four-strata strategy, when a more comprehensive overview is needed. [ABSTRACT FROM AUTHOR]

Aims: Heart failure (HF) is a progressive condition that is becoming more prevalent in the ageing population. Pulmonary hypertension is a common complicating factor in HF and negatively impacts survival. Plasma biomarkers are a potential method for determining the prognosis of patients with left heart failure with pulmonary hypertension (LHF‐PH). We aimed to analyse the prognostic capability of 33 proteins related to, among other pathways, inflammation, coagulation, and Wnt signalling in LHF‐PH. Methods: Plasma levels of 33 proteins were analysed using proximity extension assay from the plasma of 20 controls and 67 LHF‐PH patients, whereof 19 underwent heart transplantation (HT). Haemodynamics in the patients were assessed using right heart catheterization. Results: Eleven proteins had elevated plasma levels in LHF‐PH compared with controls (P < 0.01), which decreased towards the controls' levels after HT (P < 0.01). Survival analysis of these proteins showed that elevated plasma levels of growth hormone, programmed cell death 1 ligand 2, tissue factor pathway inhibitor 2, and Wnt inhibitory factor 1 (WIF‐1) were associated with worse transplantation‐free survival in LHF‐PH (P < 0.05). When adjusted for age, sex and N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) levels using multivariable cox regressions, only WIF‐1 remained prognostic [hazard ratio (95% confidence interval)] [1.013 (1.001–1.024)]. WIF‐1 levels in LHF‐PH patients also correlated with the mean right atrial pressure (rs = 0.42; P < 0.01), stroke volume index (rs = 0.41; P < 0.01), cardiac index (rs = −0.42; P < 0.01), left ventricular stroke work index (rs = −0.41; P < 0.01), and NT‐proBNP (rs = 0.63; P < 0.01). Conclusions: The present study demonstrated that LHF‐PH patients have higher plasma WIF‐1 levels than healthy controls, suggesting that plasma WIF‐1 may be a potential future prognostic biomarker in LHF‐PH. Its prognostic capability could be further refined by including it in a multi‐marker panel. Further studies are needed to establish the potential role of WIF‐1 in LHF‐PH pathophysiology in larger cohorts to determine its clinical applicability. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) is a life‐threatening disease characterized by vasoconstriction and remodeling of the pulmonary vessels. Risk stratification in PAH could potentially be improved by including novel biomarkers related to PAH pathobiology. We aimed to investigate the relationship between extracellular matrix (ECM)‐related proteins, survival, and European Society of Cardiology and European Respiratory Society (ESC/ERS) risk stratification scores in patients with PAH. Plasma samples and hemodynamics were collected from PAH patients during right heart catheterizations at diagnosis (n = 48) and early follow‐up, after treatment initiation (n = 33). Plasma levels of 14 ECM‐related proteins, with altered levels in PAH compared to healthy controls, were analyzed with proximity extension assays, and related to hemodynamics, transplant‐free survival time, and ESC/ERS risk score. Glypican‐1 levels were higher before versus after treatment initiation (p = 0.048). PAH patients with high plasma levels of matrix metalloproteinase (MMP) ‐2, MMP‐7, MMP‐9, MMP‐12, perlecan, and tissue inhibitor of metalloproteinase 4 (TIMP‐4) at baseline, had worse transplant‐free survival (p < 0.03) than patients with low levels. Hazard ratio (95% confidence interval) was for MMP‐2 1.126 (1.011–1.255), perlecan 1.0099 (1.0004–1.0196), and TIMP‐4 1.037 (1.003–1.071) in age and sex‐adjusted Cox‐regression model. MMP‐2 correlated with ESC/ERS risk scores (rs = 0.34, p = 0.019), mean right atrial pressure (rs = 0.44, p = 0.002), NT‐proBNP (rs = 0.49, p ≤ 0.001), and six‐minute walking distance (rs = −0.34, p = 0.02). The present study indicates that high levels of MMP‐2, perlecan, and TIMP‐4 are associated with poor survival in PAH. High plasma MMP‐2, correlated with poor prognosis in PAH. Further validation in larger studies is needed to better determine this association. [ABSTRACT FROM AUTHOR]

Discrimination of heart failure with preserved ejection fraction with pulmonary hypertension (HFpEF-PH) from pulmonary arterial hypertension (PAH) is crucial for clinical management but may be challenging due to similarities in clinical and comorbid characteristics. We aimed to investigate tumour and metabolism related proteins in differentiating HFpEF-PH from PAH. Sixty-nine tumour and metabolism plasma proteins were analysed with proximity extension assay in heathy controls (n = 20), patients with PAH (n = 48) and LHF-PH (n = 67) [HFpEF-PH (n = 31) and HF reduced EF-PH (n = 36)]. Haemodynamics were assessed with right heart catheterization. The plasma levels of alpha-1-microglobulin/bikunin precursor (AMBP) and lipoprotein lipase (LPL), were higher in HFpEF-PH compared to healthy controls (p < 0.01), HFrEF-PH (p < 0.05), and PAH (p < 0.001). Glyoxalase I levels were higher in HFpEF-PH and HFrEF-PH compared to controls (p < 0.001) and PAH (p < 0.001). Each of plasma AMBP, LPL, and glyoxalase I, adjusted for age and sex in multivariable logistic regression models, could differentiate HFpEF-PH from PAH, with areas under the receiver operating characteristic curve (AUC) of 0.81, 0.84 and 0.79, respectively. The combination of AMBP, LPL and glyoxalse I yielded the largest AUC of 0.87 [95% confidence interval (0.79–0.95)] in discriminating HFpEF-PH from PAH, with a sensitivity of 87.1% and a specificity of 85.4%. In HFpEF-PH, the plasma levels of AMBP correlated with pulmonary arterial wedge pressure (r s = −0.42, p = 0.018). Plasma AMBP, LPL and glyoxalase I may facilitate the distinction of HFpEF-PH from PAH. Larger clinical studies are encouraged to confirm and validate our findings. [Display omitted] • Plasma AMBP, LPL and glyoxalse I were higher in HFpEF-PH vs controls and PAH. • The combination of AMBP, LPL and glyoxalse I yielded the largest AUC in differentiating patients with HFpEF-PH from PAH. • In HFpEF-PH, plasma AMBP correlated with pulmonary arterial wedge pressure. • In LHF-PH, higher plasma sRAGE was associated with worse transplantation-free-survival (Data in breif). [ABSTRACT FROM AUTHOR]

Aims: Right ventricular dysfunction may arise because of pulmonary arterial hypertension (PAH). Development of new diagnostic methods able to identify PAH and allow for earlier treatment initiation, before the development of vascular remodelling and manifest right heart failure (HF), could potentially improve prognosis. Proteoglycans and inflammatory proteins are involved in vascular remodelling. We aimed to investigate their potential as biomarkers to differentiate PAH in a dyspnoeic population. Methods and results: Plasma from 152 patients with PAH (n = 48), chronic thrombo‐embolic pulmonary hypertension (n = 20), pulmonary hypertension due to HF with reduced (n = 36) or preserved (n = 33) ejection fraction, and HF without pulmonary hypertension (n = 15) and 20 healthy controls were analysed with proximity extension assays. Haemodynamics were assessed in the patients with right heart catheterization. Plasma prolargin levels in PAH were lower compared with all the other studied disease groups (P < 0.001) but higher than the controls' levels (P = 0.003). Receiver operating characteristic curve of prolargin as a PAH‐differentiating marker in a pooled population, encompassing all the other studied disease groups, had a sensitivity of 74% and a specificity of 83.3% (area under the curve = 0.84, P < 0.001). Prolargin correlated with the mean right atrial pressure (rs = 0.65, P < 0.001), N‐terminal pro‐brain natriuretic peptide (rs = 0.64, P < 0.001), cardiac index (rs = −0.31, P = 0.029), stroke volume index (rs = −0.41, P = 0.004), right ventricular stroke work index (rs = −0.31, P = 0.032), six‐minute walking distance (rs = −0.41, P = 0.005), and mixed venous blood oxygen saturation (rs = −0.42, P = 0.003). Conclusions: Plasma prolargin levels differentiate PAH patients from controls and the other investigated dyspnoea groups including HF. Its potential in PAH differentiation may be enhanced by inclusion in a multi‐marker panel. Larger studies are needed to evaluate its discriminative ability of PAH in relation to other dyspnoea aetiologies and its potential role in PAH risk stratification and pathobiology. [ABSTRACT FROM AUTHOR]

Aims: Metabolic derangement is implicated in the pathophysiology of heart failure (HF) and pulmonary hypertension (PH). We aimed to identify the dynamics of metabolic plasma proteins linked to end‐stage HF and associated PH in relation to haemodynamics, before and after heart transplantation (HT). Methods and results: Twenty‐one metabolic plasma proteins were analysed with proximity extension assay in 20 controls and 26 patients before and 1 year after HT. Right heart catheterizations were performed in the HF patients pre‐operatively and 1 year after HT. Plasma levels of soluble receptor for advanced glycation end products (sRAGE) and insulin‐like growth factor‐binding protein 7 (IGFBP7) were higher in HF patients compared with controls (P < 0.0001) and decreased after HT (P < 0.0001), matching controls' levels. The decrease in sRAGE after HT correlated with improved mean pulmonary arterial pressure (rs = 0.7; P < 0.0001), pulmonary arterial wedge pressure (rs = 0.73; P < 0.0001), pulmonary vascular resistance (rs = 0.65; P = 0.00062), and pulmonary arterial compliance (rs = −0.52; P = 0.0074). The change in plasma IGFBP7 after HT correlated with improved mean right atrial pressure (rs = 0.71; P = 0.00011) and N‐terminal pro‐brain natriuretic peptide (rs = 0.71; P < 0.0001). Conclusions: Our results indicate that plasma sRAGE may reflect passive pulmonary vascular congestion and the 'mechanical' state of the pulmonary vasculature in HF patients with or without related PH. Furthermore, sRAGE and IGFBP7 may provide additional insight into the pathophysiological mechanisms in HF and associated PH. Their potential clinical and therapeutic relevance in HF and associated PH need further investigation. [ABSTRACT FROM AUTHOR]

Aims: Remodelling of the extracellular matrix (ECM) is a key mechanism involved in the development and progression of heart failure (HF) but also functional in associated pulmonary hypertension (PH). Our aim was to identify plasma ECM proteins associated to end‐stage HF and secondary PH in relation to haemodynamics, before and after heart transplantation (HT). Methods and results: Twenty ECM plasma proteins were analysed with proximity extension assay in 20 controls and 26 HF patients pre‐HT and 1 year post‐HT. Right heart catherization haemodynamics were assessed in the patients during the preoperative evaluation and at the 1 year follow‐up post‐HT. Plasma levels of prolargin and matrix metalloproteinase‐2 (MMP‐2) were elevated (P < 0.0001) in HF patients compared with controls and decreased (P < 0.0001) post‐HT towards controls' levels. The decrease in prolargin post‐HT correlated with improved mean right atrial pressure (rs = 0.63; P = 0.00091), stroke volume index (rs = −0.73; P < 0.0001), cardiac index (rs = −0.64; P = 0.00057), left ventricular stroke work index (rs = −0.49; P = 0.015), and N‐terminal pro brain natriuretic peptide (rs = 0.7; P < 0.0001). The decrease in MMP‐2 post‐HT correlated with improved mean pulmonary artery pressure (rs = 0.58; P = 0.0025), mean right atrial pressure (rs = 0.56; P = 0.0046), pulmonary artery wedge pressure (rs = 0.48; P = 0.016), and N‐terminal pro brain natriuretic peptide (rs = 0.56; P = 0.0029). Conclusions: The normalization pattern in HF patients of plasma prolargin and MMP‐2 post‐HT towards controls' levels and their associations with improved haemodynamics indicate that prolargin and MMP‐2 may reflect, in part, the aberrant ECM remodelling involved in the pathophysiology of HF and associated PH. Their potential clinical use as biomarkers or targets for future therapy in HF and related PH remains to be investigated. [ABSTRACT FROM AUTHOR]