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. 2024 Aug 8;10(16):e35916.
doi: 10.1016/j.heliyon.2024.e35916. eCollection 2024 Aug 30.

Association between growth differentiation factor-15 and adverse outcomes among patients with heart failure: A systematic literature review

Ali Javaheri  1   2 , Mualla Ozcan  1 , Lauren Moubarak  3 , Karen E Smoyer  4 , Michelle I Rossulek  5 , James H Revkin  5 , John D Groarke  5 , Lisa C Tarasenko  6 , Mikhail N Kosiborod  7
Affiliations

Association between growth differentiation factor-15 and adverse outcomes among patients with heart failure: A systematic literature review

Ali Javaheri et al. Heliyon. .

Abstract

Growth differentiation factor-15 (GDF-15) is an emerging biomarker in several conditions. This SLR, conducted following PRISMA guidelines, examined the association between GDF-15 concentration and range of adverse outcomes in patients with heart failure (HF). Publications were identified from Embase® and Medline® bibliographic databases between January 1, 2014, and August 23, 2022 (congress abstracts: January 1, 2020, to August 23, 2022). Sixty-three publications met the eligibility criteria (55 manuscripts and 8 abstracts; 45 observational studies and 18 post hoc analyses of randomized controlled trials [RCTs]). Of the 19 outcomes identified, the most frequently reported longitudinal outcomes were mortality (n = 32 studies; all-cause [n = 27] or cardiovascular-related [n = 6]), composite outcomes (n = 28; most commonly mortality ± hospitalization/rehospitalization [n = 19]), and hospitalization/re-hospitalization (n = 11). The most common cross-sectional outcome was renal function (n = 22). Among longitudinal studies assessing independent relationships with outcomes using multivariate analyses (MVA), a significant increase in risk associated with higher baseline GDF-15 concentration was found in 22/24 (92 %) studies assessing all-cause mortality, 4/5 (80 %) assessing cardiovascular-related mortality, 13/19 (68 %) assessing composite outcomes, and 4/8 (50 %) assessing hospitalization/rehospitalization. All (7/7; 100 %) of the cross-sectional studies assessing the relationship with renal function by MVA, and 3/4 (75 %) assessing exercise capacity, found poorer outcomes associated with higher baseline GDF-15 concentrations. This SLR suggests GDF-15 is an independent predictor of mortality and other adverse but nonfatal outcomes in patients with HF. A better understanding of the prognostic role of GDF-15 in HF could improve clinical risk prediction models and potentially help optimize treatment regimens.

Keywords: Exercise capacity; Hospitalization; Mortality; Renal function.

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Conflict of interest statement

Ali Javaheri, Mualla Ozcan, Lauren Moubarak, Karen E. Smoyer, Michelle I. Rossulek, James H. Revkin, John D. Groarke, Lisa C. Tarasenko, Mikhail N. Kosiborod reports administrative support, article publishing charges, and writing assistance were provided by 10.13039/100004319Pfizer. Ali Javaheri reports a relationship with Mobius Scientific that includes: consulting or advisory and equity or stocks. Ali Javaheri reports a relationship with 10.13039/100004325AstraZeneca that includes: funding grants. Ali Javaheri reports a relationship with Bitterroot Bio that includes: funding grants. Lauren Moubarak reports a relationship with Envision Pharma Group that includes: employment. Karen E. Smoyer reports a relationship with Envision Pharma Group that includes: employment and equity or stocks. Michelle I. Rossulek reports a relationship with Pfizer that includes: employment and equity or stocks. John D. Groarke reports a relationship with Pfizer that includes: employment and equity or stocks. James H. Revkin reports a relationship with Pfizer that includes: employment and equity or stocks. Lisa C. Tarasenko reports a relationship with Pfizer that includes: employment and equity or stocks. Mikhail N. Kosiborod reports a relationship with 10.13039/100004325AstraZeneca that includes: consulting or advisory and funding grants. Mikhail N. Kosiborod reports a relationship with 10.13039/100001003Boehringer Ingelheim that includes: consulting or advisory and funding grants. Mikhail N. Kosiborod reports a relationship with 35Pharma, Alnylam, Amgen, Applied Therapeutics, Bayer, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics that includes: consulting or advisory. Mikhail N. Kosiborod reports a relationship with Janssen, Lexicon Pharmaceuticals, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pharmacosmos, Pfizer, Sanofi, scPharmaceuticals, Structure Therapeutics, Vifor Pharma, Youngene Therapeutics that includes: consulting or advisory. The study was sponsored by 10.13039/100004319Pfizer. Pfizer contributed to the study design, and in their role as authors, employees of Pfizer were involved in the interpretation of data, preparation, review, and approval of the manuscript and the decision to submit for publication, along with their co-authors. The study sponsors approved the manuscript from an intellectual property perspective but had no right to veto the publication. Medical writing support was provided by Diane Hoffman, PhD, and Jennifer Bodkin, PhD, of Engage Scientific Solutions, and funded by 10.13039/100004319Pfizer. Database searches, screening, data extraction and quality assessment were carried out by Lauren Moubarak, MPharm, and Karen E. Smoyer, PhD, of 10.13039/100020841Envision Value & Access, funded by 10.13039/100004319Pfizer. Ali Javaheri was supported by the Children's Discovery Institute of Washington University and St. Louis Children's Hospital (MC-FR-2020-919), and the Longer Life Foundation.

Figures

Fig. 1
Fig. 1
PRISMA flow diagram.
Fig. 2
Fig. 2
Number of publications of each type reporting on specific outcomes. Number of publications (n = 33) reporting physiological parameters are not shown. BMI = body mass index; HbA1c = hemoglobin A1c; MI = myocardial infarction.
Fig. 3
Fig. 3
Significant associations with baseline GDF-15 in observational studies. Panel A shows outcomes in longitudinal studies and panel B shows outcomes in cross-sectional studies. BMI = body mass index; GDF-15 = growth differentiation factor-15; MI = myocardial infarction; MVA = multivariate analysis; UVA = univariate analysis.
Fig. 4
Fig. 4
Hazard ratio for (A) all-cause mortality and (B) cardiac-specific mortality by baseline GDF-15 concentration. *P < 0.05 in UVA only (data not shown). Only studies with adjusted HR from MVA analysis are presented. In A), findings from 23/24 studies utilizing MVA are plotted. The other publication included GDF-15 alongside N-terminal pro B-type natriuretic peptide concentration in the outcome. In B), findings from 4/5 studies utilizing MVA are plotted. The other publication reported odds ratio only. Where relevant data are reported for multiple time points, data are presented as Author, year (mortality timepoint). Where data for both continuous and cut-offs of GDF-15 concentration are reported, only continuous has been presented. CV = cardiovascular; GDF-15 = growth differentiation factor-15; HF = heart failure; HR = hazard ratio; MVA = multivariate analysis; Q = quartile; RCT = randomized controlled trial; UVA = univariate analysis.
Fig. 5
Fig. 5
Hazard ratio for a (A) composite outcome of mortality or hospitalization/rehospitalization and (B) hospitalization/rehospitalization alone by baseline GDF-15 concentration. *P < 0.05 in UVA only (data not shown). Only studies with adjusted HR from MVA analysis are presented. In B), findings from 5/8 studies utilizing MVA to examine the relationship between hospitalization and baseline GDF-15 concentration are plotted. The other 3 studies did not report a HR, and all associations were non-significant. Where relevant data are reported for multiple time points, data are presented as Author, year (mortality timepoint). Where data for both continuous and cut-offs of GDF-15 concentration are reported, only continuous has been presented.CV = cardiovascular; GDF-15 = growth differentiation factor-15; HF = heart failure; HFrEF = heart failure with reduced ejection fraction; HFpEF = heart failure with preserved ejection fraction; HR = hazard ratio; MVA = multivariate analysis; Q = quartile; RCT = randomized controlled trial; UVA = univariate analysis.
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