# Heart Failure and Diabetes Mellitus: Biomarkers in Risk Stratification and Prognostication
## 3 Biomarkers in Diabetics with Known HF
### Biomechanical Stress Biomarkers  
#### 3.1.1 Natriuretic Peptides  
Nutriuretic peptides (NPs) are released from cardiac myocytes as a result of myocardial stretching, volume overload, inflammation, and ischemia/hypoxic injury [56]. NPs are physiological antagonists of RAAS, and they protect against cardiovascular remodeling through the attenuation of water and sodium homeostasis, suppression of apoptosis, inflammation, and fibrosis, as well as the potentiation of vasodilation and vascular separation, and attenuation of insulin resistance of the myocardium and skeletal muscles [57, 58]. In addition, there is strong evidence regarding the protective capacity of NPs in tissue, which has translated to an improvement of clinical outcomes and decreased risk of HF admission [59]. HF development is associated with a marked increase in NP serum levels, which closely relates to a risk of CV death and HF admission [58]. Nevertheless, the improvements in clinical outcomes and prognoses in patients with HFreEF and HFpEF were strongly associated with lowering NP serum levels [60]. Being conventional biomarkers of biomechanical stress, NPs have been utilized as a diagnostic and predictive tool, predominantly for HF with reduced ejection fraction (HFrEF). Although the role of NT-proBNP levels in predicting HF and CVD events in persons with prediabetes and T2 DM is not yet well established, NPs improved the risk prediction of traditional risk factors for both incident HF and total CVD events in pre-diabetes or T2 DM patients from ethnically diverse populations [61]. NPs exhibit optimistic results regarding prognostication of clinical outcomes directly related to HFrHF and HFpEF in diabetics treated with angiotensin receptor neprilysin inhibitor (ARNI), sodium-glucose cotransporter (SGLT)-2 inhibitors, and glucagon-like peptide (GLP)-1 agonists [62, 63, 64, 65]. Indeed, \begin{table}
\begin{tabular}{c c c c c} \hline \hline
**Biomarkers** & **Underlying Pathophysological** & **Possible Application** & **Advantages** & **Disadvantages** \\ \hline NPs & Biomechanical stress & HFrEF, HFpEF & Available for diagnosis, risk stratification, prognosis, and point-to-care therapy & High serum level variability, variable cut-off points in patients with AF, CKD, AO, prediction in HFrEF is higher than HFpEF \\ \hline hs-cTn & Myocardial injury & Manly HFrEF & Available for risk stratification and prognosis & No add-on prediction to NPs \\ \hline Mid-regional-pro-adrenoromedullin & Neurohumoral activation & HFrEF, HFpEF & Better than NPs in predicting short-term mortality in acute HF & No superiority to NPs in predictive ability among chronic HFrEF/HFpEF \\ \hline hs-CRP, IL-6 & Inflammation & HFrEF, HFpEF & Prediction of all-cause mortality, CVD, HF-related events & Not suitable for point-of-care therapy, no ability to increase predictive ability of NPs, not recommended by reputed medical societies \\ \hline GDF-15 & Inflammation & HFrEF, HFpEF & Available for improving predictive ability of NPs, suitable for multiple biomarker strategy and point-of-care therapy & High cost, not recommended by reputed medical societies \\ \hline sST2, galectin-3 & Fibrosis/inflammation & HFpEF & Better than NPs for predicting mortality and HF-related events in non-HF patients, low individual serum level variability & High cost, not recommended by reputed medical societies \\ \hline Collagen turn-over biomarkers & Fibrosis & HFpEF & Available for risk stratification and prognosis & High cost, not recommended by reputed medical societies \\ \hline Abbreviations: AO, abdominal obesity; AF, atrial fibrillation; CKD, chronic kidney disease; NPs, natriuretic peptides; hs-CRP, high-sensitivity C-reactive protein; sST2, soluble suppressor tumorigenicity-2; GDF-15, growth differential factor-15; IL, interleukin; HFrEF, heart failure with reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction. \\ \hline \hline \end{tabular}
\end{table} 
Table 2: Advantages and disadvantages of HF biomarkers in T2 DM patients.