# Heart Failure and Diabetes Mellitus: Biomarkers in Risk Stratification and Prognostication
## 2 Basic Underlying Mechanisms of HF Development in Diabetics
Metabolic stress-induced pro-inflammatory activation has been cited as a powerful factor contributing to the pathogenesis of T2 DM cardiomyopathy and HF [33]. Numerous inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-\(\alpha\)), interleukin-6, as well as some adipocytes, act as triggers for insulin resistance via the enhancement of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-\(\kappa\)B) and fork-head box-containing protein O subfamily (FoxO1) expression, as well as c-Jun N terminal kinase (JNK) activation, that induce the phosphorylation of IRS-1 and hamper the activation of peroxisome proliferatorator-activated receptors (PPAR)-\(\gamma\) receptors [34; 35]. These perturbations mediate insulin resistance of the myocardium and skeletal muscles, adipose tissue inflammation, markedly reduce an interaction of FoxO1 with the promoter region of the \(\beta\)-isoform of myosin heavy chain (\(\beta\)-MHC) as well as negatively regulate \(\beta\)-MHC gene expression [36]. The structure and functional abnormalities result in adverse cardiac remodeling such as diastolic and systolic dysfunction due to cardiac hypertrophy, extracellular matrix accumulation and interstitial fibrosis, resulting in progressive dilated cardiomyopathy and decreased cardiac output, eventually leading to HF [37]. The underlying pathophysiological mechanisms contributing to the development of HF in DM are reported in Figure 1.  
Of note, there is evidence that approximately one-third of patients with T2 DM demonstrate isolated diastolic filling abnormality and subclinical myocardial dysfunction, unrelated to accelerating atherosclerosis or CVD [38]. Therefore, left ventricular (LV) diastolic  
Figure 1: Underlying pathophysiological mechanisms contributing to the development of HF in patients with DM. Abbreviations: ACS, acute coronary syndrome; AGEs, advanced glycated end-products; CAD, coronary artery disease; CVD, cardiovascular disease; GRK, g-protein receptor kinase; ERS, endoplasmic reticulum stress; MI, myocardial infarction; HF, heart failure; HFFEF, heart failure with reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; IR, insulin resistance; RAAS, renin-angiotensin-aldosterone system; WAT, white adipose tissue. dysfunction and LV concentric hypertrophy may be seen as the first signs of cardiac complications in patients with T2 DM, independently from metabolic control [39; 40]. In addition, uncontrolled T2 DM with hyperglyic status, hyperinsulinemia/insulin resistance, and lipotoxicity may result in cardiotoxicity, acute and chronic LV systolic dysfunction in the absence of CAD, valvular, congenital, or hypertensive heart disease, or alcoholism [41]. In fact, several phenotypes of T2 DM-induced cardiac dysfunction may mostly relate to an overlap, but different alterations, which may be observed in failing hearts of T2 DM patients. Indeed, substantial abnormalities in contractile (myosin, actin), regulatory (troponin, tropomyosin, and tropomodulin) and structural (predominantly titin, myomesin, and P-actinin) protein expression are responsible for the occurrence of diastolic and systolic dysfunctions as a primary myocardial alteration. For example, a decreased Ca\({}^{2+}\) sensitivity along with a turnover of cardiac myosin heavy chain from V1 to V3 isoforms contributes to HFrEF [42]. Thus, an imbalance between adaptive and maladaptive molecular mechanisms of cardiac metabolism and reparation secures a link between T2 DM and cardiac dysfunction [43; 44; 45]. MicroRNA and exosome-shaped transfer of active molecules are therefore also engaged in the pathogenesis of T2 DM-induced cardiac dysfunction [46].