GDF-15: a novel biomarker of heart failure predicts short-term and long-term heart-failure rehospitalization and short-term mortality in patients with acute heart failure syndrome

Acute heart failure (AHF) represents a potentially life-threatening clinical syndrome often necessitating hospital admission. AHF may manifest de novo or in individuals with chronic heart failure (HF). There are global variations in the duration of AHF hospitalization. In numerous countries, patients are hospitalized for at least one week, experiencing an inpatient mortality rate ranging from 5–10%, and up to 25% of the patients are readmitted within a month of discharge [1].

Among patients readmitted within 30 days following discharge from an AHF hospitalization, 50% experienced relapses attributable to HF, while 23% stemmed from non-HF cardiovascular causes [2]. A quarter of patients hospitalized due to exacerbating HF exhibit signs of inadequate decongestion at discharge [3], and this is associated with an elevated risk of readmission and a worse prognosis [4]. In addition, congestion not only has a significant effect on symptoms and quality of life, but is also associated with cardiac, renal, and liver injury, which, in turn, are associated with adverse clinical outcome [5]. The gold standard for evaluating congestion in hospitalized patients the gold standard for assessing congestion in hospitalized patients involves measuring pulmonary capillary wedge pressure (PCWP) which provides a good approximation of left-ventricular filling pressure, allowing detection of hemodynamic congestion relatively early in the preclinical stage. However, PCWP measurement involves invasive catheterization, limiting its clinical utility, especially in outpatient settings. While there is currently no standardized definition of adequate decongestion, several criteria have been employed in clinical trials. These include jugular venous distention (JVD) < 8 cm of water, no more than trace peripheral edema, and the absence of orthopnea [6]. These criteria have been condensed into an orthoedema congestion score, with higher scores upon admission and discharge correlating with a heightened risk of adverse outcomes, including death or HF hospitalization within 60 days [7].

Over the past decade, there has been a surge of interest in the field of biomarkers concerning the management and care of patients with HF. New insights into the various facets of the intricate molecular interplay underlying HF have prompted the search for representative cardiac biomarkers with the anticipation that their combined use can help inform physicians of the patient’s disease state [8]. Among these biomarkers, natriuretic peptides, including B-type natriuretic peptide (BNP) and the N-terminal fragment of its prohormone (NT-proBNP), have emerged as approved biomarkers for HF [9]. Additionally, novel biomarkers such as ST-2, GDF-15, Pentraxin-3, Galectin-3, Osteopontin [10] have been the subject of investigation either individually or in combination within the HF context.

Growth-differentiation factor-15 (GDF-15) belongs to the transforming growth factor-β (TGF-β) cytokine superfamily and is primarily expressed the liver. It is also known as Prostate derived factor (PDF), Macrophage inhibitory cytokine-1(MIC-1), NSAID-activated gene (NAG-1) and Placental TGF-Beta (PTGFB). While the precise function of GDF-15 remains unclear, it is generally expressed at low levels across all tissue types under normal physiological states. However, increased expression of GDF-15 has been observed in various pathological states including pulmonary, cardiac, or renal diseases.

Multi-biomarkers (GDF-15, NT-proBNP, hsTnT) and orthoedema congestion score are rarely studied in Asian. Consequently, this study sought to examine the association between the multi-biomarker profile and congestion levels measured at admission and discharge, in relation to the outcomes of all-cause mortality and HF rehospitalization at 30, 90, and 180 days, as well as over the entire follow-up period, among patients diagnosed with AHF syndrome.

A total of 103 patients were initially screened, out of which 11 were excluded from the study due to incomplete data (6 did not meet the criteria for AHF, 2 were referred to a nearby hospital, and 3 refused to participate), leaving 92 patients who were enrolled in the study. During the course of the study, seven patients experienced intra-hospital mortality, while one patient was lost to follow-up due to inability to establish telephone contact. Consequently, a total of 84 patients were included in the final analysis (Fig. 1). The median follow-up time was 213 days.

This prospective single-center study conducted at KCMH, focusing on patients admitted for AHF syndrome regardless of ejection fraction, revealed that lower levels of GDF-15 and NT-proBNP served as valuable biomarkers for assessing the risk of HF readmission and all-cause mortality. Generally, lower levels observed upon discharge as well as a greater degree of reduction from admission to discharge were associated with a more favorable prognosis for HF readmission, while lower levels upon admission were associated with better prognosis of all-cause mortality.

Notably, a significant finding of this study was the strong correlation between reductions in GDF-15 levels and rehospitalization outcomes across all defined time points. Additionally, elevated GDF-15 levels at discharge were linked to increased hazards and incidence of early rehospitalization within both 30- and 90-day periods. Similarly, reductions in NT-proBNP were also associated with hazards and incidence of early readmission within 30 and 90 days post-discharge. These associations, which appear to be time-specific, may be attributed to non-proportional hazards observed for both GDF-15 levels at discharge and NT-proBNP reduction. However, the non-proportional hazards assumption was upheld for GDF-15 reduction, consequently resulting in the relationship being detected across all time points.

With regards to all-cause mortality, higher GDF-15 levels upon admission correlated well with increased hazards and incidence of early occurrences of death within both 30- and 90-day periods. Interestingly, higher NT-proBNP levels correlated well with increased hazards and incidence but only at a much later time when the entire follow-up period of the study was considered. Accordingly, the non-proportional hazards assumption did not hold for both of these covariates under the outcomes of all-cause mortality.

Another intriguing finding from this study is the observed association between higher levels of hsTnT, either upon admission or discharge, and a decrease in hazards and incidence of 30-day HF readmission. This finding may seem counterintuitive, as previous literature has suggested that elevated hsTnT levels are associated with an increased risk of death or HF rehospitalization. However, this discrepancy could be attributed to a limitation of this study—the patient's non-HF hospitalization status was not taken into account as a competing risk for HF readmission. Indeed, if a patient was readmitted for reasons other than HF, this would preclude HF readmission during the course of that admission but would not prevent future HF readmissions once the patient was discharged. Further data collection and analysis may be necessary to elucidate whether hsTnT increases the risk of HF readmission when considering such factors.

Finally, our study also revealed a significant association between higher orthoedema congestion score upon admission and increased hazards and incidence of all-cause mortality at 30 days. Previous clinical trials have employed an orthoedema congestion score based on the presence of orthopnea and peripheral edema. A post hoc analysis of the DOSE-HF and CARRESS-HF trials of patients with AHF with congestion (and cardiorenal syndrome in the case of CARRESS-HF) found that baseline orthoedema was moderate in 22% of patients and severe in 62% [7]. After aggressive inpatient therapy aimed at decongestion, more than a third of the patients (35%) had persistent moderate to severe congestion at discharge. Higher orthoedema scores at admission and discharge were associated with an increased risk of death at 60 days or hospitalization for HF.

GDF-15, a distant member of the transforming growth factor-β- superfamily [11], plays a crucial role in maintaining tissue homeostasis and adaptation.. During ischemia and reperfusion injury, its expression significantly increases through phosphoinositide 3-OH kinase (PI3K) and Akt-dependent signaling pathways. GDF-15 is known to protected cardiomyocytes from apoptosis as demonstrated by previous research [12]. Therefore, as our study revealed, the levels of GDF-15 can serve as predictive markers for the degree of inflammatory response and the risk of cardiovascular events.

Experimental studies suggest that various forms of cardiac stress, including pressure overload, increase the concentration of GDF-15. Animal studies have demonstrated that GDF-15 is exerts protective effects against cardiac injury due to its anti-hypertrophic [13], anti-inflammatory and anti-apoptotic properties [14]. Notably, GDF-15 is not only produced by cardiomyocytes but also by vascular smooth muscle cells, pulmonary epithelial cells, macrophages, and adipocytes in response to oxidative stress and proinflammatory signaling molecules [15].

However, clinical studies in humans indicate that higher concentrations of GDF-15 was associated with increased mortality. For example, studies by Lok et al. and Kempf et al. have shown that GDF-15 serves as a marker of marker of increased mortality in CHF [16, 17]. Lok et al. further observed that GDF-15 is an even stronger predictor than NT-proBNP [16]. Furthermore, patients with HF with reduced ejection fraction have been found to have higher levels of GDF-15 compared to those with HF with a mid-range ejection fraction [18]. Therefore, GDF-15 seems to exhibit a range functions, providing protection in certain situations while simultaneously being associated with poor outcomes in others.

Ina previous study [18], receiver operating characteristic (ROC) curves were used to estimate the associations between GDF-15 and clinical indicators in cardiac remodeling. The study found that the combination of GDF-15 and NT-proBNP (AUC = 0.905, 95%CI: 0.868–0.942, P < 0.001) outperformed NT-proBNP alone (AUC = 0.869, 95%CI: 0.825–0.913, P < 0.001) in HF. These findings suggest that incorporating GDF-15 into diagnostic assessments significantly improves the accuracy of the HF diagnosis. Plasma levels of GDF-15 indirectly reflect the degree of cardiac remodeling and fibrosis. Therefore, this study supports the use of GDF-15 as an additional prognostic factor alongside NT-proBNP.

According to a systematic review [17], there is substantial evidence indicating that GDF-15 is an independent predictor of all-cause mortality in HF. GDF-15 may provide additional predictive value for assessing the risk of HF and death in patients with MI. A multi-biomarker strategy with GDF-15 as one of the components may be superior to conventional risk scores, particularly in systemic conditions such as HF. Despite these findings, the precise role of GDF-15 in the pathophysiology of HF remains to be elucidated on a biological level. Additionally, there is a need for further research to explore how the available data on GDF-15 can be translated into therapeutic decisions regarding HF management.

In a recent meta-analysis [19] involving 6,244 patients with chronic HF, elevated circulating GDF-15 concentration is associated with a 6% increase in the risk of all-cause mortality with an increase per 1LnU in baseline GDF-15 concentration,with pooled risk ratios 1.06 (95% CI:1.03–1.10, P < 0.001) among chronic HF patients, especially among those with ischemic etiology, such as coronary atherosclerosis. Furthermore, the association was strengthened after excluding patients with a nonreduced ejection fraction, suggesting that GDF-15 could have a higher prognostic value in individuals with a reduced ejection fraction. Subgroup analyzes indicated that factors such as age, NYHA class and duration of follow-up may not affect the relationship between GDF-15 and the risk of all-cause death in chronic HF.

While our study was designed as a prospective analytical investigation, it still bears certain limitations. Firstly, it is important to acknowledge that this study was conducted at a single center and with a relatively small sample size. Therefore, further research may be necessary to bolster and validate our findings. Secondly, our patient cohort comprised only individuals admitted with AHF and excludes those who sought treatment through emergency room visits or outpatient clinics. This may introduce a selection bias and limit the generalizability of our results to the broader HF population. Lastly, the limited number of death cases observed in our study prevented us from identifying independent factors associated with this outcome effectively. Nevertheless, it's worth noting that these patients were enrolled over a relatively short timeframe, providing insights into the acute HF population in real-world settings.

As a result, future research should adopt a larger-scale approach, recruiting patients who received care through any channels offered by the hospital to yield more precise and comprehensive results. Additionally, our multivariate model was constrained by the inclusion of only a few covariates per analysis set due to the risk of model convergence failure when dealing with a limited dataset. Furthermore, our analysis primarily focused on linear, monotonic relationships between biomarkers and outcomes. Future studies may benefit from exploring more sophisticated models capable of incorporating a broader range of covariates and capturing potential non-linear relationships between these factors and outcomes.

Our study identified a significant connection between GDF-15 levels and numerous outcomes in patients with HF, including all-cause mortality and HF rehospitalization. These encouraging findings may offer an additional foundation for further research on this biomarker. Furthermore, the findings of this study may encourage the use of GDF-15 as an additional predictive marker in patients with HF in current clinical practices.

In this single-center study, we observed a high rate of mortality and rehospitalization among patients discharged after acute HF hospitalization. Notably, we observed a significant decrease in Growth Differentiation Factor-15 (GDF-15) levels during hospitalization, suggesting its potential as a dynamic marker reflecting the course of AHF. Indeed, our findings indicated that a reduction in GDF-15 levels from baseline to discharge was associated with a decreased risk of HF rehospitalization at any time point. Lower discharge GDF-15 levels, as well as reductions in NT-proBNP levels from baseline to discharge, were also associated with a reduced risk of early HF rehospitalization at both the 30- and 90-day periods. Furthermore, higher GDF-15 levels at admission were associated with an increased risk of early all-cause mortality at 30 and 90 days, while higher NT-proBNP levels upon admission reflected a higher risk of long-term mortality. These findings underscore the potential of GDF-15 as a prognostic marker and highlight its role in predicting AHF outcomes by offering valuable insights that could inform risk stratification and personalized management strategies for AHF patients. Nevertheless, further research is warranted to validate and explore the therapeutic implications of GDF-15 in AHF.