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Akhtar MS, Alavudeen SS, Raza A, Imam MT, Almalki ZS, Tabassum F, Iqbal MJ. Current understanding of structural and molecular changes in diabetic cardiomyopathy. Life Sci 2023; 332:122087. [PMID: 37714373 DOI: 10.1016/j.lfs.2023.122087] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Revised: 09/11/2023] [Accepted: 09/12/2023] [Indexed: 09/17/2023]
Abstract
Diabetic Mellitus has been characterized as the most prevalent disease throughout the globe associated with the serious morbidity and mortality of vital organs. Cardiomyopathy is the major leading complication of diabetes and within this, myocardial dysfunction or failure is the leading cause of the emergency hospital admission. The review is aimed to comprehend the perspectives associated with diabetes-induced cardiovascular complications. The data was collected from several electronic databases such as Google Scholar, Science Direct, ACS publication, PubMed, Springer, etc. using the keywords such as diabetes and its associated complication, the prevalence of diabetes, the anatomical and physiological mechanism of diabetes-induced cardiomyopathy, the molecular mechanism of diabetes-induced cardiomyopathy, oxidative stress, and inflammatory stress, etc. The collected scientific data was screened by different experts based on the inclusion and exclusion criteria of the study. This review findings revealed that diabetes is associated with inefficient substrate utilization, inability to increase glucose metabolism and advanced glycation end products within the diabetic heart resulting in mitochondrial uncoupling, glucotoxicity, lipotoxicity, and initially subclinical cardiac dysfunction and finally in overt heart failure. Furthermore, several factors such as hypertension, overexpression of renin angiotensin system, hypertrophic obesity, etc. have been seen as majorly associated with cardiomyopathy. The molecular examination showed biochemical disability and generation of the varieties of free radicals and inflammatory cytokines and becomes are the substantial causes of cardiomyopathy. This review provides a better understanding of the involved pathophysiology and offers an open platform for discussing and targeting therapy in alleviating diabetes-induced early heart failure or cardiomyopathy.
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Affiliation(s)
- Md Sayeed Akhtar
- Department of Clinical Pharmacy, College of Pharmacy, King Khalid University, Al-Fara, Abha 62223, Saudi Arabia.
| | - Sirajudeen S Alavudeen
- Department of Clinical Pharmacy, College of Pharmacy, King Khalid University, Al-Fara, Abha 62223, Saudi Arabia
| | - Asif Raza
- Department of Pharmacology, Penn State Cancer Institute, CH72, Penn State College of Medicine, Penn State Milton S. Hershey Medical Center, 500 University Drive, Hershey, PA 17033, USA
| | - Mohammad Tarique Imam
- Department of Clinical Pharmacy, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 16273, Saudi Arabia
| | - Ziad Saeed Almalki
- Department of Clinical Pharmacy, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 16273, Saudi Arabia
| | - Fauzia Tabassum
- Department of Pharmacology, College of Dentistry and Pharmacy, Buraydah Private College, Al Qassim 51418, Saudi Arabia; Department of Pharmacology, Vision College, Ishbilia, Riyadh 13226-3830, Saudi Arabia
| | - Mir Javid Iqbal
- Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA
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Bahadoran Z, Mirmiran P, Kashfi K, Ghasemi A. Vascular nitric oxide resistance in type 2 diabetes. Cell Death Dis 2023; 14:410. [PMID: 37433795 PMCID: PMC10336063 DOI: 10.1038/s41419-023-05935-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 06/18/2023] [Accepted: 06/28/2023] [Indexed: 07/13/2023]
Abstract
Vascular nitric oxide (NO•) resistance, manifested by an impaired vasodilator function of NO• in both the macro- and microvessels, is a common state in type 2 diabetes (T2D) associated with developing cardiovascular events and death. Here, we summarize experimental and human evidence of vascular NO• resistance in T2D and discuss its underlying mechanisms. Human studies indicate a ~ 13-94% decrease in the endothelium (ET)-dependent vascular smooth muscle (VSM) relaxation and a 6-42% reduced response to NO• donors, i.e., sodium nitroprusside (SNP) and glyceryl trinitrate (GTN), in patients with T2D. A decreased vascular NO• production, NO• inactivation, and impaired responsiveness of VSM to NO• [occurred due to quenching NO• activity, desensitization of its receptor soluble guanylate cyclase (sGC), and/or impairment of its downstream pathway, cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG)] are the known mechanisms underlying the vascular NO• resistance in T2D. Hyperglycemia-induced overproduction of reactive oxygen species (ROS) and vascular insulin resistance are key players in this state. Therefore, upregulating vascular NO• availability, re-sensitizing or bypassing the non-responsive pathways to NO•, and targeting key vascular sources of ROS production may be clinically relevant pharmacological approaches to circumvent T2D-induced vascular NO• resistance.
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Affiliation(s)
- Zahra Bahadoran
- Nutrition and Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Parvin Mirmiran
- Department of Clinical Nutrition, Faculty of Nutrition Sciences and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Khosrow Kashfi
- Department of Molecular, Cellular, and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, NY, 10031, USA
| | - Asghar Ghasemi
- Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Macvanin MT, Gluvic Z, Radovanovic J, Essack M, Gao X, Isenovic ER. Diabetic cardiomyopathy: The role of microRNAs and long non-coding RNAs. Front Endocrinol (Lausanne) 2023; 14:1124613. [PMID: 36950696 PMCID: PMC10025540 DOI: 10.3389/fendo.2023.1124613] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 02/16/2023] [Indexed: 03/08/2023] Open
Abstract
Diabetes mellitus (DM) is on the rise, necessitating the development of novel therapeutic and preventive strategies to mitigate the disease's debilitating effects. Diabetic cardiomyopathy (DCMP) is among the leading causes of morbidity and mortality in diabetic patients globally. DCMP manifests as cardiomyocyte hypertrophy, apoptosis, and myocardial interstitial fibrosis before progressing to heart failure. Evidence suggests that non-coding RNAs, such as long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), regulate diabetic cardiomyopathy-related processes such as insulin resistance, cardiomyocyte apoptosis and inflammation, emphasizing their heart-protective effects. This paper reviewed the literature data from animal and human studies on the non-trivial roles of miRNAs and lncRNAs in the context of DCMP in diabetes and demonstrated their future potential in DCMP treatment in diabetic patients.
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Affiliation(s)
- Mirjana T. Macvanin
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Zoran Gluvic
- University Clinical-Hospital Centre Zemun-Belgrade, Clinic of Internal Medicine, Department of Endocrinology and Diabetes, School of Medicine, University of Belgrade, Belgrade, Serbia
| | - Jelena Radovanovic
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Magbubah Essack
- King Abdullah University of Science and Technology (KAUST), Computer, Electrical, and Mathematical Sciences and Engineering (CEMSE) Division, Computational Bioscience Research Center (CBRC), Thuwal, Saudi Arabia
| | - Xin Gao
- King Abdullah University of Science and Technology (KAUST), Computer, Electrical, and Mathematical Sciences and Engineering (CEMSE) Division, Computational Bioscience Research Center (CBRC), Thuwal, Saudi Arabia
| | - Esma R. Isenovic
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
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Shah A, Isath A, Aronow WS. Cardiovascular complications of diabetes. Expert Rev Endocrinol Metab 2022; 17:383-388. [PMID: 35831991 DOI: 10.1080/17446651.2022.2099838] [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: 03/01/2022] [Accepted: 07/06/2022] [Indexed: 10/17/2022]
Abstract
INTRODUCTION Type 2 diabetes mellitus (T2DM) is the ninth leading cause of mortality globally, and the prevalence continues to rise. Among individuals with T2DM, over two-thirds of deaths are caused by the cardiovascular complications of diabetes. These complications include atherosclerosis, coronary artery disease, nephropathy, stroke, thromboembolism, peripheral vascular disease. They have been long studied, and there are several theories as to the pathophysiology of how diabetes leads to these complications. The least understood mechanism is the pathophysiology linking diabetes to heart failure. AREAS COVERED This review focuses on the mechanisms of how T2DM leads to the aforementioned complications, particularly highlighting the development of heart failure. An extensive literature review of novel therapeutic options targeting the cardiovascular effects of T2DM was completed and summarized in this review. EXPERT OPINION This review finds that most studies to date have focused on the atherosclerotic vascular complications of diabetes. The pathophysiology between T2DM and heart failure is even less understood. Currently therapies that aim to decrease the risk of heart failure in diabetes are sparse. More research is required in order to better understand the changes at a cellular level and subsequently help providers to choose therapeutics that better target cardiovascular complications.
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Affiliation(s)
- Avisha Shah
- Department of Medicine, Westchester Medical Center Health Network, NY, USA
| | - Ameesh Isath
- Department of Medicine, Westchester Medical Center Health Network, NY, USA
| | - Wilbert S Aronow
- Department of Medicine, Westchester Medical Center Health Network, NY, USA
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Dugbartey GJ, Wonje QL, Alornyo KK, Robertson L, Adams I, Boima V, Mensah SD. Combination Therapy of Alpha-Lipoic Acid, Gliclazide and Ramipril Protects Against Development of Diabetic Cardiomyopathy via Inhibition of TGF-β/Smad Pathway. Front Pharmacol 2022; 13:850542. [PMID: 35401218 PMCID: PMC8988231 DOI: 10.3389/fphar.2022.850542] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 02/21/2022] [Indexed: 12/17/2022] Open
Abstract
Background: Diabetic cardiomyopathy (DCM) is a major long-term complication of diabetes mellitus, accounting for over 20% of annual mortality rate of diabetic patients globally. Although several existing anti-diabetic drugs have improved glycemic status in diabetic patients, prevalence of DCM is still high. This study investigates cardiac effect of alpha-lipoic acid (ALA) supplementation of anti-diabetic therapy in experimental DCM. Methods: Following 12 h of overnight fasting, 44 male Sprague Dawley rats were randomly assigned to two groups of healthy control (n = 7) and diabetic (n = 37) groups, and fasting blood glucose was measured. Type 2 diabetes mellitus (T2DM) was induced in diabetic group by intraperitoneal (i.p.) administration of nicotinamide (110 mg/kg) and streptozotocin (55 mg/kg). After confirmation of T2DM on day 3, diabetic rats received monotherapies with ALA (60 mg/kg; n = 7), gliclazide (15 mg/kg; n = 7), ramipril (10 mg/kg; n = 7) or combination of the three drugs (n = 7) for 6 weeks while untreated diabetic rats received distilled water and were used as diabetic control (n = 9). Rats were then sacrificed, and blood, pancreas and heart tissues were harvested for analyses using standard methods. Results: T2DM induction caused pancreatic islet destruction, hyperglycemia, weight loss, high relative heart weight, and development of DCM, which was characterized by myocardial degeneration and vacuolation, cardiac fibrosis, elevated cardiac damage markers (plasma and cardiac creatine kinase-myocardial band, brain natriuretic peptide and cardiac troponin I). Triple combination therapy of ALA, gliclazide and ramipril preserved islet structure, maintained body weight and blood glucose level, and prevented DCM development compared to diabetic control (p < 0.001). In addition, the combination therapy markedly reduced plasma levels of inflammatory markers (IL-1β, IL-6 and TNF-α), plasma and cardiac tissue malondialdehyde, triglycerides and total cholesterol while significantly increasing cardiac glutathione and superoxide dismutase activity and high-density lipoprotein-cholesterol compared to diabetic control (p < 0.001). Mechanistically, induction of T2DM upregulated cardiac expression of TGF-β1, phosphorylated Smad2 and Smad3 proteins, which were downregulated following triple combination therapy (p < 0.001). Conclusion: Triple combination therapy of ALA, gliclazide and ramipril prevented DCM development by inhibiting TGF-β1/Smad pathway. Our findings can be extrapolated to the human heart, which would provide effective additional pharmacological therapy against DCM in T2DM patients.
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Affiliation(s)
- George J Dugbartey
- Department of Pharmacology and Toxicology, School of Pharmacy, College of Health Sciences, University of Ghana, Accra, Ghana
| | - Quinsker L Wonje
- Department of Pharmacology and Toxicology, School of Pharmacy, College of Health Sciences, University of Ghana, Accra, Ghana
| | - Karl K Alornyo
- Department of Pharmacology and Toxicology, School of Pharmacy, College of Health Sciences, University of Ghana, Accra, Ghana
| | - Louis Robertson
- Department of Pharmacology and Toxicology, School of Pharmacy, College of Health Sciences, University of Ghana, Accra, Ghana
| | - Ismaila Adams
- Department of Pharmacology and Toxicology, School of Pharmacy, College of Health Sciences, University of Ghana, Accra, Ghana
| | - Vincent Boima
- Department of Medicine and Therapeutics, University of Ghana Medical School, College of Health Sciences, University of Ghana, Accra, Ghana
| | - Samuel D Mensah
- Department of Pharmacology and Toxicology, School of Pharmacy, College of Health Sciences, University of Ghana, Accra, Ghana
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Li S, Dong S, Xu Q, Shi B, Li L, Zhang W, Zhu J, Cheng Y, Zhang G, Zhong M. Sleeve Gastrectomy-Induced AMPK Activation Attenuates Diabetic Cardiomyopathy by Maintaining Mitochondrial Homeostasis via NR4A1 Suppression in Rats. Front Physiol 2022; 13:837798. [PMID: 35360240 PMCID: PMC8961133 DOI: 10.3389/fphys.2022.837798] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 02/17/2022] [Indexed: 11/13/2022] Open
Abstract
Diabetic cardiomyopathy (DCM) is characterized by impaired diastolic and systolic myocardial performance and is a major cause of morbidity and mortality in patients with diabetes. Surgical bariatric procedures, such as sleeve gastrectomy (SG), result in remission of type 2 diabetes (T2DM) and have benefits with myocardial function. Maintaining cardiac mitochondrial homeostasis is a promising therapeutic strategy for DCM. However, whether SG surgery affects mitochondrial function and its underlying mechanism remains unclear. This study aimed to investigate the effect of SG surgery on mitochondrial homeostasis and intracellular oxidative stress in rats with DCM. We also examined cellular phenotypes and molecular mechanisms in high glucose and high fat-stimulated myocytes. The rat model of DCM was established by high-fat diet feeding and low-dose streptozotocin injection. We observed a remarkably metabolic benefit of SG, including a reduced body weight, food intake, blood glucose levels, and restored glucose tolerance and insulin sensitivity post-operatively. Also, SG ameliorated the pathological cardiac hypertrophy, myocardial fibrosis and the dysfunction of myocardial contraction and diastole, consequently delayed the progression of DCM. Also, SG restored the mitochondrial dysfunction and fragmentation through the AMPK signaling activation mediated nuclear receptor subfamily 4 group A member 1 (NR4A1)/DRP1 suppression in vivo. H9c2 cardiomyocytes showed that activation of AMPK could reverse the mitochondrial dysfunction somehow. Collectively, our study provided evidence that SG surgery could alleviate mitochondrial dysfunction in DCM. Moreover, AMPK-activated NR4A1/DRP1 repression might act as a significant reason for maintaining mitochondrial homeostasis in the myocardium, thus contributing to morphological and functional alleviation of DCM.
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Affiliation(s)
- Songhan Li
- Department of General Surgery, Shandong Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Shuohui Dong
- Department of General Surgery, Shandong Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Qian Xu
- Department of General Surgery, Shandong Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Bowen Shi
- Department of General Surgery, Shandong Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Linchuan Li
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
| | - Wenjie Zhang
- Department of General Surgery, Shandong Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Jiankang Zhu
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
| | - Yugang Cheng
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
| | - Guangyong Zhang
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
| | - Mingwei Zhong
- Department of General Surgery, Shandong Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- *Correspondence: Mingwei Zhong,
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Jankauskas SS, Kansakar U, Varzideh F, Wilson S, Mone P, Lombardi A, Gambardella J, Santulli G. Heart failure in diabetes. Metabolism 2021; 125:154910. [PMID: 34627874 PMCID: PMC8941799 DOI: 10.1016/j.metabol.2021.154910] [Citation(s) in RCA: 108] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 10/02/2021] [Accepted: 10/04/2021] [Indexed: 12/16/2022]
Abstract
Heart failure and cardiovascular disorders represent the leading cause of death in diabetic patients. Here we present a systematic review of the main mechanisms underlying the development of diabetic cardiomyopathy. We also provide an excursus on the relative contribution of cardiomyocytes, fibroblasts, endothelial and smooth muscle cells to the pathophysiology of heart failure in diabetes. After having described the preclinical tools currently available to dissect the mechanisms of this complex disease, we conclude with a section on the most recent updates of the literature on clinical management.
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Affiliation(s)
- Stanislovas S Jankauskas
- Department of Medicine, Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein-Mount Sinai Diabetes Research Center (ES-DRC), Albert Einstein College of Medicine, New York, NY 10461, USA; Department of Molecular Pharmacology, Einstein Institute for Neuroimmunology and Inflammation, Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, NY 10461, USA
| | - Urna Kansakar
- Department of Medicine, Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein-Mount Sinai Diabetes Research Center (ES-DRC), Albert Einstein College of Medicine, New York, NY 10461, USA; Department of Molecular Pharmacology, Einstein Institute for Neuroimmunology and Inflammation, Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, NY 10461, USA
| | - Fahimeh Varzideh
- Department of Medicine, Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein-Mount Sinai Diabetes Research Center (ES-DRC), Albert Einstein College of Medicine, New York, NY 10461, USA; Department of Molecular Pharmacology, Einstein Institute for Neuroimmunology and Inflammation, Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, NY 10461, USA
| | - Scott Wilson
- Department of Medicine, Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein-Mount Sinai Diabetes Research Center (ES-DRC), Albert Einstein College of Medicine, New York, NY 10461, USA
| | - Pasquale Mone
- Department of Medicine, Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein-Mount Sinai Diabetes Research Center (ES-DRC), Albert Einstein College of Medicine, New York, NY 10461, USA
| | - Angela Lombardi
- Department of Medicine, Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein-Mount Sinai Diabetes Research Center (ES-DRC), Albert Einstein College of Medicine, New York, NY 10461, USA
| | - Jessica Gambardella
- Department of Medicine, Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein-Mount Sinai Diabetes Research Center (ES-DRC), Albert Einstein College of Medicine, New York, NY 10461, USA; Department of Molecular Pharmacology, Einstein Institute for Neuroimmunology and Inflammation, Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, NY 10461, USA; International Translational Research and Medical Education (ITME), Department of Advanced Biomedical Science, "Federico II" University, 80131 Naples, Italy
| | - Gaetano Santulli
- Department of Medicine, Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein-Mount Sinai Diabetes Research Center (ES-DRC), Albert Einstein College of Medicine, New York, NY 10461, USA; Department of Molecular Pharmacology, Einstein Institute for Neuroimmunology and Inflammation, Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, NY 10461, USA; International Translational Research and Medical Education (ITME), Department of Advanced Biomedical Science, "Federico II" University, 80131 Naples, Italy.
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Kurtul BE, Kurtul A, Yalçın F. Predictive value of the SYNTAX score for diabetic retinopathy in stable coronary artery disease patients with a concomitant type 2 diabetes mellitus. Diabetes Res Clin Pract 2021; 177:108875. [PMID: 34058301 DOI: 10.1016/j.diabres.2021.108875] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 03/13/2021] [Accepted: 05/26/2021] [Indexed: 11/15/2022]
Abstract
AIMS Diabetic retinopathy (DR) is a serious complication of type 2 diabetes mellitus (T2DM) and is the most common cause of impaired vision for adults. DR is related to a number of risk factors. The aim of this study was to investigate the relationship between burden of coronary artery disease assessed by Syntax Score (SS) and DR in T2DM. METHODS A total of 96 T2DM patients undergoing coronary angiography were prospectively included in the study. Presence and severity of DR were assessed by ocular fundus examination. DR was graded as no apparent retinopathy (NDR), non-proliferative (NPDR), and proliferative DR (PDR). The SS for each patient was calculated. RESULTS The mean age was 58.0 ± 8.2 years. SS gradually increased from NDR group to PDR group. The median (IQR) value of SS was 10 (5-16) in patients with NDR, 22.8 (17-35.8) in those with NPDR, and 35.5 (28-37) in those with PDR (p < 0.001). On multivariate analysis SS [odds ratio (OR) 1.145, p = 0.001] and duration of diabetes (OR 1.753, p = 0.031) were independent factors for DR. CONCLUSIONS The SS is independently associated with the occurrence of DR in T2DM. Ophthalmologists and cardiologists must cooperate when evaluating patients with DM because of possible complications.
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Affiliation(s)
- Bengi Ece Kurtul
- Hatay Mustafa Kemal University, Tayfur Ata Sökmen Faculty of Medicine, Department of Ophthalmology, Hatay, Turkey.
| | - Alparslan Kurtul
- Hatay Mustafa Kemal University, Tayfur Ata Sökmen Faculty of Medicine, Department of Cardiology, Hatay, Turkey
| | - Fatih Yalçın
- Hatay Mustafa Kemal University, Tayfur Ata Sökmen Faculty of Medicine, Department of Cardiology, Hatay, Turkey
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Prediabetes Induced by Fructose-Enriched Diet Influences Cardiac Lipidome and Proteome and Leads to Deterioration of Cardiac Function prior to the Development of Excessive Oxidative Stress and Cell Damage. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:3218275. [PMID: 31885782 PMCID: PMC6925817 DOI: 10.1155/2019/3218275] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Revised: 10/03/2019] [Accepted: 10/16/2019] [Indexed: 02/06/2023]
Abstract
Prediabetes is a condition affecting more than 35% of the population. In some forms, excessive carbohydrate intake (primarily refined sugar) plays a prominent role. Prediabetes is a symptomless, mostly unrecognized disease which increases cardiovascular risk. In our work, we examined the effect of a fructose-enriched diet on cardiac function and lipidome as well as proteome of cardiac muscle. Male Wistar rats were divided into two groups. The control group received a normal diet while the fructose-fed group received 60% fructose-supplemented chow for 24 weeks. Fasting blood glucose measurement and oral glucose tolerance test (OGTT) showed slightly but significantly elevated values due to fructose feeding indicating development of a prediabetic condition. Both echocardiography and isolated working heart perfusion performed at the end of the feeding protocol demonstrated diastolic cardiac dysfunction in the fructose-fed group. Mass spectrometry-based, high-performance lipidomic and proteomic analyses were executed from cardiac tissue. The lipidomic analysis revealed complex rearrangement of the whole lipidome with special emphasis on defects in cardiolipin remodeling. The proteomic analysis showed significant changes in 75 cardiac proteins due to fructose feeding including mitochondria-, apoptosis-, and oxidative stress-related proteins. Nevertheless, just very weak or no signs of apoptosis induction and oxidative stress were detected in the hearts of fructose-fed rats. Our results suggest that fructose feeding induces marked alterations in the cardiac lipidome, especially in cardiolipin remodeling, which leads to mitochondrial dysfunction and impaired cardiac function. However, at the same time, several adaptive responses are induced at the proteome level in order to maintain a homeostatic balance. These findings demonstrate that even very early stages of prediabetes can impair cardiac function and can result in significant changes in the lipidome and proteome of the heart prior to the development of excessive oxidative stress and cell damage.
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10
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Zhou JB, Zhu XR, Zhao W, Yin L, Li HB, Qi L, Yang JK. Prediction of Proliferative Diabetic Retinopathy to Asymptomatic Obstructive Coronary Artery Disease in Chinese Type 2 Diabetes Individuals: An Exploratory Study. Metab Syndr Relat Disord 2019; 17:367-373. [PMID: 31145036 PMCID: PMC6708263 DOI: 10.1089/met.2018.0140] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Background: Patients with type 2 diabetes are prone to the asymptomatic obstructive coronary artery disease (AO-CAD). The association of proliferative diabetic retinopathy (PDR) with AO-CAD is unknown. The aim of the study is to explore the specific relationship of PDR with AO-CAD. Methods: We performed coronary angiography and retinal photographs in 1332 participants with unknown CAD status in a retrospective discovery set and 252 patients with non-CAD enrolled in a prospective validation cohort. Main outcome measures are prediction of PDR to AO-CAD. Results: In the case–control retrospective discovery set, investigation included 211 nondiabetic retinopathy (NDR) and 140 PDR. Individuals with PDR had a 2.16 times higher risk of AO-CAD compared with individuals without diabetic retinopathy (P < 0.01). Relative risk between individuals with PDR and the risk of AO-CAD varied by different adjusted covariates, 2.53 (1.48–4.32) by age and gender; 2.16 (1.10–4.31) by additionally other covariates. In the prospective validation set, after adjustment for covariates, the cumulative risk of AO-CAD was significantly higher in the PDR group compared with NDR group, followed up for a median of 4.3 years (hazard ratio = 3.07, 95% confidence interval 1.81–5.21, P < 0.001). Conclusions: PDR showed superior identification performance over traditional risk factors in screening for AO-CAD. PDR may predict persons at high risk of AO-CAD.
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Affiliation(s)
- Jian-Bo Zhou
- Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, China.,Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane University, New Orleans, Louisiana
| | - Xiao-Rong Zhu
- Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Wei Zhao
- Department of Geriatrics, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Lu Yin
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hong-Bing Li
- Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Lu Qi
- Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane University, New Orleans, Louisiana
| | - Jin-Kui Yang
- Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Diabetes Research and Care, Beijing, China
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Gulsin GS, Brady EM, Swarbrick DJ, Athithan L, Henson J, Baldry E, McAdam J, Marsh AM, Parke KS, Wormleighton JV, Levelt E, Yates T, Bodicoat D, Khunti K, Davies MJ, McCann GP. Rationale, design and study protocol of the randomised controlled trial: Diabetes Interventional Assessment of Slimming or Training tO Lessen Inconspicuous Cardiovascular Dysfunction (the DIASTOLIC study). BMJ Open 2019; 9:e023207. [PMID: 30928925 PMCID: PMC6475184 DOI: 10.1136/bmjopen-2018-023207] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
INTRODUCTION Despite their young age and relatively short duration of disease, younger adults with type 2 diabetes (T2D) already have diastolic dysfunction and may be at risk of incipient heart failure. Whether weight loss or exercise training improve cardiac dysfunction in people with T2D remains to be established. METHODS AND ANALYSIS Prospective, randomised, open-label, blind endpoint trial. The primary aim of the study is to determine if diastolic function can be improved by either a meal replacement plan or a supervised exercise programme, compared with guideline-directed care. A total of 90 obese participants with T2D (aged 18-65 years), diabetes duration <12 years and not on insulin treatment will be randomised to either guideline-directed clinical care with lifestyle coaching, a low-energy meal replacement diet (average ≈810 kcal/day) or a supervised exercise programme for 12 weeks. Participants undergo glycometabolic profiling, cardiopulmonary exercise testing, echocardiography and MRI scanning to assesses cardiac structure and function and dual-energy X-ray absorptiometry scanning for body composition. Key secondary aims are to assess the effects of the interventions on glycaemic control and insulin resistance, exercise capacity, blood pressure, changes in body composition and association of favourable cardiac remodelling with improvements in weight loss, exercise capacity and glycometabolic control. ETHICS AND DISSEMINATION The study has full ethical approval, and data collection was completed in August 2018. The study results will be submitted for publication within 6 months of completion. TRIAL REGISTRATION NUMBER NCT02590822; Pre-results.
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Affiliation(s)
- Gaurav Singh Gulsin
- Department of Cardiovascular Sciences, University of Leicester and the Leicester NIHR Biomedical Research Centre, Glenfield Hospital, Leicester, UK
| | - Emer M Brady
- Diabetes Research Centre, University of Leicester and the Leicester NIHR Biomedical Research Centre, Leicester General Hospital, Leicester, UK
| | - Daniel J Swarbrick
- Department of Cardiovascular Sciences, University of Leicester and the Leicester NIHR Biomedical Research Centre, Glenfield Hospital, Leicester, UK
| | - Lavanya Athithan
- Department of Cardiovascular Sciences, University of Leicester and the Leicester NIHR Biomedical Research Centre, Glenfield Hospital, Leicester, UK
| | - Joseph Henson
- National College of Sport and Exercise Medicine, University of Loughborough, Loughborough, UK
| | - Emma Baldry
- Diabetes Research Centre, University of Leicester and the Leicester NIHR Biomedical Research Centre, Leicester General Hospital, Leicester, UK
| | - John McAdam
- Department of Cardiovascular Sciences, University of Leicester and the Leicester NIHR Biomedical Research Centre, Glenfield Hospital, Leicester, UK
| | - Anna-Marie Marsh
- Department of Cardiovascular Sciences, University of Leicester and the Leicester NIHR Biomedical Research Centre, Glenfield Hospital, Leicester, UK
| | - Kelly S Parke
- Department of Cardiovascular Sciences, University of Leicester and the Leicester NIHR Biomedical Research Centre, Glenfield Hospital, Leicester, UK
| | - Joanne V Wormleighton
- Department of Cardiovascular Sciences, University of Leicester and the Leicester NIHR Biomedical Research Centre, Glenfield Hospital, Leicester, UK
| | - Eylem Levelt
- University of Leeds, Multidisciplinary Cardiovascular Research Centre and Biomedical Imaging Science Department, Leeds Institute of Cardiovascular and Metabolic Medicine, Leeds, UK
| | - Thomas Yates
- Diabetes Research Centre, University of Leicester and the Leicester NIHR Biomedical Research Centre, Leicester General Hospital, Leicester, UK
- National College of Sport and Exercise Medicine, University of Loughborough, Loughborough, UK
| | - Danielle Bodicoat
- Diabetes Research Centre, University of Leicester and the Leicester NIHR Biomedical Research Centre, Leicester General Hospital, Leicester, UK
| | - Kamlesh Khunti
- Diabetes Research Centre, University of Leicester and the Leicester NIHR Biomedical Research Centre, Leicester General Hospital, Leicester, UK
| | - Melanie J Davies
- Diabetes Research Centre, University of Leicester and the Leicester NIHR Biomedical Research Centre, Leicester General Hospital, Leicester, UK
| | - Gerry P McCann
- Department of Cardiovascular Sciences, University of Leicester and the Leicester NIHR Biomedical Research Centre, Glenfield Hospital, Leicester, UK
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12
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Gulsin GS, Athithan L, McCann GP. Diabetic cardiomyopathy: prevalence, determinants and potential treatments. Ther Adv Endocrinol Metab 2019; 10:2042018819834869. [PMID: 30944723 PMCID: PMC6437329 DOI: 10.1177/2042018819834869] [Citation(s) in RCA: 72] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Accepted: 02/08/2019] [Indexed: 12/18/2022] Open
Abstract
The prevalence of type 2 diabetes (T2D) has reached a pandemic scale. These patients are at a substantially elevated risk of developing cardiovascular disease, with heart failure (HF) being a leading cause of morbidity and mortality. Even in the absence of traditional risk factors, diabetes still confers up to a twofold increased risk of developing HF. This has led to identifying diabetes as an independent risk factor for HF and recognition of the distinct clinical entity, diabetic cardiomyopathy. Despite a wealth of research interest, the prevalence and determinants of diabetic cardiomyopathy remain uncertain. This limited understanding of the pathophysiology of diabetic heart disease has also hindered development of effective treatments. Tight blood-glucose and blood-pressure control have not convincingly been shown to reduce macrovascular outcomes in T2D. There is, however, emerging evidence that T2D is reversible and that the metabolic abnormalities can be reversed with weight loss. Increased aerobic exercise capacity is associated with significantly lower cardiovascular and overall mortality in diabetes. Whether such lifestyle modifications as weight loss and exercise may ameliorate the structural and functional derangements of the diabetic heart has yet to be established. In this review, the link between T2D and myocardial dysfunction is explored. Insights into the structural and functional perturbations that typify the diabetic heart are first described. This is followed by an examination of the pathophysiological mechanisms that contribute to the development of cardiovascular disease in T2D. Lastly, the current and emerging therapeutic strategies to prevent or ameliorate cardiac dysfunction in T2D are evaluated.
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Affiliation(s)
- Gaurav S. Gulsin
- Department of Cardiovascular Sciences, University of Leicester and the Leicester NIHR Biomedical Research Centre, Leicester, UK
| | - Lavanya Athithan
- Department of Cardiovascular Sciences, University of Leicester and the Leicester NIHR Biomedical Research Centre, Leicester, UK
| | - Gerry P. McCann
- Department of Cardiovascular Sciences, University of Leicester and the Leicester NIHR Biomedical Research Centre, Glenfield Hospital, Groby Road, Leicester LE3 9QP, UK
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13
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Murtaza G, Virk HUH, Khalid M, Lavie CJ, Ventura H, Mukherjee D, Ramu V, Bhogal S, Kumar G, Shanmugasundaram M, Paul TK. Diabetic cardiomyopathy - A comprehensive updated review. Prog Cardiovasc Dis 2019; 62:315-326. [PMID: 30922976 DOI: 10.1016/j.pcad.2019.03.003] [Citation(s) in RCA: 204] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Accepted: 03/21/2019] [Indexed: 01/04/2023]
Abstract
Diabetes causes cardiomyopathy and increases the risk of heart failure independent of hypertension and coronary heart disease. This condition called "Diabetic Cardiomyopathy" (DCM) is becoming a well- known clinical entity. Recently, there has been substantial research exploring its molecular mechanisms, structural and functional changes, and possible development of therapeutic approaches for the prevention and treatment of DCM. This review summarizes the recent advancements to better understand fundamental molecular abnormalities that promote this cardiomyopathy and novel therapies for future research. Additionally, different diagnostic modalities, up to date screening tests to guide clinicians with early diagnosis and available current treatment options has been outlined.
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Affiliation(s)
- Ghulam Murtaza
- Department of Internal Medicine, Division of Cardiology, East Tennessee State University, Johnson City, TN, USA
| | | | - Muhammad Khalid
- Department of Internal Medicine, Division of Cardiology, East Tennessee State University, Johnson City, TN, USA
| | - Carl J Lavie
- Department of Cardiology, Ochsner Clinic, New Orleans, LA, USA
| | - Hector Ventura
- Department of Cardiology, Ochsner Clinic, New Orleans, LA, USA
| | - Debabrata Mukherjee
- Division of Cardiology, Department of Internal Medicine, Texas Tech University, TX, USA
| | - Vijay Ramu
- Department of Internal Medicine, Division of Cardiology, East Tennessee State University, Johnson City, TN, USA
| | - Sukhdeep Bhogal
- Department of Internal Medicine, Division of Cardiology, East Tennessee State University, Johnson City, TN, USA
| | - Gautam Kumar
- Emory University School of Medicine, Atlanta VA Medical Center, Atlanta, GA, USA
| | | | - Timir K Paul
- Department of Internal Medicine, Division of Cardiology, East Tennessee State University, Johnson City, TN, USA.
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14
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Faconti L, Mills CE, Govoni V, Gu H, Morant S, Jiang B, Cruickshank JK, Webb AJ. Cardiac effects of 6 months' dietary nitrate and spironolactone in patients with hypertension and with/at risk of type 2 diabetes, in the factorial design, double-blind, randomized controlled VaSera trial. Br J Clin Pharmacol 2018; 85:169-180. [PMID: 30294825 DOI: 10.1111/bcp.13783] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Revised: 08/13/2018] [Accepted: 09/09/2018] [Indexed: 12/12/2022] Open
Abstract
AIMS The aims of the present study were to explore whether a long-term intervention with dietary nitrate [(NO3 - ), a potential tolerance-free source of beneficial vasoactive nitric oxide] and spironolactone (to oppose aldosterone's potential deleterious cardiovascular effects) improve cardiac structure/function, independently of blood pressure (BP), in patients with/at risk of type 2 diabetes (a population at risk of heart failure). METHODS A subsample of participants in our double-blind, randomized, factorial-design intervention (VaSera) trial of active beetroot juice as a nitrate source (≤11.2 mmol) or placebo (nitrate depleted) beetroot juice, and either ≤50 mg spironolactone or ≤16 mg doxazosin (control), had transthoracic cardiac ultrasounds at baseline (n = 105), and at 3 months and 6 months (n = 87) after the start of the intervention. Analysis was by modified intent-to-treat. RESULTS Nitrate-containing juice (n = 40) decreased left ventricular (LV) end-diastolic volume {-6.3 [95% confidence interval (CI) -11.1, -1.6] ml} and end-systolic volume [-3.2 (95% CI -5.9, -0.5) ml], and increased end-diastolic mass/volume ratio [+0.04 (95% CI 0.00, 0.07)], relative to placebo juice (n = 47). Spironolactone (n = 44) reduced relative wall thickness compared with doxazosin (n = 43) [-0.01 (95% CI -0.02, -0.00)]. Although spironolactone reduced LV mass index relative to baseline [-1.48 (95% CI -2.08, -0.88) g m-2.7 ], there was no difference vs. doxazosin [-0.85 (95% CI -1.76, 0.05) g m-2.7 ]. Spironolactone also decreased the E/A ratio [-0.12 (95% CI -0.19, -0.04)] and increased S' (a tissue-Doppler systolic function index) by 0.52 (95% CI 0.05, 1.0) cm s-1 . BP did not differ between the juices, or between the drugs. CONCLUSIONS Six months' dietary nitrate decreased LV volumes ~5%, representing new, sustained, BP-independent benefits on cardiac structure, extending mechanisms characterized in preclinical models of heart failure. Spironolactone's effects on cardiac remodelling and systolic-diastolic function, although confirmatory, were independent of BP.
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Affiliation(s)
- Luca Faconti
- Department of Clinical Pharmacology, School of Cardiovascular Medicine and Sciences, King's College London British Heart Foundation Centre, London, UK.,Department of Nutritional Sciences, School of Life Course Sciences, King's College London, London, UK.,Biomedical Research Centre, Clinical Research Facility, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Charlotte Elizabeth Mills
- Department of Nutritional Sciences, School of Life Course Sciences, King's College London, London, UK.,Biomedical Research Centre, Clinical Research Facility, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Virginia Govoni
- Department of Nutritional Sciences, School of Life Course Sciences, King's College London, London, UK.,Biomedical Research Centre, Clinical Research Facility, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Haotian Gu
- Department of Clinical Pharmacology, School of Cardiovascular Medicine and Sciences, King's College London British Heart Foundation Centre, London, UK.,Biomedical Research Centre, Clinical Research Facility, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Steven Morant
- Medicines Monitoring Unit (MEMO), University of Dundee, Dundee, UK
| | - Benju Jiang
- Department of Clinical Pharmacology, School of Cardiovascular Medicine and Sciences, King's College London British Heart Foundation Centre, London, UK.,Biomedical Research Centre, Clinical Research Facility, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - J Kennedy Cruickshank
- Department of Nutritional Sciences, School of Life Course Sciences, King's College London, London, UK.,Biomedical Research Centre, Clinical Research Facility, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Andrew James Webb
- Department of Clinical Pharmacology, School of Cardiovascular Medicine and Sciences, King's College London British Heart Foundation Centre, London, UK.,Biomedical Research Centre, Clinical Research Facility, Guy's and St Thomas' NHS Foundation Trust, London, UK
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15
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Regulation and bioactivity of the CCN family of genes and proteins in obesity and diabetes. J Cell Commun Signal 2018; 12:359-368. [PMID: 29411334 DOI: 10.1007/s12079-018-0458-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2018] [Accepted: 01/29/2018] [Indexed: 02/06/2023] Open
Abstract
Across the years the CCNs have been increasingly implicated in the development of obesity, diabetes and its complications. Evidence for this is currently derived from their dysregulation in key metabolic pathological states in humans, animal and in vitro models, and also pre-clinical effects of their bioactivities. CCN2 is the best studied in this disease process and the other CCNs are yet to be better defined. Key steps where CCNs may play a pathogenic metabolic role include: (i) obesity and insulin resistance, where CCN2 inhibits fat cell differentiation in vitro and CCN3 may induce obesity and insulin resistance; (ii) elevated blood glucose levels to diabetes mellitus onset, where CCN2 may contribute to pancreatic beta cell and islet function; and (iii) in diabetes complications, such as nephropathy, retinopathy, liver disease (NAFLD/NASH), CVD and diabetes with heart failure. In contrast, CCN1, CCN2 and possibly CCN3, may have a reparative role in wound healing in diabetes, and CCN2 in islet cell development. In terms of CCN2 regulation by a diabetes metabolic environment and related mechanisms, the author's laboratory and others have progressively shown that advanced glycation-end products, protein kinase C isoforms, saturated fatty acids, reactive oxygen species and haemodynamic factors upregulate CCN2 in relevant cell and animal systems. Recent data has suggested that CCN2, CCN3 and CCN6 may affect energy homeostasis including in regulating glycolysis and mitochondrial function. This paper will address the current data implicating CCNs in diabetes and its complications, focusing on recent aspects with translational clinical relevance and future directions.
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16
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Cai X, Zhang S, Deng D, Li H, Guan X, Fang J, Zhou Q. Myocardial perfusion at rest in uncomplicated type 2 diabetes patients without coronary artery disease evaluated by 320-multidetector computed tomography: A pilot study. Medicine (Baltimore) 2018; 97:e9762. [PMID: 29384863 PMCID: PMC5805435 DOI: 10.1097/md.0000000000009762] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Using computed tomography myocardial perfusion imaging (CTP) to investigate resting myocardial perfusion alterations in uncomplicated type 2 diabetes mellitus (T2DM) patients without obstructive coronary artery disease (CAD).A total of 34 participants with 544 myocardial segments were included prospectively: 17 uncomplicated T2DM patients with no significant coronary artery stenosis on coronary computed tomography angiography and 17 healthy controls. Myocardial perfusion was evaluated by transmural perfusion ratio (TPR). Parameters of cardiac structure and function were measured for cardiac comprehensive assessment. Analyses included descriptive statistics and group comparisons.TPR of segments 5, 7, 9, 10 to 14 were significantly reduced in T2DM group compared with controls (P < .05). When 16 myocardial segments were localized into different areas according to the wall orientations, axial levels of left ventricle and coronary artery territories, respectively, TPR of each area in T2DM group were significantly lower than those in the control group (P < .05). No significant differences were found in cardiac anatomy and function analyses between 2 groups.In uncomplicated T2DM patients without obstructive CAD, myocardial perfusion impairments were present and may develop prior to cardiac morphological and functional abnormalities, which can be early detected by CTP.
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Affiliation(s)
- Xiangyi Cai
- Medical Imaging Center, First Affiliated Hospital of Jinan University
| | - Shuihua Zhang
- Medical Imaging Center, First Affiliated Hospital of Jinan University
| | - Dabiao Deng
- Department of Radiology, Guangdong 999 Brain Hospital, Guangzhou, Guangdong, China
| | - Honglin Li
- Medical Imaging Center, First Affiliated Hospital of Jinan University
| | - Xueqing Guan
- Medical Imaging Center, First Affiliated Hospital of Jinan University
| | - Jin Fang
- Medical Imaging Center, First Affiliated Hospital of Jinan University
| | - Quan Zhou
- Medical Imaging Center, First Affiliated Hospital of Jinan University
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17
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Fujii N, Meade RD, McNeely BD, Nishiyasu T, Sigal RJ, Kenny GP. Type 2 diabetes specifically attenuates purinergic skin vasodilatation without affecting muscarinic and nicotinic skin vasodilatation and sweating. Exp Physiol 2018; 103:212-221. [DOI: 10.1113/ep086694] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Accepted: 11/28/2017] [Indexed: 01/12/2023]
Affiliation(s)
- Naoto Fujii
- Faculty of Health and Sport Sciences; University of Tsukuba; Tsukuba Japan
- Human and Environmental Physiology Research Unit; University of Ottawa; Ottawa Ontario Canada
| | - Robert D. Meade
- Human and Environmental Physiology Research Unit; University of Ottawa; Ottawa Ontario Canada
| | - Brendan D. McNeely
- Human and Environmental Physiology Research Unit; University of Ottawa; Ottawa Ontario Canada
| | - Takeshi Nishiyasu
- Faculty of Health and Sport Sciences; University of Tsukuba; Tsukuba Japan
| | - Ronald J. Sigal
- Human and Environmental Physiology Research Unit; University of Ottawa; Ottawa Ontario Canada
- Department of Medicine; Cumming School of Medicine, University of Calgary; Calgary Alberta Canada
- Clinical Epidemiology Program; Ottawa Hospital Research Institute; Ottawa Ontario Canada
| | - Glen P. Kenny
- Human and Environmental Physiology Research Unit; University of Ottawa; Ottawa Ontario Canada
- Clinical Epidemiology Program; Ottawa Hospital Research Institute; Ottawa Ontario Canada
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18
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Are targeted therapies for diabetic cardiomyopathy on the horizon? Clin Sci (Lond) 2017; 131:897-915. [PMID: 28473471 DOI: 10.1042/cs20160491] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Revised: 02/02/2017] [Accepted: 02/03/2017] [Indexed: 12/12/2022]
Abstract
Diabetes increases the risk of heart failure approximately 2.5-fold, independent of coronary artery disease and other comorbidities. This process, termed diabetic cardiomyopathy, is characterized by initial impairment of left ventricular (LV) relaxation followed by LV contractile dysfunction. Post-mortem examination reveals that human diastolic dysfunction is closely associated with LV damage, including cardiomyocyte hypertrophy, apoptosis and fibrosis, with impaired coronary microvascular perfusion. The pathophysiological mechanisms underpinning the characteristic features of diabetic cardiomyopathy remain poorly understood, although multiple factors including altered lipid metabolism, mitochondrial dysfunction, oxidative stress, endoplasmic reticulum (ER) stress, inflammation, as well as epigenetic changes, are implicated. Despite a recent rise in research interrogating these mechanisms and an increased understanding of the clinical importance of diabetic cardiomyopathy, there remains a lack of specific treatment strategies. How the chronic metabolic disturbances observed in diabetes lead to structural and functional changes remains a pertinent question, and it is hoped that recent advances, particularly in the area of epigenetics, among others, may provide some answers. This review hence explores the temporal onset of the pathological features of diabetic cardiomyopathy, and their relative contribution to the resultant disease phenotype, as well as both current and potential therapeutic options. The emergence of glucose-optimizing agents, namely glucagon-like peptide-1 (GLP-1) agonists and sodium/glucose co-transporter (SGLT)2 inhibitors that confer benefits on cardiovascular outcomes, together with novel experimental approaches, highlight a new and exciting era in diabetes research, which is likely to result in major clinical impact.
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19
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Xie J, Ikram MK, Cotch MF, Klein B, Varma R, Shaw JE, Klein R, Mitchell P, Lamoureux EL, Wong TY. Association of Diabetic Macular Edema and Proliferative Diabetic Retinopathy With Cardiovascular Disease: A Systematic Review and Meta-analysis. JAMA Ophthalmol 2017; 135:586-593. [PMID: 28472362 DOI: 10.1001/jamaophthalmol.2017.0988] [Citation(s) in RCA: 77] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Importance Previous studies on the relationship between diabetic retinopathy (DR) and cardiovascular disease (CVD) focused on the early stages of DR. Understanding whether patients with type 2 diabetes and severe stages of DR (diabetic macular edema [DME] and proliferative diabetic retinopathy [PDR]) have a higher risk of CVD will allow physicians to more effectively counsel patients. Objective To examine the association of severe stages of DR (DME and PDR) with incident CVD in patients with type 2 diabetes. Data Sources English-language publications were reviewed for articles evaluating the relationship of DR and CVD in MEDLINE, EMBASE, Current Contents, and the Cochrane Library from inception (January 1, 1950) to December 31, 2014, using the search terms diabetic retinopathy OR macular edema AND stroke OR cerebrovascular disease OR coronary artery disease OR heart failure OR myocardial infarction OR angina pectoris OR acute coronary syndrome OR coronary artery disease OR cardiomyopathy. Study Selection Among 656 studies screened for eligibility, 7604 individuals were included from 8 prospective population-based studies with data on photographic-based DR grading, follow-up visits, and well-defined incident CVD end point. Data Extraction and Synthesis Two independent reviewers conducted a systematic search of the 4 databases, and a single pooled database was developed. Incidence rate ratios (IRRs) were estimated for patients with DME, PDR, and vision-threatening DR, compared with persons without these conditions, by using individual participant data followed by a standard inverse-variance meta-analysis (2-step analysis). The review and analyses were performed from January 1, 2009, to January 1, 2017. Main Outcome and Measures Incident CVD, including coronary heart disease, stroke, or death from cardiovascular causes. Results Among 7604 patients with type 2 diabetes, the prevalence of DME was 4.6% and PDR, 7.4%. After a mean follow-up of 5.9 years (range, 3.2-10.1 years), 1203 incident CVD events, including 916 coronary heart disease cases, were reported. Persons with DME or PDR were more likely to have incident CVD (IRR, 1.39; 95% CI, 1.16-1.67) and fatal CVD (IRR, 2.33; 95% CI, 1.49-3.67) compared with those without DME or PDR. Conclusions and Relevance Patients with type 2 diabetes and DME or PDR have an increased risk of incident CVD, which suggests that these persons should be followed up more closely to prevent CVD.
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Affiliation(s)
- Jing Xie
- Centre for Eye Research Australia, University of Melbourne, East Melbourne, Victoria, Australia
| | - M Kamran Ikram
- Singapore Eye Research Institute, Singapore National Eye Centre, National University of Singapore, Singapore3Duke-NUS Medical School, National University of Singapore, Singapore
| | - Mary Frances Cotch
- Division of Epidemiology and Clinical Applications, National Eye Institute, Intramural Research Program, National Institutes of Health, Bethesda, Maryland
| | - Barbara Klein
- Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison
| | - Rohit Varma
- Department of Ophthalmology and Visual Sciences, University of Illinois College of Medicine at Chicago, Chicago
| | - Jonathan E Shaw
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | - Ronald Klein
- Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison
| | - Paul Mitchell
- Centre for Vision Research, Westmead Insitute for Medical Research and University of Sydney, Sydney, New South Wales, Australia
| | - Ecosse L Lamoureux
- Singapore Eye Research Institute, Singapore National Eye Centre, National University of Singapore, Singapore3Duke-NUS Medical School, National University of Singapore, Singapore
| | - Tien Yin Wong
- Singapore Eye Research Institute, Singapore National Eye Centre, National University of Singapore, Singapore3Duke-NUS Medical School, National University of Singapore, Singapore
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20
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Lüers C, Trippel TD, Seeländer S, Wachter R, Hasenfuss G, Lindhorst R, Bobenko A, Nolte K, Pieske B, Edelmann F. Arterial stiffness and elevated left ventricular filling pressure in patients at risk for the development or a previous diagnosis of HF—A subgroup analysis from the DIAST-CHF study. ACTA ACUST UNITED AC 2017; 11:303-313. [DOI: 10.1016/j.jash.2017.03.006] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2016] [Revised: 03/10/2017] [Accepted: 03/18/2017] [Indexed: 12/28/2022]
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21
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Khavandi K, Aghamohammadzadeh R, Luckie M, Brownrigg J, Alam U, Khattar R, Malik RA, Heagerty AM, Greenstein AS. Abnormal Remodeling of Subcutaneous Small Arteries Is Associated With Early Diastolic Impairment in Metabolic Syndrome. J Am Heart Assoc 2017; 6:JAHA.116.004603. [PMID: 28400366 PMCID: PMC5532992 DOI: 10.1161/jaha.116.004603] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Background Small artery pathophysiology is frequently invoked as a cause of obesity‐related diastolic heart failure. However, evidence to support this hypothesis is scant, particularly in humans. Methods and Results To address this, we studied human small artery structure and function in obesity and looked for correlations between vascular parameters and diastolic function. Seventeen obese patients with metabolic syndrome and 5 control participants underwent echocardiography and subcutaneous gluteal fat biopsy. Small arteries were isolated from the biopsy and pressure myography was used to study endothelial function and wall structure. In comparison with the control group, small arteries from obese participants exhibited significant endothelial dysfunction, assessed as the vasodilatory response to acetylcholine and also pathological growth of the wall. For the obese participants, multiple regression analysis revealed an association between left atrial volume and both the small artery wall thickness (β=0.718, P=0.02) and wall‐to‐lumen ratio (β=0.605, P=0.02). Furthermore, the E:E′ ratio was associated with wall‐to‐lumen ratio (β=0.596, P=0.02) and inversely associated with interleukin‐6 (β=−0.868, P=0.03). By contrast, endothelial function did not correlate with any of the echocardiographic parameters studied. Conclusions Although the small arteries studied were not cardiac in origin, our results support a role for small artery remodeling in the development of diastolic dysfunction in humans. Further direct examination of the structure and function of the myocardial resistance vasculature is now warranted, to elucidate the temporal association between metabolic risk factors, small artery injury, and diastolic impairment.
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Affiliation(s)
- Kaivan Khavandi
- Division of Cardiovascular Sciences, Manchester Academic Health Sciences Centre, University of Manchester, United Kingdom.,British Heart Foundation Centre of Excellence, The Rayne Institute, King's College London, London, United Kingdom
| | - Reza Aghamohammadzadeh
- Division of Cardiovascular Sciences, Manchester Academic Health Sciences Centre, University of Manchester, United Kingdom
| | - Matthew Luckie
- Manchester Heart Centre, Central Manchester Teaching Hospitals Foundation Trust, Manchester, United Kingdom
| | - Jack Brownrigg
- St. George's Vascular Institute, St George's, University of London, United Kingdom
| | - Uazman Alam
- Division of Cardiovascular Sciences, Manchester Academic Health Sciences Centre, University of Manchester, United Kingdom
| | - Rajdeep Khattar
- Department of Cardiology, Royal Brompton Hospital, National Heart and Lung Institute, Imperial College, London, United Kingdom
| | - Rayaz A Malik
- Department of Medicine, Weill Cornell Medical College, Doha, Qatar
| | - Anthony M Heagerty
- Division of Cardiovascular Sciences, Manchester Academic Health Sciences Centre, University of Manchester, United Kingdom
| | - Adam S Greenstein
- Division of Cardiovascular Sciences, Manchester Academic Health Sciences Centre, University of Manchester, United Kingdom
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22
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Hu X, Bai T, Xu Z, Liu Q, Zheng Y, Cai L. Pathophysiological Fundamentals of Diabetic Cardiomyopathy. Compr Physiol 2017; 7:693-711. [PMID: 28333387 DOI: 10.1002/cphy.c160021] [Citation(s) in RCA: 81] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Diabetic cardiomyopathy (DCM) was first recognized more than four decades ago and occurred independent of cardiovascular diseases or hypertension in both type 1 and type 2 diabetic patients. The exact mechanisms underlying this disease remain incompletely understood. Several pathophysiological bases responsible for DCM have been proposed, including the presence of hyperglycemia, nonenzymatic glycosylation of large molecules (e.g., proteins), energy metabolic disturbance, mitochondrial damage and dysfunction, impaired calcium handling, reactive oxygen species formation, inflammation, cardiac cell death, and cardiac hypertrophy and fibrosis, leading to impairment of cardiac contractile functions. Increasing evidence also indicates the phenomenon called "metabolic memory" for diabetes-induced cardiovascular complications, for which epigenetic modulation seemed to play an important role, suggesting that the aforementioned pathogenic bases may be regulated by epigenetic modification. Therefore, this review aims at briefly summarizing the current understanding of the pathophysiological bases for DCM. Although how epigenetic mechanisms play a role remains incompletely understood now, extensive clinical and experimental studies have implicated its importance in regulating the cardiac responses to diabetes, which are believed to shed insight into understanding of the pathophysiological and epigenetic mechanisms for the development of DCM and its possible prevention and/or therapy. © 2017 American Physiological Society. Compr Physiol 7:693-711, 2017.
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Affiliation(s)
- Xinyue Hu
- Center of Cardiovascular Diseases, the First Hospital of Jilin University, Changchun, China.,Pediatric Research Institute at the Department of Pediatrics of the University of Louisville, Louisville, Kentucky, USA
| | - Tao Bai
- Center of Cardiovascular Diseases, the First Hospital of Jilin University, Changchun, China.,Pediatric Research Institute at the Department of Pediatrics of the University of Louisville, Louisville, Kentucky, USA
| | - Zheng Xu
- Center of Cardiovascular Diseases, the First Hospital of Jilin University, Changchun, China.,Pediatric Research Institute at the Department of Pediatrics of the University of Louisville, Louisville, Kentucky, USA
| | - Qiuju Liu
- Department of Hematological Disorders the First Hospital of Jilin University, Changchun, China
| | - Yang Zheng
- Center of Cardiovascular Diseases, the First Hospital of Jilin University, Changchun, China
| | - Lu Cai
- Pediatric Research Institute at the Department of Pediatrics of the University of Louisville, Louisville, Kentucky, USA.,Wendy Novak Diabetes Care Center, University of Louisville, Louisville, Kentucky, USA
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23
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Fuchs D, Dupon PP, Schaap LA, Draijer R. The association between diabetes and dermal microvascular dysfunction non-invasively assessed by laser Doppler with local thermal hyperemia: a systematic review with meta-analysis. Cardiovasc Diabetol 2017; 16:11. [PMID: 28103890 PMCID: PMC5244618 DOI: 10.1186/s12933-016-0487-1] [Citation(s) in RCA: 70] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Accepted: 12/25/2016] [Indexed: 01/17/2023] Open
Abstract
Background/Introduction Diabetes and cardiovascular disease develop in concert with metabolic abnormalities mirroring and causing changes in the vasculature, particularly the microcirculation. The microcirculation can be affected in different parts of the body of which the skin is the most easily accessible tissue. Purpose The association between diabetes and dermal microvascular dysfunction has been investigated in observational studies. However, the strength of the association is unknown. Therefore we conducted a systematic review with meta-analysis on the association between diabetes and dermal microvascular dysfunction as assessed by laser Doppler/laser speckle contrast imaging with local thermal hyperaemia as non-invasive indicator of microvascular functionality. Methods PubMed and Ovid were systematically searched for eligible studies through March 2015. During the first selection, studies were included if they were performed in humans and were related to diabetes or glucose metabolism disorders and to dermal microcirculation. During the second step we selected studies based on the measurement technique, measurement location (arm or leg) and the inclusion of a healthy control group. A random effects model was used with the standardised mean difference as outcome measure. Calculations and imputation of data were done according to the Cochrane Handbook. Results Of the 1445 studies found in the first search, thirteen cross-sectional studies were included in the meta-analysis, comprising a total of 857 subjects. Resting blood flow was similar between healthy control subjects and diabetes patients. In contrast, the microvascular response to local skin heating was reduced in diabetic patients compared to healthy control subjects [pooled effect of −0.78 standardised mean difference (95% CI −1.06, −0.51)]. This effect is considered large according to Cohen’s effect size definition. The variability in effect size was high (heterogeneity 69%, p < 0.0001). However, subgroup analysis revealed no difference between the type and duration of diabetes and other health related factors, indicating that diabetes per se causes the microvascular dysfunction. Conclusion Our meta-analysis shows that diabetes is associated with a large reduction of dermal microvascular function in diabetic patients. The local thermal hyperaemia methodology may become a valuable non-invasive tool for diagnosis and assessing progress of diabetes-related microvascular complications, but standardisation of the technique and quality of study conduct is urgently required. Electronic supplementary material The online version of this article (doi:10.1186/s12933-016-0487-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Dagmar Fuchs
- Unilever Research and Development, Vlaardingen, Olivier van Noortlaan 120, PO Box 114, 3130 AC, Vlaardingen, The Netherlands.
| | - Pepijn P Dupon
- Unilever Research and Development, Vlaardingen, Olivier van Noortlaan 120, PO Box 114, 3130 AC, Vlaardingen, The Netherlands.,Faculty of Earth and Life Sciences, Free University Amsterdam, De Boelelaan 1085, 1081 HV, Amsterdam, The Netherlands
| | - Laura A Schaap
- Faculty of Earth and Life Sciences, Free University Amsterdam, De Boelelaan 1085, 1081 HV, Amsterdam, The Netherlands
| | - Richard Draijer
- Unilever Research and Development, Vlaardingen, Olivier van Noortlaan 120, PO Box 114, 3130 AC, Vlaardingen, The Netherlands
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24
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Koncsos G, Varga ZV, Baranyai T, Boengler K, Rohrbach S, Li L, Schlüter KD, Schreckenberg R, Radovits T, Oláh A, Mátyás C, Lux Á, Al-Khrasani M, Komlódi T, Bukosza N, Máthé D, Deres L, Barteková M, Rajtík T, Adameová A, Szigeti K, Hamar P, Helyes Z, Tretter L, Pacher P, Merkely B, Giricz Z, Schulz R, Ferdinandy P. Diastolic dysfunction in prediabetic male rats: Role of mitochondrial oxidative stress. Am J Physiol Heart Circ Physiol 2016; 311:H927-H943. [PMID: 27521417 DOI: 10.1152/ajpheart.00049.2016] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2016] [Accepted: 07/25/2016] [Indexed: 12/23/2022]
Abstract
Although incidence and prevalence of prediabetes are increasing, little is known about its cardiac effects. Therefore, our aim was to investigate the effect of prediabetes on cardiac function and to characterize parameters and pathways associated with deteriorated cardiac performance. Long-Evans rats were fed with either control or high-fat chow for 21 wk and treated with a single low dose (20 mg/kg) of streptozotocin at week 4 High-fat and streptozotocin treatment induced prediabetes as characterized by slightly elevated fasting blood glucose, impaired glucose and insulin tolerance, increased visceral adipose tissue and plasma leptin levels, as well as sensory neuropathy. In prediabetic animals, a mild diastolic dysfunction was observed, the number of myocardial lipid droplets increased, and left ventricular mass and wall thickness were elevated; however, no molecular sign of fibrosis or cardiac hypertrophy was shown. In prediabetes, production of reactive oxygen species was elevated in subsarcolemmal mitochondria. Expression of mitofusin-2 was increased, while the phosphorylation of phospholamban and expression of Bcl-2/adenovirus E1B 19-kDa protein-interacting protein 3 (BNIP3, a marker of mitophagy) decreased. However, expression of other markers of cardiac auto- and mitophagy, mitochondrial dynamics, inflammation, heat shock proteins, Ca2+/calmodulin-dependent protein kinase II, mammalian target of rapamycin, or apoptotic pathways were unchanged in prediabetes. This is the first comprehensive analysis of cardiac effects of prediabetes indicating that mild diastolic dysfunction and cardiac hypertrophy are multifactorial phenomena that are associated with early changes in mitophagy, cardiac lipid accumulation, and elevated oxidative stress and that prediabetes-induced oxidative stress originates from the subsarcolemmal mitochondria.
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Affiliation(s)
- Gábor Koncsos
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | - Zoltán V Varga
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Budapest, Hungary; Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - Tamás Baranyai
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | - Kerstin Boengler
- Institute of Physiology, Faculty of Medicine, Justus-Liebig University, Giessen, Germany
| | - Susanne Rohrbach
- Institute of Physiology, Faculty of Medicine, Justus-Liebig University, Giessen, Germany
| | - Ling Li
- Institute of Physiology, Faculty of Medicine, Justus-Liebig University, Giessen, Germany
| | - Klaus-Dieter Schlüter
- Institute of Physiology, Faculty of Medicine, Justus-Liebig University, Giessen, Germany
| | - Rolf Schreckenberg
- Institute of Physiology, Faculty of Medicine, Justus-Liebig University, Giessen, Germany
| | - Tamás Radovits
- Heart and Vascular Center, Semmelweis University, Budapest, Hungary
| | - Attila Oláh
- Heart and Vascular Center, Semmelweis University, Budapest, Hungary
| | - Csaba Mátyás
- Heart and Vascular Center, Semmelweis University, Budapest, Hungary
| | - Árpád Lux
- Heart and Vascular Center, Semmelweis University, Budapest, Hungary
| | - Mahmoud Al-Khrasani
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | - Tímea Komlódi
- Department of Medical Biochemistry, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | - Nóra Bukosza
- Institute of Pathophysiology, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | - Domokos Máthé
- Department of Biophysics and Radiation Biology, Faculty of Medicine, Semmelweis University, Budapest, Hungary; CROmed Translational Research Centers, Budapest, Hungary
| | - László Deres
- 1st Department of Internal Medicine, Faculty of Medicine, University of Pécs, Pécs, Hungary
| | - Monika Barteková
- Institute of Physiology, Faculty of Medicine, Comenius University in Bratislava, Slovakia; Institute for Heart Research, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Tomáš Rajtík
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Slovakia
| | - Adriana Adameová
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Slovakia
| | - Krisztián Szigeti
- Department of Biophysics and Radiation Biology, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | - Péter Hamar
- Institute of Pathophysiology, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | - Zsuzsanna Helyes
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine and Szentágothai Research Centre & MTA-PTE NAP B Chronic Pain Research Group, University of Pécs, Pécs, Hungary; and
| | - László Tretter
- Department of Medical Biochemistry, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | - Pál Pacher
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Budapest, Hungary; Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - Béla Merkely
- Heart and Vascular Center, Semmelweis University, Budapest, Hungary
| | - Zoltán Giricz
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Budapest, Hungary;
| | - Rainer Schulz
- Institute of Physiology, Faculty of Medicine, Justus-Liebig University, Giessen, Germany
| | - Péter Ferdinandy
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Budapest, Hungary
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25
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Bando YK, Murohara T. Heart Failure as a Comorbidity of Diabetes: Role of Dipeptidyl Peptidase 4. J Atheroscler Thromb 2015; 23:147-54. [PMID: 26607352 DOI: 10.5551/jat.33225] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
Heart failure is a primary cause of death worldwide, and it is notable that heart failure patients exhibit a high incidence of diabetes. On the other hand, comorbid diabetes significantly worsens the prognosis of heart failure, even independently of complicated coronary artery disease.To date, heart failure caused by diabetes has been designated as "diabetic cardiomyopathy (DMC)," and a recent cohort study of the large-scale (1.9 million people) research platform of linked electronic medical records in UK (CALIBER registry) demonstrated that heart failure and peripheral arterial disease are the most common initial manifestations of cardiovascular disease in type 2 diabetes. The underlying pathophysiology has been characterized as microvasculopathy, myocardial hypertrophy, and cardiac fibrosis; however, these evidences are mostly obtained under a preclinical setting, and its clinical application on DMC in terms of its diagnosis and therapeutic intervention yet has reached practical. Our group has focused on and clarified the molecular mechanisms underlying DMC both in preclinical and clinical settings and has found the primary role of "dipeptidyl peptidase-4 (DPP4)" in the pathogenesis of diabetic microvasculopathy in the heart. Moreover, there are evidences implicating the potent role of circulating DPP4 activity in the diagnosis of diastolic heart failure. The present review aimed to review the current comprehension regarding diabetes and heart failure and discuss the therapeutic and diagnostic roles of DPP4.
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Affiliation(s)
- Yasuko K Bando
- Department of Cardiology, Nagoya University Graduate School of Medicine
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26
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Leon BM, Maddox TM. Diabetes and cardiovascular disease: Epidemiology, biological mechanisms, treatment recommendations and future research. World J Diabetes 2015; 6:1246-1258. [PMID: 26468341 PMCID: PMC4600176 DOI: 10.4239/wjd.v6.i13.1246] [Citation(s) in RCA: 690] [Impact Index Per Article: 69.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2014] [Revised: 05/08/2015] [Accepted: 09/18/2015] [Indexed: 02/05/2023] Open
Abstract
The incidence of diabetes mellitus (DM) continues to rise and has quickly become one of the most prevalent and costly chronic diseases worldwide. A close link exists between DM and cardiovascular disease (CVD), which is the most prevalent cause of morbidity and mortality in diabetic patients. Cardiovascular (CV) risk factors such as obesity, hypertension and dyslipidemia are common in patients with DM, placing them at increased risk for cardiac events. In addition, many studies have found biological mechanisms associated with DM that independently increase the risk of CVD in diabetic patients. Therefore, targeting CV risk factors in patients with DM is critical to minimize the long-term CV complications of the disease. This paper summarizes the relationship between diabetes and CVD, examines possible mechanisms of disease progression, discusses current treatment recommendations, and outlines future research directions.
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27
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Yilmaz S, Canpolat U, Aydogdu S, Abboud HE. Diabetic Cardiomyopathy; Summary of 41 Years. Korean Circ J 2015; 45:266-72. [PMID: 26240579 PMCID: PMC4521103 DOI: 10.4070/kcj.2015.45.4.266] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2014] [Revised: 01/27/2015] [Accepted: 03/05/2015] [Indexed: 01/04/2023] Open
Abstract
Patients with diabetes have an increased risk for development of cardiomyopathy, even in the absence of well known risk factors like coronary artery disease and hypertension. Diabetic cardiomyopathy was first recognized approximately four decades ago. To date, several pathophysiological mechanisms thought to be responsible for this new entity have also been recognized. In the presence of hyperglycemia, non-enzymatic glycosylation of several proteins, reactive oxygen species formation, and fibrosis lead to impairment of cardiac contractile functions. Impaired calcium handling, increased fatty acid oxidation, and increased neurohormonal activation also contribute to this process. Demonstration of left ventricular hypertrophy, early diastolic and late systolic dysfunction by sensitive techniques, help us to diagnose diabetic cardiomyopathy. Traditional treatment of heart failure is beneficial in diabetic cardiomyopathy, but specific strategies for prevention or treatment of cardiac dysfunction in diabetic patients has not been clarified yet. In this review we will discuss clinical and experimental studies focused on pathophysiology of diabetic cardiomyopathy, and summarize diagnostic and therapeutic approaches developed towards this entity.
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Affiliation(s)
- Samet Yilmaz
- Turkey Yuksek Ihtisas Education and Research Hospital, Cardiology Clinic, Ankara, Turkey
| | - Ugur Canpolat
- Turkey Yuksek Ihtisas Education and Research Hospital, Cardiology Clinic, Ankara, Turkey
| | - Sinan Aydogdu
- Turkey Yuksek Ihtisas Education and Research Hospital, Cardiology Clinic, Ankara, Turkey
| | - Hanna Emily Abboud
- Division of Nephrology, University of Texas Health Science Center, San Antonio, TX, USA
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28
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Mellor KM, Brimble MA, Delbridge LM. Glucose as an agent of post-translational modification in diabetes — New cardiac epigenetic insights. Life Sci 2015; 129:48-53. [DOI: 10.1016/j.lfs.2014.03.020] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2014] [Revised: 03/11/2014] [Accepted: 03/17/2014] [Indexed: 01/07/2023]
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29
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Johnson EJ, Dieter BP, Marsh SA. Evidence for distinct effects of exercise in different cardiac hypertrophic disorders. Life Sci 2015; 123:100-6. [PMID: 25632833 PMCID: PMC4339313 DOI: 10.1016/j.lfs.2015.01.007] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2014] [Revised: 12/05/2014] [Accepted: 01/02/2015] [Indexed: 02/08/2023]
Abstract
Aerobic exercise training (AET) attenuates or reverses pathological cardiac remodeling after insults such as chronic hypertension and myocardial infarction. The phenotype of the pathologically hypertrophied heart depends on the insult; therefore, it is likely that distinct types of pathological hypertrophy require different exercise regimens. However, the mechanisms by which AET improves the structure and function of the pathologically hypertrophied heart are not well understood, and exercise research uses highly inconsistent exercise regimens in diverse patient populations. There is a clear need for systematic research to identify precise exercise prescriptions for different conditions of pathological hypertrophy. Therefore, this review synthesizes existing evidence for the distinct mechanisms by which AET benefits the heart in different pathological hypertrophy conditions, suggests strategic exercise prescriptions for these conditions, and highlights areas for future research.
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Affiliation(s)
- Emily J Johnson
- Graduate Program in Pharmaceutical Sciences, College of Pharmacy, Washington State University, Spokane, WA, USA
| | - Brad P Dieter
- Graduate Program in Movement Sciences, College of Education, University of Idaho, Moscow, ID, USA; Section of Experimental and Systems Pharmacology, College of Pharmacy, Washington State University, Spokane, WA, USA
| | - Susan A Marsh
- Section of Experimental and Systems Pharmacology, College of Pharmacy, Washington State University, Spokane, WA, USA.
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30
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Schilling JD, Mann DL. Diabetic Cardiomyopathy: Distinct and Preventable Entity or Inevitable Consequence? CURRENT CARDIOVASCULAR RISK REPORTS 2014. [DOI: 10.1007/s12170-014-0417-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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31
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Effects of exercise training on arterial function in type 2 diabetes mellitus: a systematic review and meta-analysis. Sports Med 2014; 43:1191-9. [PMID: 23912806 DOI: 10.1007/s40279-013-0085-2] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
BACKGROUND AND OBJECTIVE Controversy exists among trials assessing whether exercise can improve arterial function in type 2 diabetes mellitus (T2DM) subjects. Therefore the aim of this study was to systematically review and quantify the effects of exercise on arterial function in T2DM subjects. METHODS MEDLINE, Cochrane, Scopus and Web of Science were searched up until January 2013 for randomized controlled trials evaluating the effects of exercise interventions lasting 4 weeks or more on arterial function in T2DM subjects. Flow-mediated dilation (FMD) and nitrate-mediated dilation (NMD) of the brachial conduit artery were considered for assessment of arterial endothelial function and smooth muscle function, respectively. RESULTS Five randomized trials comparing exercise and control groups (overall n = 217) met the inclusion criteria. The mean exercise characteristics were as follows: 3.6 sessions per week, 67.5 min per session, intensity at 74.4 % of the maximum heart rate (HR(max)), for 14 weeks. The post-intervention mean difference in FMD favoured the exercise groups over the control groups (2.23 %; P < 0.0001). No significant post-intervention mean difference in NMD (1.22 %; P = 0.29) was found between the groups. Neither heterogeneity nor publication bias was detected among the trials. CONCLUSION Exercise training alone improved FMD, showing its capacity to restore arterial endothelial function in T2DM subjects. However, further research is needed to determine whether longer and/or more intense exercise interventions could enhance arterial smooth muscle function in this population.
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Dandamudi S, Slusser J, Mahoney DW, Redfield MM, Rodeheffer RJ, Chen HH. The prevalence of diabetic cardiomyopathy: a population-based study in Olmsted County, Minnesota. J Card Fail 2014; 20:304-9. [PMID: 24576788 DOI: 10.1016/j.cardfail.2014.02.007] [Citation(s) in RCA: 116] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2013] [Revised: 11/23/2013] [Accepted: 02/19/2014] [Indexed: 02/03/2023]
Abstract
BACKGROUND Diabetic cardiomyopathy defined as either systolic or diastolic dysfunction in otherwise healthy diabetic persons is not clearly understood. The prevalence and outcomes of this disease in a community-based population have not been defined. METHODS AND RESULTS Cross-sectional survey of 2042 randomly selected residents of Olmsted County, Minnesota, aged 45 years or older between June 1997 and September 2000. All patients underwent Doppler echocardiographic assessment of systolic and diastolic function. Diabetic cardiomyopathy was defined in a person with diabetes and any systolic or at least moderate diastolic dysfunction without a history of coronary disease, hypertension, significant valvular disease, or congenital heart disease. The diagnosis of diabetic cardiomyopathy was made in 23 people, corresponding to a community population prevalence rate of 1.1%. Among diabetic patients, 16.9% met criteria for diabetic cardiomyopathy and 54.4% had diastolic dysfunction. Diabetes was associated with a 1.9-fold increase in risk of any left ventricular dysfunction, a 1.7-fold increase in risk of diastolic dysfunction, and a 2.2-fold increase in risk of systolic dysfunction. Among patients with diabetic cardiomyopathy, the cumulative probability of death was 18%, development of heart failure was 22%, and development of death or heart failure was 31% at 9 years. CONCLUSION Diabetic cardiomyopathy is relatively common in the community with a prevalence of 1.1%. The morbidity and mortality of patients with diabetic cardiomyopathy is high.
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Affiliation(s)
- Sanjay Dandamudi
- The Division of Cardiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Joshua Slusser
- The Division of Biomedical Statistics and Informatics, Mayo Clinic and Foundation, Rochester, Minnesota
| | - Douglas W Mahoney
- The Division of Biomedical Statistics and Informatics, Mayo Clinic and Foundation, Rochester, Minnesota
| | - Margaret M Redfield
- The Department of Medicine, Division of Cardiovascular Diseases, Mayo Clinic and Foundation, Rochester, Minnesota
| | - Richard J Rodeheffer
- The Department of Medicine, Division of Cardiovascular Diseases, Mayo Clinic and Foundation, Rochester, Minnesota
| | - Horng H Chen
- The Department of Medicine, Division of Cardiovascular Diseases, Mayo Clinic and Foundation, Rochester, Minnesota.
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Abstract
As the link between heart failure (HF) and diabetes mellitus (DM) becomes unignorable, so the need is further increasing for pathological comprehension: What is "diabetic cardiomyopathy (DMC)?" In response to current concern, the most updated guidelines stated by the ACCF/AHA and by the ESC/EASD take one step further, including the definition of DMC, although it is a matter yet to be completed. For more than 40 years, coronary artery disease and hypertension have been considered as the main causes of diabetes-related cardiac dysfunction. HF was originally considered as a result of reduced left ventricular ejection fraction (HF-REF); however, it has been recognized that HF symptoms are often observed in patients with preserved EF (HF-PEF). DMC includes HF with both reduced and preserved entities independent of coronary stenosis and hypertension. Cardiologists are thus facing a sort of chaos without clear guidelines for the "deadly intersection" of DM and HF. Today, the increasing interest and concern have caused DMC to be revisited and the first step in controlling the chaos around DMC is to organize and analyze all of the available evidence from preclinical and clinical studies. This review aims to illustrate the current concepts of DMC by shedding light on the new molecular mechanisms. (Circ J 2014; 78: 576-583).
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Affiliation(s)
- Yasuko K Bando
- Department of Cardiology, Nagoya University Graduate School of Medicine
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Jellis CL, Sacre JW, Wright J, Jenkins C, Haluska B, Jeffriess L, Martin J, Marwick TH. Biomarker and imaging responses to spironolactone in subclinical diabetic cardiomyopathy. Eur Heart J Cardiovasc Imaging 2014; 15:776-86. [PMID: 24472731 DOI: 10.1093/ehjci/jeu013] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Subclinical diabetic cardiomyopathy (DCM) is frequent in asymptomatic subjects with type 2 diabetes (T2DM). We sought the response of functional and fibrosis markers to therapy in a trial of aldosterone antagonism for treatment of DCM. METHODS Biochemical, anthropometric, and echocardiographic data were measured in 225 subjects with T2DM. Myocardial function was evaluated with standard echocardiography and myocardial deformation; ischaemia was excluded by exercise echocardiography. Calibrated integrated backscatter and post-contrast T1 mapping from cardiac magnetic resonance imaging were used to assess myocardial structure. Amino-terminal propeptides of pro-collagen type I (PINP) and III (PIIINP), the carboxy-terminal propeptide of pro-collagen type I (PICP) and transforming growth factor beta-1 were measured from peripheral blood or urine to assess myocardial collagen turnover. RESULTS Diastolic dysfunction was identified in 81 individuals, of whom 49 (25 male, age 60 ± 10 years) were randomized to spironolactone 25 mg/day or placebo therapy for 6 months. Groups were well-matched at baseline. Spironolactone therapy was associated with improvements in diastolic filling profile (Δpeak E wave velocity -4 ± 15 vs. 9 ± 10 ms, P = 0.001; ΔE/A ratio -0.1 ± 0.3 vs. 0.2 ± 0.2, P < 0.001) and cIB values (-21.2 ± 4.5 dB vs. -18.0 ± 5.2 dB, P = 0.026; ΔcIB -5.1 ± 6.8 vs. -1.3 ± 5.2, P = 0.030). ΔcIB was independently associated with spironolactone therapy (β = 0.320, P = 0.026) but not Δblood pressure. With intervention, pro-collagen biomarkers (ΔPINP P = 0.92, ΔPICP P = 0.25, ΔPIIINP P = 0.52, and ΔTGF-β1 P = 0.71) and T1 values (P = 0.54) remained similar between groups. CONCLUSIONS Spironolactone-induced changes in myocardial structure and diastolic properties in DCM are small, and are unassociated with changes in collagen biomarkers or T1 values.
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Affiliation(s)
| | - Julian W Sacre
- School of Medicine, The University of Queensland, Brisbane, Australia
| | - Jeremy Wright
- Heart's 1st, Greenslopes Private Hospital, Brisbane, Australia
| | - Carly Jenkins
- School of Medicine, The University of Queensland, Brisbane, Australia
| | - Brian Haluska
- School of Medicine, The University of Queensland, Brisbane, Australia
| | - Leanne Jeffriess
- School of Medicine, The University of Queensland, Brisbane, Australia
| | - Jennifer Martin
- School of Medicine, The University of Queensland, Brisbane, Australia
| | - Thomas H Marwick
- School of Medicine, The University of Queensland, Brisbane, Australia Menzies Research Institute of Tasmania, Hobart, Australia
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Letonja M, Petrovič D. Is diabetic cardiomyopathy a specific entity? World J Cardiol 2014; 6:8-13. [PMID: 24527183 PMCID: PMC3920165 DOI: 10.4330/wjc.v6.i1.8] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2013] [Accepted: 12/13/2013] [Indexed: 02/06/2023] Open
Abstract
Diabetes mellitus (DM) is characterised by hyperglycemia, insulin resistance and metabolic dysregulation leading to diastolic and systolic dysfunction in diabetes. In this review, the pathogenetic and pathomorphological changes leading to diastolic and systolic dysfunction in diabetes are discussed. Changes in metabolic signalling pathways, mediators and effectors contribute to the pathogenesis of cardiac dysfunction in DM called diabetic cardiomyopathy (DC). Echocardiographic studies report on the association between DM and the presence of cardiac hypertrophy and myocardial stiffness that lead to diastolic dysfunction. More recently reported echocardiographic studies with more sensitive techniques, such as strain analysis, also observed systolic dysfunction as an early marker of DC. Depression of systolic and diastolic function is continuum and the line of separation is artificial. To conclude, according to current knowledge, DC is expected to be a common single phenotype that is caused by different pathogenetic and pathomorphological changes leading to diastolic and systolic dysfunction in diabetes.
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Montero D, Walther G, Pérez-Martin A, Vicente-Salar N, Roche E, Vinet A. Vascular smooth muscle function in type 2 diabetes mellitus: a systematic review and meta-analysis. Diabetologia 2013; 56:2122-33. [PMID: 23864267 DOI: 10.1007/s00125-013-2974-1] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2013] [Accepted: 06/05/2013] [Indexed: 01/22/2023]
Abstract
AIMS/HYPOTHESIS In type 2 diabetes, in contrast to the well-documented endothelial dysfunction, studies assessing vascular smooth muscle (VSM) function have yielded discrepant results over the last two decades. We therefore sought to determine whether or not VSM function is impaired in individuals with type 2 diabetes. METHODS We conducted a systematic search of MEDLINE, Cochrane, Scopus and Web of Science databases, from their respective inceptions until December 2012, for articles evaluating VSM function in individuals with type 2 diabetes. A meta-analysis was performed to compare the standardised mean difference (SMD) in VSM function between individuals with type 2 diabetes and age-matched controls. Subgroup analyses and meta-regression were used to identify sources of heterogeneity. RESULTS Twenty-seven articles (1,042 individuals with type 2 diabetes and 601 control subjects) were included in this analysis. VSM function was significantly impaired in diabetic compared with control subjects (SMD -0.68, 95% CI -0.84, -0.52; p < 0.001). Although moderate heterogeneity among studies was found (I (2) = 52%), no significant publication bias was detected. Subgroup analyses showed a further decline in VSM function assessed in the microcirculation compared with the macrocirculation of individuals with type 2 diabetes (p = 0.009). In meta-regression, VSM function in the microcirculation was inversely associated with BMI and triacylglycerols and was positively associated with HDL-cholesterol. CONCLUSIONS/INTERPRETATION In addition to the endothelium, the VSM is a source of vascular dysfunction in type 2 diabetes. An exacerbation of VSM function in the microcirculation may be a distinctive feature in type 2 diabetes.
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Affiliation(s)
- David Montero
- LAPEC EA4278, Avignon University, 33 rue Louis Pasteur, F-84000, Avignon, France.
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Non-invasively estimated end-systolic elastance in patients with resistant hypertension and type 2 diabetes mellitus. Heart Vessels 2013; 29:375-83. [DOI: 10.1007/s00380-013-0371-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2012] [Accepted: 05/17/2013] [Indexed: 10/26/2022]
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Asrih M, Steffens S. Emerging role of epigenetics and miRNA in diabetic cardiomyopathy. Cardiovasc Pathol 2012; 22:117-25. [PMID: 22951386 DOI: 10.1016/j.carpath.2012.07.004] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2012] [Revised: 07/06/2012] [Accepted: 07/27/2012] [Indexed: 12/11/2022] Open
Abstract
The prevalence of heart failure independent of coronary artery disease and hypertension is increasing rapidly in diabetic patients. Thus, this pathophysiology has been recognized as a distinct clinical entity termed "diabetic cardiomyopathy." Several studies support the notion that diabetes is a threatening insult for the myocardium resulting in functional, cellular, and structural changes manifesting as a cardiac myopathy. Recent data suggested that epigenetics including DNA and histone modifications as well as microRNAs play an important role in the development of cardiac diseases. The role of epigenetics in diabetes is largely recognized; however, its role in diabetes-associated cardiomyopathy remains elusive. Thus, molecular, cellular, and functional modulations in the diabetic cardiomyopathy will be investigated in this review. Moreover, particular attention will be drawn on the epigenetic mechanisms that may play an important role in the pathophysiology of diabetic cardiomyopathy.
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Affiliation(s)
- Mohamed Asrih
- Division of Cardiology, Foundation for Medical Research, University of Geneva Medical School, 1211 Geneva 4, Switzerland.
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Abstract
The study of diabetic cardiomyopathy is an area of significant interest given the strong association between diabetes and the risk of heart failure. Many unanswered questions remain regarding the clinical definition and pathogenesis of this metabolic cardiomyopathy. This article reviews the current understanding of diabetic cardiomyopathy with a particular emphasis on the unresolved issues that have limited translation of scientific discovery to patient bedside.
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Affiliation(s)
- Joel D Schilling
- Diabetic Cardiovascular Disease Center, Division of Cardiology, Department of Medicine, Washington University School of Medicine, St Louis, MO 63110, USA.
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40
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Teupe C, Rosak C. Diabetic cardiomyopathy and diastolic heart failure -- difficulties with relaxation. Diabetes Res Clin Pract 2012; 97:185-94. [PMID: 22502812 DOI: 10.1016/j.diabres.2012.03.008] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2012] [Revised: 03/11/2012] [Accepted: 03/15/2012] [Indexed: 01/14/2023]
Abstract
Diabetic patients carry a four- to five-fold increased risk of heart failure. Hyperglycaemia plays a central role in the pathogenesis of diabetic cardiomyopathy. Diabetic cardiomyopathy represents a distinct structural and functional disorder of the myocardium characterized by cardiac hypertrophy and an increased myocardial stiffness. At an early stage, diabetic cardiomyopathy is manifested by diastolic heart failure with preserved ejection fraction. In some patients, diastolic dysfunction may progress to heart failure with reduced ejection fraction and result in overt systolic heart failure. Diastolic dysfunction can accurately be diagnosed by echocardiography and BNP measurement in daily clinical practice. Early treatment is prognostically important. Optimal control of blood glucose levels and blood pressure is beneficial. So far metformin is the only antidiabetic agent not associated with harm in diabetic patients with heart failure. Incretin-based therapies potentially provide cardiovascular benefits. ACE inhibitors, angiotensin-1 receptor antagonists and beta-blockers should be preferred in heart failure therapy.
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Affiliation(s)
- C Teupe
- Department of Internal Medicine and Cardiology, Krankenhaus Sachsenhausen, Teaching Hospital, Goethe University, Frankfurt, Germany.
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Liu Y, Qi H, Wang Y, Wu M, Cao Y, Huang W, Li L, Ji Z, Sun H. Allicin protects against myocardial apoptosis and fibrosis in streptozotocin-induced diabetic rats. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2012; 19:693-698. [PMID: 22633288 DOI: 10.1016/j.phymed.2012.04.007] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/04/2011] [Revised: 02/28/2012] [Accepted: 04/18/2012] [Indexed: 06/01/2023]
Abstract
To evaluate the cardioprotective effect of allicin (AL) on myocardial injury of streptozotocin (STZ)-induced diabetic rats and to further explore its underlying mechanisms. Hyperglycemia was induced in rats by single intraperitoneal injection of STZ (40 mg/kg). Three days after STZ induction, the hyperglycemic rats (plasma glucose levels ≥ 16.7 mmol/l) were treated with AL by intraperitoneal injection at the doses of 4 mg/kg, 8 mg/kg, and 16 mg/kg daily for 28 days. The fasting blood glucose levels were measured on every 7th day during the 28 days of treatment. The body weight, blood glucose, and parameter of cardiac function were detected after 4 weeks to study the cardioprotective effects of AL on diabetic rats in vivo. The apoptotic index of cardiomyocytes was estimated by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. The expressions of Fas, Bcl-2, CTGF, and TGF-β(1) protein were studied by immunohistochemistry. Laser scanning confocal microscopy technique was utilized to observe the effects of AL on intracellular calcium concentration ([Ca(2+)](i)) in rat ventricular cardiomyocytes. AL at the doses of 4 mg/kg, 8 mg/kg, and 16 mg/kg significantly reduced blood glucose levels in a dose-dependent manner and increased body weight as well compared with the model group. Hemodynamic parameters including left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), and maximum rate of left ventricular pressure rise and fall (+dp/dtmax and -dp/dtmax) were significantly restored back to normal levels in AL-treated (8 mg/kg and 16 mg/kg) rats compared with diabetic model rats. AL markedly inhibited cardiomyocyte apoptosis induced by diabetic cardiac injury. Further investigation revealed that this inhibitory effect on cell apoptosis was mediated by increasing anti-apoptotic protein Bcl-2 and decreasing pro-apoptotic protein Fas. Additional experiments demonstrated AL abrogated myocardial fibrosis by blocking the expressions of CTGF and TGF-β(1) protein. AL shows protective action on myocardial injury in diabetic rats. The possible mechanisms were involved in reducing blood glucose, correcting hemodynamic impairment, reducing Fas expression, activating Bcl-2 expression, decreasing intracellular calcium overload, inhibiting the expressions of TGF-β(1) and CTGF, and further improving cardiac function.
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Affiliation(s)
- Yang Liu
- Department of Pharmacology, Harbin Medical University, Daqing 163319, PR China
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Patel SK, Wai B, Macisaac RJ, Grant S, Velkoska E, Ord M, Panagiotopoulos S, Jerums G, Srivastava PM, Burrell LM. The CTGF gene -945 G/C polymorphism is not associated with cardiac or kidney complications in subjects with type 2 diabetes. Cardiovasc Diabetol 2012; 11:42. [PMID: 22533709 PMCID: PMC3439260 DOI: 10.1186/1475-2840-11-42] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2012] [Accepted: 03/28/2012] [Indexed: 11/29/2022] Open
Abstract
Background Connective tissue growth factor (CTGF) has been implicated in the cardiac and kidney complications of type 2 diabetes, and the CTGF −945 G/C polymorphism is associated with susceptibility to systemic sclerosis, a disease characterised by tissue fibrosis. This study investigated the association of the CTGF −945 G/C promoter variant with cardiac complications (left ventricular (LV) hypertrophy (LVH), diastolic and systolic dysfunction) and chronic kidney disease (CKD) in type 2 diabetes. Methods The CTGF −945 G/C polymorphism (rs6918698) was examined in 495 Caucasian subjects with type 2 diabetes. Cardiac structure and function were assessed by transthoracic echocardiography. Kidney function was assessed using estimated glomerular filtration rate (eGFR) and albuminuria, and CKD defined as the presence of kidney damage (decreased kidney function (eGFR <60 ml/min/1.73 m2) or albuminuria). Results The mean age ± SD of the cohort was 62 ± 14 years, with a body mass index (BMI) of 31 ± 6 kg/m2 and median diabetes duration of 11 years [25th, 75th interquartile range; 5, 18]. An abnormal echocardiogram was present in 73% of subjects; of these, 8% had LVH alone, 74% had diastolic dysfunction and 18% had systolic ± diastolic dysfunction. CKD was present in 42% of subjects. There were no significant associations between the CTGF −945 G/C polymorphism and echocardiographic parameters of LV mass or cardiac function, or kidney function both before and after adjustment for covariates of age, gender, BMI, blood pressure and hypertension. CTGF −945 genotypes were not associated with the cardiac complications of LVH, diastolic or systolic dysfunction, nor with CKD. Conclusions In Caucasians with type 2 diabetes, genetic variation in the CTGF −945 G/C polymorphism is not associated with cardiac or kidney complications.
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Affiliation(s)
- Sheila K Patel
- Department of Medicine, Austin Health, University of Melbourne, Level 7, Lance Townsend Building, 145 Studley Road, Melbourne, VIC 3084, Australia.
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Masugata H, Senda S, Okada H, Murao K, Inukai M, Himoto T, Hosomi N, Murakami K, Noma T, Kohno M, Goda F. Association between Cardiac Function and Pulmonary Function in Hypertensive Patients. J Int Med Res 2012; 40:105-14. [DOI: 10.1177/147323001204000111] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
OBJECTIVE: This study examined the association between cardiac function and pulmonary function in hypertensive patients. METHODS: Hypertensive patients without overt cardiovascular disease were enrolled ( n = 43; mean ± SD age 71 ± 9 years). Pulmonary function was measured by the percentage of predicted forced vital capacity (%FVC) and the ratio of 1 s forced expiratory volume (FEV1) to FVC (FEV1/FVC ratio). Left ventricular ejection fraction (LVEF) and the ratio of peak early diastolic transmitral flow (E) to peak early diastolic mitral annular velocity (e′) (E/e′ ratio) were assessed using echocardiography. RESULTS: Multiple linear regression analysis revealed that E/e′ was independently associated with %FVC and that LVEF was independently associated with FEV1/FVC ratio. Both LVEF and FEV1/FVC ratio were significantly lower in hypertensive former or current smokers than in hypertensive never smokers. CONCLUSIONS: Subclinical cardiac dysfunction was independently associated with reduced pulmonary function in hypertensive patients. Hypertensive patients with decreased pulmonary function may need preventive care to prevent the progression of heart failure.
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Affiliation(s)
- H Masugata
- Department of Integrated Medicine, Kagawa University, Kagawa, Japan
| | - S Senda
- Department of Integrated Medicine, Kagawa University, Kagawa, Japan
| | - H Okada
- Department of Medical Education, Kagawa University, Kagawa, Japan
| | - K Murao
- Department of Advanced Medicine and Laboratory Medicine, Kagawa University, Kagawa, Japan
| | - M Inukai
- Department of Integrated Medicine, Kagawa University, Kagawa, Japan
| | - T Himoto
- Department of Integrated Medicine, Kagawa University, Kagawa, Japan
| | - N Hosomi
- Department of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima, Japan
| | - K Murakami
- Department of Cardiorenal and Cerebrovascular Medicine, Kagawa University, Kagawa, Japan
| | - T Noma
- Department of Cardiorenal and Cerebrovascular Medicine, Kagawa University, Kagawa, Japan
| | - M Kohno
- Department of Cardiorenal and Cerebrovascular Medicine, Kagawa University, Kagawa, Japan
| | - F Goda
- Department of Integrated Medicine, Kagawa University, Kagawa, Japan
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Nurmi L, Heikkilä HM, Vapaatalo H, Kovanen PT, Lindstedt KA. Downregulation of Bradykinin Type 2 Receptor Expression in Cardiac Endothelial Cells during Senescence. J Vasc Res 2012; 49:13-23. [DOI: 10.1159/000329615] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2011] [Accepted: 05/20/2011] [Indexed: 11/19/2022] Open
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Masugata H, Senda S, Inukai M, Murao K, Tada S, Hosomi N, Iwado Y, Noma T, Kohno M, Himoto T, Goda F. Association between high-sensitivity C-reactive protein and left ventricular diastolic function assessed by echocardiography in patients with cardiovascular risk factors. TOHOKU J EXP MED 2011; 223:263-8. [PMID: 21422746 DOI: 10.1620/tjem.223.263] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
High-sensitivity C-reactive protein (hsCRP) has been demonstrated to play a causal role in atherosclerosis and to predict cardiovascular events in the general population. On the other hand, left ventricular (LV) hypertrophy and diastolic dysfunction assessed by echocardiography can also predict cardiovascular events in patients with cardiovascular risk factors. However, there are few data regarding the relationships among hsCRP, LV hypertrophy, and diastolic function. We examined the relationships among hsCRP, LV hypertrophy, and diastolic function in 185 patients (65±11 years), who had no overt heart disease, but had cardiovascular risk factors, including hypertension, diabetes, and dyslipidemia. Echocardiography was performed to measure the left ventricular mass index (LVMI) as a parameter of LV hypertrophy. LV diastolic function was assessed by the ratio (E/A) of early (E) and late (A) diastolic transmitral flows, early diastolic mitral annular velocity (E'), and the ratio (E/E') of E to E' using Doppler echocardiography. The hsCRP was correlated with LVMI (r=0.228, p=0.002), E' (r=-0.276, p<0.001), and E/E' (r=0.419, p<0.001). The E/E' as a parameter of LV diastolic function showed the closest correlation to hsCRP. These results indicate that elevated hsCRP reflects LV diastolic dysfunction rather than LV hypertrophy. We therefore suggest that hsCRP may be a marker of subclinical LV diastolic dysfunction in patients with cardiovascular risk factors.
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Affiliation(s)
- Hisashi Masugata
- Department of Integrated Medicine, Kagawa University, Kagawa, Japan.
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CCN-2 is up-regulated by and mediates effects of matrix bound advanced glycated end-products in human renal mesangial cells. J Cell Commun Signal 2011; 5:193-200. [PMID: 21630131 DOI: 10.1007/s12079-011-0137-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2011] [Accepted: 05/02/2011] [Indexed: 01/28/2023] Open
Abstract
CCN-2, also known as connective tissue growth factor (CCN-2/CTGF) is a cysteine rich, extracellular matrix protein that acts as a pro-fibrotic cytokine in tissues in many diseases, including in diabetic nephropathy. We have published that soluble advanced glycation end products (AGEs), that are present in increased amounts in diabetes, induce CCN-2. However in vivo AGEs are known to be heavily tissue bound and whether matrix bound AGEs regulate CCN-2 has not been investigated. In this study we determined in human renal mesangial cells if CCN-2 is induced by matrix associated AGEs and if CCN-2 may then secondarily mediate effects of matrix AGEs on extracellular matrix expansion. Data generated show that CCN-2 mRNA and protein expression are induced by matrix bound AGEs, and in contrast, this was not the case for TGF-β1 mRNA regulation. Using CCN-2 adenoviral anti-sense it was found that CCN-2 mediated the up-regulation of fibronectin and the tissue inhibitor of matrix metalloproteinase, TIMP-1, that was caused by matrix bound AGEs. In conclusion, CCN-2 is induced by non-enzymatically glycated matrix and it mediates downstream fibronectin and TIMP-1 increases, thus through this mechanism potentially contributing to ECM accumulation in the renal glomerulus in diabetes.
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Diastolic dysfunction in diabetic patients assessed with Doppler echocardiography: relationship with coronary atherosclerotic burden and microcirculatory impairment. Rev Esp Cardiol 2010; 62:1395-403. [PMID: 20038406 DOI: 10.1016/s1885-5857(09)73534-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
INTRODUCTION AND OBJECTIVES Diabetes mellitus (DM) is associated with the development of both impaired left ventricular diastolic function (LVDF) and pathological changes in the coronary macro- and microcirculation. The aim of this study was to investigate the relationship between these manifestations of diabetic heart disease. METHODS The severity of atherosclerosis in the left anterior descending coronary artery (LAD) was quantified using intravascular ultrasound (IVUS) in 13 patients with DM and ischemic heart disease. The coronary flow velocity reserve (CFVR), instantaneous hyperemic diastolic velocity pressure slope index (IHDVPS) and zero-flow pressure were derived from digital intracoronary pressure and flow velocity measurements. The relationships between indices of LVDF (i.e. E/A and E/e' ratios) and intracoronary measurements were assessed. RESULTS The left ventricular ejection fraction was 66+/-7%, and the LVDF indices were: E/A=0.92+/-0.38 and E/e'=9.90+/-2.80. There was a direct proportional relationship (r=0.62; P=.02) between E/e' and coronary resistance (1.93+/-0.74 mmHg/s) and an inverse proportional relationship (r=-0.64; P=.02) between E/e' and IHDVPS (1.56+/-0.50 cm/s/mmHg). However, no significant relationship was found between either LVDF index and CFVR (2.43+/-0.56) or coronary zero-flow pressure (40.41+/-10.66 mmHg). The volume of atheroma in the proximal 20 mm of the LAD (179.34+/-57.48 .l, with an average plaque area of 8.39+/-2.20 mm2) was not related to either LVDF index. CONCLUSIONS In patients with DM and coronary atherosclerosis, there appeared to be a relationship between LVDF impairment (assessed by the E/e' ratio) and structural changes in the microcirculation.
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Ban CR, Twigg SM, Franjic B, Brooks BA, Celermajer D, Yue DK, McLennan SV. Serum MMP-7 is increased in diabetic renal disease and diabetic diastolic dysfunction. Diabetes Res Clin Pract 2010; 87:335-41. [PMID: 20096949 DOI: 10.1016/j.diabres.2010.01.004] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2009] [Revised: 12/11/2009] [Accepted: 01/04/2010] [Indexed: 01/01/2023]
Abstract
Circulating matrix metalloproteinase (MMP) levels may correlate with diabetic complications. Whether they are changed in early diabetic cardiomyopathy is not known and was examined in this study. TIMP-1 and collagen degradation products were also measured. Results from subjects with and without diastolic dysfunction were compared with those obtained for patients with varying stages of diabetic renal disease. Patients with type 2 diabetes with or without diastolic dysfunction with varying degrees of renal disease were recruited for this study. Age-matched non-diabetic subjects served as controls. MMPs (-1, -3 and -7) and TIMP-1 were measured by ELISA, MMP-2 and -9 by zymography and collagen degradation products by radioimmunoassay. Differences in the pattern of MMPs/TIMPs and collagen degradation products were observed. The most consistent change was in totalMMP-7, which was increased in those with diastolic dysfunction and those with macroalbuminuria. MMP-7 correlated with cardiac function (p<0.05 vs control, in those with diastolic dysfunction), and renal filtration function (p<0.05 vs control). In summary, we have identified novel relationships between serum MMP-7 and diabetic complications specifically in renal disease and in diastolic dysfunction. How increased circulating MMP-7 is associated with these diabetic microvascular complications and the significance of these findings will require prospective studies.
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Affiliation(s)
- C R Ban
- Alesd Hospital, Bihor County, Romania
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Sasso FC, Rambaldi PF, Carbonara O, Nasti R, Torella M, Rotondo A, Torella R, Mansi L. Perspectives of nuclear diagnostic imaging in diabetic cardiomyopathy. Nutr Metab Cardiovasc Dis 2010; 20:208-216. [PMID: 19939648 DOI: 10.1016/j.numecd.2009.08.013] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2009] [Revised: 07/23/2009] [Accepted: 08/31/2009] [Indexed: 12/21/2022]
Abstract
Diabetic cardiomyopathy is a ventricular dysfunction in the absence of coronary artery disease, valvular or hypertensive heart disease. The mechanisms underlying diabetic cardiomyopathy may involve metabolic disturbances, myocardial fibrosis, small vessel disease, microcirculation abnormalities, cardiac autonomic neuropathy and insulin resistance. Diagnostic problems emerge because no specific disease pattern characterizes the disease and because there may be coexistence in diabetes of coronary artery disease and hypertension as independent but compounding causes of biochemical, anatomical and functional alterations impairing cardiac function. In this paper we will review the role of nuclear imaging today, concentrating on the diagnostic capabilities of radionuclide ventriculography, to study the effect of insulin resistance and, more extensively, gated-single photon emission computed tomography with Tc-99m labelled agents. A broad analysis will be dedicated to: 1) positron emission tomography using perfusion agents, with the potential to quantify resting and stress blood flow and coronary flow reserve; 2) radionuclide procedures evaluating aerobic and anaerobic cardiac metabolism; and 3) cardiac neurotransmission imaging, studying the autonomic neuropathy.
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Affiliation(s)
- F C Sasso
- Unit of Internal Medicine, Department of Clinical and Experimental Medicine Magrassi-Lanzara, Second University of Naples, Naples, Italy.
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Abstract
Diabetes is associated with increased incidence of heart failure even after controlling for coronary artery disease and hypertension. Thus, as diabetic cardiomyopathy has become an increasingly recognized entity among clinicians, a better understanding of its pathophysiology is necessary for early diagnosis and the development of treatment strategies for diabetes-associated cardiovascular dysfunction. We will review recent basic and clinical research into the manifestations and the pathophysiological mechanisms of diabetic cardiomyopathy. The discussion will be focused on the structural, functional and metabolic changes that occur in the myocardium in diabetes and how these changes may contribute to the development of diabetic cardiomyopathy in affected humans and relevant animal models.
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