T2DM has become the third chronic disease affecting human life after cardiovascular diseases and tumors. Macroangiopathy is one of the main complications of T2DM. It can involve medium sized or large blood vessels, leading to stenosis and occlusion of the lumen. In severe cases, it can cause plaque rupture and shedding, and induce embolism or bleeding. The mechanism may be related to factors such as glucose and lipid metabolism disorder, blood hypercoagulability, microcirculation disorder, and decline of vascular endothelial function. The pathological basis of T2DM macroangiopathy is atherosclerosis, and its mechanism may be related to factors such as glucose and lipid metabolism disorder, blood hypercoagulability, microcirculation disorder, and vascular endothelial function decline [15]. Umemura et al. [16] revealed that the prevalence of macroangiopathy in Caucasian T2DM patients is twice that of microvascular disease, and the mortality rate is 76 times that of microvascular disease. In clinical practice, controlling blood glucose alone cannot reduce the risk of macroangiopathy. Therefore, prevention of macroangiopathy in T2DM is a difficult disease of global concern and one of the important issues to be solved urgently.
The EAT is located on the surface of the myocardium. It is a special visceral fat between the epicardium and the visceral pericardium. It is an important endocrine organ of the body and a storage warehouse of body fat energy. It is mainly distributed in the free wall of the right ventricle, the apex of the left ventricle and the free wall of the right ventricle. It can release a variety of biologically active molecules at a high rate, and communicate through signal transduction between the heart, liver, vascular endothelial cells, adipose tissue, skeletal muscle and pancreatic islet cells, forming a complex regulatory network [17]. Chen et al. [18] indicated that the EAT thickness of T2DM patients is significantly higher than that of normal subjects.
CRP is the most significant clinical marker of inflammation. It has the function of recognizing and regulating immunity. It can also enhance the reactivity of leukocytes, play a firm role in the fixation of complement, and strengthen the ability to remove cell debris in inflammation sites. By activating complement, inflammatory mediators such as histamine are released [19]. Shen et al. [20] suggested that CRP is present in atherosclerosis and produces proinflammatory and atherogenic pathways, suggesting that CRP can be used not only as an inflammatory marker, but also as an independent risk factor in the pathologic formation of atherosclerosis.
IL-6 is synthesized by fibroblasts, vascular endothelial cells, activated monocytes and other cells. It can affect inflammation and host defense through cellular and humoral immune functions and is the main circulating substance in vivo that links systemic immune response with local vascular injury [21]. Ziegler et al. [22] suggested that T2DM may be a cytokine-mediated inflammatory disease, and T2DM and atherosclerosis are both inflammatory diseases. Inflammation plays an important role in the occurrence and development of chronic vascular complications and atherosclerosis and has been considered as one of the important factors in the occurrence and development of atherosclerosis. Since IL-6 can stimulate liver cells to synthesize CPR, the changes in the levels of the two in patients also have a certain correlation. Deng et al. [23] proved that hs-CRP and IL-6 have diagnostic significance for patients with T2DM vascular disease.
Li et al. [24] confirmed that the human JAZF1 gene sequence has extremely high homology with mouse gene sequence. JAZF1 is located in the nucleus and its mRNA is common in human tissues. TAKI is an orphan nuclear receptor that plays a role in multiple metabolism-related genes, and has a regulatory effect on liver lipid metabolism. Lack of TAKI in mice can reduce the inflammation of adipose tissue, loss of mitochondrial function, reduce the formation of CD36 and foam cells, and then cause atherosclerosis [25]. Marselli et al. [26] found that PPARα-mediated transcriptional activation is inhibited by TAKI of liver cells, and PPARα regulates gene expression of multiple links in the liver, which indirectly suggests that JAZF1 can improve lipid metabolism. Animal experiment by Zhou et al. [27] indicated that JAZF1 gene overexpression can improve lipid metabolism and inhibit the accumulation of macrophages in plates, thus reducing or delaying the formation of atherosclerosis. Therefore, it is speculated that JAZF1 may play an important role in diabetic macroangiopathy, hyperlipidemia and glycolipid metabolism.
Visfatin is a factor that exists in visceral fat cells, which can combine activated insulin receptors with Insulin-Like Growth Factor, and is closely related to vascular smooth muscle maturation, atherosclerosis, immune regulation and inflammatory reactions. Ran et al. [28] have shown that inhibition of JAZF1 reduces the expression level of visfatin. However, there are few clinical reports on the correlation between EAT thickness, CRP, IL-6, Vivfatin, JAZF1 and T2DM macroangiopathy.
The results of this study showed no statistical difference in baseline characteristics among the three groups, and the diabetic course was comparable between the Complication group and the Diabetes group (P > 0.05). The WHR, FPG, 2hPG, HbA1C, CRP, IL-6, visfatin, JAZF1, HOMA-IR, and EAT thickness were all higher in the Complication Group than the Diabetes Group and the Healthy Control Group (P < 0.05, respectively), and the FIns of both the Complication Group and the Diabetes Group were lower than that of Healthy Control Group (P<0.05). It was suggested that the above indicators could predict T2DM with macrovascular lesions, especially CRP, IL-6, visfatin, JAZF1, HOMA-IR, and EAT thickness. According to the changes of the above indicators, early intervention in patients with T2DM can prevent the occurrence of disability and death to a certain extent and has important clinical significance for the treatment of T2DM macroangiopathy.
CT and MRI are the main methods to measure EAT thickness. However, due to the high price of CT and MRI, the radiation of CT and the noise of MRI, the large-scale use of CT and MRI is affected to some extent. Uygur et al. [29] have confirmed that the measurement of EAT thickness of the anterior wall of the right ventricle by chest ultrasound is consistent with the measurement results of CT and MRI. Therefore, in this study, chest ultrasound was used to measure the EAT thickness of the anterior wall of the right ventricle in the enrolled cases and healthy controls. The measurement site was the hypoechoic and anechoic region between the epicardium of the right ventricular wall and the visceral pericardium. Because of the difference in shape, the thickest part of the anterior wall of the right ventricle was measured. The results demonstrated that repeated measurements of EAT thickness at the end of the diastole showed stable results, and the measuring method was simple and reliable.
Ultrasound measurement of EAT thickness has the following advantages in predicting T2DM macroangiopathy. First, compared with the conventional method of evaluating macroangiopathy, ultrasound can measure the thickness of EAT and examine the structure and function of the heart at the same time, combining the examination to evaluate cardiac and macroangiopathy. Second, compared with CT or MRI, ultrasound examination is cheaper and easier to repeat.
Diabetes can easily lead to atherosclerosis. As atherosclerosis progresses, plaques can block the lumen and cause cardiovascular and cerebrovascular diseases. PWV is the rate of pulse conduction from the proximal end to the distal end of the arterial wall due to the expansion and retraction of the arterial wall, which can reflect the elasticity of the artery. The higher the PWV is, the harder the blood vessel wall is [30,31,32]. Studies have confirmed that PWV is an independent predictor of cardiovascular events [33, 34], and also pointed out that EAT is an independent risk factor for cardiovascular disease, which can affect the process of atherosclerosis through regulating inflammation. As the lesion area of coronary heart disease expands, the thickness of epicardial tissue also increases. As the human body ages, the expansion of elastic arteries decreases while the compliance of muscular arteries increases. The baPWV measurement includes elastic arteries and muscular arteries, which more comprehensively reflects the condition of arteriosclerosis. Pearson correlation analysis found that EAT thickness was positively correlated with CRP, IL-6, visfatin, and JAZF1 (P < 0.001), and baPWV was positively correlated with EAT thickness, CRP, IL-6, visfatin, and JAZF1 (P < 0.001), suggesting that in T2DM macroangiopathy patients, EAT thickness is closely related to inflammation and lipid metabolism. With increase in EAT thickness, the levels of CRP, IL-6, visfatin, and JAZF1 also increase, which can induce hyperglycemia, insulin resistance, and vascular endothelial dysfunction, etc., promoting the occurrence and development of atherosclerosis, leading to macroangiopathy.
A previous study found a stronger link between pericardial adipose tissue and visceral abdominal adipose tissue than other cardiovascular risk factors. Vascular calcification was associated with intrathoracic and pericardial adipose tissue, probably due to a local toxic effect on the vasculature [35]. In addition, excessive serum free fatty acids (FFA) can increase glycogen and basal insulin secretion and reduce liver insulin inactivation, resulting in hyperglycemia and insulin resistance. Diabetic hyper-FFAemia can cause vascular endothelial dysfunction through inflammation, oxidative stress pathways, and mitochondrial dysfunction, and vascular endothelial dysfunction is the initiating factor leading to atherosclerosis [36]. In the pathophysiology of atherosclerosis, inflammatory mechanisms play an important role. Persistent chronic inflammatory responses lead to damage to blood vessels, causing atherosclerosis, and plaque rupture and thrombosis [37]. He et al. [38] indicated that inflammatory factors such as TNF-α and CRP are involved in the pathophysiological process of vascular disease in patients with T2DM in plateau areas. Zhuo et al. [39] found that serum JAZF1 combined with fasting C-peptide has certain value in the diagnosis of T2DM macroangiopathy. Another study has also found that increased levels of visfatin are closely related to the severity of atherosclerotic peripheral arterial obstructive disease [40]. Chang et al. [41] confirmed that visfatin is elevated in the serum of Uyghur diabetic patients.
The results indicate that FPG, 2hPG, HbA1C, CRP, IL-6, Visfatin, JAZF1, FIns, HOMA-IR and EAT thickness are all factors affecting T2DM macroangiopathy. Therefore, CRP, IL-6, visfatin, JAZF1, and EAT thickness can be used as new targets for monitoring and treating macrovascular changes in T2MD.
Study strength and limitations
This study prospectively observed the relationship between the indicators like the EAT thickness and the incidence of T2DM macroangiopathy, and found some valuable positive indicators, which had a certain predictive value for the incidence of T2DM macroangiopathy. This study also has certain limitations. Firstly, this is a single-center trial, and selection bias cannot be completely eliminated. In addition, due to the limited time of this study, it is still unclear whether there is a cross regulation between serum CRP, IL-6, Visfatin, JAZF1, and EAT thickness, and the specific regulation mechanism still remains unelucidated which needs to be confirmed by further study. Thirdly, there are the inter- or intra- operator differences in the measurement, which may lead to a bias of EAT thickness results.