# Old and Novel Predictors for Cardiovascular Risk in Diabetic Foot Syndrome--A Narrative Review
## 5 Discussions  
### Cardio-Diabetology: The Role of Biomarkers and Inflammatory Molecules  
Pathophysiological analysis of the adipovascular axis revealed the determinant role of inflammatory markers such as IL-6 and resistin in modulating cardiovascular risk in diabetic patients [96]. Patients with DF syndrome associate metabolic disorders that modulate the associated cardiovascular risk. Hyperglycemia causes axonal and microvascular injury over time. In addition, in diabetic patients, hypertriglyceridemia is a known independent risk factor for amputations [75,130]. Clinical studies in the field associate low serum levels of adiponectin and high levels of IL-6 with the development and progression of inflammatory mechanisms involved in the pathogenesis of diabetic ulcers. In diabetic patients, microalbuminuria correlates with serum IL-6 and adipocyte levels, thus playing a dual role as a contributor to the progression of insulin resistance and the production of inflammatory cytokines [96]. Besides adiposity, oxidative stress, mitochondrial dysfunction, activation of the polyol pathway or accumulation of pro-inflammatory and advanced glycation end-products are pathophysiological mechanisms underlying the cardiovascular damage associated with DF syndrome [131, 132, 133, 134]. Hyperglycemia affects ischemic preconditioning, being associated with elevated serum catecholamines, the presence of a no-fellow phenomenon, increased oxidative stress, pro-thrombotic status and inflammation (Figure 2) [135,136]. Hyperglycemia also leads to endothelial dysfunction, with activation of various metabolic pathways mediated by protein kinase C resulting in excessive production of reactive oxygen species [75]. [PERSON] et al. [137] have shown that serum xanthine oxidase activity is an independent predictor for the occurrence of diabetic peripheral neuropathy, thus contributing to the development of DF syndrome. The administration of vitamin D for 12 weeks is accompanied by an improvement in carbohydrate metabolism, which also contributes to the healing process of diabetic ulcers [138]. Silent myocardial ischemia is common among diabetic patients, the presence of diabetic peripheral neuropathy being a risk factor associated with it; it has a screening role to detect patients at risk of developing an acute cardiovascular event [139]. In addition to IL-6, other cytokines that modulate inflammatory processes have been identified such as leptin, tumor necrosis factor-\(\alpha\), plasminogen activator inhibitor, uric acid or oxidized low-density lipoproteins [103; 140; 141; 142]. [PERSON] et al. [142] identified several lipid determinants with a role in the development and progression of diabetic neuropathy such as acylcarnitines, free fatty acids, phosphatidylinositol, and lysophosphatidylcholines, the presence of which can be identified up to 10 years earlier in a high titer. Some of these lipid compounds are also responsible for the development of cardiac autonomic dysfunction in patients with type 2 DM [143] and insulin resistance [144]. The identification of a serum cystatin C level above 0.735 mg/L is a potential biomarker for the identification of diabetes-associated complications and is correlated with the occurrence of DF and tissue loss in patients with type 2 DM [145]. In patients with type 2 diabetes, elevated homocysteine levels are associated with the presence of heart failure with a low ejection fraction and are an independent risk factor for all-cause mortality [44]. The connection between cardiac autonomic neuropathy and subclinical inflammation, with multiple prognostic implications on associated cardiovascular risk and morbidity, was examined in diabetic patients, with differential results depending on the type of molecule involved [146; 147; 148]. Heart rate variability is dependent on altered sympathetic and parasympathetic tone in young patients with DM, correlating with glycated hemoglobin values [149; 150].