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Background: Patients with group 1 pulmonary hypertension (PH) and risk factors for heart failure with preserved ejection fraction (HFpEF) demonstrate worse response to pulmonary vasodilator therapy. The mechanisms and optimal diagnostic approach to identify such patients remain unclear., Objectives: The purpose of this study was to compare exercise capacity, cardiac function, and hemodynamic responses to provocative maneuvers among patients with group 1 PH based upon pretest probability of HFpEF., Methods: Pretest probability for HFpEF was determined using the validated HFpEF-ABA algorithm based on age, body mass index, and history of atrial fibrillation among group 1 PH patients recruited to the multicenter PVDOMICS (Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics) study. Functional capacity, quality of life, and dynamic pulmonary capillary wedge pressure (PCWP) responses were compared between those with low (<25%), intermediate (25%-74%), and high (≥75%) ABA score-based HFpEF probability., Results: Among 424 patients with group 1 PH, 54% (n = 228) had intermediate HFpEF probability and 15% (n = 64) had high HFpEF probability. Resting PCWP increased progressively with higher HFpEF probability (P < 0.0001), and patients with group 1 PH and high HFpEF probability had the greatest increases in PCWP with nitric oxide, fluid challenge, and exercise (P < 0.001 for all), changes that were comparable to patients with HFpEF with no pulmonary vascular disease (n = 194), but lower than those with HFpEF and combined precapillary and postcapillary PH. Left ventricular/atrial size, diastolic function, quality of life, 6-minute walk distance, and peak VO 2 were most abnormal in patients with group 1 PH and high HFpEF probability compared with those with low or intermediate HFpEF probability (P < 0.0001 for all). Increasing HFpEF probability in group 1 PH was associated with greater risk of death (HR per decile of HFpEF probability 1.09; 95% CI: 1.05-1.13; P < 0.0001)., Conclusions: Quantifying pretest probability for HFpEF in patients with group 1 PH identifies a subset of patients with worse dynamic PCWP response indicative of subclinical left heart disease, with poorer functional status, quality of life, and survival. Further study in this group 1 PH subgroup is indicated to determine whether PH therapies are effective and safe, and also whether HFpEF-specific therapies can improve functional status and outcomes., Competing Interests: Funding Support and Author Disclosures The study was supported by grants from the National Institutes of Health/National Heart, Lung, and Blood Institute: U01 HL125218 (PI: Dr Rosenzweig), U01 HL125205 (PI: Dr Frantz), U01 HL125212 (PI: Dr Hemnes), U01 HL125208 (PI: Dr Rischard), U01 HL125175 (PI: Dr Hassoun), U01 HL125215 (PI: Dr Leopold), and U01 HL125177 (PI: Dr Beck), and by the Pulmonary Hypertension Association. Dr Reddy is supported by National Institutes of Health grant K23HL164901; has received research grants from Sleep Number, Bayer Accelerated Pulmonary Hypertension Award, United Jenesis Award, Merck, and the Earl Wood Career development award from Mayo Clinic. Dr Borlaug is supported by R01 HL128526, R01 HL162828, and U01 HL160226 from the National Institutes of Health/National Heart, Lung, and Blood Institute, and W81XWH2210245 from the U.S. Department of Defense; has received research grant funding from AstraZeneca, Axon, GlaxoSmithKline, Medtronic, Mesoblast, Novo Nordisk, and Tenax Therapeutics; has served as a consultant for Actelion, Amgen, Aria, Axon Therapies, BD, Boehringer Ingelheim, Cytokinetics, Edwards Lifesciences, Eli Lilly, Imbria, Janssen, Merck, Novo Nordisk, NGM, NXT, and VADovations; and is named inventor (U.S. Patent number 10,307,179) for the tools and approach for a minimally invasive pericardial modification procedure to treat heart failure. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Phosphodiesterases degrade cyclic GMP (cGMP), the second messenger that mediates the cardioprotective effects of natriuretic peptides. High natriuretic peptide/cGMP ratio may reflect, in part, phosphodiesterase activity. Correlates of natriuretic peptide/cGMP in patients with heart failure with preserved ejection fraction are not well understood. Among patients with heart failure with preserved ejection fraction in the RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure With Preserved Ejection Fraction) trial, we examined (1) cross-sectional correlates of circulating NT-proBNP (N-terminal pro-B-type natriuretic peptide)/cGMP ratio, (2) whether selective phosphodiesterase-5 inhibition by sildenafil changed the ratio, and (3) whether the effect of sildenafil on 24-week outcomes varied by baseline ratio., Methods and Results: In 212 subjects, NT-proBNP/cGMP ratio was calculated at randomization and 24 weeks. Correlates of the ratio and its change were examined in multivariable proportional odds models. Whether baseline ratio modified the sildenafil effect on outcomes was examined by interaction terms. Higher NT-proBNP/cGMP ratio was associated with greater left ventricular mass and troponin, the presence of atrial fibrillation, and lower estimated glomerular filtration rate and peak oxygen consumption. Compared with placebo, sildenafil did not alter the ratio from baseline to 24 weeks ( P =0.17). The effect of sildenafil on 24-week change in peak oxygen consumption, left ventricular mass, or clinical composite outcome was not modified by baseline NT-proBNP/cGMP ratio ( P -interaction >0.30 for all)., Conclusions: Among patients with heart failure with preserved ejection fraction, higher NT-proBNP/cGMP ratio associated with an adverse cardiorenal phenotype, which was not improved by selective phosphodiesterase-5 inhibition. Other phosphodiesterases may be greater contributors than phosphodiesterase-5 to the adverse phenotype associated with a high natriuretic peptide/cGMP ratio in HFpEF., Registration Information: clinicaltrials.gov. Identifier: NCT00763867.

Pulmonary hypertension (PH) associated with left heart failure (LHF) (PH-LHF) is one of the most common causes of PH. It directly contributes to symptoms and reduced functional capacity and negatively affects right heart function, ultimately leading to a poor prognosis. There are no specific treatments for PH-LHF, despite the high number of drugs tested so far. This scientific document addresses the main knowledge gaps in PH-LHF with emphasis on pathophysiology and clinical trials. Key identified issues include better understanding of the role of pulmonary venous versus arteriolar remodelling, multidimensional phenotyping to recognize patient subgroups positioned to respond to different therapies, and conduct of rigorous pre-clinical studies combining small and large animal models. Advancements in these areas are expected to better inform the design of clinical trials and extend treatment options beyond those effective in pulmonary arterial hypertension. Enrichment strategies, endpoint assessments, and thorough haemodynamic studies, both at rest and during exercise, are proposed to play primary roles to optimize early-stage development of candidate therapies for PH-LHF., (© 2024 European Society of Cardiology.)

Background: Group 1 pulmonary arterial hypertension (PAH) is a progressive fatal condition characterized by right ventricular (RV) failure with worse outcomes in connective tissue disease (CTD). Obstructive sleep apnea and sleep-related hypoxia may contribute to RV dysfunction, though the relationship remains unclear., Objectives: The aim of this study was to prospectively evaluate the association of the apnea-hypopnea index (AHI) and sleep-related hypoxia with RV function and survival., Methods: Pulmonary Vascular Disease Phenomics (National Heart, Lung, and Blood Institute) cohort participants (patients with group 1 PAH, comparators, and healthy control participants) with sleep studies were included. Multimodal RV functional measures were examined in association with AHI and percentage of recording time with oxygen saturation <90% (T90) per 10-unit increment. Linear models, adjusted for demographics, oxygen, diffusing capacity of the lungs for carbon monoxide, pulmonary hypertension medications, assessed AHI and T90, and RV measures. Log-rank test/Cox proportional hazards models adjusted for demographics, oxygen, and positive airway pressure were constructed for transplantation-free survival analyses., Results: Analysis included 186 participants with group 1 PAH with a mean age of 52.6 ± 14.1 years; 71.5% were women, 80.8% were Caucasian, and there were 43 events (transplantation or death). AHI and T90 were associated with decreased RV ejection fraction (on magnetic resonance imaging), by 2.18% (-2.18; 95% CI: -4.00 to -0.36; P = 0.019) and 0.93% (-0.93; 95% CI: -1.47 to -0.40; P < 0.001), respectively. T90 was associated with increased RV systolic pressure (on echocardiography), by 2.52 mm Hg (2.52; 95% CI: 1.61 to 3.43; P < 0.001); increased mean pulmonary artery pressure (on right heart catheterization), by 0.27 mm Hg (0.27; 95% CI: 0.05 to 0.49; P = 0.019); and RV hypertrophy (on electrocardiography), 1.24 mm (1.24; 95% CI: 1.10 to 1.40; P < 0.001). T90, but not AHI, was associated with a 17% increased 5-year risk for transplantation or death (HR: 1.17; 95% CI: 1.07 to 1.28). In non-CTD-associated PAH, T90 was associated with a 21% increased risk for transplantation or death (HR: 1.21; 95% CI: 1.08 to 1.34). In CTD-associated PAH, T90 was associated with RV dysfunction, but not death or transplantation., Conclusions: Sleep-related hypoxia was more strongly associated than AHI with measures of RV dysfunction, death, or transplantation overall and in group 1 non-CTD-associated PAH but only with RV dysfunction in CTD-associated PAH. (Pulmonary Vascular Disease Phenomics Program [PVDOMICS]; NCT02980887)., Competing Interests: Funding Support and Author Disclosures This study was supported by grants U01 HL125218 (principal investigator, Dr Rosenzweig), U01 HL125205 (principal investigator, Dr Frantz), U01 HL125212 (principal investigator, Dr Hemnes), U01 HL125208 (principal investigator, Dr Rischard), U01 HL125175 (principal investigator, Dr Hassoun), U01 HL125215 (principal investigator, Dr Leopold), and U01 HL125177 (principal investigator, Dr Beck) and the Pulmonary Hypertension Association. Dr Hill is a scientific advisory board member for Aerovate and Insmed; is a consultant for Bellerophon; and is a data and safety monitoring board member for Merck. Dr Finet has served as a clinical practice advisor for Wolters Kluwer Health-Lexicomp (forfeited compensation); and is an Item-Writing Task Force member for the American Board of Internal Medicine. Dr Kwon has received funding from the National Heart, Lung, and Blood Institute (grant 1R01HL170090-01); and has a research agreement with Circle Cardiovascular Imaging. Dr Beck has received support from the Pulmonary Hypertension Association. Dr Frantz has consulting, steering committee, and advisory board relationships with Altavant Sciences, Bayer, Gossamer Bio, Janssen, Shouti, the France Foundation, IQVIA, Tenax, UpToDate, and United Therapeutics. Dr Hassoun serves on a scientific steering committee for Merck Sharpe & Dohme; and is a scientific adviser for ARIA-CV (unrelated to the present work). Dr Hemnes serves as a consultant for Bayer, United Therapeutics, Janssen, GossamerBio, and Tenax Therapeutics; holds stock in Tenax Therapeutics; and has received grants from the National Institutes of Health, the Cardiovascular Medical Research and Education Fund, and Imara. Dr Horn has conducted research studies with Acceleron/Merck, Cereno, and Insmed. Dr Leopold is a consultant for Abbott Vascular; is a speaker for United Therapeutics; has received research funding from Astellas to her institution; and has received support from the American Heart Association (grant AIM 19AIML34980000; National Heart, Lung, and Blood Institute grant U01 HL125215). Dr Rischard has consulting relationships with Acceleron and United Therapeutics; is a steering committee member for Acceleron; and receives research support from Ismed, United Therapeutics, Bayer, Acceleron, Janssen, and Aadi Bioscience. Dr Mehra has received an honorarium from the American Academy of Sleep Medicine; has received funds for service on the American Board of Internal Medicine and as associate editor of the American Journal of Respiratory and Critical Care Medicine; has received National Institutes of Health funding; has received investigator-initiated research funds to her institution from Resmed, Inspire, and Sommetrics; and has received royalties from UpToDate. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Pulmonary hypertension (PH) in heart failure with preserved ejection fraction (HFpEF) is a common and highly morbid syndrome, but mechanisms driving PH-HFpEF are poorly understood. We sought to determine whether a well-accepted murine model of HFpEF also displays features of PH, and we sought to identify pathways that might drive early remodeling of the pulmonary vasculature in HFpEF., Methods: Eight-week-old male and female C57BL/6J mice received either N γ -nitro-L-arginine methyl ester and high-fat diet or control water and diet for 2, 5, and 12 weeks. The db/db mice were studied as a second model of HFpEF. Early pathways regulating PH were identified by bulk and single-cell RNA sequencing. Findings were confirmed by immunostain in lungs of mice or lung slides from clinically performed autopsies of patients with PH-HFpEF. ELISA was used to verify IL-1β (interleukin-1 beta) in mouse lung, mouse plasma, and also human plasma from patients with PH-HFpEF obtained at the time of right heart catheterization. Clodronate liposomes and an anti-IL-1β antibody were utilized to deplete macrophages and IL-1β, respectively, to assess their impact on pulmonary vascular remodeling in HFpEF in mouse models., Results: N γ -nitro-L-arginine methyl ester/high-fat diet-treated mice developed PH, small vessel muscularization, and right heart dysfunction. Inflammation-related gene ontologies were overrepresented in bulk RNA sequencing analysis of whole lungs, with an increase in CD68 + cells in both murine and human PH-HFpEF lungs. Cytokine profiling showed an increase in IL-1β in mouse and human plasma. Finally, clodronate liposome treatment in mice prevented PH in N γ -nitro-L-arginine methyl ester/high-fat diet-treated mice, and IL-1β depletion also attenuated PH in N γ -nitro-L-arginine methyl ester/high-fat diet-treated mice., Conclusions: We report a novel model for the study of PH and right heart remodeling in HFpEF, and we identify myeloid cell-derived IL-1β as an important contributor to PH in HFpEF., Competing Interests: Disclosures None.

Aims: Heart failure with preserved ejection fraction (HFpEF) is characterized by diastolic dysfunction, microvascular dysfunction, and myocardial fibrosis with recent evidence implicating the immune system in orchestrating cardiac remodelling., Methods and Results: Here, we show the mouse model of deoxycorticosterone acetate (DOCA)-salt hypertension induces key elements of HFpEF, including diastolic dysfunction, exercise intolerance, and pulmonary congestion in the setting of preserved ejection fraction. A modified single-cell sequencing approach, cellular indexing of transcriptomes and epitopes by sequencing, of cardiac immune cells reveals an altered abundance and transcriptional signature in multiple cell types, most notably cardiac macrophages. The DOCA-salt model results in differential expression of several known and novel genes in cardiac macrophages, including up-regulation of Trem2, which has been recently implicated in obesity and atherosclerosis. The role of Trem2 in hypertensive heart failure, however, is unknown. We found that mice with genetic deletion of Trem2 exhibit increased cardiac hypertrophy, diastolic dysfunction, renal injury, and decreased cardiac capillary density after DOCA-salt treatment compared to wild-type controls. Moreover, Trem2-deficient macrophages have impaired expression of pro-angiogenic gene programmes and increased expression of pro-inflammatory cytokines. Furthermore, we found that plasma levels of soluble TREM2 are elevated in DOCA-salt treated mice and humans with heart failure., Conclusions: Together, our data provide an atlas of immunological alterations that can lead to improved diagnostic and therapeutic strategies for HFpEF. We provide our dataset in an easy to explore and freely accessible web application making it a useful resource for the community. Finally, our results suggest a novel cardioprotective role for Trem2 in hypertensive heart failure., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Normative changes in right ventricular (RV) structure and function have not been characterized in the context of treatment-associated functional recovery (RV functional recovery [RVFnRec]). The aim of this study is to assess the clinical relevance of a proposed RVFnRec definition., Methods: We evaluated 63 incident patients with pulmonary arterial hypertension by right heart catheterization and cardiac magnetic resonance imaging at diagnosis and cardiac magnetic resonance imaging and invasive cardiopulmonary exercise testing following treatment (≈11 months). Sex, age, ethnicity matched healthy control subjects (n=62) with 1-time cardiac magnetic resonance imaging and noninvasive cardiopulmonary exercise testing were recruited from the PVDOMICS (Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics) project. We examined therapeutic cardiac magnetic resonance imaging changes relative to the evidence-based peak oxygen consumption (VO 2peak )>15 mL/(kg·min) to define RVFnRec by receiver operating curve analysis. Afterload was measured as mean pulmonary artery pressure, resistance, compliance, and elastance., Results: A drop in RV end-diastolic volume of -15 mL best defined RVFnRec (area under the curve, 0.87; P =0.0001) and neared upper 95% CI RV end-diastolic volume of controls. This cutoff was met by 22 out of 63 (35%) patients which was reinforced by freedom from clinical worsening, RVFnRec 1 out of 21 (5%) versus no RVFnRec 17 out of 42, 40% (log-rank P =0.006). A therapy-associated increase of 0.8 mL/mm Hg in compliance had the best predictive value of RVFnRec (area under the curve, 0.76; [95% CI, 0.64-0.88]; P =0.001). RVFnRec patients had greater increases in stroke volume, and cardiac output at exercise., Conclusions: RVFnRec defined by RV end-diastolic volume therapeutic decrease of -15 mL predicts exercise capacity, freedom from clinical worsening, and nears normalization. A therapeutic improvement of compliance is superior to other measures of afterload in predicting RVFnRec. RVFnRec is also associated with increased RV output reserve at exercise., Competing Interests: Disclosures Dr Rischard has consulting relationships with Bayer and receives research support from Ismed, United Therapeutics, Bayer, Acceleron, Merck, and Janssen. Dr Naeije reports relationships including consultancies, speakers fees, and membership of advisory boards with AOP Orphan Pharmaceuticals, Johnson & Johnson, Lung Biotechnology Corporation, and United Therapeutics. Dr Garcia is Chief Executive Officer and founder of Aqualung Therapeutics Corporation. Dr Frantz has consulting, steering committee, and advisory board relationships with Altavant Sciences, Bayer, Gossamer Bio, Janssen, Shouti, France Foundation, IQVIA, Tenax, UpToDate, and United Therapeutics. Dr Hassoun has served as consultant for Merck. Dr Hemnes has consulting relationships with Janssen, Merck, Gossamer, Bio, United Therapeutics, Bayer, Tenax. She owns stock in Tenax therapeutics and she has received research support from National Heart, Lung, and Blood Institute and Cardiovascular Medical Research and Education Fund. Dr Hill is the chair for an Aerovate steering committee. He is a consultant for Bellerophon and Liquidia and Merck. Dr Horn has consulting relationships with Biotronik and AADI biosciences. She serves on the DSMB for SoniVie and V-waves Ltd. She receives research support from Merck and Cereno. Dr Leopold Abbott has served as a consultant for Aria. She has research support from Astellas Pharma and United Therapeutics. Dr Rosenzweig has received consulting fees from Acceleron for a scientific advisory board meeting; and her institution receives grant support from Bayer, United Therapeutics, Janssen, and SonVie. Dr Tang served as consultant for Sequana Medical, Cardiol Therapeutics, Genomics plc, Zehna Therapeutics, Renovacor, WhiteSwell, Kiniksa, Boston Scientific, and CardiaTec Biosciences and has received honorarium from Springer Nature and American Board of Internal Medicine. The other authors report no conflicts.

Aims: Iron deficiency is common in pulmonary hypertension, but its clinical significance and optimal definition remain unclear., Methods and Results: Phenotypic data for 1028 patients enrolled in the Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics study were analyzed. Iron deficiency was defined using the conventional heart failure definition and also based upon optimal cut-points associated with impaired peak oxygen consumption (peakVO2), 6-min walk test distance, and 36-Item Short Form Survey (SF-36) scores. The relationships between iron deficiency and cardiac and pulmonary vascular function and structure and outcomes were assessed. The heart failure definition of iron deficiency endorsed by pulmonary hypertension guidelines did not identify patients with reduced peakVO2, 6-min walk test, and SF-36 (P > 0.208 for all), but defining iron deficiency as transferrin saturation (TSAT) <21% did. Compared to those with TSAT ≥21%, patients with TSAT <21% demonstrated lower peakVO2 [absolute difference: -1.89 (-2.73 to -1.04) mL/kg/min], 6-min walk test distance [absolute difference: -34 (-51 to -17) m], and SF-36 physical component score [absolute difference: -2.5 (-1.3 to -3.8)] after adjusting for age, sex, and hemoglobin (all P < 0.001). Patients with a TSAT <21% had more right ventricular remodeling on cardiac magnetic resonance but similar pulmonary vascular resistance on catheterization. Transferrin saturation <21% was also associated with increased mortality risk (hazard ratio 1.63, 95% confidence interval 1.13-2.34; P = 0.009) after adjusting for sex, age, hemoglobin, and N-terminal pro-B-type natriuretic peptide., Conclusion: The definition of iron deficiency in the 2022 European Society of Cardiology (ESC)/European Respiratory Society (ERS) pulmonary hypertension guidelines does not identify patients with lower exercise capacity or functional status, while a definition of TSAT <21% identifies patients with lower exercise capacity, worse functional status, right heart remodeling, and adverse clinical outcomes., Competing Interests: Conflict of interest P.M. has received consultancy fees from AstraZeneca, Abbott, Bayer, Boehringer-Ingelheim, Daiichi Sankyo, Novartis, Novo Nordisk, and Vifor Pharma. B.A.B. receives research grant funding from AstraZeneca, Axon, GlaxoSmithKline, Medtronic, Mesoblast, Novo Nordisk, Rivus, and Tenax Therapeutics, has served as a consultant for Actelion, Amgen, Aria, Axon Therapies, BD, Boehringer-Ingelheim, Cytokinetics, Edwards Lifesciences, Eli Lilly, Imbria, Janssen, Merck, Novo Nordisk, NGM, NXT, and VADovations, and is named inventor (US Patent no. 10307179) for the tools and approach for a minimally invasive pericardial modification procedure to treat heart failure. A.R.H. has served as a consultant for GossamerBio, Tenax Therapeutics, United Therapeutics, Merck, and Janssen. She is a stock holder in Tenax Therapeutics. W.H.W.T. is a consultant for Sequana Medical, Cardiol Therapeutics, Genomics plc, Zehna Therapeutics, Renovacor, Kiniksa, WhiteSwell, Boston Scientific, and CardiaTec Biosciences and has received honorarium from Springer Nature and American Board of Internal Medicine. All other authors reported no relevant relationships to disclose., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Right ventricular dysfunction is a hallmark of advanced pulmonary vascular, lung parenchymal, and left heart disease, yet the underlying mechanisms that govern (mal)adaptation remain incompletely characterized. Owing to the knowledge gaps in our understanding of the right ventricle (RV) in health and disease, the National Heart, Lung, and Blood Institute (NHLBI) commissioned a working group to identify current challenges in the field. These included a need to define and standardize normal RV structure and function in populations; access to RV tissue for research purposes and the development of complex experimental platforms that recapitulate the in vivo environment; and the advancement of imaging and invasive methodologies to study the RV within basic, translational, and clinical research programs. Specific recommendations were provided, including a call to incorporate precision medicine and innovations in prognosis, diagnosis, and novel RV therapeutics for patients with pulmonary vascular disease., Competing Interests: Conflict of Interest Statement Dr. Aggarwal has nothing to disclose. Dr. Aldred reports grants from NHLBI during the conduct of the study. Dr. Archer has nothing to disclose. Dr. Benza reports grants from Abbott during the conduct of the study; grants from Actelion, grants from United Therapeutics, grants from Bayer, grants from NIH/NHLBI outside the submitted work. Dr. Bristow has nothing to disclose. Dr. Brittain has nothing to disclose. Dr. Chesler reports personal fees from Endotronix, Inc. and personal fees from Aria CV outside the submitted work. Dr. de Man has nothing to disclose. Dr. Erzurum has nothing to disclose. Dr. Gladwin is a co-inventor of patents and patent applications directed to the use of recombinant neuroglobin and heme-based molecules as antidotes for CO poisoning, which have been licensed by Globin Solutions, Inc. Dr. Gladwin is a shareholder, advisor, and director in Globin Solutions, Inc. Dr. Gladwin is also co-inventor on patents directed to the use of nitrite salts in cardiovascular diseases, which were previously licensed to United Therapeutics, and is now licensed to Globin Solutions and Hope Pharmaceuticals. Dr. Gladwin is a principal investigator in a research collaboration with Bayer Pharmaceuticals to evaluate riociguat as a treatment for patients with SCD. Dr. Gladwin has served as a consultant for Epizyme, Inc., Actelion Clinical Research, Inc., Acceleron Pharma, Inc., Catalyst Biosciences, Inc., Modus Therapeutics, Sujana Biotech, LLC, Complexa Inc., Pfizer Inc., and United Therapeutics Corporation. Dr. Gladwin is also on Bayer HealthCare LLC’s Heart and Vascular Disease Research Advisory Board. Dr. Hemnes reports personal fees from Actelion, personal fees from Bayer, personal fees from Complexa, personal fees from United Therapeutics, other from PHPrecisionMed, outside the submitted work. Dr. Hassoun has served on an advisory board for Merck in 2019. Dr. Kawut reports grants from NIH, non-financial support from the ATS, and grants from Actelion, United Therapeutics, Gilead, Lung Biotech, Bayer, and Mallinkrodt to the Perelman School of Medicine for CME courses. Dr. Kawut reports grants and non-financial support from Cardiovascular Medical Research and Education Fund and non-financial support from Pulmonary Hypertension Association. Dr. Kawut has served in an advisory capacity (for grant review and other purposes) for United Therapeutics, Glaxo SmithKline, and Complexa, Inc. without financial support or in-kind benefits. Dr. Lahm reports personal fees from Bayer, personal fees from Gilead, personal fees from Actelion, other from Eli Lilly outside the submitted work. Dr. Leopold has nothing to disclose. Dr. Lima has nothing to disclose. Dr. Loscalzo is a scientific co-founder of Scipher, a startup company that uses network concepts to explore human disease treatment strategies. Dr. Maron reports other from Actelion Pharmaceuticals Inc., outside the submitted work. In addition, Dr. Maron has a patent U.S. Patent #9,605,047 issued, a patent U.S. Provisional Application ID: 62475955 pending, a patent U.S. Provisional Application Cover Sheet ID: 24624 pending, and a patent U.S. Patent application PCT/US2019/059890 pending. Dr. Mercer-Rosa has nothing to disclose. Dr. Newman has nothing to disclose. Dr. Redline reports grants and personal fees from Jazz Pharmaceuticals, personal fees from RespirCardia Inc. outside the submitted work. Dr. Rich has nothing to disclose. Dr. Rischard has nothing to disclose. Dr. Sugeng has nothing to disclose. Dr. Tang reports grants from National Institutes of Health, personal fees from Sequana Medical Inc, personal fees from Springer, personal fees from MyoKardia Inc outside the submitted work. Dr Tedford reports other from Actelion, other from Merck, personal fees from United Therapeutics, personal fees from Aria CV, personal fees from Arena pharmaceuticals, personal fees from Gradient, personal fees from Eidos Therapeutics, personal fees and other from Abbott, personal fees and other from Medtronic, personal fees from Itamar, other from Abiomed, and personal fees and other from Acceleron outside the submitted work. Dr. Tsai reports grants from National Heart, Lung, and Blood Institute (NHLBI), grants from American College of Cardiology, grants from The Rachel and Drew Katz Foundation outside the submitted work. In addition, Dr. Tsai has a patent Pharmacologic Treatment for Right Ventricular Failure (USSN 62/836,315) issued to The Trustees of Columbia University in the City of New York. Dr. Ventetuolo reports grants from NHLBI during the conduct of the study; grants from United Therapeutics, grants from American Thoracic Society, personal fees from Acceleron Pharma, personal fees from Bayer outside the submitted work. Dr. Lei Xiao has no conflict of interest to disclose. Dr. Zhao has nothing to disclose.

Background Identification of occult diastolic dysfunction often requires invasive right heart catheterization with provocative maneuvers such as fluid challenge. Non-invasive predictors of occult diastolic dysfunction have not been identified. We hypothesized that echocardiographic measures of diastolic function are associated with occult diastolic dysfunction identified at catheterization. Methods and Results We retrospectively examined hemodynamic and echocardiographic data from consecutive patients referred for right heart catheterization with fluid challenge from 2009 to 2017. A replication cohort of 52 patients who prospectively underwent simultaneous echocardiography and right heart catheterization before and after fluid challenge at Monaldi Hospital, Naples, Italy. In the retrospective cohort of 126 patients (83% female, 56+14 years), 27/126 (21%) had occult diastolic dysfunction. After adjusting for tricuspid regurgitant velocity and left atrial volume index, E velocity (odds ratio 1.8, 95% CI 1.1-2.9, P=0.01) and E/e' (odds ratio 1.9, 95% CI 1.1-3, P=0.005) were associated with occult diastolic dysfunction with an optimal threshold of E/e' >8.6 for occult diastolic dysfunction (sensitivity 70%, specificity 64%). In the prospective cohort, 5/52 (10%) patients had diastolic dysfunction after fluid challenge. Resting E/e' (odds ratio 8.75, 95% CI 2.3-33, P=0.001) and E velocity (odds ratio 7.7, 95% CI 2-29, P=0.003) remained associated with occult diastolic dysfunction with optimal threshold of E/e' >8 (sensitivity 73%, specificity 90%). Conclusions Among patients referred for right heart catheterization with fluid challenge, E velocity and E/e' are associated with occult diastolic dysfunction after fluid challenge. These findings suggest that routine echocardiographic measurements may help identify patients like to have occult diastolic dysfunction non-invasively.

Rationale: Hyponatremia is associated with decompensated heart failure and poor prognosis in patients with left ventricular systolic dysfunction., Objectives: We sought to determine if hyponatremia is associated with right heart failure and worse prognosis in patients with pulmonary arterial hypertension (PAH)., Methods: We prospectively followed 40 patients with PAH and examined the relationship between serum sodium and right heart function as well as survival., Measurements and Main Results: Subjects with hyponatremia (Na < or = 136 mEq/L) were more symptomatic (11/13 World Health Organization [WHO] class III/IV vs. 12/27 WHO class III/IV; P = 0.02), had more peripheral edema (69 vs. 26%; P = 0.009), and had higher hospitalization rates (85 vs. 41%; P = 0.009) than normonatremic subjects. Hyponatremic subjects had higher right atrial pressure (14 +/- 6 vs. 9 +/- 3 mm Hg; P < 0.001), lower stroke volume index (21 +/- 7 vs. 32 +/- 10 ml/m(2); P < 0.01), larger right ventricular:left ventricular area ratio (1.8 +/- 0.4 vs. 1.3 +/- 0.4; P < 0.001), and lower tricuspid annular plane systolic excursion (1.4 +/- 0.3 vs. 2.0 +/- 0.6 cm; P = 0.001), despite similar mean pulmonary artery pressure (49 +/- 10 vs. 47 +/- 12 mm Hg; P = 0.60). The 1- and 2-year survival estimates were 93% (95% confidence interval [CI], 73-98%) and 85% (95% CI, 65-94%), and 38% (95% CI, 14-63%) and 15% (95% CI, 2-39%) for normonatremic and hyponatremic subjects, respectively (log-rank chi(2) = 25.19, P < 0.001). The unadjusted risk of death (hazard ratio) in hyponatremic compared with normonatremic subjects was 10.16 (95% CI, 3.42-30.10, P < 0.001). Hyponatremia predicted outcome after adjusting for WHO class, diuretic use, as well as right atrial pressure and cardiac index., Conclusions: Hyponatremia is strongly associated with right heart failure and poor survival in PAH.

Several indices of right heart remodeling and function have been associated with survival in pulmonary arterial hypertension (PAH). Outcome analysis and physiological relationships between variables may help develop a consistent grading system. Patients with Group 1 PAH followed at Stanford Hospital who underwent right heart catheterization and echocardiography within 2 weeks were considered for inclusion. Echocardiographic variables included tricuspid annular plane systolic excursion (TAPSE), right ventricular (RV) fractional area change (RVFAC), free wall strain (RVFWS), RV dimensions, and right atrial volumes. The main outcome consisted of death or lung transplantation at 5 years. Mathematical relationships between variables were determined using weighted linear regression and severity thresholds for were calibrated to a 20% 1‐year mortality risk. PAH patients (n = 223) had mean (SD) age of 48.1 (14.1) years, most were female (78%), with a mean pulmonary arterial pressure of 51.6 (13.8) mmHg and pulmonary vascular resistance index of 22.5(6.3) WU/m2. Measures of right heart size and function were strongly related to each other particularly RVFWS and RVFAC (R2 = 0.82, p < 0.001), whereas the relationship between TAPSE and RVFWS was weaker (R2 = 0.28, p < 0.001). Death or lung transplantation at 5 years occurred in 78 patients (35%). Guided by outcome analysis, we ascertained a uniform set of parameter thresholds for grading the severity of right heart adaptation in PAH. Using these quantitative thresholds, we, then, validated the recently reported REVEAL‐echo score (AUC 0.68, p < 0.001). This study proposes a consistent echocardiographic grading system for right heart adaptation in PAH guided by outcome analysis. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are progressive diseases that can lead to right heart failure and death. Right ventricular dysfunction, hypertrophy and maladaptive remodelling are consequences of increased right ventricular (RV) afterload in PAH and CTEPH and are indicative of long-term outcomes. Because RV failure is the main cause of morbidity and mortality in PAH and CTEPH, successful treatments should lead to improvements in RV parameters. Riociguat is a soluble guanylate cyclase stimulator approved for the treatment of PAH and inoperable or persistent/recurrent CTEPH after pulmonary endarterectomy. This review examines the current evidence showing the effect of riociguat on the right ventricle, with particular focus on remodelling, function and structural parameters in preclinical models and patients with PAH or CTEPH. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension (PH) is a common complication of chronic obstructive pulmonary disease (COPD). Little is known about the prevalence and clinical profiles of patients with COPD‐PH. We report the clinical characteristics, hemodynamic profiles, and prognosis in a large population of patients with COPD referred for right heart catheterization (RHC). We extracted data from all patients referred for RHC between 1997 and 2017 in Vanderbilt's deidentified medical record. PH was defined as mean pulmonary artery pressure >20 mmHg. Pre‐ and postcapillary PH were defined according to contemporary guidelines. COPD was identified using a validated rules‐based algorithm requiring international classification of diseases codes relevant to COPD. We identified 6065 patients referred for RHC, of whom 1509 (24.9%) had COPD and 1213 had COPD and PH. Patients with COPD‐PH had a higher prevalence of diabetes, atrial fibrillation, and heart failure compared with COPD without PH. Approximately 55% of patients with COPD‐PH had elevated left ventricle (LV) filling pressure. Pulmonary function testing data from individuals with COPD‐PH revealed subtype differences, with precapillary COPD‐PH having lower diffusion capacity of the lungs for carbon monoxide (DLCO) values than the other COPD‐PH subtypes. Patients with COPD‐PH had significantly increased mortality compared with COPD alone (hazard ratio [HR]: 1.70, 95% confidence interval [CI]: 1.28–2.26) with the highest mortality among the combined pre‐ and postcapillary COPD‐PH subgroup (HR: 2.39; 95% CI: 1.64–3.47). PH is common among patients with COPD referred for RHC. The etiology of PH in patients with COPD is often mixed due to multimorbidity and is associated with high mortality, which may have implications for risk factor management. [ABSTRACT FROM AUTHOR]

Purpose: Transpulmonary biomarkers may provide insight into pulmonary hypertension (PH) pathophysiology, but require cardiac catheterization. We investigated whether the peripheral arterial–venous ratio (PR) could substitute for the transpulmonary ratio (TPR). Materials and methods: Blood from the pulmonary artery (PA), pulmonary arterial wedge (PAW), peripheral venous, and peripheral arterial positions was analysed for ET-1, NT-pro-BNP and cAMP levels in subjects with no PH (n = 18) and PH due to left heart disease (PH-LHD), which included combined pre- and post-capillary PH (Cpc-PH; n = 7) and isolated post-capillary PH (Ipc-PH; n = 9). Bland–Altman comparisons were made between peripheral venous and PA samples and between peripheral arterial and PAW samples. TPR was defined as [PAW]/[PA]. Results: For ET-1, Bland–Altman analysis indicated negative bias (−24%) in peripheral arterial compared to PAW concentration and positive bias (23%) in peripheral venous compared to PA concentration. There was <10% absolute bias for NT-pro-BNP and cAMP. For ET-1, there was no difference in PR between Cpc-PH and Ipc-PH (0.87 ± 0.4 vs. 0.94 ± 0.6, p = 0.8), whereas there was a difference in TPR (2.2 ± 1.1 vs. 1.1 ± 0.2, p < 0.05). Conclusions: In PH-LHD, peripheral samples may be inadequate surrogates for transpulmonary samples, particularly when measuring mediators with prominent pulmonary secretion or clearance, such as ET-1. [ABSTRACT FROM AUTHOR]

Background: Evidence-based guidelines recommend the use of parenteral prostaglandin (PP) therapy in patients with advanced pulmonary arterial hypertension (PAH). Despite this, many patients with PAH die without PP therapy. We sought to examine the frequency of PP use at a large referral center and characterize patients with PAH who died without receiving PP.Methods: We conducted a single-center retrospective cohort analysis of consecutive patients with PAH between 2008 and 2012. Clinical data and cause of death were compared between patients with PAH treated with PP (PAH-PP) and those who were not but were not documented as poor PP candidates (PAH-nonPP).Results: Of the 101 patients who received a diagnosis of PAH and died, 61 received PP therapy. Of the 40 patients not treated with PP, 10 did not have documented evaluations for PP therapy (PAH-nonPP) whereas 30 were not considered candidates or refused PP therapy. Compared with PAH-PP, PAH-nonPP had a longer 6-min walk distance, had a longer duration between time of diagnosis and date of worse functional class visit, were less likely to be diagnosed as functional class IV, and had significantly lower right atrial pressure. None of the PAH-nonPP died of progressive PAH.Conclusions: We found that most patients who die with PAH are evaluated for PP therapy at a large referral center and the small minority of PAH-nonPP tended to have less severe disease and die of non-PAH-related causes. Our data suggest that at large pulmonary hypertension (PH) centers, the vast majority of patients who are appropriate candidates receive PP therapy. [ABSTRACT FROM AUTHOR]

Objectives: Pulmonary arterial hypertension (PAH) in its advanced stages is complicated by right heart failure and often pericardial effusion. The optimal treatment of large or hemodynamically significant pericardial effusions in this group has not been defined. Methods: All patients followed at the Johns Hopkins Hospital for PAH during a 1-year period that underwent pericardiocentesis or pericardial window placement were identified. Charts were analyzed for patient characteristics, echocardiographic data, and type/outcome of procedure. Results: Six patients were identified; five underwent therapeutic drainage. Pericardiocentesis was performed in four cases; two had surgical pericardial windows. Two patients died after pericardiocentesis and one patient died after surgery. All patients died within 13 hours of the procedure. Conclusion: We found a high mortality related to pericardial fluid drainage in patients with PAH. The pathophysiologic explanation for these deaths remains unclear, but clinicians should consider conservative management in this situation if possible. [ABSTRACT FROM AUTHOR]