1
|
Wu T, Huang T, Ren H, Shen C, Qian J, Fu X, Liu S, Xie C, Lin X, Wan J, Xiong S, Ji Y, Liu M, Zheng H, Liang T, Liu W, Zou Y, Lai K, Yang M, Song Z, Lan P, Li X, Wu Y, Yang M, Li H, Huang X, Chen H, Tan J, Cai W. Metabolic Coordination Structures Contribute to Diabetic Myocardial Dysfunction. Circ Res 2025; 136:946-967. [PMID: 40190276 DOI: 10.1161/circresaha.124.326044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Revised: 03/11/2025] [Accepted: 03/14/2025] [Indexed: 04/26/2025]
Abstract
BACKGROUND Individuals with diabetes are susceptible to cardiac dysfunction and heart failure, potentially resulting in mortality. Metabolic disorders frequently occur in patients with diabetes, and diabetes usually leads to remodeling of heart structure and cardiac dysfunction. However, the contribution and underlying mechanisms of metabolic and structural coupling in diabetic cardiac dysfunction remain elusive. METHODS Two mouse models of type 2 diabetes (T2DM) were used to assess alterations in glucose/lipid metabolism and cardiac structure. The potential metabolic-structural coupling molecule ACBP (acyl-coenzyme A-binding protein) was screened from 4 published datasets of T2DM-associated heart disease. In vivo loss-of-function and gain-of-function approaches were used to investigate the role of ACBP in diabetic cardiac dysfunction. The underlying mechanisms of metabolic and structural coupling were investigated by stable-isotope tracing metabolomics, coimmunoprecipitation coupled with mass spectrometry, and chromatin immunoprecipitation sequencing. RESULTS Diabetic mouse hearts exhibit enhanced lipid metabolism and impaired ultrastructure with marked cardiac systolic and diastolic dysfunction. Analysis of 4 T2DM public datasets revealed that Acbp was a significant lipid metabolism gene whose expression was upregulated. Consistently, ACBP expression levels were markedly elevated in the hearts of patients with diabetes and diabetic mice. Moreover, we constructed cardiomyocyte-specific Acbp knockout mice that exhibited attenuation of T2DM-induced cardiac remodeling and cardiac dysfunction, including attenuation of cardiac hypertrophy, fibrosis, ultrastructural damage, and enhanced cardiomyocyte contractility and cardiac function. Conversely, cardiac-specific Acbp overexpression via adeno-associated virus type 9, which encodes Acbp under the cTnT (cardiac troponin T) promoter, recapitulated cardiac dysfunction. Mechanistically, cardiac-specific Acbp knockout enhances glucose utilization in diabetic cardiomyocytes, suggesting a potential compensatory mechanism for insufficient ATP levels, highlighting its metabolic role. In addition, combined with mass spectrometry analysis revealed that ACBP binds MyBPC3 (myosin-binding protein C3) in T2DM individuals, which potentially prevents MyBPC3 from assisting the formation of cross-bridge structures between myosin and actin, thereby impairing myocardial contraction. Importantly, chromatin immunoprecipitation sequencing revealed that peroxisome proliferator-activated receptor γ regulates the transcriptional activity of Acbp. CONCLUSIONS Our findings demonstrated that ACBP mediates the bidirectional regulation of cardiomyocyte metabolic and structural associations and identified a promising therapeutic target for ameliorating cardiac dysfunction in patients with T2DM.
Collapse
Affiliation(s)
- Teng Wu
- Guangdong Engineering & Technology Research Center for Disease-Model Animals, Laboratory Animal Center (T.W., T.H., H.R., C.S., J.Q., X.F., J.W., S.X., Y.J., M.L., H.Z., Y.Z., K.L., Maoquan Yang, Z.S., X. Li, Y.W., Ming Yang, H.L., X.H., J.T., W.C.), Sun Yat-sen University, Guangzhou, China
- Department of Biochemistry, Zhongshan School of Medicine (T.W., T.H., H.R., C.S., J.W., S.X., Y.J., M.L., H.Z., K.L., Maoquan Yang, Z.S., X. Li, Y.W., Ming Yang, J.T., W.C.), Sun Yat-sen University, Guangzhou, China
- Reproductive Medicine Center, Sun Yat-sen Memorial Hospital (T.W., T.L., W.L., P.L., H.C.), Sun Yat-sen University, Guangzhou, China
| | - Tongsheng Huang
- Guangdong Engineering & Technology Research Center for Disease-Model Animals, Laboratory Animal Center (T.W., T.H., H.R., C.S., J.Q., X.F., J.W., S.X., Y.J., M.L., H.Z., Y.Z., K.L., Maoquan Yang, Z.S., X. Li, Y.W., Ming Yang, H.L., X.H., J.T., W.C.), Sun Yat-sen University, Guangzhou, China
- Department of Biochemistry, Zhongshan School of Medicine (T.W., T.H., H.R., C.S., J.W., S.X., Y.J., M.L., H.Z., K.L., Maoquan Yang, Z.S., X. Li, Y.W., Ming Yang, J.T., W.C.), Sun Yat-sen University, Guangzhou, China
| | - Honglin Ren
- Guangdong Engineering & Technology Research Center for Disease-Model Animals, Laboratory Animal Center (T.W., T.H., H.R., C.S., J.Q., X.F., J.W., S.X., Y.J., M.L., H.Z., Y.Z., K.L., Maoquan Yang, Z.S., X. Li, Y.W., Ming Yang, H.L., X.H., J.T., W.C.), Sun Yat-sen University, Guangzhou, China
- Department of Biochemistry, Zhongshan School of Medicine (T.W., T.H., H.R., C.S., J.W., S.X., Y.J., M.L., H.Z., K.L., Maoquan Yang, Z.S., X. Li, Y.W., Ming Yang, J.T., W.C.), Sun Yat-sen University, Guangzhou, China
| | - Conghui Shen
- Guangdong Engineering & Technology Research Center for Disease-Model Animals, Laboratory Animal Center (T.W., T.H., H.R., C.S., J.Q., X.F., J.W., S.X., Y.J., M.L., H.Z., Y.Z., K.L., Maoquan Yang, Z.S., X. Li, Y.W., Ming Yang, H.L., X.H., J.T., W.C.), Sun Yat-sen University, Guangzhou, China
- Department of Biochemistry, Zhongshan School of Medicine (T.W., T.H., H.R., C.S., J.W., S.X., Y.J., M.L., H.Z., K.L., Maoquan Yang, Z.S., X. Li, Y.W., Ming Yang, J.T., W.C.), Sun Yat-sen University, Guangzhou, China
| | - Jiang Qian
- Guangdong Engineering & Technology Research Center for Disease-Model Animals, Laboratory Animal Center (T.W., T.H., H.R., C.S., J.Q., X.F., J.W., S.X., Y.J., M.L., H.Z., Y.Z., K.L., Maoquan Yang, Z.S., X. Li, Y.W., Ming Yang, H.L., X.H., J.T., W.C.), Sun Yat-sen University, Guangzhou, China
| | - Xinlu Fu
- Guangdong Engineering & Technology Research Center for Disease-Model Animals, Laboratory Animal Center (T.W., T.H., H.R., C.S., J.Q., X.F., J.W., S.X., Y.J., M.L., H.Z., Y.Z., K.L., Maoquan Yang, Z.S., X. Li, Y.W., Ming Yang, H.L., X.H., J.T., W.C.), Sun Yat-sen University, Guangzhou, China
| | - Shangyuan Liu
- GMU-GIBH Joint School of Life Sciences, The Guangdong-Hong Kong-Macau Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Medical University, China (S.L., C.X.)
| | - Chengshu Xie
- GMU-GIBH Joint School of Life Sciences, The Guangdong-Hong Kong-Macau Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Medical University, China (S.L., C.X.)
| | - Xi Lin
- ZEISS Microscopy Customer Center China, Shanghai (X. Lin)
| | - Junhong Wan
- Guangdong Engineering & Technology Research Center for Disease-Model Animals, Laboratory Animal Center (T.W., T.H., H.R., C.S., J.Q., X.F., J.W., S.X., Y.J., M.L., H.Z., Y.Z., K.L., Maoquan Yang, Z.S., X. Li, Y.W., Ming Yang, H.L., X.H., J.T., W.C.), Sun Yat-sen University, Guangzhou, China
- Department of Biochemistry, Zhongshan School of Medicine (T.W., T.H., H.R., C.S., J.W., S.X., Y.J., M.L., H.Z., K.L., Maoquan Yang, Z.S., X. Li, Y.W., Ming Yang, J.T., W.C.), Sun Yat-sen University, Guangzhou, China
| | - Shijie Xiong
- Guangdong Engineering & Technology Research Center for Disease-Model Animals, Laboratory Animal Center (T.W., T.H., H.R., C.S., J.Q., X.F., J.W., S.X., Y.J., M.L., H.Z., Y.Z., K.L., Maoquan Yang, Z.S., X. Li, Y.W., Ming Yang, H.L., X.H., J.T., W.C.), Sun Yat-sen University, Guangzhou, China
- Department of Biochemistry, Zhongshan School of Medicine (T.W., T.H., H.R., C.S., J.W., S.X., Y.J., M.L., H.Z., K.L., Maoquan Yang, Z.S., X. Li, Y.W., Ming Yang, J.T., W.C.), Sun Yat-sen University, Guangzhou, China
| | - Yuanjun Ji
- Guangdong Engineering & Technology Research Center for Disease-Model Animals, Laboratory Animal Center (T.W., T.H., H.R., C.S., J.Q., X.F., J.W., S.X., Y.J., M.L., H.Z., Y.Z., K.L., Maoquan Yang, Z.S., X. Li, Y.W., Ming Yang, H.L., X.H., J.T., W.C.), Sun Yat-sen University, Guangzhou, China
- Department of Biochemistry, Zhongshan School of Medicine (T.W., T.H., H.R., C.S., J.W., S.X., Y.J., M.L., H.Z., K.L., Maoquan Yang, Z.S., X. Li, Y.W., Ming Yang, J.T., W.C.), Sun Yat-sen University, Guangzhou, China
| | - Mengying Liu
- Guangdong Engineering & Technology Research Center for Disease-Model Animals, Laboratory Animal Center (T.W., T.H., H.R., C.S., J.Q., X.F., J.W., S.X., Y.J., M.L., H.Z., Y.Z., K.L., Maoquan Yang, Z.S., X. Li, Y.W., Ming Yang, H.L., X.H., J.T., W.C.), Sun Yat-sen University, Guangzhou, China
- Department of Biochemistry, Zhongshan School of Medicine (T.W., T.H., H.R., C.S., J.W., S.X., Y.J., M.L., H.Z., K.L., Maoquan Yang, Z.S., X. Li, Y.W., Ming Yang, J.T., W.C.), Sun Yat-sen University, Guangzhou, China
| | - Huiting Zheng
- Guangdong Engineering & Technology Research Center for Disease-Model Animals, Laboratory Animal Center (T.W., T.H., H.R., C.S., J.Q., X.F., J.W., S.X., Y.J., M.L., H.Z., Y.Z., K.L., Maoquan Yang, Z.S., X. Li, Y.W., Ming Yang, H.L., X.H., J.T., W.C.), Sun Yat-sen University, Guangzhou, China
- Department of Biochemistry, Zhongshan School of Medicine (T.W., T.H., H.R., C.S., J.W., S.X., Y.J., M.L., H.Z., K.L., Maoquan Yang, Z.S., X. Li, Y.W., Ming Yang, J.T., W.C.), Sun Yat-sen University, Guangzhou, China
| | - Ting Liang
- Reproductive Medicine Center, Sun Yat-sen Memorial Hospital (T.W., T.L., W.L., P.L., H.C.), Sun Yat-sen University, Guangzhou, China
| | - Wenyi Liu
- Reproductive Medicine Center, Sun Yat-sen Memorial Hospital (T.W., T.L., W.L., P.L., H.C.), Sun Yat-sen University, Guangzhou, China
| | - Yan Zou
- Guangdong Engineering & Technology Research Center for Disease-Model Animals, Laboratory Animal Center (T.W., T.H., H.R., C.S., J.Q., X.F., J.W., S.X., Y.J., M.L., H.Z., Y.Z., K.L., Maoquan Yang, Z.S., X. Li, Y.W., Ming Yang, H.L., X.H., J.T., W.C.), Sun Yat-sen University, Guangzhou, China
| | - Kingwai Lai
- Guangdong Engineering & Technology Research Center for Disease-Model Animals, Laboratory Animal Center (T.W., T.H., H.R., C.S., J.Q., X.F., J.W., S.X., Y.J., M.L., H.Z., Y.Z., K.L., Maoquan Yang, Z.S., X. Li, Y.W., Ming Yang, H.L., X.H., J.T., W.C.), Sun Yat-sen University, Guangzhou, China
- Department of Biochemistry, Zhongshan School of Medicine (T.W., T.H., H.R., C.S., J.W., S.X., Y.J., M.L., H.Z., K.L., Maoquan Yang, Z.S., X. Li, Y.W., Ming Yang, J.T., W.C.), Sun Yat-sen University, Guangzhou, China
| | - Maoquan Yang
- Guangdong Engineering & Technology Research Center for Disease-Model Animals, Laboratory Animal Center (T.W., T.H., H.R., C.S., J.Q., X.F., J.W., S.X., Y.J., M.L., H.Z., Y.Z., K.L., Maoquan Yang, Z.S., X. Li, Y.W., Ming Yang, H.L., X.H., J.T., W.C.), Sun Yat-sen University, Guangzhou, China
- Department of Biochemistry, Zhongshan School of Medicine (T.W., T.H., H.R., C.S., J.W., S.X., Y.J., M.L., H.Z., K.L., Maoquan Yang, Z.S., X. Li, Y.W., Ming Yang, J.T., W.C.), Sun Yat-sen University, Guangzhou, China
| | - Zeyi Song
- Guangdong Engineering & Technology Research Center for Disease-Model Animals, Laboratory Animal Center (T.W., T.H., H.R., C.S., J.Q., X.F., J.W., S.X., Y.J., M.L., H.Z., Y.Z., K.L., Maoquan Yang, Z.S., X. Li, Y.W., Ming Yang, H.L., X.H., J.T., W.C.), Sun Yat-sen University, Guangzhou, China
- Department of Biochemistry, Zhongshan School of Medicine (T.W., T.H., H.R., C.S., J.W., S.X., Y.J., M.L., H.Z., K.L., Maoquan Yang, Z.S., X. Li, Y.W., Ming Yang, J.T., W.C.), Sun Yat-sen University, Guangzhou, China
| | - Peixuan Lan
- Reproductive Medicine Center, Sun Yat-sen Memorial Hospital (T.W., T.L., W.L., P.L., H.C.), Sun Yat-sen University, Guangzhou, China
| | - Xinghui Li
- Guangdong Engineering & Technology Research Center for Disease-Model Animals, Laboratory Animal Center (T.W., T.H., H.R., C.S., J.Q., X.F., J.W., S.X., Y.J., M.L., H.Z., Y.Z., K.L., Maoquan Yang, Z.S., X. Li, Y.W., Ming Yang, H.L., X.H., J.T., W.C.), Sun Yat-sen University, Guangzhou, China
- Department of Biochemistry, Zhongshan School of Medicine (T.W., T.H., H.R., C.S., J.W., S.X., Y.J., M.L., H.Z., K.L., Maoquan Yang, Z.S., X. Li, Y.W., Ming Yang, J.T., W.C.), Sun Yat-sen University, Guangzhou, China
| | - Yandi Wu
- Guangdong Engineering & Technology Research Center for Disease-Model Animals, Laboratory Animal Center (T.W., T.H., H.R., C.S., J.Q., X.F., J.W., S.X., Y.J., M.L., H.Z., Y.Z., K.L., Maoquan Yang, Z.S., X. Li, Y.W., Ming Yang, H.L., X.H., J.T., W.C.), Sun Yat-sen University, Guangzhou, China
- Department of Biochemistry, Zhongshan School of Medicine (T.W., T.H., H.R., C.S., J.W., S.X., Y.J., M.L., H.Z., K.L., Maoquan Yang, Z.S., X. Li, Y.W., Ming Yang, J.T., W.C.), Sun Yat-sen University, Guangzhou, China
| | - Ming Yang
- Guangdong Engineering & Technology Research Center for Disease-Model Animals, Laboratory Animal Center (T.W., T.H., H.R., C.S., J.Q., X.F., J.W., S.X., Y.J., M.L., H.Z., Y.Z., K.L., Maoquan Yang, Z.S., X. Li, Y.W., Ming Yang, H.L., X.H., J.T., W.C.), Sun Yat-sen University, Guangzhou, China
- Department of Biochemistry, Zhongshan School of Medicine (T.W., T.H., H.R., C.S., J.W., S.X., Y.J., M.L., H.Z., K.L., Maoquan Yang, Z.S., X. Li, Y.W., Ming Yang, J.T., W.C.), Sun Yat-sen University, Guangzhou, China
| | - Hui Li
- Guangdong Engineering & Technology Research Center for Disease-Model Animals, Laboratory Animal Center (T.W., T.H., H.R., C.S., J.Q., X.F., J.W., S.X., Y.J., M.L., H.Z., Y.Z., K.L., Maoquan Yang, Z.S., X. Li, Y.W., Ming Yang, H.L., X.H., J.T., W.C.), Sun Yat-sen University, Guangzhou, China
| | - Xuezhe Huang
- Guangdong Engineering & Technology Research Center for Disease-Model Animals, Laboratory Animal Center (T.W., T.H., H.R., C.S., J.Q., X.F., J.W., S.X., Y.J., M.L., H.Z., Y.Z., K.L., Maoquan Yang, Z.S., X. Li, Y.W., Ming Yang, H.L., X.H., J.T., W.C.), Sun Yat-sen University, Guangzhou, China
| | - Hui Chen
- Reproductive Medicine Center, Sun Yat-sen Memorial Hospital (T.W., T.L., W.L., P.L., H.C.), Sun Yat-sen University, Guangzhou, China
| | - Jing Tan
- Guangdong Engineering & Technology Research Center for Disease-Model Animals, Laboratory Animal Center (T.W., T.H., H.R., C.S., J.Q., X.F., J.W., S.X., Y.J., M.L., H.Z., Y.Z., K.L., Maoquan Yang, Z.S., X. Li, Y.W., Ming Yang, H.L., X.H., J.T., W.C.), Sun Yat-sen University, Guangzhou, China
- Department of Biochemistry, Zhongshan School of Medicine (T.W., T.H., H.R., C.S., J.W., S.X., Y.J., M.L., H.Z., K.L., Maoquan Yang, Z.S., X. Li, Y.W., Ming Yang, J.T., W.C.), Sun Yat-sen University, Guangzhou, China
| | - Weibin Cai
- Guangdong Engineering & Technology Research Center for Disease-Model Animals, Laboratory Animal Center (T.W., T.H., H.R., C.S., J.Q., X.F., J.W., S.X., Y.J., M.L., H.Z., Y.Z., K.L., Maoquan Yang, Z.S., X. Li, Y.W., Ming Yang, H.L., X.H., J.T., W.C.), Sun Yat-sen University, Guangzhou, China
- Department of Biochemistry, Zhongshan School of Medicine (T.W., T.H., H.R., C.S., J.W., S.X., Y.J., M.L., H.Z., K.L., Maoquan Yang, Z.S., X. Li, Y.W., Ming Yang, J.T., W.C.), Sun Yat-sen University, Guangzhou, China
| |
Collapse
|
2
|
Du J, Liu J, Wang X, Wang X, Ma Y, Zhang S, Li Z, Ma J, Liu J. The role of estrogen in the sex difference for the risk factors of heart failure with preserved ejection fraction. Biol Direct 2025; 20:28. [PMID: 40065410 PMCID: PMC11895175 DOI: 10.1186/s13062-025-00618-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2024] [Accepted: 02/14/2025] [Indexed: 03/14/2025] Open
Abstract
Heart failure with preserved ejection fraction (HFpEF) is a major subtype of heart failure, primarily characterized by a normal or mildly reduced left ventricular ejection fraction along with left ventricular diastolic dysfunction. Recent studies have shown that the prevalence of HFpEF is higher in women than that in men, particularly in postmenopausal women. Concurrently, it has been observed that the incidence of risk factors contributing to HFpEF (such as obesity, hypertension, diabetes, and atrial fibrillation) also notably increases post-menopause, affecting the incidence of HFpEF. This review aimed to examine the relationship between estrogen and risk factors associated with HFpEF, clarifying the underlying mechanisms through which estrogen affects these risk factors from epidemiological and pathophysiological perspectives. This review also provides a comprehensive understanding of the association between estrogen and the risk factors for HFpEF, thus helping explore potential targets for HFpEF treatment.
Collapse
Affiliation(s)
- Jun Du
- Xi'an Medical University, Xi'an, People's Republic of China
- Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China
| | - Jiaqi Liu
- Xi'an Medical University, Xi'an, People's Republic of China
- Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China
| | - Xiaoya Wang
- Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China
| | - Xiaowu Wang
- Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China
| | - Yu Ma
- Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China
| | - Sipan Zhang
- Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China
| | - Zilin Li
- Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China
| | - Jipeng Ma
- Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
| | - Jincheng Liu
- Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
| |
Collapse
|
3
|
Barati H, Mousavi Madani A, Shadzinavaz S, Fardmanesh M. Principal Component Analysis and Near-Infrared Spectroscopy as Noninvasive Blood Glucose Assay Methods. APPLIED SPECTROSCOPY 2024:37028241300535. [PMID: 39648514 DOI: 10.1177/00037028241300535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/10/2024]
Abstract
In this paper, a new model is presented for estimation of the blood glucose level from the measured near-infrared absorbance. The model has been developed in such a way that the regression coefficients of this linear relation have been approximated by considering only the molar absorptivity of the glucose and the obtained coefficients have been utilized to estimate the blood glucose levels from the measured absorbances. The estimation of the blood glucose concentrations by this blind approach exhibited an acceptable accuracy in comparison to the more accurate principal components regression method. The blood sample absorbances have been measured using a Fourier transform infrared device while the blood glucose levels have been determined by a commercial finger-prick glucometer device.
Collapse
Affiliation(s)
- Hadi Barati
- Department of Electrical Engineering, Sharif University of Technology, Tehran, Iran
| | - Arian Mousavi Madani
- Department of Electrical Engineering, Sharif University of Technology, Tehran, Iran
| | - Sorena Shadzinavaz
- Department of Electrical Engineering, Sharif University of Technology, Tehran, Iran
| | - Mehdi Fardmanesh
- Department of Electrical Engineering, Sharif University of Technology, Tehran, Iran
| |
Collapse
|
4
|
Zhang K, Han Y, Gu F, Gu Z, Liang J, Zhao J, Chen J, Chen B, Gao M, Hou Z, Yu X, Cai T, Gao Y, Hu R, Xie J, Liu T, Li B. Association Between Body Temperature and In-Hospital Mortality Among Congestive Heart Failure Patients with Diabetes in Intensive Care Unit: A Retrospective Cohort Study. Ther Hypothermia Temp Manag 2024; 14:197-204. [PMID: 37971393 DOI: 10.1089/ther.2023.0053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2023] Open
Abstract
Body temperature (BT) has been utilized to assess patient outcomes across various diseases. However, the impact of BT on mortality in the intensive care unit (ICU) among patients with congestive heart failure (CHF) and diabetes mellitus (DM) remains unclear. We conducted a retrospective cohort study using data from the Medical Information Mart for Intensive Care (MIMIC)-IV data set. The primary outcome assessed was in-hospital mortality rates. BT was treated as a categorical variable in the analyses. The association between BT on ICU admission and in-hospital mortality was examined using multivariable logistic regression models, restricted cubic spline, and subgroup analysis. The cohort comprised 7063 patients with both DM and CHF (3135 females and 3928 males), with an average age of 71.5 ± 12.2 years. Comparative analysis of the reference group (Q4) revealed increased in-hospital mortality in Q6 and Q1 temperature groups, with fully adjusted odds ratios of 2.08 (95% confidence interval [CI]: 1.45-2.96) and 1.95 (95% CI: 1.35-2.79), respectively. Restricted cubic spline analysis demonstrated a U-shaped relationship between temperature on admission and mortality risk (p nonlinearity <0.001), with the nadir of risk observed at 36.8°C. The effect sizes and corresponding CIs below and above the threshold were 0.581 (95% CI: 0.434-0.777) and 1.674 (95% CI: 1.204-2.328), respectively. Stratified analyses further validated the robustness of this correlation. Our study establishes a nonlinear association between BT and in-hospital mortality in patients with both CHF and DM, with optimal suitable BT at 36.8°C. Further research is necessary to confirm this relationship.
Collapse
Affiliation(s)
- Kai Zhang
- Cardiovascular Surgery Department, The Second Hospital of Jilin University, Changchun, China
| | - Yu Han
- Department of Ophthalmology, First Hospital of Jilin University, Changchun, China
| | - Fangming Gu
- Cardiovascular Surgery Department, The Second Hospital of Jilin University, Changchun, China
| | - Zhaoxuan Gu
- Cardiovascular Surgery Department, The Second Hospital of Jilin University, Changchun, China
| | - JiaYing Liang
- Cardiovascular Surgery Department, The Second Hospital of Jilin University, Changchun, China
| | - JiaYu Zhao
- Cardiovascular Surgery Department, The Second Hospital of Jilin University, Changchun, China
| | - Jianguo Chen
- Bethune First College of Clinical Medicine, Jilin University, Changchun, China
| | - Bowen Chen
- Bethune First College of Clinical Medicine, Jilin University, Changchun, China
| | - Min Gao
- Department of Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Zhengyan Hou
- Bethune Second College of Clinical Medicine, Jilin University, Changchun, China
| | - Xiaoqi Yu
- Bethune Second College of Clinical Medicine, Jilin University, Changchun, China
| | - Tianyi Cai
- Bethune Second College of Clinical Medicine, Jilin University, Changchun, China
| | - Yafang Gao
- Bethune Second College of Clinical Medicine, Jilin University, Changchun, China
| | - Rui Hu
- Bethune Third College of Clinical Medicine, Jilin University, Changchun, China
| | - Jinyu Xie
- Cardiovascular Surgery Department, The Second Hospital of Jilin University, Changchun, China
| | - Tianzhou Liu
- Department of Gastrointestinal Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Bo Li
- Cardiovascular Surgery Department, The Second Hospital of Jilin University, Changchun, China
| |
Collapse
|
5
|
Liang YY, He Y, Huang P, Feng H, Li H, Ai S, Du J, Xue H, Liu Y, Zhang J, Qi L, Zhang J. Accelerometer-measured physical activity, sedentary behavior, and incidence of macrovascular and microvascular events in individuals with type 2 diabetes mellitus and prediabetes. JOURNAL OF SPORT AND HEALTH SCIENCE 2024; 14:100973. [PMID: 39214513 PMCID: PMC11863271 DOI: 10.1016/j.jshs.2024.100973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Revised: 01/22/2024] [Accepted: 02/28/2024] [Indexed: 09/04/2024]
Abstract
BACKGROUND Physical activity (PA) is considered beneficial for lowering cardiovascular risks following type 2 diabetes mellitus (T2DM) and prediabetes, but existing evidence relies mainly on self-reported measurements. We aimed to describe the intensity-specific dose-response associations of PA and sedentary behavior (SB) with macrovascular and microvascular events among individuals with T2DM and prediabetes. METHODS This study included 11,474 individuals with T2DM and prediabetes from the UK Biobank. PA, including total PA, moderate-to-vigorous intensity PA (MVPA), light-intensity PA (LPA), and SB, were measured by accelerometers over 7 days. MVPA was categorized according to the American Diabetes Association guideline-recommended level (at least 150 min/week), and total PA, LPA, and SB were grouped by tertiles. The outcomes were incidences of macrovascular events, microvascular events, heart failure (HF), and their combination (composite events). The events were ascertained using the International Classification of Diseases-10 (ICD-10) codes on the hospital or death records. RESULTS During a median follow-up of 6.8 years, 1680 cases were documented, including 969 macrovascular events, 839 microvascular events, and 284 incidents of HF. Accelerometer-measured PA, irrespective of intensity, was inversely associated with the risk of composite events and each outcome in the dose-response patterns. Regarding categorized PA, engagement in total PA (high vs. low) was associated with decreased risk of macrovascular events (hazard ratio (HR) = 0.80; 95% confidence interval (95%CI): 0.67-0.95), microvascular events (HR = 0.76; 95%CI: 0.63-0.93), and HF (HR = 0.46; 95%CI: 0.32-0.66). Adherence to MVPA, but not LPA, above the guideline-recommended level (at least 150 min/week) was associated with reduced risk of macrovascular events (HR = 0.80; 95%CI: 0.68-0.95), microvascular events (HR = 0.76; 95%CI: 0.63-0.92), and HF (HR = 0.65; 95%CI: 0.46-0.92). The minimum dose of MVPA for lowering the risk of composite events was approximately 59.0 min/week. More time spent in SB was associated with an increased risk of composite events (high vs. low, HR = 1.17; 95%CI: 1.02-1.35) and HF (high vs. low, HR = 1.54; 95%CI: 1.09-2.20). Replacement of 30 min of SB (HR = 0.73; 95%CI: 0.65-0.81) and LPA (HR = 0.74; 95%CI: 0.66-0.83) with MVPA dramatically reduced the risk of composite events. CONCLUSION Adherence to a higher amount of accelerometer-measured PA, especially MVPA at least 59 min/week, is associated with reduced risks of macrovascular and microvascular events among individuals with T2DM and prediabetes. Replacement of SB and LPA with MVPA helped lower the risk of diabetic vascular events.
Collapse
Affiliation(s)
- Yannis Yan Liang
- Center for Sleep and Circadian Medicine, The Affiliated Brain Hospital, Guangzhou Medical University, Guangzhou 510370, China; Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou Medical University, Guangzhou 510260, China; Institute of Psycho-neuroscience, The Affiliated Brain Hospital, Guangzhou Medical University, Guangzhou 510370, China
| | - Yu He
- Center for Sleep and Circadian Medicine, The Affiliated Brain Hospital, Guangzhou Medical University, Guangzhou 510370, China; Division of Nephrology, Department of Medicine, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, China
| | - Piao Huang
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Southern Medical University, Guangzhou 510080, China
| | - Hongliang Feng
- Center for Sleep and Circadian Medicine, The Affiliated Brain Hospital, Guangzhou Medical University, Guangzhou 510370, China; Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou Medical University, Guangzhou 510260, China
| | - Haiteng Li
- Division of Nephrology, Department of Medicine, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, China
| | - Sizhi Ai
- Center for Sleep and Circadian Medicine, The Affiliated Brain Hospital, Guangzhou Medical University, Guangzhou 510370, China; Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou Medical University, Guangzhou 510260, China
| | - Jing Du
- Center for Sleep and Circadian Medicine, The Affiliated Brain Hospital, Guangzhou Medical University, Guangzhou 510370, China; Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou Medical University, Guangzhou 510260, China
| | - Huachen Xue
- Center for Sleep and Circadian Medicine, The Affiliated Brain Hospital, Guangzhou Medical University, Guangzhou 510370, China; Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou Medical University, Guangzhou 510260, China
| | - Yaping Liu
- Center for Sleep and Circadian Medicine, The Affiliated Brain Hospital, Guangzhou Medical University, Guangzhou 510370, China; Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou Medical University, Guangzhou 510260, China
| | - Jun Zhang
- Division of Nephrology, Department of Medicine, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, China
| | - Lu Qi
- Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA 70112, USA; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
| | - Jihui Zhang
- Center for Sleep and Circadian Medicine, The Affiliated Brain Hospital, Guangzhou Medical University, Guangzhou 510370, China; Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou Medical University, Guangzhou 510260, China.
| |
Collapse
|
6
|
Zheng H, Wu K, Wu W, Huang Z, Wang X, Fu P, Wang Y, Chen Z, Cai Z, Cai Z, Lan Y, Wu S, Chen Y. Relationship of the trajectory of the triglyceride-glucose index with heart failure: the Kailuan study. Lipids Health Dis 2024; 23:257. [PMID: 39164722 PMCID: PMC11334604 DOI: 10.1186/s12944-024-02254-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Accepted: 08/13/2024] [Indexed: 08/22/2024] Open
Abstract
BACKGROUND A high triglyceride-glucose index (TyG) is associated with a higher risk of incident heart failure. However, the effects of longitudinal patterns of TyG index on the risk of heart failure remain to be characterized. Therefore, in the present study, we aimed to characterize the relationship between the trajectory of TyG index and the risk of heart failure. METHODS We performed a prospective study of 56,149 participants in the Kailuan study who attended three consecutive surveys in 2006-2007, 2008-2009, and 2010-2011 and had no history of heart failure or cancer before the third wave survey (2010-2011). The TyG index was calculated as ln [fasting triglycerides (mg/dL) × fasting plasma glucose (mg/dL)/2], and we used latent mixture modeling to characterize the trajectory of the TyG index over the period 2006-2010. Additionally, Cox proportional risk models were used to calculate the hazard ratio (HR) and 95% confidence interval (CI) for incident heart failure for the various TyG index trajectory groups. RESULTS From 2006 to 2010, four different TyG trajectories were identified: low-stable (n = 13,554; range, 7.98-8.07), moderate low-stable (n = 29,435; range, 8.60-8.65), moderate high-stable (n = 11,262; range, 9.31-9.30), and elevated-stable (n = 1,898; range, 10.04-10.25). A total of 1,312 new heart failure events occurred during a median follow-up period of 10.04 years. After adjustment for potential confounders, the hazard ratios (HRs) and 95% confidence intervals (CIs) for incident heart failure for the elevated-stable, moderate high-stable, and moderate low-stable groups were 1.55 (1.15, 2.08), 1.32 (1.08, 1.60), and 1.17 (0.99, 1.37), respectively, compared to the low-stable group. CONCLUSIONS Higher TyG index trajectories were associated with a higher risk of heart failure. This suggests that monitoring TyG index trajectory may help identify individuals at high risk for heart failure and highlights the importance of early control of blood glucose and lipids for the prevention of heart failure.
Collapse
Affiliation(s)
- Huancong Zheng
- Department of Cardiology, Second Affiliated Hospital of Shantou University Medical College, 69 Dongxia North Road, Shantou, 515000, China
- Shantou University Medical College, Shantou, China
| | - Kuangyi Wu
- Department of Cardiology, Second Affiliated Hospital of Shantou University Medical College, 69 Dongxia North Road, Shantou, 515000, China
- Shantou University Medical College, Shantou, China
| | - Weiqiang Wu
- Department of Cardiology, Second Affiliated Hospital of Shantou University Medical College, 69 Dongxia North Road, Shantou, 515000, China
| | - Zegui Huang
- Department of Cardiology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xianxuan Wang
- Department of Physiology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Peng Fu
- Department of Cardiology, Second Affiliated Hospital of Shantou University Medical College, 69 Dongxia North Road, Shantou, 515000, China
- Shantou University Medical College, Shantou, China
| | - Yuxian Wang
- Department of Cardiology, Second Affiliated Hospital of Shantou University Medical College, 69 Dongxia North Road, Shantou, 515000, China
- Shantou University Medical College, Shantou, China
| | - Zekai Chen
- Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Zefeng Cai
- Department of Cardiology, Second Affiliated Hospital of Shantou University Medical College, 69 Dongxia North Road, Shantou, 515000, China
| | - Zhiwei Cai
- Department of Cardiology, Second Affiliated Hospital of Shantou University Medical College, 69 Dongxia North Road, Shantou, 515000, China
- Shantou University Medical College, Shantou, China
| | - Yulong Lan
- Department of Cardiology, Second Affiliated Hospital of Shantou University Medical College, 69 Dongxia North Road, Shantou, 515000, China
| | - Shouling Wu
- Department of Cardiology, Kailuan General Hospital, 57 Xinhua East Road, Tangshan, 063000, China.
| | - Youren Chen
- Department of Cardiology, Second Affiliated Hospital of Shantou University Medical College, 69 Dongxia North Road, Shantou, 515000, China.
| |
Collapse
|
7
|
Alanazi AH, Selim MS, Yendamuri MR, Zhang D, Narayanan SP, Somanath PR. The impact of diabetes mellitus on blood-tissue barrier regulation and vascular complications: Is the lung different from other organs? Tissue Barriers 2024:2386183. [PMID: 39072526 DOI: 10.1080/21688370.2024.2386183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 07/12/2024] [Accepted: 07/16/2024] [Indexed: 07/30/2024] Open
Abstract
Diabetes Mellitus presents a formidable challenge as one of the most prevalent and complex chronic diseases, exerting significant strain on both patients and the world economy. It is recognized as a common comorbidity among severely ill individuals, often leading to a myriad of micro- and macro-vascular complications. Despite extensive research dissecting the pathophysiology and molecular mechanisms underlying vascular complications of diabetes, relatively little attention has been paid to potential lung-related complications. This review aims to illuminate the impact of diabetes on prevalent respiratory diseases, including chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), idiopathic pulmonary fibrosis (IPF), tuberculosis (TB), pneumonia infections, and asthma, and compare the vascular complications with other vascular beds. Additionally, we explore the primary mechanistic pathways contributing to these complications, such as the expression modulation of blood-tissue-barrier proteins, resulting in increased paracellular and transcellular permeability, and compromised immune responses rendering diabetes patients more susceptible to infections. The activation of inflammatory pathways leading to cellular injury and hastening the onset of these respiratory complications is also discussed.
Collapse
Affiliation(s)
- Abdulaziz H Alanazi
- Clinical and Experimental Therapeutics, University of Georgia, Augusta, GA, USA
- Charlie Norwood VA Medical Center, Augusta, GA, USA
- Department of Clinical Practice, College of Pharmacy, Northern Border University, Rafha, Saudi Arabia
| | - Mohamed S Selim
- Clinical and Experimental Therapeutics, University of Georgia, Augusta, GA, USA
- Charlie Norwood VA Medical Center, Augusta, GA, USA
| | - Manyasreeprapti R Yendamuri
- Clinical and Experimental Therapeutics, University of Georgia, Augusta, GA, USA
- Charlie Norwood VA Medical Center, Augusta, GA, USA
| | - Duo Zhang
- Clinical and Experimental Therapeutics, University of Georgia, Augusta, GA, USA
- Charlie Norwood VA Medical Center, Augusta, GA, USA
| | - S Priya Narayanan
- Clinical and Experimental Therapeutics, University of Georgia, Augusta, GA, USA
- Charlie Norwood VA Medical Center, Augusta, GA, USA
| | - Payaningal R Somanath
- Clinical and Experimental Therapeutics, University of Georgia, Augusta, GA, USA
- Charlie Norwood VA Medical Center, Augusta, GA, USA
| |
Collapse
|
8
|
Lyu L, Wang X, Xu J, Liu Z, He Y, Zhu W, Lin L, Hao B, Liu H. Association between triglyceride glucose-body mass index and long-term adverse outcomes of heart failure patients with coronary heart disease. Cardiovasc Diabetol 2024; 23:162. [PMID: 38724999 PMCID: PMC11080126 DOI: 10.1186/s12933-024-02213-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 03/25/2024] [Indexed: 05/13/2024] Open
Abstract
BACKGROUND The triglyceride glucose-body mass index (TyG-BMI) is recognized as a reliable surrogate for evaluating insulin resistance and an effective predictor of cardiovascular disease. However, the link between TyG-BMI index and adverse outcomes in heart failure (HF) patients remains unclear. This study examines the correlation of the TyG-BMI index with long-term adverse outcomes in HF patients with coronary heart disease (CHD). METHODS This single-center, prospective cohort study included 823 HF patients with CHD. The TyG-BMI index was calculated as follows: ln [fasting triglyceride (mg/dL) × fasting blood glucose (mg/dL)/2] × BMI. To explore the association between the TyG-BMI index and the occurrences of all-cause mortality and HF rehospitalization, we utilized multivariate Cox regression models and restricted cubic splines with threshold analysis. RESULTS Over a follow-up period of 9.4 years, 425 patients died, and 484 were rehospitalized due to HF. Threshold analysis revealed a significant reverse "J"-shaped relationship between the TyG-BMI index and all-cause mortality, indicating a decreased risk of all-cause mortality with higher TyG-BMI index values below 240.0 (adjusted model: HR 0.90, 95% CI 0.86-0.93; Log-likelihood ratio p = 0.003). A distinct "U"-shaped nonlinear relationship was observed with HF rehospitalization, with the inflection point at 228.56 (adjusted model: below: HR 0.95, 95% CI 0.91-0.98; above: HR 1.08, 95% CI 1.03-1.13; Log-likelihood ratio p < 0.001). CONCLUSIONS This study reveals a nonlinear association between the TyG-BMI index and both all-cause mortality and HF rehospitalization in HF patients with CHD, positioning the TyG-BMI index as a significant prognostic marker in this population.
Collapse
Affiliation(s)
- Lyu Lyu
- Department of Cardiology, The Second Medical Center, Chinese PLA General Hospital, Beijing, China
- Medical School of Chinese PLA, Beijing, China
| | - Xinhong Wang
- Department of Cardiology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Juan Xu
- Department of General Surgery, Affiliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou, China
| | - Zhenzhen Liu
- Department of Cardiology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yanru He
- Department of Cardiology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Wenjing Zhu
- Department of Cardiology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Lin Lin
- Department of Cardiology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Benchuan Hao
- Department of Cardiology, The Second Medical Center, Chinese PLA General Hospital, Beijing, China.
- Medical School of Chinese PLA, Beijing, China.
| | - Hongbin Liu
- Department of Cardiology, The Second Medical Center, Chinese PLA General Hospital, Beijing, China.
| |
Collapse
|
9
|
Soh CH, de Sá AGC, Potter E, Halabi A, Ascher DB, Marwick TH. Use of the energy waveform electrocardiogram to detect subclinical left ventricular dysfunction in patients with type 2 diabetes mellitus. Cardiovasc Diabetol 2024; 23:91. [PMID: 38448993 PMCID: PMC10918872 DOI: 10.1186/s12933-024-02141-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2023] [Accepted: 01/22/2024] [Indexed: 03/08/2024] Open
Abstract
BACKGROUND Recent guidelines propose N-terminal pro-B-type natriuretic peptide (NT-proBNP) for recognition of asymptomatic left ventricular (LV) dysfunction (Stage B Heart Failure, SBHF) in type 2 diabetes mellitus (T2DM). Wavelet Transform based signal-processing transforms electrocardiogram (ECG) waveforms into an energy distribution waveform (ew)ECG, providing frequency and energy features that machine learning can use as additional inputs to improve the identification of SBHF. Accordingly, we sought whether machine learning model based on ewECG features was superior to NT-proBNP, as well as a conventional screening tool-the Atherosclerosis Risk in Communities (ARIC) HF risk score, in SBHF screening among patients with T2DM. METHODS Participants in two clinical trials of SBHF (defined as diastolic dysfunction [DD], reduced global longitudinal strain [GLS ≤ 18%] or LV hypertrophy [LVH]) in T2DM underwent 12-lead ECG with additional ewECG feature and echocardiography. Supervised machine learning was adopted to identify the optimal combination of ewECG extracted features for SBHF screening in 178 participants in one trial and tested in 97 participants in the other trial. The accuracy of the ewECG model in SBHF screening was compared with NT-proBNP and ARIC HF. RESULTS SBHF was identified in 128 (72%) participants in the training dataset (median 72 years, 41% female) and 64 (66%) in the validation dataset (median 70 years, 43% female). Fifteen ewECG features showed an area under the curve (AUC) of 0.81 (95% CI 0.787-0.794) in identifying SBHF, significantly better than both NT-proBNP (AUC 0.56, 95% CI 0.44-0.68, p < 0.001) and ARIC HF (AUC 0.67, 95%CI 0.56-0.79, p = 0.002). ewECG features were also led to robust models screening for DD (AUC 0.74, 95% CI 0.73-0.74), reduced GLS (AUC 0.76, 95% CI 0.73-0.74) and LVH (AUC 0.90, 95% CI 0.88-0.89). CONCLUSIONS Machine learning based modelling using additional ewECG extracted features are superior to NT-proBNP and ARIC HF in SBHF screening among patients with T2DM, providing an alternative HF screening strategy for asymptomatic patients and potentially act as a guidance tool to determine those who required echocardiogram to confirm diagnosis. Trial registration LEAVE-DM, ACTRN 12619001393145 and Vic-ELF, ACTRN 12617000116325.
Collapse
Affiliation(s)
- Cheng Hwee Soh
- Imaging Research Laboratory, Baker Heart and Diabetes Institute, PO Box 6492, Melbourne, VIC, 3004, Australia
- Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, Australia
| | - Alex G C de Sá
- Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, Australia
- Computational Biology and Clinical Informatics, Baker Heart and Diabetes Institute, Melbourne, Australia
- School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Australia
- Systems and Computational Biology, Bio21 Institute, Parkville, Australia
| | - Elizabeth Potter
- Imaging Research Laboratory, Baker Heart and Diabetes Institute, PO Box 6492, Melbourne, VIC, 3004, Australia
| | - Amera Halabi
- Imaging Research Laboratory, Baker Heart and Diabetes Institute, PO Box 6492, Melbourne, VIC, 3004, Australia
| | - David B Ascher
- Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, Australia
- Computational Biology and Clinical Informatics, Baker Heart and Diabetes Institute, Melbourne, Australia
- School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Australia
- Systems and Computational Biology, Bio21 Institute, Parkville, Australia
| | - Thomas H Marwick
- Imaging Research Laboratory, Baker Heart and Diabetes Institute, PO Box 6492, Melbourne, VIC, 3004, Australia.
- Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, Australia.
- Menzies Institute for Medical Research, Hobart, Australia.
| |
Collapse
|
10
|
Liu C, Wu T, Ren N. Glucagon-like peptide-1 receptor agonists for the management of diabetic peripheral neuropathy. Front Endocrinol (Lausanne) 2024; 14:1268619. [PMID: 38313844 PMCID: PMC10836428 DOI: 10.3389/fendo.2023.1268619] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Accepted: 12/27/2023] [Indexed: 02/06/2024] Open
Abstract
Diabetes mellitus is a prevalent chronic disease characterized by hyperglycemia. Diabetic peripheral neuropathy (DPN) is one of the complications of diabetes mellitus and is caused by neuron injury induced by hyperglycemic circumstances. The incidence of DPN varies among different countries and regions, ranging from nearly 20% to over 70%. Patients with DPN may encounter symmetric pain or discomfort of the extremes, leading to reduced quality of life and even amputation. The pharmacological management for painful DPN mainly includes antidepressants due to their analgesic effects. Nevertheless, effective therapies to impact the pathogenesis and progression of DPN are lacking. Glucagon-like peptide-1 receptor (GLP-1R) agonists show efficacy in controlling blood glucose and serve as a treatment modality for diabetes mellitus. In recent years, evidence has been proposed that GLP-1R agonists exert neuroprotective effects through modulating inflammation, oxidative stress, and mitochondrial dysfunction. On the other hand, clinical evidence on the potential of GLP-1R agonists for treating DPN is still controversial and limited. This narrative review summarizes the preclinical and clinical studies investigating the capacity of GLP-1R agonists as therapeutic agents for DPN.
Collapse
Affiliation(s)
- Chunyan Liu
- Department of Endocrinology, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Tianqiang Wu
- Department of Integrated Traditional Chinese and Western Medicine, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Na Ren
- Department of Endocrinology, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China
| |
Collapse
|
11
|
Azizian H, Farhadi Z, Bader M, Alizadeh Ghalenoei J, Ghafari MA, Mahmoodzadeh S. GPER activation attenuates cardiac dysfunction by upregulating the SIRT1/3-AMPK-UCP2 pathway in postmenopausal diabetic rats. PLoS One 2023; 18:e0293630. [PMID: 38134189 PMCID: PMC10745199 DOI: 10.1371/journal.pone.0293630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Accepted: 10/16/2023] [Indexed: 12/24/2023] Open
Abstract
Postmenopausal diabetic women are at higher risk to develop cardiovascular diseases (CVD) compared with nondiabetic women. Alterations in cardiac cellular metabolism caused by changes in sirtuins are one of the main causes of CVD in postmenopausal diabetic women. Several studies have demonstrated the beneficial actions of the G protein-coupled estrogen receptor (GPER) in postmenopausal diabetic CVD. However, the molecular mechanisms by which GPER has a cardioprotective effect are still not well understood. In this study, we used an ovariectomized (OVX) type-two diabetic (T2D) rat model induced by high-fat diet/streptozotocin to investigate the effect of G-1 (GPER-agonist) on sirtuins, and their downstream pathways involved in regulation of cardiac metabolism and function. Animals were divided into five groups: Sham-Control, T2D, OVX+T2D, OVX+T2D+Vehicle, and OVX+T2D+G-1. G-1 was administrated for six weeks. At the end, hemodynamic factors were measured, and protein levels of sirtuins, AMP-activated protein kinase (AMPK), and uncoupling protein 2 (UCP2) were determined by Western blot analysis. In addition, cardiac levels of oxidative stress biomarkers were measured. The findings showed that T2D led to left ventricular dysfunction and signs of oxidative stress in the myocardium, which were accompanied by decreased protein levels of Sirt1/2/3/6, p-AMPK, and UCP2 in the heart. Moreover, the induction of the menopausal state exacerbated these changes. In contrast, treatment with G-1 ameliorated the hemodynamic changes associated with ovariectomy by increasing Sirt1/3, p-AMPK, UCP2, and improving oxidative status. The results provide evidence of the cardioprotective effects of GPER operating through Sirt1/3, p-AMPK, and UCP2, thereby improving cardiac function. Our results suggest that increasing Sirt1/3 levels may offer new therapeutic approaches for postmenopausal diabetic CVD.
Collapse
Affiliation(s)
- Hossein Azizian
- Yazd Neuroendocrine Research Center, School of Medicine, Shahid Sadoughi University of Medical Sciences and Health Services, Yazd, Iran
| | - Zeinab Farhadi
- Yazd Neuroendocrine Research Center, School of Medicine, Shahid Sadoughi University of Medical Sciences and Health Services, Yazd, Iran
| | - Michael Bader
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
- Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt‐Universität zu Berlin, Berlin, Germany
- University of Lübeck, Institute for Biology, Lübeck, Germany
| | - Jalil Alizadeh Ghalenoei
- Yazd Neuroendocrine Research Center, School of Medicine, Shahid Sadoughi University of Medical Sciences and Health Services, Yazd, Iran
| | - Mohammad Amin Ghafari
- Yazd Neuroendocrine Research Center, School of Medicine, Shahid Sadoughi University of Medical Sciences and Health Services, Yazd, Iran
| | - Shokoufeh Mahmoodzadeh
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
| |
Collapse
|
12
|
Na L, Cui W, Li X, Chang J, Xue X. Association between the triglyceride-glucose index and left ventricular global longitudinal strain in patients with coronary heart disease in Jilin Province, China: a cross-sectional study. Cardiovasc Diabetol 2023; 22:321. [PMID: 37993858 PMCID: PMC10666388 DOI: 10.1186/s12933-023-02050-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Accepted: 11/01/2023] [Indexed: 11/24/2023] Open
Abstract
BACKGROUND This study aimed to investigate the association between the triglyceride-glucose (TyG) index and left ventricular global longitudinal strain (GLS) in patients with coronary heart disease and to examine the role of left ventricular GLS in detecting early changes in cardiac function in patients with coronary heart disease in the subclinical stage. METHODS A cross-sectional study involving 178 participants with symptomatic coronary artery disease excluding myocardial infarction or left ventricular dysfunction was conducted in Jilin Province, China. Basic clinical, biochemical, and echocardiographic data were obtained from all participants. Myocardial strain parameters were compared between patients with higher TyG index and those with lower TyG index, and the association between the gradually elevated TyG index and on subclinical cardiac function in patients with coronary heart disease was evaluated. RESULTS The GLS of left ventricle was lower in the higher TyG index group than in the lower TyG index group. As the TyG index increases, the GLS progressively decreases. The results remained stable after adjusting for confounding factors. CONCLUSIONS A higher TyG index maybe independently associated with subclinical left ventricular dysfunction in patients with coronary heart disease.
Collapse
Affiliation(s)
- Lin Na
- Department of Cardiology, The Second Hospital of Jilin University, Changchun, China
| | - Wenjing Cui
- Department of Cardiology, Xi'an International Medical Center Hospital, Xi'an, China
| | - Xinqi Li
- Department of Cardiology, The Second Hospital of Jilin University, Changchun, China
| | - Jing Chang
- Clinical Laboratory, The Second Hospital of Jilin University, Changchun, China.
| | - Xin Xue
- Department of Cardiology, The Second Hospital of Jilin University, Changchun, China.
| |
Collapse
|
13
|
Saha S, Fang X, Green CD, Das A. mTORC1 and SGLT2 Inhibitors-A Therapeutic Perspective for Diabetic Cardiomyopathy. Int J Mol Sci 2023; 24:15078. [PMID: 37894760 PMCID: PMC10606418 DOI: 10.3390/ijms242015078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 09/27/2023] [Accepted: 10/04/2023] [Indexed: 10/29/2023] Open
Abstract
Diabetic cardiomyopathy is a critical diabetes-mediated co-morbidity characterized by cardiac dysfunction and heart failure, without predisposing hypertensive or atherosclerotic conditions. Metabolic insulin resistance, promoting hyperglycemia and hyperlipidemia, is the primary cause of diabetes-related disorders, but ambiguous tissue-specific insulin sensitivity has shed light on the importance of identifying a unified target paradigm for both the glycemic and non-glycemic context of type 2 diabetes (T2D). Several studies have indicated hyperactivation of the mammalian target of rapamycin (mTOR), specifically complex 1 (mTORC1), as a critical mediator of T2D pathophysiology by promoting insulin resistance, hyperlipidemia, inflammation, vasoconstriction, and stress. Moreover, mTORC1 inhibitors like rapamycin and their analogs have shown significant benefits in diabetes and related cardiac dysfunction. Recently, FDA-approved anti-hyperglycemic sodium-glucose co-transporter 2 inhibitors (SGLT2is) have gained therapeutic popularity for T2D and diabetic cardiomyopathy, even acknowledging the absence of SGLT2 channels in the heart. Recent studies have proposed SGLT2-independent drug mechanisms to ascertain their cardioprotective benefits by regulating sodium homeostasis and mimicking energy deprivation. In this review, we systematically discuss the role of mTORC1 as a unified, eminent target to treat T2D-mediated cardiac dysfunction and scrutinize whether SGLT2is can target mTORC1 signaling to benefit patients with diabetic cardiomyopathy. Further studies are warranted to establish the underlying cardioprotective mechanisms of SGLT2is under diabetic conditions, with selective inhibition of cardiac mTORC1 but the concomitant activation of mTORC2 (mTOR complex 2) signaling.
Collapse
Affiliation(s)
- Sumit Saha
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA; (S.S.); (X.F.); (C.D.G.)
| | - Xianjun Fang
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA; (S.S.); (X.F.); (C.D.G.)
| | - Christopher D. Green
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA; (S.S.); (X.F.); (C.D.G.)
| | - Anindita Das
- Division of Cardiology, Pauley Heart Center, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA
| |
Collapse
|
14
|
Bell DSH, McGill JB, Jerkins T. Management of the 'wicked' combination of heart failure and chronic kidney disease in the patient with diabetes. Diabetes Obes Metab 2023; 25:2795-2804. [PMID: 37409564 DOI: 10.1111/dom.15181] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 05/30/2023] [Accepted: 05/30/2023] [Indexed: 07/07/2023]
Abstract
Patients with type 2 diabetes are at an increased risk of developing heart failure and chronic kidney disease. The presence of these co-morbidities substantially increases the risk of morbidity as well as mortality in patients with diabetes. The clinical focus has historically centred around reducing the risk of cardiovascular disease by targeting hyperglycaemia, hyperlipidaemia and hypertension. Nonetheless, patients with type 2 diabetes who have well-controlled blood glucose, blood pressure and lipid levels may still go on to develop heart failure, kidney disease or both. Major diabetes and cardiovascular societies are now recommending the use of treatments such as sodium-glucose co-transporter-2 inhibitors and non-steroidal mineralocorticoid receptor antagonists, in addition to currently recommended therapies, to promote cardiorenal protection through alternative pathways as early as possible in individuals with diabetes and cardiorenal manifestations. This review examines the most recent recommendations for managing the risk of cardiorenal progression in patients with type 2 diabetes.
Collapse
Affiliation(s)
| | - Janet B McGill
- Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Terri Jerkins
- Midstate Endocrine Associates, Nashville, Tennessee, USA
| |
Collapse
|
15
|
Tokarek J, Budny E, Saar M, Stańczak K, Wojtanowska E, Młynarska E, Rysz J, Franczyk B. Molecular Processes Involved in the Shared Pathways between Cardiovascular Diseases and Diabetes. Biomedicines 2023; 11:2611. [PMID: 37892985 PMCID: PMC10604380 DOI: 10.3390/biomedicines11102611] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Revised: 09/17/2023] [Accepted: 09/18/2023] [Indexed: 10/29/2023] Open
Abstract
Cardiovascular diseases and diabetes mellitus are currently among the diseases with the highest morbidity and mortality. The pathogenesis and development of these diseases remain strongly connected, along with inflammation playing a major role. Therefore, the treatment possibilities showing a positive impact on both of these diseases could be especially beneficial for patients. SGLT-2 inhibitors and GLP-1 receptor agonists present this dual effect. Moreover, the hostile composition of the gut microbiota could influence the progression of these conditions. In this review, the authors present the latest knowledge on and innovations in diabetes mellitus and CVD-with the focus on the molecular mechanisms and the role of the microbiota.
Collapse
Affiliation(s)
- Julita Tokarek
- Department of Nephrocardiology, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland (K.S.); (E.W.)
| | - Emilian Budny
- Department of Nephrocardiology, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland (K.S.); (E.W.)
| | - Maciej Saar
- Department of Nephrocardiology, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland (K.S.); (E.W.)
| | - Kamila Stańczak
- Department of Nephrocardiology, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland (K.S.); (E.W.)
| | - Ewa Wojtanowska
- Department of Nephrocardiology, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland (K.S.); (E.W.)
| | - Ewelina Młynarska
- Department of Nephrocardiology, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland (K.S.); (E.W.)
| | - Jacek Rysz
- Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Beata Franczyk
- Department of Nephrocardiology, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland (K.S.); (E.W.)
| |
Collapse
|
16
|
Elendu C, Amaechi DC, Elendu TC, Ashna M, Ross-Comptis J, Ansong SO, Egbunu EO, Okafor GC, Jingwa KA, Akintunde AA, Ogah CM, Edeko MO, Ibitoye AV, Ogunseye MO, Alakwe-Ojimba CE, Omeludike EK, Oguine CA, Afuh RN, Olawuni CA, Ekwem OR, Oyedele BA, Pius EI, Asekhauno MO, Ladele JA, Okoro CB, Monika Pouekoua BC, Adenikinju JS, Agu-ben CM, Aborisade O. Heart failure and diabetes: Understanding the bidirectional relationship. Medicine (Baltimore) 2023; 102:e34906. [PMID: 37713837 PMCID: PMC10508577 DOI: 10.1097/md.0000000000034906] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Accepted: 08/03/2023] [Indexed: 09/17/2023] Open
Abstract
Heart failure and diabetes mellitus are 2 common and closely intertwined chronic conditions that often coexist in individuals. The relationship between heart failure and diabetes is bidirectional, meaning that each condition can influence the development and progression of the other. Understanding this complex interplay is crucial for optimizing the management and outcomes of patients with these comorbidities. This review comprehensively analyzed the literature to examine the bidirectional relationship between heart failure and diabetes. We searched various electronic databases and included studies that explored the pathophysiological mechanisms, epidemiology, clinical implications, and therapeutic considerations associated with this relationship. The bidirectional relationship between heart failure and diabetes is multifactorial and involves several interconnected mechanisms. Diabetes is a recognized risk factor for heart failure, increasing the risk of its development and accelerating its progression. On the other hand, heart failure can contribute to the development of insulin resistance and worsen glycemic control in patients with diabetes. Shared risk factors, such as obesity, hypertension, and dyslipidemia, contribute to development of both conditions. Additionally, hyperglycemia, insulin resistance, chronic inflammation, oxidative stress, and mitochondrial dysfunction play significant roles in the pathogenesis of heart failure in individuals with diabetes. The bidirectional relationship between heart failure and diabetes has important clinical implications. Patients with heart failure and diabetes have worse outcomes, including higher hospitalization rates, morbidity, and mortality, than those without diabetes. Optimal management strategies should target both conditions simultaneously, focusing on lifestyle modifications, pharmacotherapy, glycemic control, and cardiovascular risk reduction.
Collapse
|
17
|
Forzano I, Avvisato R, Varzideh F, Jankauskas SS, Cioppa A, Mone P, Salemme L, Kansakar U, Tesorio T, Trimarco V, Santulli G. L-Arginine in diabetes: clinical and preclinical evidence. Cardiovasc Diabetol 2023; 22:89. [PMID: 37072850 PMCID: PMC10114382 DOI: 10.1186/s12933-023-01827-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Accepted: 04/06/2023] [Indexed: 04/20/2023] Open
Abstract
L-Arginine (L-Arg), is a semi-essential amino acid involved in the formation of nitric oxide. The functional relevance of L-Arg in diabetes mellitus has been evaluated both in animal models and in human subjects. In the literature there are several lines of evidence indicating that L-Arg has beneficial effects in diabetes and numerous studies advocate its administration to attenuate glucose intolerance in diabetic patients. Here we present a comprehensive overview of the main studies exploring the effects of L-Arg in diabetes, including preclinical and clinical reports on this topic.
Collapse
Affiliation(s)
- Imma Forzano
- Department of Medicine, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Fleischer Institute for Diabetes Research (FIDAM), Einstein - Mount Sinai Diabetes Research Center (ES-DRC), Albert Einstein University College of Medicine, New York, NY, USA
| | - Roberta Avvisato
- Department of Medicine, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Fleischer Institute for Diabetes Research (FIDAM), Einstein - Mount Sinai Diabetes Research Center (ES-DRC), Albert Einstein University College of Medicine, New York, NY, USA
| | - Fahimeh Varzideh
- Department of Medicine, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Fleischer Institute for Diabetes Research (FIDAM), Einstein - Mount Sinai Diabetes Research Center (ES-DRC), Albert Einstein University College of Medicine, New York, NY, USA
| | - Stanislovas S Jankauskas
- Department of Medicine, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Fleischer Institute for Diabetes Research (FIDAM), Einstein - Mount Sinai Diabetes Research Center (ES-DRC), Albert Einstein University College of Medicine, New York, NY, USA
| | - Angelo Cioppa
- Department of Medicine, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Fleischer Institute for Diabetes Research (FIDAM), Einstein - Mount Sinai Diabetes Research Center (ES-DRC), Albert Einstein University College of Medicine, New York, NY, USA
- Montevergine Clinic, Mercogliano (AV), Italy
| | - Pasquale Mone
- Department of Medicine, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Fleischer Institute for Diabetes Research (FIDAM), Einstein - Mount Sinai Diabetes Research Center (ES-DRC), Albert Einstein University College of Medicine, New York, NY, USA
| | | | - Urna Kansakar
- Department of Medicine, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Fleischer Institute for Diabetes Research (FIDAM), Einstein - Mount Sinai Diabetes Research Center (ES-DRC), Albert Einstein University College of Medicine, New York, NY, USA
| | | | - Valentina Trimarco
- Department of Medicine, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Fleischer Institute for Diabetes Research (FIDAM), Einstein - Mount Sinai Diabetes Research Center (ES-DRC), Albert Einstein University College of Medicine, New York, NY, USA
- Department of Neuroscience, Reproductive Sciences and Dentistry, "Federico II" University, Naples, Italy
| | - Gaetano Santulli
- Department of Medicine, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Fleischer Institute for Diabetes Research (FIDAM), Einstein - Mount Sinai Diabetes Research Center (ES-DRC), Albert Einstein University College of Medicine, New York, NY, USA.
- Department of Molecular Pharmacology, Institute for Neuroimmunology and Inflammation (INI), Albert Einstein College of Medicine, New York, NY, USA.
| |
Collapse
|
18
|
El‐Battrawy I, Demmer J, Abumayyaleh M, Crack C, Pilsinger C, Zhou X, Mügge A, Akin I, Aweimer A. The impact of sacubitril/valsartan on outcome in patients suffering from heart failure with a concomitant diabetes mellitus. ESC Heart Fail 2023; 10:943-954. [PMID: 36479630 PMCID: PMC10053359 DOI: 10.1002/ehf2.14239] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 10/26/2022] [Accepted: 11/08/2022] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Guidelines classify sacubitril/valsartan as a significant part of medical treatment of heart failure with reduced ejection fraction (HFrEF). Data have shown that the HbA1c levels in patients with diabetes mellitus could be impacted by sacubitril/valsartan. A possible positive effect in diabetes patients treated with sacubitril/valsartan on outcome and echocardiography parameters is not well studied yet. AIMS The aim of the present study was to compare the impact of sacubitril/valsartan on life-threatening arrhythmias, atrial fibrillation, different echocardiography parameters and congestion rate in patients suffering from HFrEF according to the diagnosis diabetes mellitus or no diabetes mellitus. METHODS AND RESULTS Consecutive 240 patients with HFrEF from 2016 to 2020 were treated with sacubitril/valsartan and separated to concomitant diabetes mellitus (n = 87, median age 68 years interquartile range (IQR) [32-87]) or no diabetes mellitus (n = 153, median age 66 year IQR [34-89]). Different comorbidities and outcome data were evaluated over a follow-up period of 24 months. Arterial hypertension (87% vs. 64%; P < 0.01) and coronary artery disease (74% vs. 60%; P = 0.03) were more often documented in patients with diabetes mellitus compared with patients without diabetes mellitus. Over the follow-up of 24 months several changes were noted in both subgroups: Median left ventricular ejection fraction (EF) increased significantly in non-diabetes (27% IQR [3-44] at baseline to 35% IQR [13-64]; P < 0.001), but not in diabetic patients (29% IQR [10-65] at baseline to 30% IQR [13-55]; P = 0.11). Accordingly, NT-proBNP and troponin-I levels decreased significantly in non-diabetes patients (NT-brain natriuretic peptide [NT-proBNP] from median 1445 pg/mL IQR [12.6-74 676] to 491 pg/mL IQR [13-4571]; P < 0.001, troponin-I levels from 0.099 ng/mL IQR [0.009-138.69] to 0.023 ng/mL IQR [0.006-0.635]; P < 0.001), but not in diabetic patients (NT-proBNP from 1395 pg/mL IQR [100-29 924] to 885 pg/mL IQR [159-4331]; P = 0.06, troponin-I levels from 0.05 ng/mL IQR [0.013-103.0] to 0.020 ng/mL IQR [0.015-0.514]; P = 0.27). No significant change of laboratory parameters e. g. glomerular filtration rate, potassium level and creatinine levels were found in diabetes or non-diabetes patients. Comparing further echocardiography data, left atrial surface area, right atrial surface area, E/A ratio did not show a significant change either in the diabetes or non-diabetes group. However, the tricuspid annular plane systolic excursion was significantly increased in non-diabetes mellitus patients (from 17 mm IQR [3-31] to 18 mm [2.5-31]; P = 0.04), and not in diabetic s patients (17.5 mm IQR [8-30] to 18 mm IQR [14-31]; P = 0.70); the systolic pulmonary artery pressure remained unchanged in both groups. During follow-up, a similar rate of ventricular tachyarrhythmias was observed in both groups. The congestion rate decreased significantly in both groups, in diabetes patients (44.4% before sacubitril/valsartan and 13.5% after 24 months treatment; P = 0.0009) and in non-diabetic patients (28.4% before sacubitril/valsartan and 8.4% after 24 months treatment; P = 0.0004). The all-cause mortality rate was higher in patients with diabetes mellitus as compared with those without diabetes (25% vs. 8.1%; P < 0.01). CONCLUSIONS Sacubitril/valsartan reverses cardiac remodelling in non-diabetes patients. However, it reduces the congestion rate in diabetes and non-diabetes patients. The rates of ventricular tachyarrhythmias were similar in DM compared with non-DM over follow-up. The mortality rate remained to be over follow-up higher in diabetes patients compared with non-diabetes; however, it was lower compared with published data on diabetes and concomitant HFrEF not treated with sacubitril/valsartan.
Collapse
Affiliation(s)
- Ibrahim El‐Battrawy
- Department of Cardiology and Angiology, Bergmannsheil University HospitalsRuhr University of Bochum44789BochumGermany
| | | | | | | | | | | | - Andreas Mügge
- Department of Cardiology and Angiology, Bergmannsheil University HospitalsRuhr University of Bochum44789BochumGermany
| | | | - Assem Aweimer
- Department of Cardiology and Angiology, Bergmannsheil University HospitalsRuhr University of Bochum44789BochumGermany
| |
Collapse
|
19
|
Sanganalmath SK, Dubey S, Veeranki S, Narisetty K, Krishnamurthy P. The interplay of inflammation, exosomes and Ca 2+ dynamics in diabetic cardiomyopathy. Cardiovasc Diabetol 2023; 22:37. [PMID: 36804872 PMCID: PMC9942322 DOI: 10.1186/s12933-023-01755-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 01/25/2023] [Indexed: 02/22/2023] Open
Abstract
Diabetes mellitus is one of the prime risk factors for cardiovascular complications and is linked with high morbidity and mortality. Diabetic cardiomyopathy (DCM) often manifests as reduced cardiac contractility, myocardial fibrosis, diastolic dysfunction, and chronic heart failure. Inflammation, changes in calcium (Ca2+) handling and cardiomyocyte loss are often implicated in the development and progression of DCM. Although the existence of DCM was established nearly four decades ago, the exact mechanisms underlying this disease pathophysiology is constantly evolving. Furthermore, the complex pathophysiology of DCM is linked with exosomes, which has recently shown to facilitate intercellular (cell-to-cell) communication through biomolecules such as micro RNA (miRNA), proteins, enzymes, cell surface receptors, growth factors, cytokines, and lipids. Inflammatory response and Ca2+ signaling are interrelated and DCM has been known to adversely affect many of these signaling molecules either qualitatively and/or quantitatively. In this literature review, we have demonstrated that Ca2+ regulators are tightly controlled at different molecular and cellular levels during various biological processes in the heart. Inflammatory mediators, miRNA and exosomes are shown to interact with these regulators, however how these mediators are linked to Ca2+ handling during DCM pathogenesis remains elusive. Thus, further investigations are needed to understand the mechanisms to restore cardiac Ca2+ homeostasis and function, and to serve as potential therapeutic targets in the treatment of DCM.
Collapse
Affiliation(s)
- Santosh K Sanganalmath
- Department of Internal Medicine, Division of Cardiovascular Medicine, University of Nevada Las Vegas School of Medicine, Las Vegas, NV, 89102, USA.
| | - Shubham Dubey
- Department of Biomedical Engineering, Schools of Medicine and Engineering, University of Alabama at Birmingham, University Blvd., Birmingham, AL, 35294, USA
| | - Sudhakar Veeranki
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, 40506, USA
| | | | - Prasanna Krishnamurthy
- Department of Biomedical Engineering, Schools of Medicine and Engineering, University of Alabama at Birmingham, University Blvd., Birmingham, AL, 35294, USA
| |
Collapse
|
20
|
The Cardioprotective Effect of Corosolic Acid in the Diabetic Rats: A Possible Mechanism of the PPAR-γ Pathway. Molecules 2023; 28:molecules28030929. [PMID: 36770602 PMCID: PMC9919720 DOI: 10.3390/molecules28030929] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 01/09/2023] [Accepted: 01/10/2023] [Indexed: 01/18/2023] Open
Abstract
The study was conducted to determine whether corosolic acid could protect the myocardium of diabetic rats from damage caused by isoproterenol (ISO) and, if so, how peroxisome proliferator-activated receptor gamma (PPAR-γ) activation might contribute into this protection. Diabetes in the rats was induced by streptozotocin (STZ), and it was divided into four groups: the diabetic control group, diabetic rats treated with corosolic acid, diabetic rats treated with GW9662, and diabetic rats treated with corosolic acid plus GW9662. The study was carried out for 28 days. The diabetic control and ISO control groups showed a decrease in mean arterial pressure (MAP) and diastolic arterial pressure (DAP) and an increase in systolic arterial pressure (SAP). The rat myocardium was activated by corosolic acid treatment, which elevated PPAR-γ expression. A histopathological analysis showed a significant reduction in myocardial damage by reducing myonecrosis and edema. It was found that myocardial levels of CK-MB and LDH levels were significantly increased after treatment with corosolic acid. By decreasing lipid peroxidation and increasing endogenous antioxidant levels, corosolic acid therapy showed a significant improvement over the ISO diabetic group. In conclusion, our results prove that corosolic acid can ameliorate ISO-induced acute myocardial injury in rats. Based on these results, corosolic acid seems to be a viable new target for the treatment of cardiovascular diseases and other diseases of a similar nature.
Collapse
|
21
|
Matsuzaki A, Momo K, Watanabe A, Koshizuka H, Kashiwabara Y, Tanaka K, Sasaki T. Risk Assessment for Heart Failure in Patients with Type 2 Diabetes Mellitus Treated with Dipeptidyl Peptidase 4 Inhibitor Using a Large Claims Dataset. Biol Pharm Bull 2023; 46:1217-1222. [PMID: 37661401 DOI: 10.1248/bpb.b23-00073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/05/2023]
Abstract
Heart failure is a prevalent comorbidity in patients with diabetes mellitus (DM). However, it is unclear whether the risk factors for heart failure in DM patients treated with dipeptidyl peptidase-4 (DPP-4) inhibitors are the same as those for the general population. In this study, we evaluated the factors of new-onset heart failure in working-age patients with diabetes who started DPP-4 inhibitor therapy. This study included 7938 working-age patients. The primary endpoint of the study was the proportion of patients developing heart failure within 12 months of starting DPP-4 inhibitor therapy, which was found to be 1.89% (n = 150). In these patients, risk factors of new-onset heart failure were aging, history of atrial fibrillation, and hypertension but not sex, smoking, high body mass index, weight gain of over 10 kg from 20 years of age, levels of low-density lipoprotein or glycated hemoglobin A1c (HbA1c), history of angina pectoris, myocardial infarction, and chronic kidney disease. We confirmed that cardiovascular comorbidities are risk factors for new-onset heart failure in patients with DM, while general risk factors are not. In conclusion, physicians and pharmacists need to carefully monitor working-age patients with cardiovascular history who start DPP-4 inhibitor therapy even if they do not exhibit general risk factors for heart failure.
Collapse
Affiliation(s)
- Airi Matsuzaki
- Department of Pharmacy, Showa University Koto Toyosu Hospital
- Department of Hospital Pharmaceutics, School of Pharmacy, Showa University
| | - Kenji Momo
- Department of Hospital Pharmaceutics, School of Pharmacy, Showa University
| | - Ayako Watanabe
- Department of Pharmacy, Showa University Koto Toyosu Hospital
- Department of Hospital Pharmaceutics, School of Pharmacy, Showa University
| | - Hiromi Koshizuka
- Department of Pharmacy, Showa University Koto Toyosu Hospital
- Department of Hospital Pharmaceutics, School of Pharmacy, Showa University
| | - Yuka Kashiwabara
- Department of Pharmacy, Showa University Koto Toyosu Hospital
- Department of Hospital Pharmaceutics, School of Pharmacy, Showa University
| | - Katsumi Tanaka
- Department of Hospital Pharmaceutics, School of Pharmacy, Showa University
| | - Tadanori Sasaki
- Department of Appropriate Medication Therapy Management (MTM), School of Pharmacy, Showa University
| |
Collapse
|
22
|
Huo D, Liu YY, Zhang C, Zeng LT, Fan GQ, Zhang LQ, Pang J, Wang Y, Shen T, Li XF, Li CB, Zhang TM, Cai JP, Cui J. Serum glycoprotein non-metastatic melanoma protein B (GPNMB) level as a potential biomarker for diabetes mellitus-related cataract: A cross-sectional study. Front Endocrinol (Lausanne) 2023; 14:1110337. [PMID: 36875463 PMCID: PMC9978497 DOI: 10.3389/fendo.2023.1110337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Accepted: 02/06/2023] [Indexed: 02/18/2023] Open
Abstract
BACKGROUND Diabetes mellitus (DM), a metabolic disease that has attracted significant research and clinical attention over the years, can affect the eye structure and induce cataract in patients diagnosed with DM. Recent studies have indicated the relationship between glycoprotein non-metastatic melanoma protein B (GPNMB) and DM and DM-related renal dysfunction. However, the role of circulating GPNMB in DM-associated cataract is still unknown. In this study, we explored the potential of serum GPNMB as a biomarker for DM and DM-associated cataract. METHODS A total of 406 subjects were enrolled, including 60 and 346 subjects with and without DM, respectively. The presence of cataract was evaluated and serum GPNMB levels were measured using a commercial enzyme-linked immunosorbent assay kit. RESULTS Serum GPNMB levels were higher in diabetic individuals and subjects with cataract than in those without DM or cataract. Subjects in the highest GPNMB tertile group were more likely to have metabolic disorder, cataract, and DM. Analysis performed in subjects with DM elucidated the correlation between serum GPNMB levels and cataract. Receiver operating characteristic (ROC) curve analysis also indicated that GPNMB could be used to diagnose DM and cataract. Multivariable logistic regression analysis illustrated that GPNMB levels were independently associated with DM and cataract. DM was also found to be an independent risk factor for cataract. Further surveys revealed the combination of serum GPNMB levels and presence of DM was associated with a more precise identification of cataract than either factor alone. CONCLUSIONS Increased circulating GPNMB levels are associated with DM and cataract and can be used as a biomarker of DM-associated cataract.
Collapse
Affiliation(s)
- Da Huo
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, China
| | - Yuan-Yuan Liu
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, China
| | - Chi Zhang
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, China
| | - Lv-Tao Zeng
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, China
| | - Guo-Qing Fan
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, China
| | - Li-Qun Zhang
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, China
| | - Jing Pang
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, China
| | - Yao Wang
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, China
| | - Tao Shen
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, China
| | - Xue-Fei Li
- Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Chuan-Bao Li
- Department of Laboratory Medicine, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Tie-Mei Zhang
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, China
| | - Jian-Ping Cai
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, China
- *Correspondence: Ju Cui, ; ; Jian-Ping Cai,
| | - Ju Cui
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, China
- *Correspondence: Ju Cui, ; ; Jian-Ping Cai,
| |
Collapse
|
23
|
Ouyang Y, Tang L, Hu S, Tian G, Dong C, Lai H, Wang H, Zhao J, Wu H, Zhang F, Yang H. Shengmai san-derived compound prescriptions: A review on chemical constituents, pharmacokinetic studies, quality control, and pharmacological properties. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 107:154433. [PMID: 36191550 DOI: 10.1016/j.phymed.2022.154433] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Revised: 08/26/2022] [Accepted: 09/02/2022] [Indexed: 06/16/2023]
Abstract
BACKGROUND Shengmai San Formula (SMS), composed of Ginseng Radix et Rhizoma, Ophiopogon Radix and Schisandra chinensis Fructus, was a famous formula in Tradition Chinese Medicine (TCM). With the expansion of clinical applications, SMS was developed to different dosage forms, including Shengmai Yin Oral liquid (SMY), Shengmai Capsule (SMC), Shengmai Granule (SMG), Shengmai Injection (SMI) and Dengzhan Shengmai Capsule (DZSMC). These above SMS-derived compound prescriptions (SSCPs) play an important role in the clinical treatment. This review is aimed to providing a comprehensive perspective of SSCP. METHODS The relevant literatures were collected from classical TCM books and a variety of databases, including PubMed, Google Scholar, Science Direct, Springer Link, Web of Science, China National Knowledge Infrastructure, and Wanfang Data. RESULTS The chemical constituents of SSCPs, arrived from the individual medicinal materials including Ginseng Radix et Rhizoma, Ophiopogon Radix, Schisandra chinensis Fructus, Erigerontis Herba, were firstly summarized respectively. Then the pharmacokinetics studies, quality control, and pharmacological properties of SSCPs were all reviewed. The active compounds, pharmacokinetics characterizes, quality control markers, the effects and mechanisms of pharmacology of the different dosage forms of SSCPs were summarized. Furthermore, the research deficiencies of SSCPs and an innovative research paradigm for Chinese materia medica (CMM) formula were proposed. CONCLUSIONS SMS, as a famous CMM formula, has great values in drug research and in clinical treatment especially for cardiocerebrovascular diseases. This article firstly make a comprehensive and systematic review on SMS.
Collapse
Affiliation(s)
- Yi Ouyang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China.
| | - Liying Tang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Shaowei Hu
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Guanghuan Tian
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China; Zunyi Medical University, Zunyi, China
| | - Caihong Dong
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China; Jiangxi University of Traditional Chinese Medicine, Jiangxi, China
| | - Huaqing Lai
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China; Zunyi Medical University, Zunyi, China
| | - Huanhuan Wang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Jie Zhao
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Hongwei Wu
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China.
| | - Fangbo Zhang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China.
| | - Hongjun Yang
- Medical Experimental Center, China Academy of Chinese Medical Sciences, Beijing, China.
| |
Collapse
|
24
|
Ghosh N, Fenton S, van Hout I, Jones GT, Coffey S, Williams MJ, Sugunesegran R, Parry D, Davis P, Schwenke DO, Chatterjee A, Katare R. Therapeutic knockdown of miR-320 improves deteriorated cardiac function in a pre-clinical model of non-ischemic diabetic heart disease. MOLECULAR THERAPY. NUCLEIC ACIDS 2022; 29:330-342. [PMID: 35950211 PMCID: PMC9356207 DOI: 10.1016/j.omtn.2022.07.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 07/08/2022] [Indexed: 11/17/2022]
Abstract
Non-ischemic diabetic heart disease (NiDHD) is characterized by diastolic dysfunction and decreased or preserved systolic function, eventually resulting in heart failure. Accelerated apoptotic cell death because of alteration of molecular signaling pathways due to dysregulation in microRNAs (miRNAs) plays a significant role in the development of NiDHD. Here, we aimed to determine the pathological role of cardiomyocyte-enriched pro-apoptotic miR-320 in the development of NiDHD. We identified a marked upregulation of miR-320 that was associated with downregulation of its target protein insulin growth factor-1 (IGF-1) in human right atrial appendage tissue in the late stages of cardiomyopathy in type 2 diabetic db/db mice and high-glucose-cultured human ventricular cardiomyocytes (AC-16 cells). In vitro knockdown of miR-320 in high-glucose-exposed AC-16 cells using locked nucleic acid (LNA) anti-miR-320 markedly reduced high-glucose-induced apoptosis by restoring IGF-1 and Bcl-2. Finally, in vivo knockdown of miR-320 in 24-week-old type 2 diabetic db/db mice reduced cardiomyocyte apoptosis and interstitial fibrosis while restoring vascular density. This resulted in partial recovery of the impaired diastolic and systolic function. Our study provides evidence that miR-320 is a late-responding miRNA that aggravates apoptosis and cardiac dysfunction in the diabetic heart, and that therapeutic knockdown of miR-320 is beneficial in partially restoring the deteriorated cardiac function.
Collapse
Affiliation(s)
- Nilanjan Ghosh
- Department of Physiology-HeartOtago, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
| | - Sonya Fenton
- Department of Physiology-HeartOtago, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
| | - Isabelle van Hout
- Department of Physiology-HeartOtago, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
| | - Gregory T. Jones
- Department of Surgical Sciences, University of Otago, Dunedin, New Zealand
| | - Sean Coffey
- Department of Medicine, University of Otago, Dunedin, New Zealand
| | | | | | - Dominic Parry
- Department of Cardiothoracic Surgery, University of Otago, Dunedin, New Zealand
| | - Philip Davis
- Department of Cardiothoracic Surgery, University of Otago, Dunedin, New Zealand
| | - Daryl O. Schwenke
- Department of Physiology-HeartOtago, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
| | - Anirudha Chatterjee
- Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
- Honorary Professor, UPES University, Dehradun, India
| | - Rajesh Katare
- Department of Physiology-HeartOtago, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
| |
Collapse
|
25
|
Khaksari M, Raji-Amirhasani A, Bashiri H, Ebrahimi MN, Azizian H. Protective effects of combining SERMs with estrogen on metabolic parameters in postmenopausal diabetic cardiovascular dysfunction: The role of cytokines and angiotensin II. Steroids 2022; 183:109023. [PMID: 35358567 DOI: 10.1016/j.steroids.2022.109023] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Accepted: 03/23/2022] [Indexed: 12/20/2022]
Abstract
INTRODUCTION The beneficial effects of the administration of selective estrogen receptor modulators (SERMs) and estrogen (E2), alone or in combination with each other, have been reported in postmenopausal diabetic cardiovascular dysfunction. In the present study, we determined the mechanism of action of SERMs and E2 on inflammatory balance, angiotensin II (Ang II) serum levels, and glycemic profile in a postmenopausal diabetic rat model. METHODS Ovariectomized rats with type 2 diabetes received daily SERMs (tamoxifen and raloxifene) and E2 for one month. After treatment, cardiovascular risk indices, glycemic profile, and serum Ang II, TNF-α and IL-10 levels were measured. RESULTS Type 2 diabetes caused an abnormal glycemic profile, which was exacerbated by ovariectomy. All treatments inhibited the effects of diabetes and ovariectomy on the glycemic profile, with combined treatments (SERMs + E2) showing stronger effects. Cardiovascular risk indices that became abnormal by diabetes and worsened by ovariectomy were improved in all treatment modalities. Also, combined treatment reduced serum Ang II, TNF-α, and the ratio of TNF-α to IL-10, indicating an improvement in inflammatory balance. CONCLUSION Our study showed the administration of SERMs and E2, alone or in combination, could be an effective alternative in the treatment of menopausal diabetes, and generally, the beneficial effects of combined treatments were more effective than the effects of E2 or SERMs alone. It appears that E2 or SERMs benefit the cardiovascular system by improving inflammatory balance and reducing Ang II levels.
Collapse
Affiliation(s)
- Mohammad Khaksari
- Endocrinology and Metabolism Research Center, Kerman University of Medical Sciences, Kerman, Iran.
| | - Alireza Raji-Amirhasani
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Hamideh Bashiri
- Cardiovascular Research Center, Kerman University of Medical Sciences, Kerman, Iran
| | | | - Hossein Azizian
- Neurobiomedical Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| |
Collapse
|
26
|
Govender RD, Al-Shamsi S, Alnababteh AH, Shah SM. Heart Failure and the Risk of Recurrent Cardiovascular Events in Patients Attending Outpatient Clinics in the United Arab Emirates. Heart Views 2022; 23:144-149. [PMID: 36479172 PMCID: PMC9721174 DOI: 10.4103/heartviews.heartviews_14_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 09/11/2022] [Indexed: 06/17/2023] Open
Abstract
BACKGROUND Heart failure (HF) prognosticates a death sentence, and despite recent advances in treatment, long-term outcomes for patients with advanced HF are very poor, with only a 50%-60% survival rate at 5 years. This is alarming for the approximately 26 million people worldwide living with HF. AIMS AND OBJECTIVES This study aimed to investigate the relationship between HF and the risk of recurrent cardiovascular disease (CVD) events or CVD death among the national population in the United Arab Emirates (UAE). MATERIALS AND METHODS A retrospective study was conducted from April 2008 to September 2019 including 240 patients ≥18 years with a previous vascular event. Patient outcomes such as CVD death, the occurrence of a recurrent vascular event, or until the end of the study period, whichever occurred first. RESULTS Twenty-three patients (9.6%) had a concomitant diagnosis of HF and this doubled the risk of recurrent CVD events or death over 9 years. HF, age, lower body mass index, and atrial fibrillation were significant predictors of recurrent CVD or mortality. The mean age was 65 years and the risk of a CVD event or death increased at a rate of 3% for every increasing year of age. Patients with HF have approximately a 65% likelihood of survival at 5 years, whereas those without HF have about an 85% at 5-year survival. CONCLUSION HF is a strong predictor of recurrent CVD events or mortality in UAE patients with established CVD. Thus, aggressive management of modifiable risk factors for vascular disease through multidisciplinary teams guides clinicians toward meticulous control of CVD risk factors to improve disease prognosis and premature death.
Collapse
Affiliation(s)
- Romona Devi Govender
- Department of Family Medicine, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates
| | - Saif Al-Shamsi
- Department of Internal Medicine, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates
| | - Asma H. Alnababteh
- Department of Institute of Public Health, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates
| | - Syed M. Shah
- Department of Institute of Public Health, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates
| |
Collapse
|
27
|
Abstract
Diabetes is a metabolic disorder that affects millions of people worldwide. Diabetic heart disease (DHD) comprises coronary artery disease, heart failure, cardiac autonomic neuropathy, peripheral arterial disease, and diabetic cardiomyopathy. The onset and progression of DHD have been attributed to molecular alterations in response to hyperglycemia in diabetes. In this context, microRNAs (miRNAs) have been demonstrated to have a significant role in the development and progression of DHD. In addition to their effects on the host cells, miRNAs can be released into circulation after encapsulation within the exosomes. Exosomes are extracellular nanovesicles ranging from 30 to 180 nm in diameter secreted by all cell types. They carry diverse cargos that are altered in response to various conditions in their parent cells. Exosomal miRNAs have been extensively studied in recent years due to their role and therapeutic potential in DHD. This review will first provide an overview of exosomes, their biogenesis and function, followed by the role of exosomes in cardiovascular disease and then focuses on the known role of exosomes and associated miRNAs in DHD.
Collapse
Affiliation(s)
- Dhananjie Chandrasekera
- Department of Physiology, School of Biomedical Sciences, HeartOtago, University of Otago, 270, Great King Street, Dunedin, New Zealand.
| | - Rajesh Katare
- Department of Physiology, School of Biomedical Sciences, HeartOtago, University of Otago, 270, Great King Street, Dunedin, New Zealand.
| |
Collapse
|
28
|
Soleimani AA, Ghasmpour G, Mohammadi A, Gholizadeh M, Abkenar BR, Najafi M. Focal adhesion kinase-related pathways may be suppressed by metformin in vascular smooth muscle cells in high glucose conditions. Endocrinol Diabetes Metab 2022; 5:e351. [PMID: 35633523 PMCID: PMC9258994 DOI: 10.1002/edm2.351] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Revised: 05/09/2022] [Accepted: 05/13/2022] [Indexed: 12/16/2022] Open
Abstract
Introduction Cardiovascular diseases are known as one of the important causes of death in patients with diabetes mellitus. Metformin is used as an oral medication for reducing blood sugar. In this study, the effects of metformin were investigated on the FAK gene expression levels, pFAK protein values, cell viability and migration rate of VSMCs in high glucose conditions. Materials and methods The FAK gene expression levels and pFAK protein values were evaluated in VSMCs treated with different doses of metformin (1, 5 and 7 mM), based on cell viability using RT‐qPCR, western blotting and MTT techniques. The cellular migration was evaluated by scratch assay. Results The FAK gene expression levels reduced significantly in metformin‐treated VSMCs at 24 h and 48 h periods (p < .0008 and p < .0001, respectively). The pFAK protein values reduced significantly at 24 h (5 mM and 7 mM metformin doses) and 48 h periods (p < .001). In agreement with pFAK protein values, cellular migration reduced significantly at 24 h and 48 h periods (p < .001). Conclusion The results showed that metformin may suppress the proliferation and migration of VSMCs via FAK‐related pathways and may retard the progression of vessel stenosis in diabetes.
Collapse
Affiliation(s)
- Ali Akbar Soleimani
- Clinical Biochemistry Department, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Ghasem Ghasmpour
- Clinical Biochemistry Department, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Asghar Mohammadi
- Clinical Biochemistry Department, Faculty of Medicine, Tarbiat Mdares University, Tehran, Iran
| | - Masoomeh Gholizadeh
- Clinical Biochemistry Department, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Golestan, Iran
| | - Borhan Rahimi Abkenar
- Clinical Biochemistry Department, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Najafi
- Clinical Biochemistry Department, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran.,Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
| |
Collapse
|
29
|
Dennis M, Howpage S, McGill M, Dutta S, Koay Y, Lal LN, Lal S, Wu T, Ugander M, Wang A, Munoz PA, Wong J, Constantino MI, O'Sullivan J, Twigg SM, Puranik R. Myocardial fibrosis in type 2 diabetes is associated with functional and metabolomic parameters. Int J Cardiol 2022; 363:179-184. [PMID: 35724800 DOI: 10.1016/j.ijcard.2022.06.049] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 05/30/2022] [Accepted: 06/15/2022] [Indexed: 12/28/2022]
Affiliation(s)
- Mark Dennis
- Sydney Medical School, University of Sydney, Sydney, Australia; Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia; Department of Aged Care, LifeHouse Hospital, Sydney, Australia.
| | - Sashie Howpage
- Sydney Medical School, University of Sydney, Sydney, Australia; Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, Australia
| | - Margaret McGill
- Sydney Medical School, University of Sydney, Sydney, Australia; Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, Australia
| | | | - Yen Koay
- Heart Research Institute, Sydney, Australia
| | - Lisa Nguyen Lal
- Sydney Medical School, University of Sydney, Sydney, Australia
| | - Sean Lal
- Sydney Medical School, University of Sydney, Sydney, Australia; Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia
| | - Ted Wu
- Sydney Medical School, University of Sydney, Sydney, Australia; Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, Australia
| | - Martin Ugander
- Sydney Medical School, University of Sydney, Sydney, Australia; Kolling Institute, Royal North Shore Hospital, and Charles Perkins Centre, University of Sydney, Sydney, Australia; Department of Clinical Physiology, Karolinska University Hospital, and Karolinska Institutet, Stockholm, Sweden
| | - Alexandra Wang
- Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia; University of New South, Wales
| | - Phillip A Munoz
- Department of Respiratory Medicine, Royal Prince Alfred Hospital, Sydney, Australia
| | - Jencia Wong
- Sydney Medical School, University of Sydney, Sydney, Australia; Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, Australia
| | - Maria I Constantino
- Sydney Medical School, University of Sydney, Sydney, Australia; Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, Australia
| | - John O'Sullivan
- Sydney Medical School, University of Sydney, Sydney, Australia; Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia; Heart Research Institute, Sydney, Australia
| | - Stephen M Twigg
- Sydney Medical School, University of Sydney, Sydney, Australia; Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, Australia
| | - Rajesh Puranik
- Sydney Medical School, University of Sydney, Sydney, Australia; Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia
| |
Collapse
|
30
|
Triglyceride-glucose index associates with incident heart failure: a cohort study. DIABETES & METABOLISM 2022; 48:101365. [PMID: 35660526 DOI: 10.1016/j.diabet.2022.101365] [Citation(s) in RCA: 53] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 05/11/2022] [Accepted: 05/19/2022] [Indexed: 11/22/2022]
Abstract
AIMS Triglyceride-glucose (TyG) index has been proposed as a simple surrogate marker of insulin resistance. However, few studies have investigated the association of TyG index with heart failure (HF). We aimed to explore the relationship between TyG index and incident HF. METHODS A total of 138,620 participants from the Kailuan study were included for analysis. TyG index was calculated as ln [fasting triglyceride (mg/dL) × fasting glucose (mg/dL) / 2]. Cox proportional hazard models were used to investigate the association between TyG index and the risk of HF. Restricted cubic spline analysis was applied to evaluate the dose-response relationship between TyG index and the risk of HF. RESULTS There were 1602 incident HF cases among the 138,620 participants during a median follow-up of 8.78 years. Compared with those in the lowest quartile group of TyG index, participants with the highest quartile of TyG index had a 24% higher risk of HF (HR=1.24, 95%CI=1.07-1.44) after adjusting for other risk factors. Restricted cubic spline analysis showed a significant J-shaped dose-response relationship between TyG index and risk of HF (P for non-linearity < 0.001). The significant association was still observed among the men and participants with or without abdominal obesity in subgroup analyses. CONCLUSION The TyG index was positively associated with the risk of HF, which indicates that the TyG index might be useful to identify people at high-risk for developing HF.
Collapse
|
31
|
Gostomska-Pampuch K, Gamian A, Rawicz-Pruszyński K, Gęca K, Tkaczuk-Włach J, Jonik I, Ożga K, Staniszewska M. Proteins in human body fluids contain in vivo antigen analog of the melibiose-derived glycation product: MAGE. Sci Rep 2022; 12:7520. [PMID: 35525899 PMCID: PMC9079080 DOI: 10.1038/s41598-022-11638-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 04/27/2022] [Indexed: 01/16/2023] Open
Abstract
Melibiose-derived AGE (MAGE) is an advanced glycation end-product formed in vitro in anhydrous conditions on proteins and protein-free amino acids during glycation with melibiose. Our previous studies revealed the presence of MAGE antigen in the human body and tissues of several other species, including muscles, fat, extracellular matrix, and blood. MAGE is also antigenic and induces generation of anti-MAGE antibody. The aim of this paper was to identify the proteins modified by MAGE present in human body fluids, such as serum, plasma, and peritoneal fluids. The protein-bound MAGE formed in vivo has been isolated from human blood using affinity chromatography on the resin with an immobilized anti-MAGE monoclonal antibody. Using mass spectrometry and immunochemistry it has been established that MAGE epitope is present on several human blood proteins including serum albumin, IgG, and IgA. In serum of diabetic patients, mainly the albumin and IgG were modified by MAGE, while in healthy subjects IgG and IgA carried this modification, suggesting the novel AGE can impact protein structure, contribute to auto-immunogenicity, and affect function of immunoglobulins. Some proteins in peritoneal fluid from cancer patients modified with MAGE were also observed and it indicates a potential role of MAGE in cancer.
Collapse
Affiliation(s)
- Kinga Gostomska-Pampuch
- Department of Biochemistry and Immunochemistry, Wroclaw Medical University, Chalubinskiego 10, 50-368, Wrocław, Poland
- Laboratory of Medical Microbiology, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigla 12, 53-114, Wrocław, Poland
| | - Andrzej Gamian
- Laboratory of Medical Microbiology, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigla 12, 53-114, Wrocław, Poland
| | - Karol Rawicz-Pruszyński
- Department of Surgical Oncology, Medical University of Lublin, Radziwillowska 13, 20-080, Lublin, Poland
| | - Katarzyna Gęca
- Department of Surgical Oncology, Medical University of Lublin, Radziwillowska 13, 20-080, Lublin, Poland
| | - Joanna Tkaczuk-Włach
- Diagnostic Techniques Unit, Collegium Maximum, Medical University of Lublin, Staszica 4/6, 20-081, Lublin, Poland
| | - Ilona Jonik
- Faculty of Science and Health, The John Paul II Catholic University of Lublin, Konstantynów 1J, 20-708, Lublin, Poland
| | - Kinga Ożga
- Faculty of Science and Health, The John Paul II Catholic University of Lublin, Konstantynów 1J, 20-708, Lublin, Poland
| | - Magdalena Staniszewska
- Faculty of Science and Health, The John Paul II Catholic University of Lublin, Konstantynów 1J, 20-708, Lublin, Poland.
| |
Collapse
|
32
|
Qiu Y, Buffonge S, Ramnath R, Jenner S, Fawaz S, Arkill KP, Neal C, Verkade P, White SJ, Hezzell M, Salmon AHJ, Suleiman MS, Welsh GI, Foster RR, Madeddu P, Satchell SC. Endothelial glycocalyx is damaged in diabetic cardiomyopathy: angiopoietin 1 restores glycocalyx and improves diastolic function in mice. Diabetologia 2022; 65:879-894. [PMID: 35211778 PMCID: PMC8960650 DOI: 10.1007/s00125-022-05650-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Accepted: 10/28/2021] [Indexed: 12/28/2022]
Abstract
AIMS/HYPOTHESIS Diabetic cardiomyopathy (DCM) is a serious and under-recognised complication of diabetes. The first sign is diastolic dysfunction, which progresses to heart failure. The pathophysiology of DCM is incompletely understood but microcirculatory changes are important. Endothelial glycocalyx (eGlx) plays multiple vital roles in the microcirculation, including in the regulation of vascular permeability, and is compromised in diabetes but has not previously been studied in the coronary microcirculation in diabetes. We hypothesised that eGlx damage in the coronary microcirculation contributes to increased microvascular permeability and hence to cardiac dysfunction. METHODS We investigated eGlx damage and cardiomyopathy in mouse models of type 1 (streptozotocin-induced) and type 2 (db/db) diabetes. Cardiac dysfunction was determined by echocardiography. We obtained eGlx depth and coverage by transmission electron microscopy (TEM) on mouse hearts perfusion-fixed with glutaraldehyde and Alcian Blue. Perivascular oedema was assessed from TEM images by measuring the perivascular space area. Lectin-based fluorescence was developed to study eGlx in paraformaldehyde-fixed mouse and human tissues. The eGlx of human conditionally immortalised coronary microvascular endothelial cells (CMVECs) in culture was removed with eGlx-degrading enzymes before measurement of protein passage across the cell monolayer. The mechanism of eGlx damage in the diabetic heart was investigated by quantitative reverse transcription-PCR array and matrix metalloproteinase (MMP) activity assay. To directly demonstrate that eGlx damage disturbs cardiac function, isolated rat hearts were treated with enzymes in a Langendorff preparation. Angiopoietin 1 (Ang1) is known to restore eGlx and so was used to investigate whether eGlx restoration reverses diastolic dysfunction in mice with type 1 diabetes. RESULTS In a mouse model of type 1 diabetes, diastolic dysfunction (confirmed by echocardiography) was associated with loss of eGlx from CMVECs and the development of perivascular oedema, suggesting increased microvascular permeability. We confirmed in vitro that eGlx removal increases CMVEC monolayer permeability. We identified increased MMP activity as a potential mechanism of eGlx damage and we observed loss of syndecan 4 consistent with MMP activity. In a mouse model of type 2 diabetes we found a similar loss of eGlx preceding the development of diastolic dysfunction. We used isolated rat hearts to demonstrate that eGlx damage (induced by enzymes) is sufficient to disturb cardiac function. Ang1 restored eGlx and this was associated with reduced perivascular oedema and amelioration of the diastolic dysfunction seen in mice with type 1 diabetes. CONCLUSIONS/INTERPRETATION The association of CMVEC glycocalyx damage with diastolic dysfunction in two diabetes models suggests that it may play a pathophysiological role and the enzyme studies confirm that eGlx damage is sufficient to impair cardiac function. Ang1 rapidly restores the CMVEC glycocalyx and improves diastolic function. Our work identifies CMVEC glycocalyx damage as a potential contributor to the development of DCM and therefore as a therapeutic target.
Collapse
Affiliation(s)
- Yan Qiu
- Bristol Renal, Bristol Heart Institute, Translational Health Sciences, University of Bristol, Bristol, UK.
| | - Stanley Buffonge
- Bristol Renal, Bristol Heart Institute, Translational Health Sciences, University of Bristol, Bristol, UK
| | - Raina Ramnath
- Bristol Renal, Bristol Heart Institute, Translational Health Sciences, University of Bristol, Bristol, UK
| | - Sophie Jenner
- Bristol Renal, Bristol Heart Institute, Translational Health Sciences, University of Bristol, Bristol, UK
| | - Sarah Fawaz
- Bristol Renal, Bristol Heart Institute, Translational Health Sciences, University of Bristol, Bristol, UK
| | - Kenton P Arkill
- Biodiscovery Institute, Medicine, University of Nottingham, Nottingham, UK
| | - Chris Neal
- Bristol Renal, Bristol Heart Institute, Translational Health Sciences, University of Bristol, Bristol, UK
| | - Paul Verkade
- School of Biochemistry, University of Bristol, Bristol, UK
| | - Stephen J White
- Department of Life Sciences, Manchester Metropolitan University, Manchester, UK
| | - Melanie Hezzell
- Bristol Veterinary School, University of Bristol, Langford, UK
| | - Andrew H J Salmon
- Bristol Renal, Bristol Heart Institute, Translational Health Sciences, University of Bristol, Bristol, UK
- Renal Service, Specialist Medicine and Health of Older People, North Shore Hospital, Waitemata District Health Board, Takapuna, Auckland, New Zealand
| | - M-Saadeh Suleiman
- Bristol Heart Institute, Translational Health Sciences, University of Bristol, Bristol, UK
| | - Gavin I Welsh
- Bristol Renal, Bristol Heart Institute, Translational Health Sciences, University of Bristol, Bristol, UK
| | - Rebecca R Foster
- Bristol Renal, Bristol Heart Institute, Translational Health Sciences, University of Bristol, Bristol, UK
| | - Paolo Madeddu
- Bristol Heart Institute, Translational Health Sciences, University of Bristol, Bristol, UK
| | - Simon C Satchell
- Bristol Renal, Bristol Heart Institute, Translational Health Sciences, University of Bristol, Bristol, UK
| |
Collapse
|
33
|
Wan SH, Slusser JP, Hodge DO, Chen HH. Outcomes of Patients With Diabetes Versus Patients Without Diabetes Hospitalized With Acute Heart Failure. Am J Cardiol 2022; 165:65-71. [PMID: 34930613 DOI: 10.1016/j.amjcard.2021.11.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 10/29/2021] [Accepted: 11/02/2021] [Indexed: 11/16/2022]
Abstract
The objective is to define the clinical echocardiographic characteristics and cardiovascular outcome in patients with acute heart failure (HF) with versus without diabetes mellitus (DM). Demographic, clinical, laboratory, and echocardiographic data were collected in Olmsted County adults hospitalized for acute HF between 2005 and 2008. Analyses were performed for mortality and acute HF hospitalization outcomes stratified by diabetic status, systolic function, and diastolic function. There were 912 subjects who met inclusion criteria, and mean age was 79 (SD 13.1) years with 53% women. Prevalence of DM was 42% in the study population, and those with DM had worse diastolic function and increased mortality and HF rehospitalization. Among those with DM and acute HF, reduced left ventricular ejection fraction and worse diastolic function conferred increased HF rehospitalization (p = 0.010 and p = 0.022, respectively). In conclusion, DM is common in those hospitalized for acute HF and is associated with worse long-term clinical outcomes. The subgroup of DM with acute HF and left ventricular systolic dysfunction or diastolic dysfunction had worse HF rehospitalization outcomes.
Collapse
Affiliation(s)
- Siu-Hin Wan
- Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.
| | | | | | - Horng H Chen
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota
| |
Collapse
|
34
|
Liu Y, Miao J. An Emerging Role of Defective Copper Metabolism in Heart Disease. Nutrients 2022; 14:nu14030700. [PMID: 35277059 PMCID: PMC8838622 DOI: 10.3390/nu14030700] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Revised: 01/31/2022] [Accepted: 02/04/2022] [Indexed: 01/02/2023] Open
Abstract
Copper is an essential trace metal element that significantly affects human physiology and pathology by regulating various important biological processes, including mitochondrial oxidative phosphorylation, iron mobilization, connective tissue crosslinking, antioxidant defense, melanin synthesis, blood clotting, and neuron peptide maturation. Increasing lines of evidence obtained from studies of cell culture, animals, and human genetics have demonstrated that dysregulation of copper metabolism causes heart disease, which is the leading cause of mortality in the US. Defects of copper homeostasis caused by perturbed regulation of copper chaperones or copper transporters or by copper deficiency resulted in various types of heart disease, including cardiac hypertrophy, heart failure, ischemic heart disease, and diabetes mellitus cardiomyopathy. This review aims to provide a timely summary of the effects of defective copper homeostasis on heart disease and discuss potential underlying molecular mechanisms.
Collapse
Affiliation(s)
- Yun Liu
- Key Laboratory of Molecular Target & Clinical Pharmacology and the State & NMPA Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China;
- Division of Endocrinology, Boston Children’s Hospital, Boston, MA 02115, USA
| | - Ji Miao
- Division of Endocrinology, Boston Children’s Hospital, Boston, MA 02115, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
- Correspondence:
| |
Collapse
|
35
|
Dab H, Chehidi A, Tlili M, Ben Saad A, Khabir A, Zourgui L. Cardiac extracellular matrix modulation in a rat-diabetic model: biochemical and anti-oxidant beneficial effect of pomegranate ( Punica granatum) peel extract. Biomarkers 2021; 27:50-59. [PMID: 34766858 DOI: 10.1080/1354750x.2021.2006312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
CONTEXT Disorders associated with diabetes and the beneficial effects of pomegranate peel extract (PPE) were widely reported. However effect of diabetes and PPE on extracellular matrix (ECM) remodelling needs further investigation. OBJECTIVES The focus of this study was to investigate the involvement of diabetes in cardiac ECM and the beneficial effects of PPE. METHODS Diabetes was induced by alloxan. PPE group was injected with 100 mg/kg of PPE. The phenolic profile of PPE was analyzed by HPLC. ECM was detected by ELISA. MMP-1, -8, -13 were determined by a colorimetric assay. RESULTS Compared to control fibronectin and laminin plasma content was higher respectively by 69% and 42% (p < 0.05) in diabetes. LV content of hydroxyproline and total collagen was higher by 195% (p < 0.01) and 56% (p < 0.05) in the diabetic group compared to control and restored at a similar level to controls in the PPE group. Compared to control, collagenase activity was significantly reduced by 32% (p < 0.05) and 35% (p < 0.05) respectively in ALX and PPF groups. There is no significant difference in collagenase activities in diabetic rats after and before PPE injection. CONCLUSION Diabetes is involved in cardiac ECM remodelling which can be improved by PPE. These findings will be useful for more understanding diabetes-induced cardiac disorders.
Collapse
Affiliation(s)
- Houcine Dab
- Research Unit of "Valorization of Active Biomolecules", Higher Institute of Applied Biology of Medenine, University of Gabes, Gabes, Tunisia
| | - Amel Chehidi
- Research Unit of "Valorization of Active Biomolecules", Higher Institute of Applied Biology of Medenine, University of Gabes, Gabes, Tunisia
| | - Mounira Tlili
- Faculty of Sciences of Bizerte, Laboratory of Integrative Physiology, University of Carthage, Carthage, Tunisia
| | - Anwar Ben Saad
- Faculty of Sciences of Gafsa, Research of Macromolecular Biochemistry and Genetics, University of Gafsa, Gafsa, Tunisia
| | - Abdelmajid Khabir
- Department of Pathology, Habib Bourguiba Hospital, Medenine, Tunisia
| | - Lazhar Zourgui
- Research Unit of "Valorization of Active Biomolecules", Higher Institute of Applied Biology of Medenine, University of Gabes, Gabes, Tunisia
| |
Collapse
|
36
|
Ghio S, Mercurio V, Attanasio A, Asile G, Tocchetti CG, Paolillo S. Prognostic impact of diabetes in chronic and acute heart failure. Heart Fail Rev 2021; 28:577-583. [PMID: 34811630 DOI: 10.1007/s10741-021-10193-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/11/2021] [Indexed: 12/14/2022]
Abstract
A strong, bidirectional relationship exists between diabetes mellitus (DM) and heart failure (HF) and DM is responsible of the activation of several molecular and pathophysiological mechanisms that may, on the long term, damage the heart. However, the prognostic role of DM in the context of chronic and acute HF is still not yet defined and there are several gaps of evidence in the literature on this topic. These gaps are related to the wide phenotypic heterogeneity of patients with chronic and acute HF and to the concept that not all diabetic patients are the same, but there is the necessity to better characterize the disease and each single patient, also considering the role of other possible comorbidities. The aim of the present review is to summarize the pathophysiological mechanisms subtending the negative effect of DM in HF and analyze the available data exploring the prognostic impact of such comorbidity in both chronic and acute HF.
Collapse
Affiliation(s)
- Stefano Ghio
- Divisione Di Cardiologia, Fondazione IRCCS Policlinico S.Matteo, 27100, Pavia, Italy.
| | - Valentina Mercurio
- Dipartimento Di Scienze Mediche Traslazionali, Università Degli Studi Di Napoli Federico II, Napoli, Italy
| | - Andrea Attanasio
- Divisione Di Cardiologia, Fondazione IRCCS Policlinico S.Matteo, 27100, Pavia, Italy.,Dipartimento Di Medicina Molecolare, Università Di Pavia, Pavia, Italy
| | - Gaetano Asile
- Dipartimento Di Scienze Biomediche Avanzate, Università Degli Studi Di Napoli Federico II, Napoli, Italy
| | - Carlo Gabriele Tocchetti
- Dipartimento Di Scienze Mediche Traslazionali, Università Degli Studi Di Napoli Federico II, Napoli, Italy
| | - Stefania Paolillo
- Dipartimento Di Scienze Biomediche Avanzate, Università Degli Studi Di Napoli Federico II, Napoli, Italy.,Mediterranea Cardiocentro, Napoli, Italy
| |
Collapse
|
37
|
Valle MS, Russo C, Malaguarnera L. Protective role of vitamin D against oxidative stress in diabetic retinopathy. Diabetes Metab Res Rev 2021; 37:e3447. [PMID: 33760363 DOI: 10.1002/dmrr.3447] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Revised: 02/01/2021] [Accepted: 02/15/2021] [Indexed: 02/06/2023]
Abstract
Diabetic retinopathy (DR) is a microvascular complication of diabetes mellitus. There is much evidence showing that a high level of mitochondrial overproduction of reactive oxygen species in the diabetic retina contributes in modifying cellular signalling and leads to retinal cell damage and finally to the development of DR pathogenesis. In the last few decades, it has been reported that vitamin D is involved in DR pathogenesis. Vitamin D, traditionally known as an essential nutrient crucial in bone metabolism, has also been proven to be a very effective antioxidant. It has been demonstrated that it modulates the production of advanced glycosylated end products, as well as several pathways including protein kinase C, the polyol pathway leading to the reduction of free radical formation. It prevents the translocation of nuclear factor kappa B, preventing the inflammatory response, acting as an immunomodulator, and modulates autophagy and apoptosis. In this review, we explore the molecular mechanisms by which vitamin D protects the eye from oxidative stress, in order to evaluate whether vitamin D supplementation may be useful to mitigate the deleterious effects of free radicals in DR.
Collapse
Affiliation(s)
- Maria Stella Valle
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Cristina Russo
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Lucia Malaguarnera
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| |
Collapse
|
38
|
Triposkiadis F, Xanthopoulos A, Bargiota A, Kitai T, Katsiki N, Farmakis D, Skoularigis J, Starling RC, Iliodromitis E. Diabetes Mellitus and Heart Failure. J Clin Med 2021; 10:3682. [PMID: 34441977 PMCID: PMC8396967 DOI: 10.3390/jcm10163682] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 08/17/2021] [Accepted: 08/17/2021] [Indexed: 12/12/2022] Open
Abstract
Diabetes mellitus (DM) is a major risk factor for new-onset heart failure (HF) and vice versa. The pathogenesis of new-onset HF in DM is complex and has been largely attributed to the toxic cardiovascular effects of hyperglycemia and relevant metabolic abnormalities (diabetic cardiomyopathy) as well as the frequently coexisting morbidities such as hypertension (HTN), coronary artery disease (CAD), and diabetic nephropathy. In patients with type 1 DM (T1DM), HF develops in the setting of a dysregulated immune response, whereas in most patients with type 2 DM (T2DM), against a background of overweight/obesity. HF prevention in DM is feasible with rigorous treatment of cardiovascular risk factors and selective antidiabetic agents. Conversely, development of new-onset T2DM in HF (cardiogenic DM) is common and has been attributed to an increase in the resistance to insulin, especially in the skeletal muscle, liver, and adipose tissue as well as in diminished insulin secretory response to hyperglycemia by pancreatic β-cells. Cardiogenic DM further deteriorates cardiac dysfunction and adversely affects outcome in HF. Novel lifesaving medications employed in HF management such as sacubitril/valsartan and sodium glucose cotransporter 2 inhibitors (SGLT-2i) have a favorable metabolic profile and lower the incidence of cardiogenic diabetes. Whether mitigation of cardiogenic DM should be a treatment target in HF deserves further investigation.
Collapse
Affiliation(s)
- Filippos Triposkiadis
- Department of Cardiology, University General Hospital of Larissa, 411 10 Larissa, Greece; (A.X.); (J.S.)
| | - Andrew Xanthopoulos
- Department of Cardiology, University General Hospital of Larissa, 411 10 Larissa, Greece; (A.X.); (J.S.)
| | - Alexandra Bargiota
- Department of Endocrinology and Metabolic Diseases, University General Hospital of Larissa, 411 10 Larissa, Greece;
| | - Takeshi Kitai
- National Cerebral and Cardiovascular Center, Osaka 564-8565, Japan;
| | - Niki Katsiki
- Second Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, Hippokration Hospital, 54124 Thessaloniki, Greece;
| | - Dimitrios Farmakis
- University of Cyprus Medical School, P.O. Box 20537, Nicosia 1678, Cyprus;
| | - John Skoularigis
- Department of Cardiology, University General Hospital of Larissa, 411 10 Larissa, Greece; (A.X.); (J.S.)
| | - Randall C. Starling
- Kaufman Center for Heart Failure Treatment and Recovery, Heart, Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, OH 44195, USA;
| | - Efstathios Iliodromitis
- Second Department of Cardiology, National and Kapodistrian University of Athens, Attikon University Hospital, 12462 Athens, Greece;
| |
Collapse
|
39
|
Shahim B, Ben-Yehuda O, Chen S, Redfors B, Madhavan MV, Kar S, Lim DS, Asch FM, Weissman NJ, Cohen DJ, Arnold SV, Liu M, Lindenfeld J, Abraham WT, Mack MJ, Stone GW. Impact of Diabetes on Outcomes After Transcatheter Mitral Valve Repair in Heart Failure: COAPT Trial. JACC-HEART FAILURE 2021; 9:559-567. [PMID: 34325886 DOI: 10.1016/j.jchf.2021.03.011] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 03/10/2021] [Accepted: 03/10/2021] [Indexed: 10/20/2022]
Abstract
OBJECTIVES This paper sought to determine whether diabetes influences the outcomes of transcatheter mitral valve repair (TMVr) in patients with heart failure (HF) and secondary mitral regurgitation (SMR). BACKGROUND Diabetes is associated with worse outcomes in patients with HF. METHODS The COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With functional Mitral Regurgitation) trial randomized HF patients with 3+ or 4+ SMR to MitraClip plus guideline-directed medical therapy (GDMT) versus GDMT alone. Two-year outcomes were evaluated in patients with versus without diabetes. RESULTS Of 614 patients, 229 (37.3%) had diabetes. Diabetic patients had higher 2-year rates of death than those without diabetes (40.8% vs 32.3%, respectively; adjusted P = 0.04) and tended to have higher rates of HF hospitalization (HFH) (HFH: 50.1% vs 43.0%, respectively; adjusted P = 0.07). TMVr reduced the 2-year rate of death consistently in patients with (30.3% vs 49.9%, respectively; adjusted HR: 0.51; 95% CI: 0.32 to 0.81) and without (27.0% vs 38.3%, respectively; adjusted HR: 0.57; 95% CI: 0.39-0.84) diabetes (Pinteraction = 0.72). TMVr also consistently reduced the 2-year rates of HFH in patients with (32.2% vs 54.8%, respectively; adjusted HR: 0.41; 95% CI: 0.28-0.58) and without (41.5% vs 59.0%, respectively; adjusted HR: 0.54: 95% CI 0.35-0.82) diabetes (Pinteraction = 0.33). Greater movements in quality-of-life (QOL) and exercise capacity occurred with TMVr than with GDMT alone, regardless of diabetic status. CONCLUSIONS Among HF patients with severe SMR in the COAPT trial, those with diabetes had a worse prognosis. Nonetheless, diabetic and nondiabetic patients had consistent reductions in the 2-year rates of death and HFH and improvements in QOL and functional capacity following TMVr treatment using the MitraClip than with maintenance on GDMT alone. (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation [COAPT]; NCT01626079).
Collapse
Affiliation(s)
- Bahira Shahim
- Clinical Trials Center, Cardiovascular Research Foundation, New York, New York, USA
| | - Ori Ben-Yehuda
- Clinical Trials Center, Cardiovascular Research Foundation, New York, New York, USA; NewYork-Presbyterian Hospital/Columbia University Irving Medical Center, New York, New York, USA; Division of Cardiology, University of California San Diego, San Diego, California, USA
| | - Shmuel Chen
- Clinical Trials Center, Cardiovascular Research Foundation, New York, New York, USA; NewYork-Presbyterian Hospital/Columbia University Irving Medical Center, New York, New York, USA
| | - Björn Redfors
- Clinical Trials Center, Cardiovascular Research Foundation, New York, New York, USA; NewYork-Presbyterian Hospital/Columbia University Irving Medical Center, New York, New York, USA; Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Mahesh V Madhavan
- Clinical Trials Center, Cardiovascular Research Foundation, New York, New York, USA; NewYork-Presbyterian Hospital/Columbia University Irving Medical Center, New York, New York, USA
| | - Saibal Kar
- Los Robles Regional Medical Center, Thousand Oaks, California, USA; Bakersfield Heart Hospital, Bakersfield, California, USA
| | - D Scott Lim
- Division of Cardiology, University of Virginia, Charlottesville, Virginia, USA
| | - Federico M Asch
- MedStar Health Research Institute, Washington, DC, USA; Georgetown University, Washington, DC, USA
| | - Neil J Weissman
- MedStar Health Research Institute, Washington, DC, USA; Georgetown University, Washington, DC, USA
| | - David J Cohen
- Clinical Trials Center, Cardiovascular Research Foundation, New York, New York, USA; St. Francis Hospital, Roslyn, New York, USA
| | - Suzanne V Arnold
- University of Missouri-Kansas City School of Medicine, Kansas City, Missouri, USA; Saint Luke's Mid America Heart Institute, Kansas City, Missouri, USA
| | - Mengdan Liu
- Clinical Trials Center, Cardiovascular Research Foundation, New York, New York, USA
| | - JoAnn Lindenfeld
- Advanced Heart Failure and Cardiac Transplantation Section, Vanderbilt Heart and Vascular Institute, Nashville, Tennessee, USA
| | - William T Abraham
- Division of Cardiovascular Medicine, the Ohio State University, Columbus, Ohio, USA
| | | | - Gregg W Stone
- Clinical Trials Center, Cardiovascular Research Foundation, New York, New York, USA; The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
| |
Collapse
|
40
|
Jiao X, Guo H, Zhang G, Yin X, Li H, Chen Y. In-hospital fasting hyperglycemia and increased risk of mortality after acute coronary syndrome: a systematic overview and meta-analysis. Int J Diabetes Dev Ctries 2021. [DOI: 10.1007/s13410-020-00850-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
|
41
|
Bowman PRT, Smith GL, Gould GW. Run for your life: can exercise be used to effectively target GLUT4 in diabetic cardiac disease? PeerJ 2021; 9:e11485. [PMID: 34113491 PMCID: PMC8162245 DOI: 10.7717/peerj.11485] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Accepted: 04/27/2021] [Indexed: 12/25/2022] Open
Abstract
The global incidence, associated mortality rates and economic burden of diabetes are now such that it is considered one of the most pressing worldwide public health challenges. Considerable research is now devoted to better understanding the mechanisms underlying the onset and progression of this disease, with an ultimate aim of improving the array of available preventive and therapeutic interventions. One area of particular unmet clinical need is the significantly elevated rate of cardiomyopathy in diabetic patients, which in part contributes to cardiovascular disease being the primary cause of premature death in this population. This review will first consider the role of metabolism and more specifically the insulin sensitive glucose transporter GLUT4 in diabetic cardiac disease, before addressing how we may use exercise to intervene in order to beneficially impact key functional clinical outcomes.
Collapse
Affiliation(s)
- Peter R T Bowman
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom
| | - Godfrey L Smith
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Gwyn W Gould
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom
| |
Collapse
|
42
|
Narumanchi S, Wang H, Perttunen S, Tikkanen I, Lakkisto P, Paavola J. Zebrafish Heart Failure Models. Front Cell Dev Biol 2021; 9:662583. [PMID: 34095129 PMCID: PMC8173159 DOI: 10.3389/fcell.2021.662583] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 04/06/2021] [Indexed: 01/02/2023] Open
Abstract
Heart failure causes significant morbidity and mortality worldwide. The understanding of heart failure pathomechanisms and options for treatment remain incomplete. Zebrafish has proven useful for modeling human heart diseases due to similarity of zebrafish and mammalian hearts, fast easily tractable development, and readily available genetic methods. Embryonic cardiac development is rapid and cardiac function is easy to observe and quantify. Reverse genetics, by using morpholinos and CRISPR-Cas9 to modulate gene function, make zebrafish a primary animal model for in vivo studies of candidate genes. Zebrafish are able to effectively regenerate their hearts following injury. However, less attention has been given to using zebrafish models to increase understanding of heart failure and cardiac remodeling, including cardiac hypertrophy and hyperplasia. Here we discuss using zebrafish to study heart failure and cardiac remodeling, and review zebrafish genetic, drug-induced and other heart failure models, discussing the advantages and weaknesses of using zebrafish to model human heart disease. Using zebrafish models will lead to insights on the pathomechanisms of heart failure, with the aim to ultimately provide novel therapies for the prevention and treatment of heart failure.
Collapse
Affiliation(s)
- Suneeta Narumanchi
- Unit of Cardiovascular Research, Minerva Foundation Institute for Medical Research, Biomedicum Helsinki, Helsinki, Finland
| | - Hong Wang
- Unit of Cardiovascular Research, Minerva Foundation Institute for Medical Research, Biomedicum Helsinki, Helsinki, Finland
| | - Sanni Perttunen
- Unit of Cardiovascular Research, Minerva Foundation Institute for Medical Research, Biomedicum Helsinki, Helsinki, Finland
| | - Ilkka Tikkanen
- Unit of Cardiovascular Research, Minerva Foundation Institute for Medical Research, Biomedicum Helsinki, Helsinki, Finland.,Abdominal Center Nephrology, University of Helsinki, Helsinki University Hospital, Helsinki, Finland
| | - Päivi Lakkisto
- Unit of Cardiovascular Research, Minerva Foundation Institute for Medical Research, Biomedicum Helsinki, Helsinki, Finland.,Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki University Hospital, Helsinki, Finland
| | - Jere Paavola
- Unit of Cardiovascular Research, Minerva Foundation Institute for Medical Research, Biomedicum Helsinki, Helsinki, Finland
| |
Collapse
|
43
|
Favaloro LE, Ratto RD, Musso C. Heart Failure And Diabetes: Perspective Of A Dangerous Association. Curr Hypertens Rev 2021; 17:85-93. [PMID: 33823781 DOI: 10.2174/1573402117666210406111927] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 02/08/2021] [Accepted: 03/01/2021] [Indexed: 11/22/2022]
Abstract
The relationship between diabetes and risk of heart failure has been described in previous trials, releasing the importance of the hyperglycemic state that added to other risk factors, favors the development of coronary heart disease. The mechanism by which in the absence of hypertension, obesity and/or dyslipidemia, diabetic patients develop cardiomyopathyhas been less studied. Recently, the Sodium Glucose Co-transporter type 2 inhibitors (SGLT2 inhibitors) used for the treatment of heart failure patients with or without diabetes has been a breakthrough in the field of medicine. This review describes the established pathophysiology of diabetic cardiomyopathy and SGLT2 inhibitors, their mechanisms of action, and benefits in this group of patients.
Collapse
Affiliation(s)
- Liliana Ehtel Favaloro
- Heart Failure Department, Hospital Universitario Fundación Favaloro, Buenos Aires. Argentina
| | - Roxana Daniela Ratto
- Heart Failure Department, Hospital Universitario Fundación Favaloro, Buenos Aires. Argentina
| | - Carla Musso
- Diabetes Metabolic Department, Hospital Universitario Fundación Favaloro, Buenos Aires. Argentina
| |
Collapse
|
44
|
Wikstrom J, Liu Y, Whatling C, Gan LM, Konings P, Mao B, Zhang C, Ji Y, Xiao YF, Wang Y. Diastolic dysfunction and impaired cardiac output reserve in dysmetabolic nonhuman primate with proteinuria. J Diabetes Complications 2021; 35:107881. [PMID: 33612386 DOI: 10.1016/j.jdiacomp.2021.107881] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Revised: 01/23/2021] [Accepted: 01/23/2021] [Indexed: 11/16/2022]
Abstract
BACKGROUND Cardiorenal complications are common in patients with dysmetabolism and diabetes. The present study aimed to examine if a nonhuman primate (NHP) model with spontaneously developed metabolic disorder and diabetes develops similar complications to humans, such as proteinuria and cardiac dysfunction at resting condition or diminished cardiac functional reserve following dobutamine stress echocardiography (DSE). METHODS AND RESULTS A total of 66 dysmetabolic and diabetic cynomolgus (Macaca fascicularis) NHPs were enrolled to select 19 NHPs (MetS) with marked metabolic disorders and diabetes (fasting blood glucose: 178 ± 18 vs. 61 ± 3 mg/dL) accompanied by proteinuria (ACR: 134 ± 34 vs. 1.5 ± 0.4 mg/mmol) compared to 8 normal NHPs (CTRL). Under resting condition, MetS NHPs showed mild left ventricular (LV) diastolic dysfunction (E/A: 1 ± 0.06 vs. 1.5 ± 0.13), but with preserved ejection fraction (EF: 65 ± 2 vs. 71 ± 3%) compared to CTRL. DSE with an intravenous infusion of dobutamine at ascending doses (5, 10, 20, 30 and 40 μg/kg/min, 7 min for each dose) resulted in a dose-dependent increase in cardiac function, however, with a significantly diminished magnitude at the highest dose of dobutamine infusion (40 μg/kg/min) in both diastole (E/A: -12 ± 3 vs. -38 ± 5%) and systole (EF: 25 ± 3 vs. 33 ± 5%) as well as ~42% reduced cardiac output reserve (COR: 63 ± 8 vs. 105 ± 18%, p < 0.02) in the MetS compared to CTRL NHPs. CONCLUSION These data demonstrate that MetS NHPs with cardiorenal complications: proteinuria, LV diastolic dysfunction and preserved LV systolic function under resting conditions displayed compromised cardiac functional reserve under dobutamine stress. Based on these phenotypes, this NHP model of diabetes with cardiorenal complications can be used as a highly translational model mimic human disease for pharmaceutical research.
Collapse
Affiliation(s)
- Johannes Wikstrom
- Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
| | - Yongqiang Liu
- Crown Bioscience Inc., 6 West Beijing Road, Taicang, Jiangsu, China
| | - Carl Whatling
- Translational Science and Experimental Medicine, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Li-Ming Gan
- Early Clinical Development, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Peter Konings
- Quantitative Biology, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden
| | - Binchen Mao
- Crown Bioscience Inc., 6 West Beijing Road, Taicang, Jiangsu, China
| | - Chao Zhang
- Crown Bioscience Inc., 6 West Beijing Road, Taicang, Jiangsu, China
| | - Yanqin Ji
- Crown Bioscience Inc., 6 West Beijing Road, Taicang, Jiangsu, China
| | - Yong-Fu Xiao
- Crown Bioscience Inc., 6 West Beijing Road, Taicang, Jiangsu, China
| | - Yixin Wang
- Crown Bioscience Inc., 6 West Beijing Road, Taicang, Jiangsu, China.
| |
Collapse
|
45
|
Karwi QG, Ho KL, Pherwani S, Ketema EB, Sun QY, Lopaschuk GD. Concurrent diabetes and heart failure: interplay and novel therapeutic approaches. Cardiovasc Res 2021; 118:686-715. [PMID: 33783483 DOI: 10.1093/cvr/cvab120] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 03/29/2021] [Indexed: 12/12/2022] Open
Abstract
Diabetes mellitus increases the risk of developing heart failure, and the co-existence of both diseases worsens cardiovascular outcomes, hospitalization and the progression of heart failure. Despite current advancements on therapeutic strategies to manage hyperglycemia, the likelihood of developing diabetes-induced heart failure is still significant, especially with the accelerating global prevalence of diabetes and an ageing population. This raises the likelihood of other contributing mechanisms beyond hyperglycemia in predisposing diabetic patients to cardiovascular disease risk. There has been considerable interest in understanding the alterations in cardiac structure and function in the diabetic patients, collectively termed as "diabetic cardiomyopathy". However, the factors that contribute to the development of diabetic cardiomyopathies is not fully understood. This review summarizes the main characteristics of diabetic cardiomyopathies, and the basic mechanisms that contribute to its occurrence. This includes perturbations in insulin resistance, fuel preference, reactive oxygen species generation, inflammation, cell death pathways, neurohormonal mechanisms, advanced glycated end-products accumulation, lipotoxicity, glucotoxicity, and posttranslational modifications in the heart of the diabetic. This review also discusses the impact of antihyperglycemic therapies on the development of heart failure, as well as how current heart failure therapies influence glycemic control in diabetic patients. We also highlight the current knowledge gaps in understanding how diabetes induces heart failure.
Collapse
Affiliation(s)
- Qutuba G Karwi
- Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada
| | - Kim L Ho
- Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada
| | - Simran Pherwani
- Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada
| | - Ezra B Ketema
- Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada
| | - Qiu Yu Sun
- Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada
| | - Gary D Lopaschuk
- Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada
| |
Collapse
|
46
|
Forskolin Protected against Streptozotocin-Induced Diabetic Cardiomyopathy via Inhibition of Oxidative Stress and Cardiac Fibrosis in Mice. BIOMED RESEARCH INTERNATIONAL 2021; 2021:8881843. [PMID: 33564685 PMCID: PMC7867442 DOI: 10.1155/2021/8881843] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 01/11/2021] [Accepted: 01/21/2021] [Indexed: 12/22/2022]
Abstract
Background Diabetic cardiomyopathy is one of the cardiac complications in diabetes patients, eventually resulting in heart failure and increasing morbidity and mortality. Oxidative stress is a critical pathological feature in diabetic hearts, contributing to the development of DCM. Forskolin (FSK) was shown to reduce oxidative stress. This study was aimed at investigating the effects of FSK on diabetic hearts and the relevant molecular mechanisms. Methods Streptozotocin- (STZ-) induced diabetes in mice was treated with FSK through intraperitoneal injection. Cardiac functions were evaluated by echocardiography. Hematoxylin-eosin and Masson trichrome staining was employed to determine heart morphological changes and cardiac fibrosis, respectively. Cardiac fibrosis-related markers were detected by western blot. Superoxide dismutase activity, reduced/oxidized glutathione ratio, and malondialdehyde concentration in left ventricles were determined using respective commercial kits. Results Abnormal cardiac diastolic dysfunction and cardiac fibrosis were observed in diabetic hearts. FSK treatment significantly improved the cardiac diastolic function and attenuated the abnormal morphological change in diabetic hearts. Moreover, FSK treatment in diabetic mice decreased the expression of fibronectin, collagen I, TGF-β, and α-SMA and reduced myocardial fibrosis. Furthermore, we observed that FSK significantly blocked oxidative stress in diabetic hearts. Conclusions Our study demonstrates that FSK protects against the development of DCM in STZ-induced diabetes in mice. Our study suggests that FSK might be a potential target for drug development in treating DCM.
Collapse
|
47
|
Kashiwagi A, Araki S, Maegawa H. Sodium-glucose cotransporter 2 inhibitors represent a paradigm shift in the prevention of heart failure in type 2 diabetes patients. J Diabetes Investig 2021; 12:6-20. [PMID: 32563214 PMCID: PMC7779279 DOI: 10.1111/jdi.13329] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 06/12/2020] [Accepted: 06/16/2020] [Indexed: 02/06/2023] Open
Abstract
Recent major clinical trials of the use of sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with type 2 diabetes have shown that they reduce three-point major adverse cardiovascular events, cardiovascular death, hospitalization for heart failure (HF) and a composite renal outcome. These beneficial effects of SGLT2 inhibitors are also evident in type 2 diabetes patients with a previous history of atherosclerotic cardiovascular disease or advanced renal disease. HF is a major determinant of the prognosis of diabetes patients. Although HF with low ejection fraction can be effectively treated with antihypertensive drugs, these treatments do not reduce mortality in HF patients with preserved ejection fraction (HFpEF). HFpEF is clinically characterized by left ventricular diastolic dysfunction, perivascular fibrosis and stiffness of cardiomyocytes, defined as "cardiomyopathy". Therefore, HFpEF is considered to be an entirely separate entity to HF with low ejection fraction. Recent studies have suggested that HFpEF might be treatable using SGLT2 inhibitors, which ameliorate visceral adiposity, insulin resistance, hyperglycemia, hyperlipidemia, volume overload, hypertension and cardiac inflammation. In the final part of the present review, we discuss the biochemical and molecular mechanisms of the effects of SGLT2 inhibitors in type 2 diabetes patients with HFpEF. These involve amelioration of the low nitric oxide production and oxidative stress, a reduction in cardiac inflammatory cytokine signaling, inhibition of Ca2+ overload, and an improvement in cardiac energy metabolism as a result of ketone body production. Investigations of the beneficial effects of SGLT2 inhibitors on cardiorenal outcomes, including hospitalization for HF, are now being carried out in preclinical and clinical studies.
Collapse
Affiliation(s)
| | - Shinchi Araki
- Department of MedicineShiga University of Medical ScienceOtsuJapan
| | - Hiroshi Maegawa
- Department of MedicineShiga University of Medical ScienceOtsuJapan
| |
Collapse
|
48
|
Overvad M, Diaz LJ, Bjerregaard P, Pedersen ML, Larsen CVL, Senftleber N, Grarup N, Hansen T, Jørgensen ME. The effect of diabetes and the common diabetogenic TBC1D4 p.Arg684Ter variant on cardiovascular risk in Inuit in Greenland. Sci Rep 2020; 10:22081. [PMID: 33328529 PMCID: PMC7745023 DOI: 10.1038/s41598-020-79132-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Accepted: 11/30/2020] [Indexed: 02/07/2023] Open
Abstract
Cardiovascular disease (CVD) is a well-known complication of diabetes, but the association has not been studied among Inuit in Greenland. The aim was to examine the association between diabetes and incident CVD among Inuit in Greenland and determine if the common diabetogenic TBC1D4 variant confers increased risk of CVD. We followed an initial study population of 4127 adults in Greenland who had participated in at least one population-based health survey, in national registers. We used Poisson regression to calculate incidence rate ratios (IRR) of cardiovascular endpoints, comparing participants with and without diabetes and comparing homozygous TBC1D4 carriers with heterozygous carriers and non-carriers combined. Close to 10% had diabetes and age range was 18-96 years (45% male). Of the 3924 participants without prior CVD, 362 (~ 9%) had CVD events during a median follow-up of 10 years. Multivariate IRR for the effect of diabetes on CVD was 1.12 (95% CI: 0.80, 1.57) p = 0.50. Using a recessive genetic model, we compared homozygous TBC1D4 carriers with wildtype and heterozygous carriers combined, with a multivariate IRR of 1.20 (95% CI: 0.69, 2.11) p = 0.52. Neither diabetes nor the TBC1D4 variant significantly increased CVD risk among Inuit in Greenland in adjusted models.
Collapse
Affiliation(s)
- Maria Overvad
- Steno Diabetes Center Copenhagen, Gentofte, Denmark.
| | | | - Peter Bjerregaard
- National Institute of Public Health, University of Southern Denmark, Odense, Denmark
| | - Michael Lynge Pedersen
- Greenland Center for Health Research, University of Greenland, Nuuk, Greenland
- Queen Ingrid Primary Health Care Center, Nuuk, Greenland
| | - Christina Viskum Lytken Larsen
- National Institute of Public Health, University of Southern Denmark, Odense, Denmark
- Greenland Center for Health Research, University of Greenland, Nuuk, Greenland
| | - Ninna Senftleber
- Steno Diabetes Center Copenhagen, Gentofte, Denmark
- The Bioinformatics Centre, Department of Biology, University of Copenhagen, Copenhagen, Denmark
| | - Niels Grarup
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Torben Hansen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Marit Eika Jørgensen
- National Institute of Public Health, University of Southern Denmark, Odense, Denmark
- Steno Diabetes Center Copenhagen, Gentofte, Denmark
- Greenland Center for Health Research, University of Greenland, Nuuk, Greenland
| |
Collapse
|
49
|
Pan X, Xu S, Li J, Tong N. The Effects of DPP-4 Inhibitors, GLP-1RAs, and SGLT-2/1 Inhibitors on Heart Failure Outcomes in Diabetic Patients With and Without Heart Failure History: Insights From CVOTs and Drug Mechanism. Front Endocrinol (Lausanne) 2020; 11:599355. [PMID: 33335511 PMCID: PMC7736403 DOI: 10.3389/fendo.2020.599355] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 10/28/2020] [Indexed: 02/05/2023] Open
Abstract
Patients with type 2 diabetes (T2D) have a higher risk of heart failure (HF) than healthy people, and the prognosis of patients with diabetes and current or previous HF is worse than that of patients with only diabetes. We reviewed the HF outcomes in recently published cardiovascular outcome trials (CVOTs) of three new classes of anti-diabetic agents, namely, dipeptidyl peptidase-4 inhibitors (DPP-4is), glucagon-like-peptide 1 receptor agonists (GLP-1RAs), and sodium glucose cotransporter-2 inhibitors (SGLT-2is) or SGLT-2 and SGLT-1 dual inhibitors and divided the patients into two groups based on the history of HF (with or without) and analyzed their risks of HHF based on the receipt of the aforementioned anti-diabetes drug types. Since the follow-up period differed among the trials, we expressed the rate of HHF as events/1,000 person-years to describe the HF outcome. At last we pooled the data and analyzed their different effects and mechanisms on heart failure outcomes. Although DPP-4is did not increase the risk of HHF in T2D patients with a history of HF, they were associated with a significantly higher risk of HHF among patients without history of HF. Some GLP-1RAs reduced the risk of macrovascular events, but none of these drugs reduced the risk of HHF in patients with T2D irrespective of their HF history. It was not clarified whether SGLT-1/2is can improve the prognosis of macrovascular events in patients with T2D, but these drugs reduced the risk of HHF regardless of patients' histories of HF. This information may be useful or referential for the "precise" selection of hyperglycemic medications. Further researches still needed to clarify the mechanisms of these anti-diabetic medications.
Collapse
Affiliation(s)
| | | | | | - Nanwei Tong
- Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu, China
| |
Collapse
|
50
|
Li H, Fan J, Chen C, Wang DW. Subcellular microRNAs in diabetic cardiomyopathy. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:1602. [PMID: 33437801 PMCID: PMC7791206 DOI: 10.21037/atm-20-2205] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Cardiovascular complications are the leading causes of diabetes-related morbidity and mortality. The high incidence and poor prognosis of heart failure in diabetic patients have been associated, in part, to the presence of an underlying cardiomyopathy characterized by cardiac hypertrophy, cardiomyocytes apoptosis, and fibrosis. It has been unclear about the mechanism that connects diabetes mellitus to the development of cardiovascular dysfunction. Micro(mi)RNAs represent a class of small, 18- to 28-nucleotide-long, non-coding RNA molecules. MiRNAs typically suppress gene expression at the post-transcriptional levels by binding directly to the 3'-UTR of the target mRNAs in the cytoplasm. Interestingly, recent studies suggest that miRNAs may also regulate gene expression in a positive manner. Our recent studies have shown that subcellular miRNAs, such as cytosol-, mitochondria- and nucleus-localized miRNAs, were dramatically dysregulated in diabetic cardiomyopathy. Specifically, cytoplasm localized miRNAs regulate genes expression in a post-transcriptional manner. Nuclear localized miRNAs regulate gene transcription or chromosomal reconstruction through the non-canonical mechanism. Mitochondrial miRNAs stimulate, rather than repress, the translation of specific mitochondrial genome-encoded transcripts. By reviewing these latest discovered functions of subcellular miRNAs in diabetic animal models, we identified new mechanistic insights for diabetic cardiomyopathy. Understanding the nature of subcellular miRNAs will provide new therapeutic targets against diabetes-associated cardiac complications in the near future.
Collapse
Affiliation(s)
- Huaping Li
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China
| | - Jiahui Fan
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China
| | - Chen Chen
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China
| | - Dao Wen Wang
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China
| |
Collapse
|