Evidence map›Paper›PMID 36126144›Full record

Trial reportCirculation. Heart failure2022

Proteomic Analysis of Effects of Spironolactone in Heart Failure With Preserved Ejection Fraction.

Ali Javaheri, Ahmed Diab, Lei Zhao, Chenao Qian, Jordana B Cohen, Payman Zamani, Anupam Kumar, Zhaoqing Wang, Christina Ebert, Joseph Maranville and 15 more

Open access · bronzeAbstract readRandomized Controlled Trial
PubMed Full text at PMC Publisher
In one paragraph

Trial report in Circulation. Heart failure, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.

0numbers the graph read from it
0cells of the map it votes in
15citing papers in PubMed
2.8field-weighted citation impact, top 8% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

15 citing papers in PubMed, 24 citations in OpenAlex.

  1. Trial
  2. Trial
  3. Trial
  4. Review
  5. Review
  6. Article
  7. Review
  8. Review
  9. Review
  10. Article
  11. Proteome-Wide Genetic Investigation of Large Artery Stiffness.JACC. Basic to translational science · 2024
    Article
  12. Review
  13. Proteomic Associations of Adverse Outcomes in Human Heart Failure.Journal of the American Heart Association · 2024
    Article
  14. Article
  15. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

25 authors at 8 institutions in 6 countries.

Ali Javaheri *Washington University School of Medicine, St. Louis, MO (A.J., A.D., D.L.M.).ORCID 0000-0001-6657-331X
Ahmed Diab *Washington University School of Medicine, St. Louis, MO (A.J., A.D., D.L.M.).ORCID 0000-0002-1891-3620
Lei ZhaoBristol Myers Squibb Company, Lawrenceville, NJ (L.Z., Z.W., C.E., J.M., E.K., M.B., K.K., P.S., D.A.S., D.A.G., F.R.-V.).
Chenao QianPerelman School of Medicine' University of Pennsylvania School of Medicine/Hospital of the University of Pennsylvania, Philadelphia (C.Q., J.B.C., P.Z., A.K.' T.P.C.' J.A.C.).
Jordana B CohenPerelman School of Medicine' University of Pennsylvania School of Medicine/Hospital of the University of Pennsylvania, Philadelphia (C.Q., J.B.C., P.Z., A.K.' T.P.C.' J.A.C.).ORCID 0000-0003-4649-079X
Payman ZamaniPerelman School of Medicine' University of Pennsylvania School of Medicine/Hospital of the University of Pennsylvania, Philadelphia (C.Q., J.B.C., P.Z., A.K.' T.P.C.' J.A.C.).ORCID 0000-0002-9345-5834
Anupam KumarPerelman School of Medicine' University of Pennsylvania School of Medicine/Hospital of the University of Pennsylvania, Philadelphia (C.Q., J.B.C., P.Z., A.K.' T.P.C.' J.A.C.).
Zhaoqing WangBristol Myers Squibb Company, Lawrenceville, NJ (L.Z., Z.W., C.E., J.M., E.K., M.B., K.K., P.S., D.A.S., D.A.G., F.R.-V.).
Christina EbertBristol Myers Squibb Company, Lawrenceville, NJ (L.Z., Z.W., C.E., J.M., E.K., M.B., K.K., P.S., D.A.S., D.A.G., F.R.-V.).
Joseph MaranvilleBristol Myers Squibb Company, Lawrenceville, NJ (L.Z., Z.W., C.E., J.M., E.K., M.B., K.K., P.S., D.A.S., D.A.G., F.R.-V.).
Erika KvikstadBristol Myers Squibb Company, Lawrenceville, NJ (L.Z., Z.W., C.E., J.M., E.K., M.B., K.K., P.S., D.A.S., D.A.G., F.R.-V.).
Michael BassoBristol Myers Squibb Company, Lawrenceville, NJ (L.Z., Z.W., C.E., J.M., E.K., M.B., K.K., P.S., D.A.S., D.A.G., F.R.-V.).
Vanessa van EmpelDepartment of Cardiology, Maastricht University Medical Center, the Netherlands (V.v.E.).ORCID 0000-0002-6864-0296
A Mark RichardsCardiovascular Research Institute, National University of Singapore (A.M.R.).ORCID 0000-0002-2023-8177
Robert N DoughtyChristchurch Heart Institute, University of Otago, Christchurch, New Zealand (A.M.R., R.N.D.).
Ernst RietzschelDepartment of Cardiovascular Diseases, Ghent University Hospital, Belgium (E.R.).
Karl KammerhoffBristol Myers Squibb Company, Lawrenceville, NJ (L.Z., Z.W., C.E., J.M., E.K., M.B., K.K., P.S., D.A.S., D.A.G., F.R.-V.).
Joseph GogainSomaLogic Inc, Boulder, CO (J.G.).ORCID 0000-0001-7748-4822
Peter SchaferBristol Myers Squibb Company, Lawrenceville, NJ (L.Z., Z.W., C.E., J.M., E.K., M.B., K.K., P.S., D.A.S., D.A.G., F.R.-V.).
Dietmar A SeiffertBristol Myers Squibb Company, Lawrenceville, NJ (L.Z., Z.W., C.E., J.M., E.K., M.B., K.K., P.S., D.A.S., D.A.G., F.R.-V.).
David A GordonBristol Myers Squibb Company, Lawrenceville, NJ (L.Z., Z.W., C.E., J.M., E.K., M.B., K.K., P.S., D.A.S., D.A.G., F.R.-V.).
Francisco Ramirez-ValleBristol Myers Squibb Company, Lawrenceville, NJ (L.Z., Z.W., C.E., J.M., E.K., M.B., K.K., P.S., D.A.S., D.A.G., F.R.-V.).ORCID 0000-0002-8625-5869
Douglas L MannWashington University School of Medicine, St. Louis, MO (A.J., A.D., D.L.M.).ORCID 0000-0002-2516-0145
Thomas P CappolaPerelman School of Medicine' University of Pennsylvania School of Medicine/Hospital of the University of Pennsylvania, Philadelphia (C.Q., J.B.C., P.Z., A.K.' T.P.C.' J.A.C.).
Julio A ChirinosPerelman School of Medicine' University of Pennsylvania School of Medicine/Hospital of the University of Pennsylvania, Philadelphia (C.Q., J.B.C., P.Z., A.K.' T.P.C.' J.A.C.).ORCID 0000-0001-9035-5670
Bristol-Myers Squibb (Belgium) · BEHospital of the University of Pennsylvania · USWashington University in St. Louis · USGhent University Hospital · BEMaastricht University Medical Centre · NLNational University of Singapore · SGNew Zealand Brain Research Institute · NZSomaLogic (United States) · US

Funding

Subclinical Vascular Contributions to Alzheimer's Disease: The Multi-Ethnic Study of Atherosclerosis (MESA) Multisite Study of AD (Renewal)R01AG058969 · NIA · WAKE FOREST UNIVERSITY HEALTH SCIENCES · PI Timothy M. Hughes, YONGMEI LIU · 2018 to 2026
$33.4M
Understanding the relationship between obesity and tongue fat in humans and ratsP01HL094307 · NHLBI · UNIVERSITY OF PENNSYLVANIA · PI PACK, ALLAN I · 2009 to 2020
$23.7M
VASCULAR EFFECTS OF DIETARY SALT IN HUMANS WITH SALT-RESISTANT BPR01HL104106 · NHLBI · UNIVERSITY OF DELAWARE · PI EDWARDS, DAVID G, FARQUHAR, WILLIAM B · 2011 to 2021
$4.5M
Targeting Skeletal Muscle Perfusion and Oxidative Capacity in HFpEFR01HL155599 · NHLBI · UNIVERSITY OF PENNSYLVANIA · PI ZAMANI, PAYMAN · 2021 to 2025
$3.9M
Multidrug Metabolic Approach to Improve Exercise and Skeletal Muscle Oxidative Capacity in HFpEFR01HL157264 · NHLBI · UNIVERSITY OF PENNSYLVANIA · PI ZAMANI, PAYMAN · 2021 to 2025
$3.5M
Blockade of calcium channels and beta adrenergic receptors for physiologic abnormalities in heart failure with preserved ejection fraction (BLOCK HFpEF)R01HL153646 · NHLBI · UNIVERSITY OF PENNSYLVANIA · PI COHEN, JORDANA B. · 2020 to 2024
$3.2M
Efficacy of Potassium Nitrate in Heart Failure with Preserved Ejection FractionR01HL121510 · NHLBI · UNIVERSITY OF PENNSYLVANIA · PI CHIRINOS MEDINA, JULIO ALONSO · 2015 to 2019
$3.1M
Apolipoprotein M: a novel regulator of myocardial AutophagyR01HL155344 · NHLBI · WASHINGTON UNIVERSITY · PI JAVAHERI, ALI · 2021 to 2025
$3.1M
Developing Oral LT3 Therapy for Heart FailureR33HL146390 · NHLBI · UNIVERSITY OF PENNSYLVANIA · PI CAPPOLA, ANNE R, CAPPOLA, THOMAS P. · 2020 to 2022
$2.2M
Efficacy of Fenofibrate for COVID-19: A phase II randomized controlled trialU01TR003734 · NCATS · UNIVERSITY OF PENNSYLVANIA · PI CHIRINOS MEDINA, JULIO ALONSO · 2021 to 2021
$1.8M
HeartShare: Next-Generation Phenomics to Define Heart Failure Subtypes and Treatment Targets - Clinical CentersU01HL160277 · NHLBI · UNIVERSITY OF PENNSYLVANIA · PI JULIO ALONSO CHIRINOS MEDINA · 2021 to 2026
$1.7M
Genetic determinants of thoracic aortic stiffness and remodelingK24AG070459 · NIA · UNIVERSITY OF PENNSYLVANIA · PI CHIRINOS MEDINA, JULIO ALONSO · 2021 to 2025
$975k
NCATS NIH HHS U01 TR003734NHLBI NIH HHS K08 HL138262NHLBI NIH HHS P01 HL094307NHLBI NIH HHS R01 HL104106NHLBI NIH HHS R01 HL121510NHLBI NIH HHS R01 HL153646NHLBI NIH HHS R01 HL155344NHLBI NIH HHS R01 HL155599NHLBI NIH HHS R01 HL157264NHLBI NIH HHS R03 HL146874NHLBI NIH HHS R33 HL146390NHLBI NIH HHS R56 HL136730NHLBI NIH HHS U01 HL160277NIA NIH HHS K24 AG070459NIA NIH HHS R01 AG058969
6 · The paper itself

Abstract

backgroundThe TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial) suggested clinical benefits of spironolactone treatment among patients with heart failure with preserved ejection fraction enrolled in the Americas. However, a comprehensive assessment of biologic pathways impacted by spironolactone therapy in heart failure with preserved ejection fraction has not been performed.

methodsWe conducted aptamer-based proteomic analysis utilizing 5284 modified aptamers to 4928 unique proteins on plasma samples from TOPCAT participants from the Americas (n=164 subjects with paired samples at baseline and 1 year) to identify proteins and pathways impacted by spironolactone therapy in heart failure with preserved ejection fraction. Mean percentage change from baseline was calculated for each protein. Additionally, we conducted pathway analysis of proteins altered by spironolactone.

resultsSpironolactone therapy was associated with proteome-wide significant changes in 7 proteins. Among these, CARD18 (caspase recruitment domain-containing protein 18), PKD2 (polycystin 2), and PSG2 (pregnancy-specific glycoprotein 2) were upregulated, whereas HGF (hepatic growth factor), PLTP (phospholipid transfer protein), IGF2R (insulin growth factor 2 receptor), and SWP70 (switch-associated protein 70) were downregulated. CARD18, a caspase-1 inhibitor, was the most upregulated protein by spironolactone (-0.5% with placebo versus +66.5% with spironolactone,

conclusionsProteomic analysis in the TOPCAT trial revealed proteins and pathways altered by spironolactone, including the caspase inhibitor CARD18 and multiple pathways that involved collagens. In addition to effects on fibrosis, our studies suggest potential antiapoptotic effects of spironolactone in heart failure with preserved ejection fraction, a hypothesis that merits further exploration.

Indexed as

Biological ProductsHeart FailureInsulinsApelinCaspasesHumansLiver X ReceptorsMineralocorticoid Receptor AntagonistsPhospholipid Transfer ProteinsProteomeProteomicsSpironolactoneStroke VolumeTreatment OutcomeApelinBiological ProductsCaspasesInsulinsLiver X ReceptorsMineralocorticoid Receptor AntagonistsPhospholipid Transfer ProteinsProteomeSpironolactoneAmericascaspaseglycoproteinheart failurespironolactone

Identifiers

PMID36126144
PMCPMC9504263
OpenAlexW4296514769

What OpenQuestion holds

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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.