Cardiac myocytes produce and secrete GDF-15 in response to oxidative stress, stimulation with angiotensin II or proinflammatory cytokines, ischemia, and mechanical stretch. GDF-15 is induced in hypertrophic and dilated cardiomyopathy after volume overload, ischemia and heart failure. High levels of GDF-15 have been associated with a variety of diseases, including kidney dysfunction, cancer, diabetes, and cardiovascular disease (Figure 1).
Furthermore, high levels of GDF-15 have been reported to be associated with higher cardiovascular morbidity and all-cause mortality in general [5]. To date, several studies have focused on the association of GDF-15 with heart failure, coronary artery disease, stroke and other major cardiac events. There is evidence that GDF-15 could also be used as a prognostic biomarker in diabetes and obesity [8].
GDF-15 has also been investigated as a prognostic biomarker for diabetic nephropathy and the exacerbation of this major vascular complication of diabetes [10]. This review covers all aspects of possible validated use of GDF-15 in cardiovascular disease and the main parameters of the metabolic syndrome. Today, automated GDF-15 immunoassay is available on Roche Cobaselectrochemiluminescence systems (Roche Diagnostics International Ltd, Rotkreuz, Switzerland).
Samples (35 µL) were incubated for 9 min with a biotinylated anti-GDF-15 monoclonal antibody and another anti-.
GDF-15 AND OBESITY , DIABETES , METABOLIC SYNDROME
Another interesting feature of GDF-15 is that high peaks of glucose and insulin increase the transcription and release of GDF-15. This characteristic of GDF-15 could be useful to explain high levels in subjects with obesity, diabetes and insulin resistance in general [11]. Additionally, this study was the first to link GDF-15 to appetite, but without a strong association with mealtime appetite.
This finding is suggested to be consistent with GDF-15 being a marker of cellular and tissue stress. The high levels of GDF-15 in obese subjects and patients with T2DM may be due to long-term higher glucose and insulin levels in these populations [11]. GDF-15 as a prognostic marker for diabetes and obesity has been associated with beta cell dysfunction [9].
A cross-sectional study of 160 obese patients examined the relationship between GDF-15 and beta cell function, following an OGTT test [9]. The strong relationship of GDF-15 with beta cell function led to a possible novel role of GDF-15 as a therapeutic target in this context[9]. Regarding fasting, only c-peptide (r:0.313, p<0.001) had an independent statistically significant prognostic value of GDF-15 concentrations [9], [15].
GDF-15 has been studied as a prognostic marker of cardiovascular risk and overall mortality, both of which are elevated in patients with metabolic syndrome with or without T2DM [15]. This study was the first to independently link GDF-15 with the risk of future insulin resistance. However, in this study GDF-15 was higher only in IGT patients, not in IFG, reflecting peripheral insulin resistance [19].
GDF-15 was measured in 39 obese children (BMI > 95th percentile) without comorbidities and 20 age-matched normal weight controls[21]. No statistically significant difference was observed between the two subgroups, although GDF-15 levels were higher in obese children [21]. Further follow-up studies are needed to investigate the future predictive value of GDF-15.
D IABETIC N EPHROPATHY
A large prospective study with 8,592 people from the PREVEND cohort attempted to investigate the prognostic value of GDF-15 regarding albuminuria in patients with T2DM [ 10 ]. In this study, GDF-15 was related to faster decline of eGFR and faster progression to end-stage renal failure[ 10 ]. In these patients, the increase in GDF-15 levels reflects the endothelial damage, and thus the microvascular consequences of diabetes, even before the appearance of macroalbuminuria.
Thus, preventive treatment can reduce the risk for renal and cardiovascular disease in these patients [10]. GDF-15 has also been associated with cancer, and particularly with the progression and metastasis of malignant tumors [30]. Recently, a study investigated the association of GDF-15 and cancer incidence in patients with T2DM [ 30 ].
This study enrolled 919 patients with T2DM, without a history of cancer, who were followed up for 60 months [30]. GDF-15 was found to be a statistically significant predictor independent of age, kidney disease and severity of diabetes [30]. The main components of this association are the inflammation, the adipokines and the adipose tissue dysfunction in this population [30].
In addition, there is evidence that GDF-15 is overexpressed in some types of malignancies due to p53 activation [32]. GDF-15 could be used for cancer screening in the diabetic population and in the general population for diabetes and cancer screening[30].
GDF-15 AND PULMONARY DISEASES
This cohort analysis enrolled 694 smokers and found that high levels of GDF-15 have independent prognostic value as biomarker of the occurrence of CVD in patients with COPD [36]. Smoking has been observed to upregulate GDF-15 via both PI3K pathway for MUC5AC and Smad1 pathway, which increases through the mucus secretion and reduces the aging [40]. COPD patients had higher levels of GDF-15 in lung tissue, causing higher incidence of respiratory inflammation, mucus secretion, and muscle dysfunction with subsequent respiratory atrophy and poor quality of life [ 2 ].
GDF-15 was recently proposed as a therapeutic target in muscle loss – a major clinical complication of PAH – in these patients [35]. The study enrolled 30 patients with PAH and supported that higher levels of GDF-15 are prognostic for patients with muscle loss responding to therapy [35]. To date, GDF-15 has been linked to muscle loss in many diseases, including cancer, anorexia nervosa and bariatric surgery [35].
In all these cases, GDF-15 through its central receptor GFRAL suppresses appetite and thus leads to weight loss [35]. Interestingly, in PAH GDF-15 also acts directly on the muscle, by contributing to the increase in atrogin-1, and in Muscle RING finger protein-1 (MURF1) [35]. The proteolytic pathway appears to be involved, and according to this study, antagonizing TAK1 and NF-κB pathway can reduce, and therefore increase, atrogin-1 expression.
In addition to muscle loss due to proteolysis, a possible autocrine and endocrine role of GDF-15 in PAH has recently been suggested, and the pulmonary endothelium could be responsible for the high concentration of GDF-15 [ 35 ]. The major muscle-related complication in PAH is dysfunction, including loss of strength, reduced capillary density, enlargement of type 2 muscle fibers, increased glycolytic metabolism and thus increased proteolysis, and muscle atrophy [41].
GDF-15 AND CARDIOVASCULAR DISEASE
Thus, GDF-15 has been proposed to be a prognostic biomarker regarding the treatment of acute coronary syndrome. To date, two studies are the most significant that focus on the role of GDF-15 in the development of heart failure [76]. Higher levels of GDF-15 have a positive association with adverse outcome and death regardless of valsartan treatment[55].
In addition, neurohormones and proinflammatory cytokines have been found to contribute to GDF-15 secretion. All this contributed to the assumption that GDF-15 is an indicator of these stressful events [55]. High GDF-15 concentration is independently associated with lower hemoglobin levels, longer DTB time and reduced LVEF[61].
However, only high GDF-15 levels were strong predictors of the incidence of death in both subgroups [64]. Also, very useful for the follow-up of these patients seems to be the correlation of GDF-15 with bleeding [65]. The prognostic value of GDF-15 in cardiovascular disease is also great in patients with acute myocardial infarction, as shown in a cohort study of 847 patients [54].
Thirty-one prospective studies increased the evidence for the role of GDF-15 in cardiovascular disease [54]. Finally, publications attempting to focus on the role of GDF-15 in cardiovascular risk, particularly in patients with T2DM are limited [1]. Furthermore, NTproBNP with the addition of GDF-15 may contribute to further protection against death after ACS [65].
Another recent study investigated the prognostic value of GDF-15 in patients with COPD regarding subclinical coronary disease [36]. There is little information on the pathophysiological role of GDF-15 in diabetes, CAD, hypertension and diabetes associated with cardiovascular disease. Further understanding of GDF-15 signaling pathways may help discover new therapies against diabetes and cardiovascular complications.
Finally, in this review, we presented the association between GDF-15 and cardiometabolic syndrome. GDF-15 and TRAIL-R2 are strong predictors of long-term mortality in patients with acute myocardial infarction.