Evidence map›Paper›PMID 33983831›Full record

ReviewCirculation research2021

From Systemic Inflammation to Myocardial Fibrosis: The Heart Failure With Preserved Ejection Fraction Paradigm Revisited.

Walter J Paulus, Michael R Zile

Open access · bronzeAbstract readReview
PubMed Full text at PMC Publisher
In one paragraph

Review in Circulation research, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 244 papers, 5 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
244citing papers in PubMed, 5 pooled it
32.0field-weighted citation impact, top 1% 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

244 citing papers in PubMed, 5 syntheses or guidelines pooled it, 331 citations in OpenAlex.

  1. Pooled it
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  3. Immunology of heart failure with preserved ejection fraction.Expert review of clinical immunology · 2025
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  17. The High-Sensitivity C-Reactive Protein-Albumin-Lymphocyte Index Is a Prognostic Marker for All-Cause and Cardiovascular Mortality in Patients With ST-Elevation Myocardial Infarction.Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions · 2026
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  20. Prediabetes and the risk of atrial fibrillation and heart failure: a propensity-matched analysis in a real-world cohort.Clinical research in cardiology : official journal of the German Cardiac Society · 2026
    Article

184 more citing papers are in PubMed but not listed here.

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

2 authors at 2 institutions in 2 countries.

Walter J PaulusAmsterdam University Medical Centers, The Netherlands (W.J.P.).
Michael R ZileRHJ Department of Veterans Affairs Medical Center, Medical University of South Carolina, Charleston (M.R.Z.).
Amsterdam University Medical Centers · NLMedical University of South Carolina · US

Funding

Systems Mechanobiology Modeling for Patient-Specific Cardiac Fibrosis PredictionsR01HL144927 · NHLBI · UNIVERSITY OF ARKANSAS AT FAYETTEVILLE · PI RICHARDSON, WILLIAM JAMES · 2019 to 2023
$1.8M
Extracellular Matrix in Hypertensive Heart Disease & Transition to Heart FailureR01HL123478 · NHLBI · MEDICAL UNIVERSITY OF SOUTH CAROLINA · PI ZILE, MICHAEL R · 2015 to 2018
$1.5M
Macrophage Expression of SPARC Contributes to Pressure-Overload Dependent Change in Collagen Content and Myocardial StiffnessI01CX001608 · VA · RALPH H JOHNSON VA MEDICAL CENTER · PI BRADSHAW, AMY D, ZILE, MICHAEL R · 2018 to 2021
–
BLRD VA I01 BX005943CSRD VA I01 CX001608NHLBI NIH HHS R01 HL123478NHLBI NIH HHS R01 HL144927
6 · The paper itself

Abstract

In accordance with the comorbidity-inflammation paradigm, comorbidities and especially metabolic comorbidities are presumed to drive development and severity of heart failure with preserved ejection fraction through a cascade of events ranging from systemic inflammation to myocardial fibrosis. Recently, novel experimental and clinical evidence emerged, which strengthens the validity of the inflammatory/profibrotic paradigm. This evidence consists among others of (1) myocardial infiltration by immunocompetent cells not only because of an obesity-induced metabolic load but also because of an arterial hypertension-induced hemodynamic load. The latter is sensed by components of the extracellular matrix like basal laminin, which also interact with cardiomyocyte titin; (2) expression in cardiomyocytes of inducible nitric oxide synthase because of circulating proinflammatory cytokines. This results in myocardial accumulation of degraded proteins because of a failing unfolded protein response; (3) definition by machine learning algorithms of phenogroups of patients with heart failure with preserved ejection fraction with a distinct inflammatory/profibrotic signature; (4) direct coupling in mediation analysis between comorbidities, inflammatory biomarkers, and deranged myocardial structure/function with endothelial expression of adhesion molecules already apparent in early preclinical heart failure with preserved ejection fraction (HF stage A, B). This new evidence paves the road for future heart failure with preserved ejection fraction treatments such as biologicals directed against inflammatory cytokines, stimulation of protein ubiquitylation with phosphodiesterase 1 inhibitors, correction of titin stiffness through natriuretic peptide-particulate guanylyl cyclase-PDE9 (phosphodiesterase 9) signaling and molecular/cellular regulatory mechanisms that control myocardial fibrosis.

Indexed as

BiomarkersCollagenComorbidityConnectinExtracellular MatrixFibrosisHeart FailureHemodynamicsHumansHypertensionImmunity, CellularInflammationLamininMachine LearningMyocardiumMyocytes, CardiacBiomarkersCollagenConnectinLamininNitric Oxide Synthase Type IINOS2 protein, humanTTN protein, humanbiomarkerfibrosisheart failureinflammationobesity

Identifiers

PMID33983831
PMCPMC8351796
OpenAlexW3163897922

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

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.