Barr RG, Lima JAC, Prince MR
… +41 more, Ambale-Venkatesh B, Abraham T, Agarwal PP, Arora G, Balasubramanian A, Barjaktarevic I, Bello NA, Bluemke DA, Budoff MJ, Carr JC, Chaudhuri D, Cooper CB, Couper D, Finn JP, Freed BH, Han MK, Hansel NN, Hsu JJ, Kitzman DW, Krishnan JA, LaBounty TM, Lee YJ, Liu J, Lloyd SG, Markl M, Mukherjee M, Beussink-Nelson L, Ohar J, Ortega VE, Paine R, Peters SP, Schroeder JD, Shen W, Shepshelovich D, Sun Y, Vogel-Claussen J, Watson KE, Wells JM, Wieben O, Woodruff PG, Shah SJ
Circ Heart Fail
· 2025 Dec · PMID 41190426
·
Full text
BACKGROUND: Although chronic obstructive pulmonary disease (COPD) and heart failure with preserved ejection fraction often coexist with overlapping clinical features, they are usually studied separately. The SPIROMICS HF...BACKGROUND: Although chronic obstructive pulmonary disease (COPD) and heart failure with preserved ejection fraction often coexist with overlapping clinical features, they are usually studied separately. The SPIROMICS HF (Subpopulations and Intermediate Outcome Measures in COPD and Heart Failure Study) is testing hypotheses that new computed tomography emphysema subtypes are associated with specific cardiovascular phenotypes (eg, , ), common airway branch variants are associated with right heart dysfunction, and symptomatic tobacco-exposed persons with preserved spirometry have signs of increased left ventricular afterload. METHODS: SPIROMICS is a multicenter observational study of COPD with extensive pulmonary phenotyping of participants with ≥20 pack-years smoking and nonsmoking controls. COPD and COPD severity were defined by standard spirometric criteria and symptomatic tobacco-exposed persons with preserved spirometry by ≥20 pack-years, normal spirometry, and COPD Assessment Test score >10. SPIROMICS HF selected all participants in SPIROMICS visit 5 at major sites. Its comprehensive speckle-tracking echocardiography, which included physiological perturbations of leg raise and low-intensity exercise, was harmonized prospectively with the Multi-Ethnic Study of Atherosclerosis Early Heart Failure and HeartSHARE (Combining Omics, Deep Phenotyping, and Electronic Health Records for Heart Failure Subtypes and Treatment Targets) studies. The cardiopulmonary magnetic resonance imaging protocol with gadolinium administration included myocardial fibrosis sequences, pulmonary angiography, time-resolved 3-dimensional cine magnetic resonance imaging (4-dimensional flow) of venous return, and metronome-paced tachypnea to induce dynamic hyperinflation. Coronary artery calcium was assessed on computed tomography scans. The Kansas City Cardiomyopathy Questionnaire was administered. RESULTS: Of the final sample of 753 participants, 57% had COPD (15% mild, 27% moderate, and 15% severe), 18% had symptomatic tobacco-exposed persons with preserved spirometry, 16% were smoking controls, and 8% were nonsmoking controls. Reproducibility of the main measures from speckle-tracking echocardiography (intraclass correlation coefficient, 0.83-0.99), exercise echocardiography (intraclass correlation coefficient, 0.71-0.99) and magnetic resonance imaging (intraclass correlation coefficient, 0.57-0.99) were good-to-excellent, including in severe COPD. CONCLUSIONS: SPIROMICS HF aims to characterize and understand cardiopulmonary interactions in COPD and COPD-related phenotypes to inform targeted treatments for combined cardiopulmonary failure.
BACKGROUND: There are currently no robust clinical markers for assessing prognosis in patients with heart failure (HF) with recovered left ventricular ejection fraction (LVEF). This study sought to investigate whether NT...BACKGROUND: There are currently no robust clinical markers for assessing prognosis in patients with heart failure (HF) with recovered left ventricular ejection fraction (LVEF). This study sought to investigate whether NT-proBNP (N-terminal pro-B-type natriuretic peptide) measured at the time of LVEF recovery is an independent predictor of prognosis among patients with HF with recovered LVEF. METHODS: This retrospective cohort study (2009-2024) included 3935 patients with HF with recovered LVEF (previous LVEF of ≤40% with subsequent improvement to ≥50%) and available NT-proBNP data at the time of LVEF recovery. Patients were categorized into 7 different NT-proBNP groups, which were compared using Kaplan-Meier analysis and multivariable Cox regression to evaluate the outcome of LVEF relapse (decrease in LVEF by ≥10% to <50%) and the composite outcome of HF hospitalization or all-cause death. RESULTS: The median value of NT-proBNP at the time of LVEF recovery was 1341 pg/mL (interquartile range, 400-4207). The probability of remaining free from LVEF relapse and the composite outcome decreased across NT-proBNP groups. After multivariable adjustment, NT-proBNP was an independent predictor of both LVEF relapse and the composite outcome, with higher NT-proBNP levels associated with higher risk of both outcomes in a dose-response manner. Even near-normal NT-proBNP levels (125-299 pg/mL) were associated with poorer prognosis relative to normal levels (<125 pg/mL), with a 46% higher risk of LVEF relapse and 82% higher risk of the composite outcome. This relationship was consistent and similar across age, sex, atrial fibrillation status, and renal function, but was modified by body mass index, with higher body mass index associated with higher risk. Notably, NT-proBNP was predictive of the composite outcome even when patients sustained LVEF recovery without experiencing LVEF relapse. CONCLUSIONS: NT-proBNP is an independent and robust predictor of prognosis in patients with HF with recovered LVEF and may therefore be used to guide further optimization of pharmacotherapy.
Myte R, Mattsson A, Poole M
… +7 more, Little DJ, Nyström P, Henderson A, Claggett BL, Gasparyan SB, Solomon SD, McMurray JJV
Circ Heart Fail
· 2025 Dec · PMID 41170566
·
Full text
BACKGROUND: Patients with cardiovascular conditions like heart failure (HF) often exhibit significant heterogeneity of the risk of clinical events. In clinical trials, large risk heterogeneity can result in an underestim...BACKGROUND: Patients with cardiovascular conditions like heart failure (HF) often exhibit significant heterogeneity of the risk of clinical events. In clinical trials, large risk heterogeneity can result in an underestimation of treatment effects derived from Cox proportional hazards models. This occurs due to selection bias when estimating the hazard ratio, stemming from a disproportionate reduction of event-free patients in the control group compared with an effective active group over time, ultimately reducing the statistical power. Therefore, it is important to explore alternative analysis methods for outcome trials that are robust with respect to risk heterogeneity. METHODS: We used clinical data from 2 dapagliflozin HF trials-DAPA-HF (Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction) and DELIVER (Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction) to characterize the extent of risk heterogeneity and nonproportionality of hazards in HF. We then evaluated a candidate method for estimating treatment effects in HF outcome trials, namely the survival proportional odds model, and compared this to traditional Cox regression in a simulation study. RESULTS: In the dapagliflozin trials, nonproportional hazards were a larger issue in the HFpEF population of the DELIVER trial compared with the more homogeneous heart failure with reduced ejection fraction population of the DAPA-HF trial. In simulations of populations with varying degrees of heterogeneity, the survival proportional odds model was more robust to heterogeneity and demonstrated higher power compared with traditional Cox regression in high heterogeneity populations, while performing similarly or slightly worse in more or less heterogeneous populations. Reanalyses of the dapagliflozin trials confirmed these findings, with the survival proportional odds model providing consistently higher power in the DELIVER trial and similar power in the DAPA-HF trial. CONCLUSIONS: In HF trials, the survival proportional odds model is a viable and more robust alternative for analyzing time to event outcomes, also providing an intuitive interpretation of the treatment effect directly linked to survival probability: improved odds of being event-free in the active group compared with the control group. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifiers: NCT03036124 and NCT03619213.
Kristiansson RS, Spangler D, Linder W
… +1 more, Winblad U
Circ Heart Fail
· 2025 Dec · PMID 41170562
·
Full text
BACKGROUND: Patients with heart failure tend to experience higher rates of hospital readmissions compared with other ambulatory care-sensitive conditions. In Sweden, the nationwide Care Coordination Act (CCA) was introdu...BACKGROUND: Patients with heart failure tend to experience higher rates of hospital readmissions compared with other ambulatory care-sensitive conditions. In Sweden, the nationwide Care Coordination Act (CCA) was introduced in January 2018 with the goal of improving care coordination, resulting in a reduction of readmissions and length of stay. There is insufficient knowledge regarding the effect of this reform on patients with heart failure. METHODS: We studied the association of implementing CCA on all-cause 30-day readmissions and length of stay for patients over 65 years of age with code I50 (Heart Failure). The data set included all admissions with a primary diagnosis of heart failure among elderly, multimorbid patients between 2015 and 2019. An interrupted time series analysis using hierarchical mixed models with random effects clustered at the hospital ward level was conducted. RESULTS: A total of 111 414 admissions were included. The average readmission rate for patients with heart failure was 26.8% before and 26.7% after the CCA. The average length of stay was 8.4 days before the CCA and 8.1 days after. Mortality within 30 days was 7.3% before the CCA and 7.5% after. There were no significant differences between the periods before and after. In an analysis assessing the overall linear time trend 2 of 21 regions showed a reduction in readmissions and 10 in length of stay. CONCLUSIONS: After introducing the CCA, no detectable impact was found on readmissions or mortality for patients with heart failure, which is in line with previous studies, such as those studying the US Hospital Readmission Reduction Program. Although no overall association with length of stay could be identified, it was reduced in several Swedish regions. The heterogeneity between regions could be used to understand the specific components needed to achieve the reduction of readmissions in future studies.
Moustafa A, Kholeif Z, Miranda WR
… +4 more, Connolly HM, Stephens EH, Dearani JA, Egbe AC
Circ Heart Fail
· 2025 Dec · PMID 41082342
·
Full text
BACKGROUND: Fontan conversion (FC) is associated with a lower risk of atrial arrhythmias and thromboembolism, but it is unknown whether FC improves long-term survival. The purpose of this study was to assess the impact o...BACKGROUND: Fontan conversion (FC) is associated with a lower risk of atrial arrhythmias and thromboembolism, but it is unknown whether FC improves long-term survival. The purpose of this study was to assess the impact of FC on transplant-free survival. METHOD: Adults with Fontan palliation were divided into 3 groups: (1) atriopulmonary Fontan connection; (2) atriopulmonary Fontan and subsequent FC to total cavopulmonary connection (TCPC); (3) TCPC at initial Fontan operation. The risk of death/transplant was compared between the 3 groups using Cox regression analysis. RESULTS: We studied 534 patients (age 27±9 years; males [N=298; 56%]). Patients were divided into atriopulmonary Fontan group (N=199, 37%); FC-TCPC (N=138, 26%); and TCPC (N=197, 37%). The FC-TCPC and TCPC groups have similar 15-year incidence of death/transplant (42% versus 47%; =0.8), even after excluding the 8% operative mortality in the FC-TCPC group (38% versus 47%; =0.3). On multivariable analyses, neither FC nor the type of Fontan connection was associated with death/transplant. Rather, the risk factors for death/transplant were older age, hepatorenal dysfunction, heart failure, and higher Fontan pressures. The prevalence and severity of these comorbidities increased with age, suggesting that these factors reflect the duration of Fontan physiology, rather than the type of Fontan connection. CONCLUSIONS: These findings, in addition to the high operative mortality associated with FC, suggest that this may not be the optimal treatment option for most adults with atriopulmonary Fontan presenting with Fontan failure. Duration of Fontan physiology rather than the type of Fontan connection may be the main determinant of outcomes.
Shah P, Zheng Y, Pieske B
… +14 more, Melenovsky V, Lam CSP, Sliwa K, Butler J, Ezekowitz JA, deFilippi CR, O'Connor CM, Sandhu RK, Roessig L, Tromp J, Westerhout CM, Voors AA, Armstrong PW, VICTORIA Study Group
Circ Heart Fail
· 2026 Feb · PMID 41058565
·
Full text
BACKGROUND: Patients with heart failure and reduced ejection fraction (HFrEF) have a high residual risk for heart failure hospitalizations and cardiovascular death. We aimed to use multimodality data to identify unique H...BACKGROUND: Patients with heart failure and reduced ejection fraction (HFrEF) have a high residual risk for heart failure hospitalizations and cardiovascular death. We aimed to use multimodality data to identify unique HFrEF subgroups with high residual risk. METHODS: In this VICTORIA substudy (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction), clinical, electrocardiographic, echocardiographic, quantitative biomarker, and targeted proteomics data were collected. Agglomerative hierarchical clustering was performed using 105 variables to define HFrEF phenogroups. Cox regression estimated the relationship between the HFrEF phenogroups and the primary composite outcome of cardiovascular death or heart failure hospitalization. External validation of the phenogroups was performed in the BIOSTAT-CHF cohort (Biology Study to Tailored Treatment in Chronic Heart Failure). Multinomial logistic regression identified the most important variables in defining the HFrEF phenogroups. RESULTS: There were 564 participants; after clustering, the optimal number of HFrEF phenogroups was 3. Phenogroup 1 was young, well-treated with guideline-directed medical therapy, and least likely to have an implantable cardioverter defibrillator. Phenogroup 2 had the highest prevalence of atrial fibrillation and pathological Q-waves on electrocardiography. Phenogroup 3 was older, had more biventricular dysfunction, and had advanced renal disease. A stepwise increase in the risk of the primary composite outcome was observed from HFrEF phenogroup 1 to 3 (hazard ratio, 7.0 [95% CI, 4.1-12.0]; ≤0.01). The phenogroups were externally validated in BIOSTAT-CHF, and phenogroup 3 had similar patient characteristics (eg, older with more significant renal dysfunction) and had the highest event rate at 1 year (41% [95% CI, 38%-45%]). After multinomial regression, GDF-15 (growth differentiation factor 15) was the most important variable in discriminating the 3 HFrEF phenogroups in both VICTORIA and BIOSTAT-CHF. CONCLUSIONS: We identified and externally validated unique HFrEF subpopulations with shared biological characteristics that differentiated residual risk for cardiovascular death or heart failure hospitalization. GDF-15 was the most important protein used to distinguish the 3 HFrEF phenogroups. These findings may inform study entry criteria for future HFrEF trials focused on the development of novel therapeutics. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT02861534.
Jung C, Lang A, Duse DA
… +15 more, Bruno RR, Pöss J, Wolff G, Ceglarek U, Zeymer U, Fuernau G, Zweck E, Desch S, Freund A, Isermann B, Pfeiler S, Wernly B, Kelm M, Thiele H, Gerdes N
BACKGROUND: Cardiogenic shock (CS) is a severe complication of acute myocardial infarction (AMI) leading to poor outcomes. Specific biomarkers, with subsequent validation of their prognostic relevance in CS, are urgently...BACKGROUND: Cardiogenic shock (CS) is a severe complication of acute myocardial infarction (AMI) leading to poor outcomes. Specific biomarkers, with subsequent validation of their prognostic relevance in CS, are urgently needed to improve therapies and outcomes. Accordingly, the present study investigated the plasma proteome using proximity extension assay technology to identify novel specific biomarkers with subsequent validation of their prognostic relevance in CS. METHODS: Using proximity extension assay (Olink Explore, 2942 proteins), the proteomic signature in the plasma of 9 AMI patients without shock and 8 AMI patients with CS (AMICS; exploration cohort) at admission was analyzed. Candidate biomarkers were measured in the plasma of 421 patients with AMICS from the CULPRIT-SHOCK cohort (Culprit Lesion Only PCI Versus Multivessel PCI in Cardiogenic Shock; REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT01927549, validation cohort). Their prognostic relevance was assessed for 180-day survival as the primary end point. RESULTS: Proteome profiling was successful for 2925 proteins and identified VEGFR1 (vascular endothelial growth factor receptor 1, also known as Flt1) as elevated in AMICS compared with nonshock AMI in the exploration cohort (<0.001). In patients from the independent validation cohort, nonsurvivors had markedly higher VEGFR1 levels (6.8 versus 3.8 ng/L; <0.001). In Cox regression, VEGFR1 levels were independently associated with a higher 180-day mortality risk even after adjusting for the Simplified Acute Physiology Score II (per ng/L; adjusted hazard ratio, 1.06 [95% CI, 1.03-1.09]; <0.001) and yielded incremental prognostic information in addition to serum lactate levels (<0.001). The levels of VEGFR1 in surviving (30 days; n=29) and nonsurviving (n=21) patients with AMICS were determined at different time points (days 0, 1, and 5) in a third cohort, showing continuously higher levels in nonsurvivors. CONCLUSIONS: Plasma proteomic screening identified VEGFR1 as an early biomarker in patients with AMICS that provided independent prognostic information in a large cohort of well-defined patients with AMICS.
BACKGROUND: The purpose of the current study was to investigate the clinical implications of elevated donor-derived cell-free DNA (dd-cfDNA) levels in heart transplantation recipients without evidence of rejection observ...BACKGROUND: The purpose of the current study was to investigate the clinical implications of elevated donor-derived cell-free DNA (dd-cfDNA) levels in heart transplantation recipients without evidence of rejection observed on endomyocardial biopsy. METHODS: We retrospectively analyzed dd-cfDNA samples from all consecutive heart transplantation recipients between 2019 and 2023, excluding those with multiorgan transplants. Each sample was paired with an endomyocardial biopsy (<30 days). A positive biopsy was defined based on International Society for Heart and Lung Transplantation criteria of ≥1R/1B or antibody-mediated rejection >0. Elevated dd-cfDNA was defined as ≥0.12%, with a subanalysis using a threshold of 0.20%. Graft dysfunction was defined as an ejection fraction<50%. We excluded dd-cfDNA samples with concurrent histologically positive biopsy results, focusing on those with positive dd-cfDNA and negative biopsy findings. A mixed model Cox regression approach was applied to assess for mortality and graft dysfunction. RESULTS: Of 643 dd-cfDNA samples from 227 patients, 238 samples (37%) from 110 patients showed positive dd-cfDNA results with negative endomyocardial biopsy. The median age was 56 years, with 27% females and 53% White patients. The median time from heart transplantation to sample collection was 5 months (interquartile range, 3-12). Among the positive samples, the median dd-cfDNA level was 0.24% (interquartile range, 0.16%-0.53%) with 63% exceeding 0.20%. A higher prevalence of prior treated antibody-mediated rejection was observed in the dd-cfDNA positive group (15% versus 5%; =0.002). Patients with elevated dd-cfDNA results ≥ 0.20% demonstrated a near 5-fold increased risk of mortality (hazard ratio, 4.6 [95% CI, 1.6-13.4]; =0.005) and a 3-fold risk of graft dysfunction (hazard ratio, 3.4 [95% CI, 1.0-11.9]; =0.054) compared with those with negative dd-cfDNA. CONCLUSIONS: In our cohort, patients with positive dd-cfDNA levels and negative biopsy results had higher rates of adverse outcomes, including graft dysfunction and mortality.
The discovery of the PLN-R14del (deletion of arginine 14 [p.Arg14del] within the phospholamban protein) genetic mutation, characterized by a deletion of R14 in phospholamban, in a large Greek family marked a significant...The discovery of the PLN-R14del (deletion of arginine 14 [p.Arg14del] within the phospholamban protein) genetic mutation, characterized by a deletion of R14 in phospholamban, in a large Greek family marked a significant milestone in understanding the cause of its associated cardiomyopathy. Since its initial identification in 2006, this mutation has been found in numerous patients across 11 countries. PLN-R14del carriers commonly exhibit both dilated cardiomyopathy and arrhythmogenic cardiomyopathy, accounting for a significant portion of annual heart transplants in the Netherlands. Under physiological conditions, PLN plays a crucial role in regulating the calcium pump SERCA2a (sarco[endo]plasmic reticulum calcium ATPase 2a) within cardiomyocytes. While the normal function of PLN has been extensively studied, the precise mechanisms underlying the pathogenesis of PLN-R14del-induced heart disease remain uncertain and subject to ongoing debate. The current review systematically summarizes existing literature on the PLN-R14del mutation, elucidating its pathological phenotypes and discussing its implications in PLN-R14del cardiomyopathy. Current knowledge is consolidated, and unresolved questions are addressed with the aim to contribute to a deeper understanding of PLN-R14del-associated cardiac pathology. Finally, this review provides guidance for future research to advance diagnosis and therapeutic approaches for affected individuals.
Stroeks SLVM, Merlo M, Mora-Ayestaran N
… +32 more, Jason M, Tayal U, Wang P, Cannatà A, Sikking MA, Dal Ferro M, Peiro B, Willemars M, Hellebrekers DMEI, van Leeuwen REW, Setti M, Gonzalez-Lopez E, Krapels IPC, Pio Loco Detto Gava C, van den Wijngaard A, Henkens MTHM, Iseppi M, Raafs AG, Hoes MF, van Empel VPM, Jones EAV, Nabben M, Taylor M, Brunner HG, Ochoa JP, Dominguez F, Lakdawala NK, Sinagra G, Garcia-Pavia P, Mestroni L, Heymans SRB, Verdonschot JAJ
BACKGROUND: Dilated cardiomyopathy (DCM) is a genetically heterogeneous disease, presenting diverse clinical phenotypes and outcomes based on the underlying gene affected. The influence of sex on the gene-specific long-t...BACKGROUND: Dilated cardiomyopathy (DCM) is a genetically heterogeneous disease, presenting diverse clinical phenotypes and outcomes based on the underlying gene affected. The influence of sex on the gene-specific long-term prognosis of patients with genetic DCM remains unclear. This study aims to determine the effect of sex on the long-term prognosis per underlying genogroup. METHODS: A retrospective cohort study was conducted using data from 4 international referral centers. Baseline and longitudinal clinical data of patients with DCM, with a median follow-up of 6.7 years (interquartile range, 3.5-11.9 years), were collected. The study included men and women with DCM who had undergone genetic testing. Patients were categorized into 7 genotype groups: cytoskeletal/Z-disk, desmosomal, nuclear envelope, motor sarcomeric, , other genetic, and genotype negative. The main outcomes measured were left ventricular reverse remodeling, mortality, heart failure hospitalization, heart transplantation, and malignant ventricular arrhythmias. RESULTS: Among 1716 patients, 1130 (66%) were men and 510 (30%) had a (likely) pathogenic variant. Ventricular remodeling was gene-dependent in women, with TTN patients exhibiting the highest rate (=0.003) and desmosomal patients the lowest (=0.04) compared with the genotype-negative group. After a median follow-up of 6.7 years, 334 men (29%) and 140 women (24%) reached the primary end point. Men with a (likely) pathogenic variant had the poorest prognosis, showing a higher rate of major adverse events (adjusted hazard ratio, 1.48 [95% CI, 1.12-1.95]; =0.02) and malignant ventricular arrhythmias (adjusted hazard ratio, 1.83 [95% CI, 1.16-2.88]; =0.009) compared with genotype-negative women. Prognosis varied by gene in men (log-rank <0.0001) but not in women (log-rank =0.1). The cytoskeletal/Z-disk, desmosomal, and nuclear envelope groups had the worst prognosis in men. CONCLUSIONS: The genetic architecture and sex are critical predictors of left ventricular reverse remodeling and long-term prognosis in DCM. These factors should be integrated into individualized risk prediction models to enhance clinical outcomes in patients with DCM.
Melenovsky V, Jarolim P, Kutilkova E
… +9 more, Jenca D, Binova J, Al-Hiti H, Franekova J, Kikerlova S, Yarnykh S, Adamova M, Miklovic M, Borlaug BA
Circ Heart Fail
· 2025 Dec · PMID 40985143
·
Full text
BACKGROUND: Some, but not all, patients with heart failure (HF) develop pulmonary vascular disease (PVD), which contributes to poor prognosis. Mechanisms leading to PVD in HF are poorly understood. We aimed to analyze tr...BACKGROUND: Some, but not all, patients with heart failure (HF) develop pulmonary vascular disease (PVD), which contributes to poor prognosis. Mechanisms leading to PVD in HF are poorly understood. We aimed to analyze transpulmonary gradients of proteins consumed or elaborated across the lungs to identify mediators of PVD by unbiased proteomics. METHODS: Overall, 21 controls and 160 patients with HF with reduced ejection fraction underwent pulmonary artery catheterization with blood sampling from postcapillary (wedged balloon) and precapillary (unwedged) position to obtain transpulmonary gradients. The samples from controls and HF from the highest (Q4, n=40) and lowest quartile (Q1, n=40) of pulmonary vascular resistance (PVR) were analyzed using the proteomic proximity extension assay (Olink) of 275 proteins. Venous blood concentrations or transpulmonary gradients were analyzed to identify biomarkers or potential mediators of PVD. RESULTS: Comparison of Q1 and Q4 of PVR identified PSP-D (pulmonary surfactant-associated protein D) as a marker of PVD. Examination of gradients across the lungs in high PVR HF revealed significant uptake of 18 proteins, mostly associated with inflammation (chemokines, oncostatin-M, MMP9 [matrix metalloproteinase 9]) or with TGF (transforming growth factor)/activin pathway (GDF2 [growth differentiation factor 2]/BMP9 [bone morphogenic protein 9]), and release of 5 proteins, notably IL (interleukin) 6 and IL33. In contrast, these protein gradients were negligible in controls and low PVR patients with HF. Active pulmonary release of IL6 contributed to systemic elevation of IL6 and correlated with right ventricular function. CONCLUSIONS: The lungs of patients with HF with high PVR display abnormal uptake and release of proinflammatory cytokines from IL6/gp130 family (IL6, IL33, oncostatin-M), along with increased transpulmonary uptake of GDF2/BMP9. The study shows that proteins orchestrating inflammation or pulmonary vessel remodeling in group 1 pulmonary hypertension, are also operating in patients with PVD due to HF. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT06331208.