Impact of diabetes on the predictive value of heart failure biomarkers

Epidemiological studies have confirmed that the presence of diabetes mellitus (DM) is associated with an increased risk of developing heart failure (HF) [1, 2]. Indeed, HF is often the first cardiovascular manifestation observed in diabetic patients [3]. The increased risk of HF persists even after adjustment for confounders such as coronary artery disease and hypertension. Further, diabetic patients with HF have a poor prognosis [4].

It is challenging to stratify risk for patients with HF. Established risk factors such as left ventricular ejection fraction (LVEF), New York Heart Association (NYHA) functional class, comorbidities (DM, anemia, and renal insufficiency), and treatment strategies do not fully explain the mortality risk associated with HF patients [5‐7]. Prognostication may be refined by measurement of biomarkers for different pathophysiological processes not reflected by established mortality risk factors [8] Circulating biomarkers measured in patients with HF are classified into seven pathophysiological pathways, including myocardial stretch, myocyte injury, extracellular matrix, inflammation, renal dysfunction, neurohormonal activation, and oxidative stress [9, 10]. In recent years, there is a growing interest in relation to the clinical usefulness of these biomarkers in patients with diabetes [11] as well as to their pathogenic role in the development of vasculopathy [12, 13]. Some of these biomarkers have been shown to be associated with the risk of diabetes [14‐16] and their serum levels were described to be modified by medical treatment [17]. It is unclear whether systemic diseases such as DM may affect the predictive value of these HF biomarkers. Accordingly, our aim in the present study was to assess whether DM had any impact on the predictive value of a multi-biomarker panel in patients with HF. We included the following biomarkers: N-terminal pro-brain natriuretic peptide (NT-proBNP; myocardial stretch and neurohormonal activation), neprilysin (neurohormonal activation), galectin-3 (extracellular matrix), ST2 (inflammation, stretch, and extracellular matrix), high-sensitivity troponin T (hs-TnT; myocardial injury), cystatin-C (renal dysfunction), high-sensitivity C reactive protein (hs-CRP; inflammation), and soluble transferrin receptor (sTfR; oxidative stress).

We included 1069 consecutive ambulatory HF patients in the study. Table 1 lists the clinical characteristics of the total cohort and statistical differences based on the presence or absence of DM. The mean age was 66.2 ± 12.8 years, and 72% of the patients were men. The predominant HF etiology was ischaemic heart disease (51%), and the mean LVEF was 33.5 ± 13.3%. In total, 385 patients (36%) had DM. Upon inclusion, 198 and 151 patients were receiving oral antidiabetic medication and insulin, respectively; 39 patients were taking both. During follow-up, these numbers increased to 285 and 241, respectively (166 patients were receiving both treatments). As expected, many of the clinical characteristics were different between nondiabetic and diabetic patients (Table 1). For example, serum concentrations of five of the eight studied biomarkers were higher in diabetic patients: NTproBNP (p = 0.07), hs-TnT (p < 0.001), galectin-3 (p < 0.001), cystatin-C (p = 0.001), and sTfR (p = 0.005) (Table 1). After adjustment for age, sex, body mass index, and estimated glomerular filtration rate, NTproBNP (p = 0.01), hs-TnT (p < 0.001), and sTfR (p < 0.05) levels remained significantly higher in diabetic patients, while levels of galectin-3 (p = 0.1), cystatin-C (p = 0.86), hs-CRP (p = 0.62), sNEP (p = 0.61), and ST2 (p = 0.28) were no longer significantly different between the two groups.

During a mean follow-up period of 4.9 ± 2.8 years (6.6 ± 2.3 years for patients who did not die in the follow-up period), 534 patients died. Of the patients who died, 284 died from cardiovascular causes: 137 of progressive HF, 67 of sudden death, 26 of acute myocardial infarction, four of stroke, six during cardiovascular procedures, and 31 of other cardiovascular causes. One hundred and ninety-six patients died of noncardiovascular causes, while the cause of death was unknown in 54 patients. As expected, both all-cause and cardiovascular mortality were higher in diabetic patients (57.7 vs. 45.6%, p < 0.001 and 34.8 vs. 24.2%, respectively; p < 0.001).

There were no interactions between the majority of the biomarkers and DM with respect to prediction of risk of all-cause or cardiovascular death (Fig. 1). However, ST2 significantly interacted with DM for all-cause (p = 0.02) and cardiovascular (p = 0.03) death.

Figure 1 shows the HRs and 95% CIs of Cox regression analyses for each biomarker for nondiabetic and diabetic patients, both for all-cause (left) and cardiovascular (right) death. In diabetic patients, the HRs for ST2 were 1.27 (95% CI 1.16–1.40, p < 0.001) and 1.23 (95% CI 1.09–1.39, p = 0.001) for all-cause and cardiovascular death, respectively. In nondiabetic patients, the HRs for ST2 were 1.53 (95% CI 1.35–1.73, p < 0.001) and 1.64 (95% CI 1.31–2.05, p < 0.001) for all-cause and cardiovascular death, respectively. Survival curves for diabetic and nondiabetic patients based on the best cut-off of ST2 values are shown in Fig. 2. Divergence of the curves and HRs are also mildly higher in nondiabetic than in diabetic patients. Table 2 shows, in a sensitivity analysis, multivariable Cox regression analyses performed in the 265 diabetic patients with all the biomarker studied. Hs-TnT, ST2 and cystatin-C remained statistically associated with all-cause death and hs-TnT, ST2 and galectin-3 with cardiovascular mortality. Finally, Discrimination analysis using a simple clinical model and the studied biomarkers and the best short combinations of them, according also to the previous multivariable analysis are shown in Table 3. Results show that the combination of two biomarker such as hs-TnT and ST2 significantly improved discrimination, as assessed by confidence intervals.

The present study was performed in a large cohort of ambulatory patients with HF and included a long-term follow-up. The three main findings were as follows. First, the levels of most of the biomarkers that we studied were higher in diabetic patients; however, when we adjusted for confounders, only NT-proBNP, hs-TnT, and sTfR were significantly higher in diabetic patients. Secondly, independent of the finding stated above, we did not find any differences between nondiabetic and diabetic patients for most of the biomarkers with respect to prognostic value for all-cause and cardiovascular mortality. Finally sST2 which was a significantly predictor for both all-cause and cardiovascular death in both diabetic and nondiabetic subjects was associated with an appreciably higher risk in the nondiabetic patients. This biomarker together with hs-TnT were the only markers that were independently associated with both all-cause and cardiovascular mortality in the diabetic patients of our cohort. Some of the biomarkers that we investigated have been shown in previous studies to be predictors of the incidence of cardiovascular events and prognosis in diabetic patients and some of them have also shown to help in distinguishing those individuals with a high risk of CV disease among diabetic subjects [19]. In elderly patients with DM, NT-proBNP is a strong independent predictor of short-term cardiovascular mortality, including patients without preexisting cardiovascular disease [20]. Also, in type 2 diabetic patients with microalbuminuria but without known coronary artery disease, NT-proBNP has been shown to be strongly associated with future CV events [17]. Moreover, hs-TnT levels in diabetic subjects were recently described as the strongest predictor (in addition to sST2 and hs-CRP) of short-term outcome in patients with stable coronary artery disease [21]. Also in type 2 diabetic patients, normal hs-TnT level has a high negative predictive value for future adverse CV events [22]. In the present study there were no interactions between the majority of the biomarkers and DM with respect to prediction of risk of all-cause or cardiovascular death. However, ST2 significantly interacted with DM for all-cause and cardiovascular death being associated with a higher risk in nondiabetic compared to diabetic patients. Experimental and human studies have suggested relationships between ST2 and myocardial stretch, fibrosis, adverse cardiac remodelling, inflammation, impaired haemodynamics, and vascular disease [23]. Indeed, in experimental studies ST2 appears to play a pivotal role in LV remodeling; this process comprises changes in cardiac structure, myocardial composition, myocyte deformation, and multiple biochemical and molecular alterations that impact heart function and reserve capacity [24]. The currently available data are insufficient to allow us to determine conclusively whether the value of ST2 as a marker of cardiac remodelling is different in patients with and without diabetes. That is, patients with diabetes may be affected by other variables such as advanced glycation end products, inflammatory markers, or microvascular damage that may be involved in the remodelling process and thus could explain the difference in the prognostic value of ST2 concentrations between patients with and without DM. On the other hand, the source of ST2 is not well established; although it is known to be produced by both cardiac fibroblasts and cardiomyocytes in response to injury or stress, nonmyocardial production by endothelial cells has also been suggested [25]. The multivariable Cox regression analysis showed that ST2 together with hs-TnT were the only biomarkers analysed in the present study that were independently associated with heart failure prognosis (all-cause and cardiovascular mortality) in diabetic patients. Moreover, the combination of two biomarkers (ST2 together with hs-TnT) increased the predictive value of HF prognosis compared to what is obtained when only one of them is determined.

Diabetes is widely recognized as a significant risk factor for the development of HF and is an independent risk factor for increased mortality among individuals with HF. Indeed, HF is one of the most common initial manifestation of cardiovascular disease in patients with T2D [3]. Thus, it is of clinical interest to investigate whether the biomarkers used for assessing the prognosis of heart failure perform similarly in diabetic and non-diabetic subjects (both with regard to its serum concentrations and as to its prognostic value). To our knowledge there are no studies to date that have specifically addressed whether current predictive biomarkers used in the general population with heart failure are also useful in patients with diabetes. Our conclusion is that, in our cohort of HF patients, biomarkers used in the general population to predict the clinical course of heart failure are also useful in patients with diabetes. In these patients, among all the biomarkers analysed only hs-TnT and ST2 were independently associated with both all-cause and cardiovascular mortality. The use of a combination of biomarkers (multimarker strategy) in predicting the risk of death seems to be in diabetic patients as good as in the general population with HF [10], improving discrimination, mainly when two biomarkers are combined.

DM has little impact on the predictive power of the HF biomarkers NT-proBNP, hs-TnT, galectin-3, hs-CRP, cystatin-C, sTfR, and neprilysin. Only ST2, which had predictive value in both diabetic and nondiabetic patients, was associated with a higher risk in nondiabetic patients.