Observational Study

. 2022 Aug 16;80(7):697-718.

doi: 10.1016/j.jacc.2022.05.038.

Clinical Characteristics and Transplant-Free Survival Across the Spectrum of Pulmonary Vascular Disease

Anna R Hemnes¹, Jane A Leopold², Milena K Radeva³, Gerald J Beck³, Aiden Abidov⁴, Micheala A Aldred⁵, John Barnard³, Erika B Rosenzweig⁶, Barry A Borlaug⁷, Wendy K Chung⁸, Suzy A A Comhair⁹, Ankit A Desai⁵, Hilary M Dubrock¹⁰, Serpil C Erzurum¹¹, J Emanuel Finet¹², Robert P Frantz⁷, Joe G N Garcia¹³, Mark W Geraci¹⁴, Michael P Gray¹⁵, Gabriele Grunig¹⁶, Paul M Hassoun¹⁷, Kristin B Highland¹⁸, Nicholas S Hill¹⁹, Bo Hu³, Deborah H Kwon¹², Miriam S Jacob¹², Christine L Jellis¹², A Brett Larive³, Jason K Lempel²⁰, Bradley A Maron², Stephen C Mathai¹⁷, Kevin McCarthy²¹, Reena Mehra²², Rawan Nawabit²³, John H Newman²⁴, Mitchell A Olman⁹, Margaret M Park¹², Jose A Ramos¹⁸, Rahul D Renapurkar²⁰, Franz P Rischard²⁵, Susan G Sherer³, W H Wilson Tang¹², James D Thomas²⁶, Rebecca R Vanderpool²⁷, Aaron B Waxman²⁸, Jennifer D Wilcox²⁹, Jason X-J Yuan³⁰, Evelyn M Horn³¹; PVDOMICS Study Group

Affiliations

¹ Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA. Electronic address: anna.r.hemnes@vumc.org.
² Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
³ Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio, USA.
⁴ Division of Cardiology, Wayne State University, Detroit, Michigan, USA.
⁵ Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
⁶ Department of Pediatrics and Medicine, Columbia University, New York, New York, USA.
⁷ Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA.
⁸ Department of Pediatrics, Columbia University, New York, New York, USA.
⁹ Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA.
¹⁰ Department of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota, USA.
¹¹ Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
¹² Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio, USA.
¹³ Department of Medicine, University of Arizona, Tucson, Arizona, USA.
¹⁴ Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
¹⁵ Department of Cardiology, The University of Sydney, Sydney, New South Wales, Australia.
¹⁶ Department of Environmental Medicine, New York University Grossman School of Medicine, New York, New York, USA.
¹⁷ Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
¹⁸ Respiratory Institute, Cleveland Clinic, Cleveland, Ohio, USA.
¹⁹ Division of Pulmonary, Critical Care, and Sleep Medicine, Tufts Medical Center, Boston, Massachusetts, USA.
²⁰ Imaging Institute, Cleveland Clinic, Cleveland, Ohio, USA.
²¹ Respiratory Solutions, ERT, Inc, Cleveland, Ohio, USA.
²² Neurologic and Respiratory Institutes, Cleveland Clinic, Cleveland, Ohio, USA.
²³ Pediatrics Institute, Cleveland Clinic, Cleveland, Ohio, USA.
²⁴ Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
²⁵ Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, University of Arizona, Tucson, Arizona, USA.
²⁶ Bluhm Cardiovascular Institute, Northwestern Medicine, Chicago, Illinois, USA.
²⁷ Division of Cardiovascular Medicine, The Ohio State University, Columbus, Ohio, USA.
²⁸ Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
²⁹ Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic Cleveland, Ohio, USA.
³⁰ Department of Medicine, University of California, San Diego, California, USA.
³¹ Perkin Heart Failure Center, Division of Cardiology, Weill Cornell Medicine, New York, New York, USA.

PMID: 35953136
PMCID: PMC9897285
DOI: 10.1016/j.jacc.2022.05.038

Observational Study

Clinical Characteristics and Transplant-Free Survival Across the Spectrum of Pulmonary Vascular Disease

Anna R Hemnes et al. J Am Coll Cardiol. 2022.

. 2022 Aug 16;80(7):697-718.

doi: 10.1016/j.jacc.2022.05.038.

Authors

Affiliations

¹ Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA. Electronic address: anna.r.hemnes@vumc.org.
² Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
³ Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio, USA.
⁴ Division of Cardiology, Wayne State University, Detroit, Michigan, USA.
⁵ Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
⁶ Department of Pediatrics and Medicine, Columbia University, New York, New York, USA.
⁷ Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA.
⁸ Department of Pediatrics, Columbia University, New York, New York, USA.
⁹ Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA.
¹⁰ Department of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota, USA.
¹¹ Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
¹² Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio, USA.
¹³ Department of Medicine, University of Arizona, Tucson, Arizona, USA.
¹⁴ Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
¹⁵ Department of Cardiology, The University of Sydney, Sydney, New South Wales, Australia.
¹⁶ Department of Environmental Medicine, New York University Grossman School of Medicine, New York, New York, USA.
¹⁷ Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
¹⁸ Respiratory Institute, Cleveland Clinic, Cleveland, Ohio, USA.
¹⁹ Division of Pulmonary, Critical Care, and Sleep Medicine, Tufts Medical Center, Boston, Massachusetts, USA.
²⁰ Imaging Institute, Cleveland Clinic, Cleveland, Ohio, USA.
²¹ Respiratory Solutions, ERT, Inc, Cleveland, Ohio, USA.
²² Neurologic and Respiratory Institutes, Cleveland Clinic, Cleveland, Ohio, USA.
²³ Pediatrics Institute, Cleveland Clinic, Cleveland, Ohio, USA.
²⁴ Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
²⁵ Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, University of Arizona, Tucson, Arizona, USA.
²⁶ Bluhm Cardiovascular Institute, Northwestern Medicine, Chicago, Illinois, USA.
²⁷ Division of Cardiovascular Medicine, The Ohio State University, Columbus, Ohio, USA.
²⁸ Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
²⁹ Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic Cleveland, Ohio, USA.
³⁰ Department of Medicine, University of California, San Diego, California, USA.
³¹ Perkin Heart Failure Center, Division of Cardiology, Weill Cornell Medicine, New York, New York, USA.

PMID: 35953136
PMCID: PMC9897285
DOI: 10.1016/j.jacc.2022.05.038

Abstract

Background: PVDOMICS (Pulmonary Vascular Disease Phenomics) is a precision medicine initiative to characterize pulmonary vascular disease (PVD) using deep phenotyping. PVDOMICS tests the hypothesis that integration of clinical metrics with omic measures will enhance understanding of PVD and facilitate an updated PVD classification.

Objectives: The purpose of this study was to describe clinical characteristics and transplant-free survival in the PVDOMICS cohort.

Methods: Subjects with World Symposium Pulmonary Hypertension (WSPH) group 1-5 PH, disease comparators with similar underlying diseases and mild or no PH and healthy control subjects enrolled in a cross-sectional study. PH groups, comparators were compared using standard statistical tests including log-rank tests for comparing time to transplant or death.

Results: A total of 1,193 subjects were included. Multiple WSPH groups were identified in 38.9% of PH subjects. Nocturnal desaturation was more frequently observed in groups 1, 3, and 4 PH vs comparators. A total of 50.2% of group 1 PH subjects had ground glass opacities on chest computed tomography. Diffusing capacity for carbon monoxide was significantly lower in groups 1-3 PH than their respective comparators. Right atrial volume index was higher in WSPH groups 1-4 than comparators. A total of 110 participants had a mean pulmonary artery pressure of 21-24 mm Hg. Transplant-free survival was poorest in group 3 PH.

Conclusions: PVDOMICS enrolled subjects across the spectrum of PVD, including mild and mixed etiology PH. Novel findings include low diffusing capacity for carbon monoxide and enlarged right atrial volume index as shared features of groups 1-3 and 1-4 PH, respectively; unexpected, frequent presence of ground glass opacities on computed tomography; and sleep alterations in group 1 PH, and poorest survival in group 3 PH. PVDOMICS will facilitate a new understanding of PVD and refine the current PVD classification. (Pulmonary Vascular Disease Phenomics Program PVDOMICS [PVDOMICS]; NCT02980887).

Keywords: phenotyping; pulmonary hypertension.

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Conflict of interest statement

Funding Support and Author Disclosures The study received 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 was supported by the Pulmonary Hypertension Association. Dr Hemnes has served 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, CMREF, and Imara. Dr Leopold is supported by the National Institutes of Health grant U01 125215 and the American Heart Association 19AIML34980000; receives salary support from the Massachusetts Medical Society; has received research funding (to her institution) from Astellas; has served as a consultant for Abbott Vascular and United Therapeutics; and has served as a site principal investigator for a study sponsored by Aria CV. Dr Abidov is supported by research grants from Astellas Pharma, Boehringer Ingelheim, and Kiniksa outside of the submitted work. 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 Borlaug has received research grants from National Institutes of Health/NHLBI, AstraZeneca, Medtronic, GlaxoSmithKline, Mesoblast, Novartis, and Tenax Therapeutics; and has received consulting fees from Actelion, Amgen, Aria, Axon Therapies, Boehringer Ingelheim, Edwards Lifesciences, Eli Lilly, Imbria, Janssen, Merck, Novo Nordisk, and VADovations. Dr Dubrock has received consulting fees from Janssen Pharmaceuticals; and has served on advisory boards for Janssen Pharmaceuticals and United Therapeutics. Dr Finet is a consultant to Wolters Kluwer Health, Clinical Drug Information Ad Honorem. 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 Garcia is CEO and founder of Aqualing Therapeutics. Dr Hassoun has served as scientific advisor for Merck Sharp & Dohme, an activity unrelated to the current work. Dr Highland has grants/contracts with Acceleron Pharmaceuticals, Actelion Pharmaceuticals (Janssen), Bayer Healthcare, Boehringer Ingelheim, Eiger Pharmaceuticals, Eli Lilly, Gossamer Bio, United Therapeutics, and Viela Bio (Horizon); has served as a consultant and/or member of a steering or advisory committee with Acceleron Pharmaceuticals, Actelion Pharmaceuticals (Janssen), Boehringer Ingelheim, Forsee, Genentech, Gossamer Bio, and United Therapeutics; and has served on the Speakers Bureau for Actelion Pharmaceuticals (Janssen), Bayer Healthcare, Boehringer Ingelheim, and United Therapeutics. Dr Hill has received research grants for Acceleron, Aerovate. Altavant, Gossamer. Liquidia, Merck, and United Therapeutics; and has served on advisory boards for Acceleron, Aerovate, Altavant, Gossamer, and Liquidia. Dr Maron has relationships with Deerfield Corporation, Actelion Sciences, and Tenax Therapeutics; and has U.S. Patent #9,605,047, Patent pending PCT/US2019/059890, Patent application 2021/133937. Dr Mathai has served as a consultant for Acceleron, Actelion, Bayer, and United Therapeutics. Dr Mehra is supported by National Institutes of Health grants U01HL125177 and UH3HL140144 and the American Heart Association AHA 18SFRN34170013; has received royalties from Up to Date; has received compensation from the American Board of Internal Medicine; and has received an honorarium from the American Academy of Sleep Medicine. M.M. Park has served on the Speakers Bureau of Lantheus Medical Imaging (Definity contrast). Dr Rischard has consulting relationships with Acceleron and United Therapeutics; is on a Steering Committee for Acceleron; and receives research support from Ismed, United Therapeutics, Bayer, Acceleron, Janssen, and AADI. Dr Thomas has served as a consultant for GE, Abbott, egnite, EchoIQ, and Caption Health; as well as spouse employment for Caption Health. Dr Horn has served on the Data and Safety Monitoring Board of AADi Biosciences and SoniVie; has served on the Clinical Events Committee for V-wave; and has served as a consultant for Biotronik. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Figures

None — **CENTRAL ILLUSTRATION PVDOMICS Protocol Elements, Enrollment, and Key Findings**
PVDOMICS is a precision medicine initiative to characterize pulmonary vascular disease using deep phenotyping. PVDOMICS tests the hypothesis that integration of clinical metrics with omic measures will enhance understanding of pulmonary vascular disease and facilitate an updated pulmonary vascular disease classification. Subjects across the spectrum of pulmonary vascular disease, comparators, and healthy control subjects were enrolled including mild and mixed etiology pulmonary vascular disease. Novel findings include enlarged right atrial volume in groups 1–4 pulmonary hypertension; unexpected, frequent presence of ground glass opacities on computed tomography and sleep alterations in group 1 pulmonary hypertension; and poorest survival in group 3 PH. PVDOMICS will facilitate new understanding of pulmonary vascular disease and refine the current pulmonary vascular disease classification. Hemnes AR, et al. J Am Coll Cardiol. 2022;80(7):697–718.

**Figure 1. Enrollment and Subject Final Diagnosis**
STROBE diagram depicting enrollment and patient classification according to primary World Symposium on Pulmonary Hypertension diagnosis or disease comparator. mPAP = mean pulmonary artery pressure; PE = pulmonary embolism; PH = pulmonary hypertension; PVR = pulmonary vascular resistance; PWP = pulmonary wedge pressure; SAE = serious adverse event.

**Figure 2. Selected Clinical Variables Across the Spectrum of Pulmonary Vascular Disease**
Spider plots of selected clinical variables across the spectrum of pulmonary vascular disease including disease comparators. Presented are characteristics of cardiac physiology: **(A)** N-terminal-pro-brain natriuretic peptide (NT-proBNP), **(B)** 6-minute walk distance (6MWD), **(C)** sleep study (% recording time <90% saturation), **(D)** ground glass on chest computed tomography (CT), **(E)** diffusing capacity for carbon monoxide (DLCO), and **(F)** echocardiographic (ECHO) right atrial (RA) volume index. *Significant difference across PH or comparator groups. Median values shown. Comparator group 5 not included in statistical comparisons. †Significant difference at level 0.05 between comparators and PH participants within group. G = group.

**FIGURE 3. Transplant-free Survival in PVDOMICS Cohort**
Kaplan-Meier estimates of transplant-free survival given with HRs and 95% CIs. **(A)** Transplant-free survival in all enrollees. **(B)** Transplant-free survival in comparator group. **(C)** Transplant-free survival in pulmonary hypertension group. **(D)** Transplant-free survival in prevalent pulmonary hypertension. **(E)** Transplant-free survival in incident pulmonary hypertension. PH = pulmonary hypertension; PVD = pulmonary vascular disease.

See this image and copyright information in PMC

Comment in

Pulmonary Hypertension: Dissecting a Complex Phenotype.
Wilkins MR. Wilkins MR. J Am Coll Cardiol. 2022 Aug 16;80(7):719-721. doi: 10.1016/j.jacc.2022.05.039. J Am Coll Cardiol. 2022. PMID: 35953137 No abstract available.

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Clinical Characteristics and Transplant-Free Survival Across the Spectrum of Pulmonary Vascular Disease

Affiliations

Clinical Characteristics and Transplant-Free Survival Across the Spectrum of Pulmonary Vascular Disease

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Comment in

References

Publication types

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Grants and funding

LinkOut - more resources

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Medical