Association Between Growth Differentiation Factor-15 and Heart Failure Complicating Acute Myocardial Infarction

Background Growth differentiation factor-15 (GDF15) is an emerging biomarker in cardiovascular diseases. We aimed to evaluate the association of GDF15 levels at admission with HF occurrence during hospitalization for acute myocardial infarction (AMI). Methods Our prospective study included all patients admitted from June 2016 to February 2018 for type 1 AMI in the coronary care unit of the DijonBourgogne University Hospital. In-hospital severe heart failure (HF) was defined as Killip class >2. Serum levels of GDF15 were obtained from blood samples were taken on admission. Results – Among the 284 AMI patients, median age was 67 years, and 27% were women. GDF15 levels were strongly correlated with age and positively correlated with most cardiovascular risk factors (hypertension and diabetes) and inflammation (CRP>3 mg/L). When compared with patients without HF (274/284), GDF15 in patients with inhospital HF (10/284) was more than two times Cardiol Cardiovasc Med 2020; 4 (6): 773-789 DOI: 10.26502/fccm.92920174 Cardiology and Cardiovascular Medicine Vol. 4 No. 6 – December 2020. [ISSN 2572-9292] 774 higher. Multivariate regression showed that GDF15 >5,000 ng/L was an independent marker of HF. Conclusions These results suggest that GDF15 could be an integrative biomarker for severe inhospital HF in patients with AMI. Further studies are needed to elucidate the underlying mechanisms linking this cytokine to the development of HF. Clinical Trial BIOCARDIS 2016 – 9205AAO034S02117, from June 2016 to February 2018


Background
Patients with acute myocardial infarction (AMI) constitute a large and heterogeneous group in terms of severe outcomes and subsequent death. Heart failure (HF) is a frequent complication of AMI and is associated with high mortality and re-hospitalization rates [1]. HF has an incidence ranging from 14% to 36% in AMI [2]. It is characterized by signs such as crackles, lung rales, tachycardia, pulmonary edema, hypotension and electrocardiographic abnormalities.
The gravity of HF is indicated through the Killip classification. Both severe (cardiogenic shock) and less severe states of HF have major adverse consequences and may require specific treatments. Therefore, adequate stratification of patients who are at risk of developing HF in the context of post-AMI may be helpful in estimating prognosis and could be used to guide the cardiologist in clinical decision making. Indeed, cardiac biomarkers such as cardiac-Troponin (c-Tn) or N-Terminal pro-Brain Natriuretic Peptide (NT-proBNP) [3,4] currently provide prognostic information for both short-and long-term risk in patients with AMI. However, newer and more specific biomarkers may be helpful in providing additional information that is not provided by classic biomarkers.
Growth differentiation factor 15 (GDF15) is a stressresponsive cytokine which belongs to the transforming growth factor-β superfamily, but which finally appears to be closer to the glial cell-derived neurotrophic factors [5]. Although GDF15 is weakly expressed in normal healthy conditions in human tissues (except in the placenta), GDF15 can be produced by many cardiovascular and noncardiovascular cell types under certain pathological situations mainly related to inflammatory stress.
Circulating levels of GDF15 reflect acute and chronic cellular stressors which are associated with aging and disease [6,7]. Indeed, in cardiovascular (CV) diseases, GDF15 is an emerging biomarker [8] with strong predictive value for all-cause mortality. In patients with AMI, GDF15 has been recognized as a consistent biomarker of mortality and has been used for long-term follow-up in patients with non STelevation MI [9-13]. In this context, GDF15 provides prognostic information in addition to what is provided by other clinical or biochemical biomarkers including cTnT and NT-proBNP [10, [14][15][16]. Other data also suggest that GDF15 can be used as a biomarker in acute or chronic HF [17][18][19][20][21]. Initial studies by Kempf et al. led  reduced ejection fractions [19], and a significant increase in GDF15 in the 6 months following the event was associated in a worse outcome, suggesting that beyond hemodynamic burden (NT-proBNP), inflammatory status (GDF15) may be involved in both HF syndromes [20]. In a meta-analysis including 20,920 HF patients, GDF15 was found to be a strong prognostic biomarker of all-cause mortality [21]. However, there are currently few data concerning the use of GDF15 as a prognostic marker for HF in a context of AMI.
Therefore, the aim of the present study was to evaluate the prognostic value of GDF15 levels at admission as a predictor of HF occurrence during hospitalization for AMI. Echocardiography was used to determine left ventricular ejection fraction (LVEF).

Determination of serum GDF15
Blood samples were collected, on admission, from a vein of the arm, and immediately centrifuged at 4°C to separate the serum. The samples were then stored at -80°C until use. Serum GDF15 was measured in duplicate using a commercially available kit (DGD150, R&D systems, MN). The minimum detectable concentration was 2 ng/L, and the coefficient of variation between duplicates did not exceed 10%.

Statistical analysis
Statistical analysis was performed as described before [24].
Bivariate linear regression analyses were used to adjust GDF15 with age.

Baseline characteristics
The study flow chart is presented in Figure 1.

Association between GDF15 levels and study variables
Predictors of GDF15 are shown in Table 2.

Associations between GDF15 levels and HF
GDF15 levels were much higher in patients with HF

Study limitations
The small number of patients who developed HF (n=10) and the resulting lack of statistical power limited our ability to draw firm conclusions from our results. Additionally, it was a single-center study and the sensitivity of the test to predict in-hospital HF was low. However, both clinicians and technicians were blinded to the results. Moreover, the association between the biomarker and the event (HF) was significant (p=0.021), and the result was further supported by both univariate regression analysis (p<0.001) and AUC (p= 0.021), which persisted even after adjustment for major determinants of HF (p=0.013). Larger studies are needed to confirm these preliminary findings.

Conclusions
To conclude, our preliminary study shows that GDF15 could be an integrative biomarker of severe

Consent to publish
Not applicable.