# Heart Failure and Diabetes Mellitus: Biomarkers in Risk Stratification and Prognostication
## 3 Biomarkers in Diabetics with Known HF
### Biomarkers of Inflammation and Fibrosis
#### 3.2.6 Other Biomarkers of Fibrosis  
Novel biomarkers (matrix metalloproteinases (MMPs) and tissue inhibitors of MMP (TIMP), collagen degradation products) have been discussed considerably in the context of risk stratification in T2 DM with HF but have not yet been tested directly in large clinical trials. Therefore, the clinical perspectives of these biomarkers are not yet known [13]. Despite serious concerns regarding the essential ability of these circulating biomarkers to reflect both quantitative and qualitative morphological changes in the cardiac extracellular matrix,there is a large body of evidence drawn from preclinical and clinical studies that suggests a promising role of collagen turn-over biomarkers in the development of adverse cardiac remodeling and HF [145]. The potential of T2 DM to lead primarily to the development of HFpEF depends on impaired collagen homeostasis and cardiac fibrosis. Indeed, there is a disproportion in the circulating levels of collagen synthesis biomarkers (procollagen type I N-terminal propeptide (PINP), procollagen type III N-terminal propeptide (PIIINP), and biomarkers of collagen degradation (c-terminal telopeptide of collagen type I (CTx)) among HF patients with left ventricular ejection fraction < 50%. In fact, circulating levels of these biomarkers were positively correlated with the severity of HF, which was confirmed by NT-proBNP, E/E', and left atrial volume [146]. Moreover, elevated circulating levels of procollagen I N-terminal peptide (PINP) and procollagen III N-terminal peptide (PIIINP), MMP-1, MMP-3, MMP-9, and TIMP-1 were associated with higher rates of CV mortality and HF hospitalization in patients with overt HFrEF and HFmrEF [147,148]. Surprisingly, long-term prognosis of HF outpatients was comparable, regardless of whether patients had HFpEF or HFrEF [149]. In contrast, the MESA (Multi-Ethnic Study of Atherosclerosis) trial showed that high levels of circulating ICTP and PIIINP were solely associated with incident HFpEF, but not HFrEF [150]. However, [PERSON] et al. (2019) [151] reported that collagen Lysyl oxidase-like 2 (Loxl2), which is up-regulated in the cardiac interstitial in HF, was found to be a powerful trigger for cardiac fibroblasts via PI3K/AKT to express TGF-\(\beta\)2, promoting the fibroblast-to-myofibroblast transformation. Moreover, LOXL2 concentrations were elevated in the serum of HF patients and positively correlated with BNP and NT-proBNP [151]. Overall, biomarkers of collagen homeostasis transformation could be strongly linked to inflammation, apoptosis, vascular function, extracellular matrix remodeling, blood pressure control, and energy metabolism, and therefore did not have high specificity for HF development or progression [152]. When added to conventional biomarkers, such as BNP, NT-pro-BNP, and sST2, circulating biomarkers reflecting excessive myocardial collagen type-I cross-linking and extracellular matrix remodeling were able to substantially increase the predictive ability of the entire model, especially in HFpEF patients with T2 DM, atrial fibrillation, or hypertension [153,154].