Potential Biomarkers as Early Detection of Diabetic Cardiomyopathy

Diabetes mellitus (DM) is one of the most prevalent and burdensome among chronic disease worldwide. Its complications accelerate mortality rate within population. Diabetic cardiomyopathy (DCM) is one of diabetes macrovascular complications, which symptoms are frequently unforeseen. Advances in pathogenesis understanding DCM underlying mechanisms remain not fully perceived. Current diagnostic approach of DCM can hardly determine diabetic patients with asymptomatic cardiomyopathy. Previous studies suggested biomarkers might detect early stage DCM. There are numerous selective biomarkers representing several pathophysiological pathways, such as myocardial fibrosis, inflammatory response, cardiomyocyte apoptosis, and metabolic dysregulation in the development of diabetic heart anomaly. It was also reported those biomarkers are useful for the prognostic assessment of the disease. However, not all biomarkers are cardiac specific and can be an auspicious diagnostic tool candidate. Recent studies show that there are certain biomarkers, such as microRNA, H-FABP, IGFBP7, and some other novel cardiac biomarkers were more specifically associated with the pathological mechanism of DCM. In this review, we aimed to discuss the role of several potential cardiac biomarkers as early detection in DCM that may predict future incident of DCM, and contribute to improving mortality prediction in patients with subclinical DCM. Review Article Potential Biomarkers as Early Detection of Diabetic Cardiomyopathy Hariadi1, Maria Thalia Giani2, Silvia Handika Anggraeni2 PKU Muhammadiyah Karanganyar Hospital, Karanganyar, Central Java, Indonesia. Faculty of Medicine, Universitas Sebelas Maret. Surakarta.

novel biomarkers, which involved in DCM underlying mechanisms at the molecular level, such as microRNA, Galectin-3, and fibroblast growth factor 21 (FGF21). Each biomarker has important role in pathophysiology of DCM and may benefit in diabetic related heart disease early diagnostic. In this review, authors aimed to determine the potential biomarkers in early detection of DCM.

Molecular Mechanism Underlying Diabetic Cardiomyopathy
Early progress of diabetic cardiomyopathy (DCM) is usually asymptomatic and characterized by increased fibrosis tissue and myocardial stiffness.
In this state, early diastolic filling begin to decrease, cause impaired atrial filling and enlargement, as well as an elevated LV end-diastolic pressure. The pathophysiology mechanism underlies diabetic cardiomyopathy could be seen in Figure 1 [7] . Furthermore, hyperglycemia stimulates AGEs and ROS production within cardiomyocytes, which trigger local inflammation and interstitial fibrosis.

Diabetes increases glucose level and Fatty
Ultimately, persisted condition leads to cardiac dysfunction [7] .
Underlying familiar pathological factors in the development of DCM are multifactorial [8] . Recent theories stated that metabolic dysregulation has essential role in DCM progressivity. Cardiac metabolism is mainly regulated by peroxisome proliferator-activated receptor (PPAR) gene in biomolecular level [9] . The gene target of PPAR is pyruvate dehydrogenase kinase 4 (PDK4) which encodes the enzyme that catalyze glucose oxidation and is chronically elevated in the diabetic heart. In addition, the uptake activity of FA and glucose in cardiomyocyte is also transcriptionally regulated by PPAR. Under diabetic state, despite the higher FA oxidation rate, myocardial lipid accumulation is a paramount of diabetic heart and ultimately catalyze DCM development [10][11] . It is also characterized by Nf-κB activation, augmented ER stress and mitochondrial dysfunction, which are linked to myocardial injury [12] .

Fibroblast Growth Factor 21
Fibroblast growth factor 21 (FGF21) is a secreted protein which functions as a metabolic regulator, insulin sensitivity, and ketogenesis [26] . Regulation of FGF21 expression on the cell is controlled by peroxisome proliferator-activated receptor-γ (PPARγ). It is released into blood by hepatocytes, brown adipose tissue and skeletal muscle [27][28] . FGF21 September 2021 | Vol 2 | Article 7 requires some receptors (mainly FGFR1 and FGFR4) and β-klotho to perform its roles [27] . So it is considered if FGF21 could be a potential marker for early detection of cardiometabolic risk [38] .
Serum FGF21 levels were compared between prediabetic, diabetic, and healthy in a recent crosssectional study. The study showed that serum FGF21 levels were significantly increased in those two first groups. The cut off value for the diagnosis of T2DM in this material had sensitivity and specificity of 82.5% and 60%, respectively [39] .
Although the specificity of this biomarker examination still low, this marker may benefit in early DCM screening.

Heart-type fatty acid-binding protein
Heart-type fatty acid-binding protein (H-FABP) is a protein in myocardium that functions in citric acid cycle. It transports the hydrophobic long-chain fatty acids from cell membrane to mitochondria [40] . In

Insulin-like growth factor-binding proteins
Insulin-like growth factor-binding proteins (IGFBP7) is a member of the IGFBP family, produced by tissues and organs, including the lung, brain, prostate, bladder, colon, and liver. Furthermore, preclinical study showed that IGFBP7 overexpression in r1-IGFBP-rP1-treated mice significantly increase the production of TGF-ß1, collagen, and fibronectin [53] . In addition, IGFBP7 has role in increasing fibrosis and cardiac hypertrophy in diabetes by modulating insulin receptor activity signaling pathway. It causes cardiac stiffness that leads to diastolic dysfunction [49,54,55] . It shows that alteration of IGFBP7 concentration could be potential cardiac biomarker for DCM because its early arise in asymptomatic DCM and correlation with diastolic dysfunction degree, which describe cardiac stiffness due to fibrogenesis activity.

Matrix metalloproteinases (MMP) and tissue inhibitors of metalloproteinases (TIMP)
Matrix metalloproteinases (MMP) is one of the proteolytic enzymes. It is induced by inflammatory signals to mediate change in extracellular matrix.
MMP has role in vascular remodeling. Activation of its regulation also alters the morphology of the endothelial plaque and could cause rupture of plaque. MMP also participates in cardiac September 2021 | Vol 2 | Article 7 remodelling causing myocardiac infarction and progression of dilated cardiomyopathy [56] .
MMP maintains structural integrity of the heart and blood vessels. It also maintains framework for cell anchoring, function, phenotype, and communication. MMP is responsible to promote cell survival or apoptosis, growth factor and cause diastolic stiffness. Another function of MMPs is as a potent protein-degradating and modifying enzymes [56] . This study showed that it may lead to collagen degradation impairment and contribute to the matrix deposition in DCM. Serum TIMP-2 level could act as a marker for early diagnosis of DCM [59] .
MMP-7 also related to diastolic dysfunction and complications of microvascular. Patient with diastolic dysfunction shows an elevation in MMP-9 and reduction in TIMP-1/MMP-9 [60] . There is another investigation demonstrated that serum MMP can be a quantitative biomarkers for myocardial fibrosis. Fibrosis and cardiac event in female with cardiac hypertrophic cadiomyopathy can also be detected using MMP-9 [61] . It is also histone modification [65] .

Transforming growth factor-β (TGF-β)
Transforming  TGF-β also may predict future prognosis and severity of the disease. Moreover TGF-β detection is a less invasive procedure than current available examination tool.

Conclusion
Achieving early diagnosis of asymptomatic DCM is