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Current Advances in the Study of Diabetic Cardiomyopathy: from Clinicopathological Features to Molecular Therapeutics (Review)

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Current Advances in the Study of Diabetic Cardiomyopathy: from Clinicopathological Features to Molecular Therapeutics (Review) MOLECULAR MEDICINE REPORTS 20: 2051-2062, 2019 Current advances in the study of diabetic cardiomyopathy: From clinicopathological features to molecular therapeutics (Review) LIN SUN1, MING YU2, TONG ZHOU1, SIWEN ZHANG1, GUANGYU HE1, GUIXIA WANG1 and XIAOKUN GANG1 1Department of Endocrinology and Metabolism, The First Hospital of Jilin University; 2Department of Cardiology, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130021, P.R. China Received October 8, 2018; Accepted May 29, 2019 DOI: 10.3892/mmr.2019.10473 Abstract. The incidence of diabetes mellitus has become 1. Introduction a major public health concern due to lifestyle alterations. Moreover, the complications associated with diabetes mellitus Cardiovascular disease has become a major global health deeply influence the quality of life of patients. Diabetic issue which is attributed to multiple factors, including diet, cardiomyopathy (DC) is a type of diabetes mellitus complica- smoking, lifestyle and environmental change (1). The sharp tion characterized by functional and structural damage in the increase in the diabetic population has been proposed to be myocardium but not accompanied by coronary arterial disease. closely associated with the rising prevalence of cardiovas- Currently, diagnosing and preventing DC is still a challenge cular disease. According to statistics, the number of diabetic for physicians due to its atypical symptoms. For this reason, patients worldwide has currently increased to 1.8 billion, and it is necessary to summarize the current knowledge on DC, has doubled since the year 2000. It is predicted that the global especially in regards to the underlying molecular mechanisms diabetes population will increase from 285 million to 439 toward the goal of developing useful diagnostic approaches million between 2010 and 2030 (2). Compared to non-diabetic and effective drugs based on these mechanisms. There exist individuals of the same age, the risk of heart failure in male several review articles which have focused on these points, and female diabetic patients is increased 2-fold and 5-fold, but there still remains a lot to learn from published studies. In respectively (3). this review, the features, diagnosis and molecular mechanisms Diabetic cardiomyopathy (DC) was firstly proposed by of DC are reviewed. Furthermore, potential therapeutic and Rubler et al (4) in 1972. At that time, four cases of heart failure prophylactic drugs are discussed. in patients with diabetic glomerulosclerosis were autopsied but no other causes of heart failure other than diabetes were found. Thus, the concept of DC was proposed. DC is currently Contents defined as an obvious change in myocardial structure and function in diabetic patients, excluding ischemic diseases, 1. Introduction hypertension, or other diseases that can induce myocardial 2. Epidemiology and features of DC damages (5,6). 3. Diagnosis of DC In a recent review, the correlation between hyperinsulinemia 4. The pathogenesis of DC or insulin resistance, cardiac dysfunction and hyperglycemia 5. The molecular mechanism of DC was discussed (7). The authors also summarized the recent 6. Treatment of diabetic cardiomyopathy advances in the research on DC, its pathogenesis and the under- 7. Conclusions lying molecular mechanisms, and the promising prophylactic and curative approaches (7). Here, we aimed to summarize the current advances in DC with strong emphasis on the molecular mechanisms. 2. Epidemiology and features of DC Correspondence to: Dr Guixia Wang or Dr Xiaokun Gang, Department of Endocrinology and Metabolism, The First Hospital The incidence of DC is not yet clear due to a lack of large data of Jilin University, 71 Xinmin Street, Changchun, Jilin 130021, P. R. Ch i na of outcomes from different populations with diabetes mellitus E-mail: [email protected] (DM). A higher prevalence rate (40 to 60%) of diastolic dysfunc- E‑mail: [email protected] tion in type 2 DM (T2DM) patients has been reported in the literature (8). Autopsies have revealed that DC has a number of Key words: diabetes mellitus, diabetic cardiomyopathy, molecular pathological features, including cardiomyocyte hypertrophy, mechanisms, characteristics, diagnosis, review interstitial fibrosis, periodic-acid-Schiff (PAS)-positive infiltration, thickening of the basal membrane of coronary arterioles, and myocardium microvascular lesions (9-11). The 2052 SUN et al: CLINICOPATHOLOGICAL AND MOLECULAR MECHANISMS OF DC structural changes in DC are characterized by a near-normal by 2D‑STE, which cannot be detected through conventional left ventricular end-diastolic volume, increased left ventricular methods (26). weight and thickness, cardiac hypertrophy and fibrosis, and fat deposition (12,13). The functional alterations include an Magnetic resonance imaging (MRI). MRI is a highly sensitive impaired diastolic function without obvious decreased systolic tool that not only detects abnormal wall motion and cardiac function, and a decreased ventricular wall elasticity (14). hypertrophy, but also provides information concerning arrhythmias and cardiomyopathy. Rijzewijk et al (27) believe 3. Diagnosis of DC that contrast-enhanced MRI can be used to predict the progres- sion of ventricular arrhythmias, myocardial steatosis and heart Currently, the diagnosis of early DC has not yet made substan- failure in patients with a history of ischemic heart disease. tial progress, and the mainstream methods for DC diagnosis Cardiac MRI can detect myocardial metabolic abnormalities include imaging methods and serum biomarkers. The patho- through different radioactive elements and positron emission logical changes in early DC include cardiac hypertrophy, tomography (PET) (28). fibrosis and lipid deposition. Abnormal cardiac function is characterized by early diastolic dysfunction and late systolic Cardiac catheterization and coronary angiography. Cardiac dysfunction. The diagnostic criteria for DC refer to the method catheterization is currently the best technique for assessing of Tarquini et al (15), which are mainly as follows: Presence intracardiac hemodynamics and is considered to be the gold of DM, exclusion of coronary artery disease, valvular or standard for the diagnosis of diastolic cardiac dysfunction, but congenital heart disease, exclusion of hypertensive heart it is not widely used due to its invasiveness (29,30). Left and disease, exclusion of viral myocarditis by endomyocardial right ventricular catheterization can be employed to assess left biopsy and left ventricular ejection fraction (LVEF) <50%, left ventricular end-diastolic pressure and mean pulmonary arte- ventricular end-diastolic volume index (LVEDVI) >97 ml/m2. rial wedge pressure, respectively (29,30). The left ventricular For distinguishing these pathological features, the following end-diastolic pressure >16 mmHg or a pulmonary capillary methods can be employed. wedge pressure >12 mmHg can be used as criteria for the diagnosis of diastolic dysfunction (31). Coronary angiography Echocardiography and Doppler imaging. In the early is mainly used to determine coronary artery stenosis, which stages of DC, echocardiography can be the prior method for tends to occur in late DC (32-34). assessing cardiac structural and functional abnormalities in diabetic patients due to its inexpensive and non-invasive Serum biomarkers advantages (16,17). Tissue Doppler imaging (TDI) measures Matrix metalloproteinases (MMPs) and matrix metallopro‑ left ventricular isovolumetric diastolic time, early mitral teinase inhibitory factors. Previous studies have found that annular diastolic motion velocity (Ve), late diastolic motion extracellular matrix proteins are associated with persistent velocity (Va) and the Ve/Va ratio (18). By comparing these ventricular remodeling (35,36). MMPs are endogenous data, cardiac diastolic function images can be divided into 2 proteolytic enzymes that degrade type I and type III collagen types: Restricted mitral flow pattern and unrestricted mitral during the development of heart failure, thereby promoting flow pattern. Unrestricted mitral flow patterns include normal, myocardial fibrosis; they can also affect the expression of impaired and false normalization (16-18). This technique has microRNAs (miRNAs) and cause myocardial contractile high sensitivity and specificity, and is currently considered to dysfunction (37-39). During the process of myocardial be a reliable method for evaluating left ventricular diastolic fibrosis, serum MMPs (especially MMP‑9) are increased, function in patients with coronary heart disease (19,20). while tissue inhibitory factors of MMPs are decreased (40). Intravenous contrast echocardiography is based on the elevated Ban et al (41) measured serum MMP-7 in patients with DC sonic reflectivity of contrast agents; therefore, the contrast via enzyme-linked immunosorbent assay (ELISA), and injection can aid in the accurate monitoring of the endocardial found that MMP‑7 was significantly higher in patients with borders, and the measuring of ventricular size and ventricular diastolic dysfunction than in patients with normal diastolic motion. The complement of intra-cardiac echocardiography functions. (ICE) into 2D‑echocardiography provides an improved evaluation of left ventricular function (21). A previous study Homocysteine (Hcy). Hcy is a type of sulfur-containing amino demonstrated that alterations in the contractility, systolic acid that is an intermediate metabolite of methionine. It has function and microcirculation can
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