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Khattab E, Kyriakou M, Leonidou E, Sokratous S, Mouzarou A, Myrianthefs MM, Kadoglou NPE. Critical Appraisal of Pharmaceutical Therapy in Diabetic Cardiomyopathy-Challenges and Prospectives. Pharmaceuticals (Basel) 2025; 18:134. [PMID: 39861195 PMCID: PMC11768626 DOI: 10.3390/ph18010134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Revised: 01/06/2025] [Accepted: 01/10/2025] [Indexed: 01/27/2025] Open
Abstract
Diabetes mellitus (DM) is a multifaceted disorder with a pandemic spread and a remarkable burden of cardiovascular mortality and morbidity. Diabetic cardiomyopathy (DBCM) has been increasingly recognized as the development of cardiac dysfunction, which is accompanied by heart failure (HF) symptoms in the absence of obvious reasons like ischemic heart disease, hypertension, or valvulopathies. Several pathophysiological mechanisms have been proposed, including metabolic disorders (e.g., glycation products), oxidative stress, low-grade inflammation, mitochondrial dysfunction, etc., which should guide the development of new therapeutic strategies. Up to now, HF treatment has not differed between patients with and without diabetes, which limits the expected benefits despite the high cardiovascular risk in the former group. However, DBCM patients may require different management, which prioritize anti-diabetic medications or testing other novel therapies. This review aims to appraise the challenges and prospectives of the individualized pharmaceutical therapy for DBCM.
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Affiliation(s)
- Elina Khattab
- Department of Cardiology, Nicosia General Hospital, 2029 Nicosia, Cyprus; (E.K.); (M.K.); (S.S.); (M.M.M.)
| | - Michaelia Kyriakou
- Department of Cardiology, Nicosia General Hospital, 2029 Nicosia, Cyprus; (E.K.); (M.K.); (S.S.); (M.M.M.)
| | - Elena Leonidou
- Department of Cardiology, Limassol General Hospital, 3304 Limassol, Cyprus;
| | - Stefanos Sokratous
- Department of Cardiology, Nicosia General Hospital, 2029 Nicosia, Cyprus; (E.K.); (M.K.); (S.S.); (M.M.M.)
| | - Angeliki Mouzarou
- Department of Cardiology, Pafos General Hospital, 8026 Paphos, Cyprus;
| | - Michael M. Myrianthefs
- Department of Cardiology, Nicosia General Hospital, 2029 Nicosia, Cyprus; (E.K.); (M.K.); (S.S.); (M.M.M.)
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Hu F, Lin C. TRPM2 knockdown attenuates myocardial apoptosis and promotes autophagy in HFD/STZ-induced diabetic mice via regulating the MEK/ERK and mTORC1 signaling pathway. Mol Cell Biochem 2024; 479:3307-3328. [PMID: 38308007 PMCID: PMC11511773 DOI: 10.1007/s11010-024-04926-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Accepted: 01/05/2024] [Indexed: 02/04/2024]
Abstract
Diabetic cardiomyopathy (DCM) is a major complication of diabetes. Transient receptor potential melastatin 2 (TRPM2) activity increases in diabetic oxidative stress state, and it is involved in myocardial damage and repair. We explore the protective effect of TRPM2 knockdown on the progression of DCM. A type 2 diabetes animal model was established in C57BL/6N mice by long-term high-fat diet (HFD) feeding combined with a single injection of 100-mg/kg streptozotocin (STZ). Genetic knockdown of TRPM2 in heart was accomplished by the intravenous injection via the tail vein of adeno-associated virus type 9 carrying TRPM2 shRNA. Neonatal rat ventricular myocytes was exposed to 45 mM of high-glucose (HG) stimulation for 72 h in vitro to mimic the in vivo conditions. Western blot, real-time quantitative PCR (RT-qPCR), immunohistochemistry and fluorescence, electron, CCK-8, and flow cytometry were used to evaluate the phenotype of cardiac inflammation, fibrosis, apoptosis, and autophagy. Mice with HFD/STZ-induced diabetes exhibited systolic and diastolic dysfunction, as demonstrated by increased myocardial apoptosis and autophagy inhibition in the heart. Compared to control group, the protein expression of TRPM2, bax, cleaved caspase-3, and P62 was significantly elevated, and the protein expression of bcl-2 and LC3-II was significantly decreased in the myocardial tissues of the HFD/STZ-induced diabetes group. Knockdown of TRPM2 significantly reversed the HFD/STZ-induced myocardial apoptosis and autophagy inhibition. TRPM2 silencing attenuated HG-induced apoptosis and autophagy inhibition in primary cardiomyocytes via regulating the MEK/ERK mTORC1 signaling pathway. TRPM2 knockdown attenuates hyperglycemia-induced myocardial apoptosis and promotes autophagy in HFD/STZ-induced diabetic mice or HG-stimulated cardiomyocytes via regulating the MEK/ERK and mTORC1 signaling pathway.
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Affiliation(s)
- Feng Hu
- Department of Cardiology, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian, China.
| | - Chaoyang Lin
- Department of Cardiology, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian, China
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Han Q, Li Y, Yu Y, Yuan H, Wang Z, Guo Y, Shi J, Xue Y, Liu X. Exploring the mechanism of diabetic cardiomyopathy treated with Qigui Qiangxin mixture based on UPLC-Q/TOF-MS, network pharmacology and experimental validation. Sci Rep 2024; 14:12119. [PMID: 38802644 PMCID: PMC11130275 DOI: 10.1038/s41598-024-63088-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Accepted: 05/24/2024] [Indexed: 05/29/2024] Open
Abstract
Despite its effectiveness in treating diabetic cardiomyopathy (DCM), Qigui Qiangxin Mixture (QGQXM) remains unclear in terms of its active ingredients and specific mechanism of action. The purpose of this study was to explore the active ingredients and mechanism of action of QGQXM in the treatment of DCM through the comprehensive strategy of serum pharmacology, network pharmacology and combined with experimental validation. The active ingredients of QGQXM were analyzed using Ultra-performance liquid chromatography coupled with quadrupole time of flight mass spectrometry (UPLC-Q/TOF-MS). Network pharmacology was utilized to elucidate the mechanism of action of QGQXM for the treatment of DCM. Finally, in vivo validation was performed by intraperitoneal injection of STZ combined with high-fat feeding-induced DCM rat model. A total of 25 active compounds were identified in the drug-containing serum of rats, corresponding to 121 DCM-associated targets. GAPDH, TNF, AKT1, PPARG, EGFR, CASP3, and HIF1 were considered as the core therapeutic targets. Enrichment analysis showed that QGQXM mainly treats DCM by regulating PI3K-AKT, MAPK, mTOR, Insulin, Insulin resistance, and Apoptosis signaling pathways. Animal experiments showed that QGQXM improved cardiac function, attenuated the degree of cardiomyocyte injury and fibrosis, and inhibited apoptosis in DCM rats. Meanwhile, QGQXM also activated the PI3K/AKT signaling pathway, up-regulated Bcl-2, and down-regulated Caspase9, which may be an intrinsic mechanism for its anti-apoptotic effect. This study preliminarily elucidated the mechanism of QGQXM in the treatment of DCM and provided candidate compounds for the development of new drugs for DCM.
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Affiliation(s)
- Quancheng Han
- Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China
| | - Yan Li
- Cardiology Department, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jing Shi Road, Lixia District, Jinan, People's Republic of China
| | - Yiding Yu
- Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China
| | - Huajing Yuan
- Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China
| | - Ziqi Wang
- Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China
| | - Yonghong Guo
- Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China
| | - Jingle Shi
- Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China
| | - Yitao Xue
- Cardiology Department, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jing Shi Road, Lixia District, Jinan, People's Republic of China.
| | - Xiujuan Liu
- Cardiology Department, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jing Shi Road, Lixia District, Jinan, People's Republic of China.
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Li M, Liu L, Zhang C, Deng L, Zhong Y, Liao B, Li X, Wan Y, Feng J. The latest emerging drugs for the treatment of diabetic cardiomyopathy. Expert Opin Pharmacother 2024; 25:641-654. [PMID: 38660817 DOI: 10.1080/14656566.2024.2347468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Accepted: 04/22/2024] [Indexed: 04/26/2024]
Abstract
INTRODUCTION Diabetic cardiomyopathy (DCM) is a serious complication of diabetes mellitus involving multiple pathophysiologic mechanisms. In addition to hypoglycemic agents commonly used in diabetes, metabolism-related drugs, natural plant extracts, melatonin, exosomes, and rennin-angiotensin-aldosterone system are cardioprotective in DCM. However, there is a lack of systematic summarization of drugs for DCM. AREAS COVERED In this review, the authors systematically summarize the most recent drugs used for the treatment of DCM and discusses them from the perspective of DCM pathophysiological mechanisms. EXPERT OPINION We discuss DCM drugs from the perspective of the pathophysiological mechanisms of DCM, mainly including inflammation and metabolism. As a disease with multiple pathophysiological mechanisms, the combination of drugs may be more advantageous, and we have discussed some of the current studies on the combination of drugs.
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Affiliation(s)
- Minghao Li
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
| | - Lin Liu
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
| | - Chunyu Zhang
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
| | - Li Deng
- Department of Rheumatology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Yi Zhong
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
| | - Bin Liao
- Department of Cardiovascular Surgery, Metabolic Vascular Diseases Key Laboratory of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Xiuying Li
- Department of Pharmacy, The Affiliated Hospital of Southwest Medical University; Department of Pathophysiology, School of Basic Medical Science, Southwest Medical University, Luzhou, China
| | - Ying Wan
- Department of Pharmacy, The Affiliated Hospital of Southwest Medical University; Department of Pathophysiology, School of Basic Medical Science, Southwest Medical University, Luzhou, China
| | - Jian Feng
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
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Yin J, Fu X, Luo Y, Leng Y, Ao L, Xie C. A Narrative Review of Diabetic Macroangiopathy: From Molecular Mechanism to Therapeutic Approaches. Diabetes Ther 2024; 15:585-609. [PMID: 38302838 PMCID: PMC10942953 DOI: 10.1007/s13300-024-01532-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Accepted: 01/11/2024] [Indexed: 02/03/2024] Open
Abstract
Diabetic macroangiopathy, a prevalent and severe complication of diabetes mellitus, significantly contributes to the increased morbidity and mortality rates among affected individuals. This complex disorder involves multifaceted molecular mechanisms that lead to the dysfunction and damage of large blood vessels, including atherosclerosis (AS) and peripheral arterial disease. Understanding the intricate pathways underlying the development and progression of diabetic macroangiopathy is crucial for the development of effective therapeutic interventions. This review aims to shed light on the molecular mechanism implicated in the pathogenesis of diabetic macroangiopathy. We delve into the intricate interplay of chronic inflammation, oxidative stress, endothelial dysfunction, and dysregulated angiogenesis, all of which contribute to the vascular complications observed in this disorder. By exploring the molecular mechanism involved in the disease we provide insight into potential therapeutic targets and strategies. Moreover, we discuss the current therapeutic approaches used for treating diabetic macroangiopathy, including glycemic control, lipid-lowering agents, and vascular interventions.
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Affiliation(s)
- Jiacheng Yin
- Hospital of Chengdu University of Traditional Chinese Medicine No, 39 Shi-er-Qiao Road, Chengdu, 610072, Sichuan Province, People's Republic of China
| | - Xiaoxu Fu
- Hospital of Chengdu University of Traditional Chinese Medicine No, 39 Shi-er-Qiao Road, Chengdu, 610072, Sichuan Province, People's Republic of China
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, No. 39 Shi-er-Qiao Road, Chengdu, 610072, Sichuan Province, People's Republic of China
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-er-Qiao Road, Chengdu, 610072, Sichuan Province, People's Republic of China
| | - Yue Luo
- Hospital of Chengdu University of Traditional Chinese Medicine No, 39 Shi-er-Qiao Road, Chengdu, 610072, Sichuan Province, People's Republic of China
| | - Yuling Leng
- Hospital of Chengdu University of Traditional Chinese Medicine No, 39 Shi-er-Qiao Road, Chengdu, 610072, Sichuan Province, People's Republic of China
| | - Lianjun Ao
- Hospital of Chengdu University of Traditional Chinese Medicine No, 39 Shi-er-Qiao Road, Chengdu, 610072, Sichuan Province, People's Republic of China
| | - Chunguang Xie
- Hospital of Chengdu University of Traditional Chinese Medicine No, 39 Shi-er-Qiao Road, Chengdu, 610072, Sichuan Province, People's Republic of China.
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, No. 39 Shi-er-Qiao Road, Chengdu, 610072, Sichuan Province, People's Republic of China.
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-er-Qiao Road, Chengdu, 610072, Sichuan Province, People's Republic of China.
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Matta A, Ohlmann P, Nader V, Levai L, Kang R, Carrié D, Roncalli J. A review of the conservative versus invasive management of ischemic heart failure with reduced ejection fraction. Curr Probl Cardiol 2024; 49:102347. [PMID: 38103822 DOI: 10.1016/j.cpcardiol.2023.102347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Accepted: 12/13/2023] [Indexed: 12/19/2023]
Abstract
Heart failure is increasing in terms of prevalence, morbidity, and mortality rates. Clinical trials and studies are focusing on heart failure as it is the destiny end-stage for several cardiovascular disorders. Recently, medical therapy has dramatically progressed with novel classes of medicines providing better quality of life and survival outcomes. However, heart failure remains a heavy impactful factor on societies and populations. Current guidelines from the American and European cardiac societies are not uniform with respect to the class and level of treatment recommendations for coronary artery disease patients with heart failure and reduced ejection fraction. The discrepancy among international recommendations, stemming from the lack of evidence from adequately powered randomized trials, challenges physicians in choosing the optimal strategy. Hybrid therapy including optimal medical therapy with revascularization strategies are commonly used for the management of ischemic heart failure. Coronary artery bypass graft (CABG) has proved its efficacy on improving long term outcome and prognosis while no large randomized clinical trials for percutaneous coronary intervention (PCI) are still available. Regardless of the lack of data and recommendations, the trends of performing PCI in ischemic heart failure prevailed over CABG whereas lesion complexity, chronic total occlusion and complete revascularization achievement are limiting factors. Lastly, regenerative medicine seems a promising approach for advanced heart failure enhancing cardiomyocytes proliferation, reverse remodeling, scar size reduction and cardiac function restoration.
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Affiliation(s)
- Anthony Matta
- Department of Cardiology, Civilian Hospital of Colmar, Colmar, France.
| | - Patrick Ohlmann
- Department of Cardiology, University Hospital of Strasbourg, Strasbourg, France
| | - Vanessa Nader
- Department of Cardiology, Civilian Hospital of Colmar, Colmar, France
| | - Laszlo Levai
- Department of Cardiology, Civilian Hospital of Colmar, Colmar, France
| | - Ryeonshi Kang
- Department of Cardiology, University Hospital of Toulouse, Toulouse, France
| | - Didier Carrié
- Department of Cardiology, University Hospital of Toulouse, Toulouse, France
| | - Jerome Roncalli
- Department of Cardiology, University Hospital of Toulouse, Toulouse, France
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Sanganalmath SK, Dubey S, Veeranki S, Narisetty K, Krishnamurthy P. The interplay of inflammation, exosomes and Ca 2+ dynamics in diabetic cardiomyopathy. Cardiovasc Diabetol 2023; 22:37. [PMID: 36804872 PMCID: PMC9942322 DOI: 10.1186/s12933-023-01755-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 01/25/2023] [Indexed: 02/22/2023] Open
Abstract
Diabetes mellitus is one of the prime risk factors for cardiovascular complications and is linked with high morbidity and mortality. Diabetic cardiomyopathy (DCM) often manifests as reduced cardiac contractility, myocardial fibrosis, diastolic dysfunction, and chronic heart failure. Inflammation, changes in calcium (Ca2+) handling and cardiomyocyte loss are often implicated in the development and progression of DCM. Although the existence of DCM was established nearly four decades ago, the exact mechanisms underlying this disease pathophysiology is constantly evolving. Furthermore, the complex pathophysiology of DCM is linked with exosomes, which has recently shown to facilitate intercellular (cell-to-cell) communication through biomolecules such as micro RNA (miRNA), proteins, enzymes, cell surface receptors, growth factors, cytokines, and lipids. Inflammatory response and Ca2+ signaling are interrelated and DCM has been known to adversely affect many of these signaling molecules either qualitatively and/or quantitatively. In this literature review, we have demonstrated that Ca2+ regulators are tightly controlled at different molecular and cellular levels during various biological processes in the heart. Inflammatory mediators, miRNA and exosomes are shown to interact with these regulators, however how these mediators are linked to Ca2+ handling during DCM pathogenesis remains elusive. Thus, further investigations are needed to understand the mechanisms to restore cardiac Ca2+ homeostasis and function, and to serve as potential therapeutic targets in the treatment of DCM.
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Affiliation(s)
- Santosh K Sanganalmath
- Department of Internal Medicine, Division of Cardiovascular Medicine, University of Nevada Las Vegas School of Medicine, Las Vegas, NV, 89102, USA.
| | - Shubham Dubey
- Department of Biomedical Engineering, Schools of Medicine and Engineering, University of Alabama at Birmingham, University Blvd., Birmingham, AL, 35294, USA
| | - Sudhakar Veeranki
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, 40506, USA
| | | | - Prasanna Krishnamurthy
- Department of Biomedical Engineering, Schools of Medicine and Engineering, University of Alabama at Birmingham, University Blvd., Birmingham, AL, 35294, USA
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Chen Y, Wang Y, Zhang Y, Li M, Zhang W, Zhou Y, Liu X, Fu J, Lu Z, Xu Q, Liu T, Li Z, Li X, Zhou J. Association of peripheral neuropathy with subclinical left ventricular dysfunction in patients with type 2 diabetes. J Diabetes Complications 2023; 37:108406. [PMID: 36682230 DOI: 10.1016/j.jdiacomp.2023.108406] [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: 08/02/2022] [Revised: 01/09/2023] [Accepted: 01/11/2023] [Indexed: 01/15/2023]
Abstract
OBJECTIVES The impacts of diabetic peripheral neuropathy (DPN) on clinical manifestations of left ventricular (LV) function in patients suffering from type 2 diabetes mellitus (T2DM) and the preserved LV ejection fraction (LVEF) lack a full evaluation. This study was carried out to investigate the correlation of peripheral neuropathy with subclinical LV systolic dysfunction, accompanied by the exploration of the relevant clinical features of peripheral neuropathy in these patients. METHODS A retrospective analysis was conducted depending on the data of 101 consecutive inpatients with T2DM and preserved LVEF (all ≥ 50 %), without coronary artery disease and other histories of heart disease. All subjects received both a nerve conduction assessment and a speckle-tracking echocardiography examination. Global longitudinal strain (GLS) was conducted to assess the subclinical LV systolic function. RESULTS Forty-six (46 %) patients were diagnosed as DPN according to electrophysiological examination and clinical assessment. A significant difference was revealed in GLS between patients with and without DPN (16.5 ± 2.8 vs. 19.3 ± 3.4, p < 0.001). Multiple logistic regression analysis indicated GLS as one of the independent determinative factors for DPN (odds ratio, 0.68; P < 0.001). In addition, motor-sensory nerve conduction exhibited a significant positive correlation with GLS, which may not be revealed between the types of peripheral nerve damage. CONCLUSIONS Despite the preserved LVEF, the subclinical LV myocardial dysfunction may have occurred in T2DM patients with DPN. Peripheral nerve conduction was significantly correlated with GLS. An early assessment of nerve conduction may exert a dual warning significance for the progression of subclinical LV dysfunction in asymptomatic patients with T2DM.
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Affiliation(s)
- Yanyan Chen
- Department of Endocrinology, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi, China
| | - Yi Wang
- Department of Endocrinology, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi, China
| | - Ying Zhang
- Department of Endocrinology, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi, China
| | - Mengying Li
- Department of Endocrinology, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi, China
| | - Weiqing Zhang
- Department of Endocrinology, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi, China
| | - Yingni Zhou
- Department of Endocrinology, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi, China
| | - Xiangyang Liu
- Department of Endocrinology, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi, China
| | - Jianfang Fu
- Department of Endocrinology, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi, China
| | - Zuowei Lu
- Department of Endocrinology, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi, China
| | - Qian Xu
- Department of Endocrinology, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi, China
| | - Tao Liu
- Department of Endocrinology, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi, China
| | - Zeping Li
- Nanchang University Queen Mary School, Nanchang, China
| | - Xiaomiao Li
- Department of Endocrinology, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi, China.
| | - Jie Zhou
- Department of Endocrinology, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi, China.
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Lee KS, Noh J, Park SM, Choi KM, Kang SM, Won KC, Cho HJ, Moon MK. Evaluation and Management of Patients With Diabetes and Heart Failure: A Korean Diabetes Association and Korean Society of Heart Failure Consensus Statement. INTERNATIONAL JOURNAL OF HEART FAILURE 2023; 5:1-20. [PMID: 36818141 PMCID: PMC9902644 DOI: 10.36628/ijhf.2022.0028] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 01/16/2023] [Accepted: 01/16/2023] [Indexed: 05/25/2023]
Abstract
Diabetes mellitus is a major risk factor for the development of heart failure. Furthermore, the prognosis of heart failure is worse in patients with diabetes mellitus than in those without it. Therefore, early diagnosis and proper management of heart failure in patients with diabetes mellitus are important. This review discusses the current criteria for diagnosis and screening tools for heart failure and the currently recommended pharmacological therapies for heart failure. We also highlight the effects of anti-diabetic medications on heart failure.
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Affiliation(s)
- Kyu-Sun Lee
- Division of Cardiology, Department of Internal Medicine, Seoul National University Hospital and Seoul National University College of Medicine, Seoul, Korea
| | - Junghyun Noh
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Inje University Ilsan Paik Hospital, Goyang, Korea
| | - Seong-Mi Park
- Division of Cardiology, Department of Internal Medicine, Korea University College of Medicine, Anam Hospital, Seoul, Korea
| | - Kyung Mook Choi
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Seok-Min Kang
- Division of Cardiology, Department of Internal Medicine, Severance Cardiovascular Hospital, Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Kyu-Chang Won
- Division of Endocrinology, Department of Internal Medicine, Yeungnam University Medical Center, Daegu, Korea
| | - Hyun-Jai Cho
- Division of Cardiology, Department of Internal Medicine, Seoul National University Hospital and Seoul National University College of Medicine, Seoul, Korea
| | - Min Kyong Moon
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea
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Lee KS, Noh J, Park SM, Choi KM, Kang SM, Won KC, Cho HJ, Moon MK. Evaluation and Management of Patients with Diabetes and Heart Failure: A Korean Diabetes Association and Korean Society of Heart Failure Consensus Statement. Diabetes Metab J 2023; 47:10-26. [PMID: 36727161 PMCID: PMC9925146 DOI: 10.4093/dmj.2022.0420] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Accepted: 01/17/2023] [Indexed: 01/28/2023] Open
Abstract
Diabetes mellitus is a major risk factor for the development of heart failure. Furthermore, the prognosis of heart failure is worse in patients with diabetes mellitus than in those without it. Therefore, early diagnosis and proper management of heart failure in patients with diabetes mellitus are important. This review discusses the current criteria for diagnosis and screening tools for heart failure and the currently recommended pharmacological therapies for heart failure. We also highlight the effects of anti-diabetic medications on heart failure.
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Affiliation(s)
- Kyu-Sun Lee
- Division of Cardiology, Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
| | - Junghyun Noh
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Inje University Ilsan Paik Hospital, Goyang, Korea
| | - Seong-Mi Park
- Division of Cardiology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea
| | - Kyung Mook Choi
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Seok-Min Kang
- Division of Cardiology, Department of Internal Medicine, Severance Cardiovascular Hospital, Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Kyu-Chang Won
- Division of Endocrinology, Department of Internal Medicine, Yeungnam University Medical Center, Daegu, Korea
| | - Hyun-Jai Cho
- Division of Cardiology, Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
| | - Min Kyong Moon
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea
| | - The Committee of Clinical Practice Guidelines
- Division of Cardiology, Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Inje University Ilsan Paik Hospital, Goyang, Korea
- Division of Cardiology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
- Division of Cardiology, Department of Internal Medicine, Severance Cardiovascular Hospital, Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, Korea
- Division of Endocrinology, Department of Internal Medicine, Yeungnam University Medical Center, Daegu, Korea
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea
| | - Korean Diabetes Association and Committee of Clinical Practice Guidelines
- Division of Cardiology, Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Inje University Ilsan Paik Hospital, Goyang, Korea
- Division of Cardiology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
- Division of Cardiology, Department of Internal Medicine, Severance Cardiovascular Hospital, Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, Korea
- Division of Endocrinology, Department of Internal Medicine, Yeungnam University Medical Center, Daegu, Korea
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea
| | - Korean Society of Heart Failure
- Division of Cardiology, Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Inje University Ilsan Paik Hospital, Goyang, Korea
- Division of Cardiology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
- Division of Cardiology, Department of Internal Medicine, Severance Cardiovascular Hospital, Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, Korea
- Division of Endocrinology, Department of Internal Medicine, Yeungnam University Medical Center, Daegu, Korea
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea
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11
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Xiong SP, Sun HJ, Cao X, Wu ZY, Zhu MY, Cao L, Nie XW, Bian JS. Polysulfide Protects Against Diabetic Cardiomyopathy Through Sulfhydration of Peroxisome Proliferator-Activated Receptor-γ and Sirtuin 3. Antioxid Redox Signal 2023; 38:1-17. [PMID: 36322712 DOI: 10.1089/ars.2022.0024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Aims: Diabetic cardiomyopathy (DCM) is characterized by cardiac dysfunction and heart failure. However, the effective therapy for DCM is still lacking. Polysulfide contains chains of sulfur atoms, and accumulative evidence has shown that it actively participates in mammalian physiology or pathophysiology. Nevertheless, the potential effects and mechanisms of polysulfide in DCM need further investigation. In the present study, Na2S4, a polysulfide donor, was employed to investigate the therapeutic effects of polysulfide in DCM. Results: Our results showed that Na2S4 protected cardiomyocytes against high glucose (HG)-induced cardiomyocyte injury. The pathological changes in DCM including cell death, oxidative stress, mitochondrial dysfunction and cardiac hypertrophy were improved by Na2S4 treatment. The left ventricular contractile function in streptozotocin (STZ)-induced diabetic mice was significantly improved by Na2S4. Mechanistically, Na2S4 upregulated and sulfhydrated peroxisome proliferator-activated receptor-γ (PPARγ) and sirtuin 3 (SIRT-3) in cardiomyocytes. Suppression of PPARγ or SIRT-3 with their specific inhibitors or blockade of sulfhydration abolished the protective effects of Na2S4. Moreover, mutations of PPARγ or SIRT-3 at specific cysteines diminished the benefits of Na2S4 in HG-challenged cardiomyocytes. Innovation and Conclusion: We demonstrated that Na2S4 prevented the development of DCM via sulfhydration of both PPARγ and SIRT-3. Our results imply that polysulfide may be a potential and promising agent to treat DCM. Antioxid. Redox Signal. 38, 1-17.
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Affiliation(s)
- Si-Ping Xiong
- Department of Pathology, The Eighth Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China.,Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Hai-Jian Sun
- Department of Pharmacognosy, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China.,Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Xu Cao
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Zhi-Yuan Wu
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Meng-Yuan Zhu
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Lei Cao
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Xiao-Wei Nie
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.,Shenzhen Key Laboratory of Respiratory Diseases, Shenzhen People's Hospital (The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China
| | - Jin-Song Bian
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.,Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, China
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12
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Sharma K, Rani V. Organosulfur Compounds in Aged Garlic Extract Ameliorate Glucose Induced Diabetic Cardiomyopathy by Attenuating Oxidative Stress, Cardiac Fibrosis, and Cardiac Apoptosis. Cardiovasc Hematol Agents Med Chem 2023; 22:66-82. [PMID: 36825728 DOI: 10.2174/1871525721666230223145218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 12/26/2022] [Accepted: 12/26/2022] [Indexed: 02/25/2023]
Abstract
BACKGROUND Diabetic cardiomyopathy has emerged as a major cause of cardiac fibrosis, hypertrophy, diastolic dysfunction, and heart failure due to uncontrolled glucose metabolism in patients with diabetes mellitus. However, there is still no consensus on the optimal treatment to prevent or treat the cardiac burden associated with diabetes, which urges the development of dual antidiabetic and cardioprotective cardiac therapy based on natural products. This study investigates the cardiotoxic profile of glucose and the efficacy of AGE against glucose-induced cardiotoxicity in H9c2 cardiomyocytes. METHODS The cellular metabolic activity of H9c2 cardiomyocytes under increasing glucose concentration and the therapeutic efficacy of AGE were investigated using the MTT cell cytotoxicity assay. The in vitro model was established in six groups known as 1. control, 2. cells treated with 25 μM glucose, 3. 100 μM glucose, 4. 25 μM glucose +35 μM AGE, 5. 100 μM glucose + 35 μM AGE, and 6. 35 μM AGE. Morphological and nuclear analyses were performed using Giemsa, HE, DAPI, and PI, respectively, whereas cell death was simultaneously assessed using the trypan blue assay. The antioxidant potential of AGE was evaluated by DCFH-DA assay, NO, and H202 scavenging assay. The activities of the antioxidant enzymes catalase and superoxide dismutase were also investigated. The antiglycative potential of AGE was examined by antiglycation assays, amylase zymography, and SDS PAGE. These results were then validated by in silico molecular docking and qRTPCR. RESULTS Hyperglycemia significantly reduced cellular metabolic activity of H9c2 cardiomyocytes, and AGE was found to preserve cell viability approximately 2-fold by attenuating oxidative, fibrosis, and apoptotic signaling molecules. In silico and qRTPCR studies confirmed that organosulfur compounds target TNF-α, MAPK, TGF-β, MMP-7, and caspase-9 signaling molecules to ameliorate glucose-induced cardiotoxicity. CONCLUSION AGE was found to be an antidiabetic and cardioprotective natural product with exceptional therapeutic potential for use as a novel herb-drug therapy in the treatment of diabetic cardiomyopathy in future therapies.
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Affiliation(s)
- Kumkum Sharma
- Department of Biotechnology, Transcriptome Lab, Centre for Emerging Diseases, Jaypee Institute of Information Technology, Noida, Sector- 62, Uttar Pradesh, India
| | - Vibha Rani
- Department of Biotechnology, Transcriptome Lab, Centre for Emerging Diseases, Jaypee Institute of Information Technology, Noida, Sector- 62, Uttar Pradesh, India
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13
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Marfella R, D'Onofrio N, Mansueto G, Grimaldi V, Trotta MC, Sardu C, Sasso FC, Scisciola L, Amarelli C, Esposito S, D'Amico M, Golino P, De Feo M, Signoriello G, Paolisso P, Gallinoro E, Vanderheyden M, Maiello C, Balestrieri ML, Barbato E, Napoli C, Paolisso G. Glycated ACE2 reduces anti-remodeling effects of renin-angiotensin system inhibition in human diabetic hearts. Cardiovasc Diabetol 2022; 21:146. [PMID: 35932065 PMCID: PMC9356400 DOI: 10.1186/s12933-022-01573-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Accepted: 07/15/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND High glycated-hemoglobin (HbA1c) levels correlated with an elevated risk of adverse cardiovascular outcomes despite renin-angiotensin system (RAS) inhibition in type-2 diabetic (T2DM) patients with reduced ejection fraction. Using the routine biopsies of non-T2DM heart transplanted (HTX) in T2DM recipients, we evaluated whether the diabetic milieu modulates glycosylated ACE2 (GlycACE2) levels in cardiomyocytes, known to be affected by non-enzymatic glycosylation, and the relationship with glycemic control. OBJECTIVES We investigated the possible effects of GlycACE2 on the anti-remodeling pathways of the RAS inhibitors by evaluating the levels of Angiotensin (Ang) 1-9, Ang 1-7, and Mas receptor (MasR), Nuclear-factor of activated T-cells (NFAT), and fibrosis in human hearts. METHODS We evaluated 197 first HTX recipients (107 non-T2DM, 90 T2DM). All patients were treated with angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB) at hospital discharge. Patients underwent clinical evaluation (metabolic status, echocardiography, coronary CT-angiography, and endomyocardial biopsies). Biopsies were used to evaluate ACE2, GlycACE2, Ang 1-9, Ang 1-7, MasR, NAFT, and fibrosis. RESULTS GlycACE2 was higher in T2DM compared tonon-T2DM cardiomyocytes. Moreover, reduced expressions of Ang 1-9, Ang 1-7, and MasR were observed, suggesting impaired effects of RAS-inhibition in diabetic hearts. Accordingly, biopsies from T2DM recipients showed higher fibrosis than those from non-T2DM recipients. Notably, the expression of GlycACE2 in heart biopsies was strongly dependent on glycemic control, as reflected by the correlation between mean plasma HbA1c, evaluated quarterly during the 12-month follow-up, and GlycACE2 expression. CONCLUSION Poor glycemic control, favoring GlycACE2, may attenuate the cardioprotective effects of RAS-inhibition. However, the achievement of tight glycemic control normalizes the anti-remodeling effects of RAS-inhibition. TRIAL REGISTRATION https://clinicaltrials.gov/ NCT03546062.
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Affiliation(s)
- Raffaele Marfella
- Department of Advanced Medical and Surgical Sciences, Università degli Studi della Campania "Luigi Vanvitelli", Piazza Miraglia, 2, 80138, Naples, Italy.,Mediterranea Cardiocentro, Naples, Italy
| | - Nunzia D'Onofrio
- Department of Precision Medicine, The University of Campania "Luigi Vanvitelli", 80138, Naples, Italy
| | - Gelsomina Mansueto
- Department of Advanced Medical and Surgical Sciences, Università degli Studi della Campania "Luigi Vanvitelli", Piazza Miraglia, 2, 80138, Naples, Italy
| | - Vincenzo Grimaldi
- Department of Advanced Medical and Surgical Sciences, Università degli Studi della Campania "Luigi Vanvitelli", Piazza Miraglia, 2, 80138, Naples, Italy
| | - Maria Consiglia Trotta
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", 80138, Naples, Italy
| | - Celestino Sardu
- Department of Advanced Medical and Surgical Sciences, Università degli Studi della Campania "Luigi Vanvitelli", Piazza Miraglia, 2, 80138, Naples, Italy.
| | - Ferdinando Carlo Sasso
- Department of Advanced Medical and Surgical Sciences, Università degli Studi della Campania "Luigi Vanvitelli", Piazza Miraglia, 2, 80138, Naples, Italy
| | - Lucia Scisciola
- Department of Advanced Medical and Surgical Sciences, Università degli Studi della Campania "Luigi Vanvitelli", Piazza Miraglia, 2, 80138, Naples, Italy
| | - Cristiano Amarelli
- Unit of Cardiac Surgery and Transplants, AORN Ospedali dei Colli-Monaldi Hospital, 80131, Naples, Italy
| | | | - Michele D'Amico
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", 80138, Naples, Italy
| | - Paolo Golino
- Cardiology Division, University "L. Vanvitelli" - Monaldi Hospital, 80131, Naples, Italy
| | - Marisa De Feo
- Department of Cardio-Thoracic Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Giuseppe Signoriello
- Statistical Unit-Department of Mental Health and Public Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Pasquale Paolisso
- Cardiovascular Center Aalst, OLV-Clinic, Aalst, Belgium.,Department of Advanced Biomedical Sciences, University of Naples Federico II, Naples, Italy
| | - Emanuele Gallinoro
- Cardiology Division, University "L. Vanvitelli" - Monaldi Hospital, 80131, Naples, Italy.,Cardiovascular Center Aalst, OLV-Clinic, Aalst, Belgium
| | | | - Ciro Maiello
- Unit of Cardiac Surgery and Transplants, AORN Ospedali dei Colli-Monaldi Hospital, 80131, Naples, Italy
| | - Maria Luisa Balestrieri
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", 80138, Naples, Italy
| | - Emanuele Barbato
- Cardiovascular Center Aalst, OLV-Clinic, Aalst, Belgium.,Department of Advanced Biomedical Sciences, University of Naples Federico II, Naples, Italy
| | - Claudio Napoli
- Department of Advanced Medical and Surgical Sciences, Università degli Studi della Campania "Luigi Vanvitelli", Piazza Miraglia, 2, 80138, Naples, Italy
| | - Giuseppe Paolisso
- Department of Advanced Medical and Surgical Sciences, Università degli Studi della Campania "Luigi Vanvitelli", Piazza Miraglia, 2, 80138, Naples, Italy.,Mediterranea Cardiocentro, Naples, Italy
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14
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Syed AA, Reza MI, Shafiq M, Kumariya S, Katekar R, Hanif K, Gayen JR. Cissus quadrangularis extract mitigates diabetic cardiomyopathy by inhibiting RAAS activation, inflammation, and oxidative stress. Biomarkers 2022; 27:743-752. [PMID: 35896310 DOI: 10.1080/1354750x.2022.2107703] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
IntroductionDiabetic cardiomyopathy (DCM) is an age-related disease, and its progression is accompanied by hyperglycemia, cardiac dysfunction, and myocardial structural and functional abnormalities. Cissus quadrangularis, a traditional medicinal plant, contains polyphenols, flavonoids, phytosterols, carbohydrates, and ascorbic acid. It is used to treat osteoporosis, asthma, haemorrhoids, and menstrual disorders. In the current research, we have investigated the effect of ethanolic extract of C. quadrangularis (EECQ) against a high-fat diet (HFD)/streptozotocin-induced DCM by estimating cardiac biomarkers, inflammatory markers and ROS production.Material and methodsRats were fed with an HFD for 12 weeks, followed by single-shot low-dose streptozotocin (35mg/kg; i.p.). The treatment was performed by EECQ (200 mg/kg/day, orally) for six weeks. ResultsThe extract EECQ improves glucose, insulin tolerance tests, and hypercholesteremia. DCM is characterized by cardiac dysfunction, cardiac biomarkers CKMB, and LDH, which were attenuated by the EECQ treatment. The hypertrophic biomarker ANP, BNP expression and cardiomyocyte surface area were decreased by EECQ. Moreover, EECQ also alleviated the biomarkers Angiotensin II and renin level. EECQ also reduced oxidative stress, ROS production and cardiac inflammation.ConclusionThus, these findings suggested that EECQ could be used as a possible therapeutic regiment to treat DCM.
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Affiliation(s)
- Anees Ahmed Syed
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow 226031, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad- 201002, India
| | - Mohammad Irshad Reza
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow 226031, India
| | - Mohammed Shafiq
- Pharmacology Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow 226031, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad- 201002, India
| | - Sanjana Kumariya
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow 226031, India
| | - Roshan Katekar
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow 226031, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad- 201002, India
| | - Kashif Hanif
- Pharmacology Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow 226031, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad- 201002, India
| | - Jiaur R Gayen
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow 226031, India.,Pharmacology Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow 226031, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad- 201002, India
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15
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Ani C, Shavlik D, Knutsen S, Abudayyeh I, Banta J, O'Brien E, Mentz RJ, Bertoni AG, Fraser G. Glycemic status, non-traditional risk and left ventricular structure and function in the Jackson Heart Study. BMC Cardiovasc Disord 2022; 22:186. [PMID: 35448969 PMCID: PMC9022283 DOI: 10.1186/s12872-022-02605-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 03/31/2022] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Left ventricular structure and function abnormalities may be an early marker of cardiomyopathy among African Americans with diabetes (DM) even in the absence of coronary artery disease (CAD), arrhythmia, valvular heart disease and end-stage renal disease (ESRD). This study examined the association of prediabetes (PDM), DM and HbA1c with left ventricular structure and function among Jackson Heart Study (JHS) participants without traditional risk factors. METHODS Retrospective cross-sectional analyses of the association of PDM, DM and HbA1c with, left ventricular ejection fraction (LV EF), fractional shortening (LV FS), stroke volume index (SVI), cardiac index (CI), left ventricular end diastolic volume index (LVEDVI), left ventricular end systolic volume index (LVESVI), relative wall thickness (RWT), myocardial contraction fraction (MCF) and left ventricular mass index (LVMI). The study was conducted in 2234 adult JHS participants without preexisting CAD, arrhythmia, valvular heart disease or ESRD. Statistical analyses included descriptive, univariate and covariate adjusted linear regression analyses. Sensitivity analyses to explore the impact of hypertension on study outcomes were also carried out. RESULTS DM compared with no DM was associated with lower, SVI (- 0.96 ml/m2, p = 0.029), LVEDVI (- 1.44 ml/m2 p = 0.015), and MCF (- 1.90% p = 0.007) but higher CI (0.14 L/min/m2, p < 0.001), RWT (0.01 cm, p = 0.002) and LVMI (2.29 g/m2, p = 0.009). After further control for DM duration, only CI remaining significantly higher for DM compared with no DM participants (0.12 L/min/m2, p = 0.009). PDM compared with no PDM was associated with lower, SVI (- 0.87 ml/m2, P = 0.024), LVEDVI (- 1.15 ml/m2 p = 0.003) and LVESVI (- 0.62 ml/m2 p = 0.025). HbA1c ≥ 8.0% compared with HbA1c < 5.7% was associated with lower SVI (- 2.09 ml/m2, p = 0.004), LVEDVI (- 2.11 ml/m2 p = 0.032) and MCF (- 2.94% p = 0.011) but higher CI (0.11 L/min/m2, p = 0.043) and RWT (0.01 cm, p = 0.035). CONCLUSIONS Glycemic status is associated with important left ventricular structure and function changes among African Americans without prior CAD, arrhythmia, valvular heart disease and ESRD. Longitudinal studies may further elucidate these relationships.
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Affiliation(s)
- Chizobam Ani
- Loma Linda University (LLU), Loma Linda, USA.
- Department of Internal Medicine, Charles R Drew University of Medicine and Science (CDU), Los Angeles, USA.
- University of California Los Angeles (UCLA), Los Angeles, USA.
| | | | | | | | | | | | | | - Alain G Bertoni
- Wake Forest School of Medicine (Department of Epidemiology and Prevention), Winston-Salem, USA
| | - Gary Fraser
- Loma Linda University (LLU), Loma Linda, USA
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16
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Hyperkalemia as a limiting factor of neurohormonal blockade/modulation in everyday clinical practice. Rev Port Cardiol 2022; 41:521-527. [DOI: 10.1016/j.repc.2021.04.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 03/16/2021] [Accepted: 04/07/2021] [Indexed: 11/15/2022] Open
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17
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Unraveling and Targeting Myocardial Regeneration Deficit in Diabetes. Antioxidants (Basel) 2022; 11:antiox11020208. [PMID: 35204091 PMCID: PMC8868283 DOI: 10.3390/antiox11020208] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 01/13/2022] [Accepted: 01/20/2022] [Indexed: 02/04/2023] Open
Abstract
Cardiomyopathy is a common complication in diabetic patients. Ventricular dysfunction without coronary atherosclerosis and hypertension is driven by hyperglycemia, hyperinsulinemia and impaired insulin signaling. Cardiomyocyte death, hypertrophy, fibrosis, and cell signaling defects underlie cardiomyopathy. Notably, detrimental effects of the diabetic milieu are not limited to cardiomyocytes and vascular cells. The diabetic heart acquires a senescent phenotype and also suffers from altered cellular homeostasis and the insufficient replacement of dying cells. Chronic inflammation, oxidative stress, and metabolic dysregulation damage the population of endogenous cardiac stem cells, which contribute to myocardial cell turnover and repair after injury. Therefore, deficient myocardial repair and the progressive senescence and dysfunction of stem cells in the diabetic heart can represent potential therapeutic targets. While our knowledge of the effects of diabetes on stem cells is growing, several strategies to preserve, activate or restore cardiac stem cell compartments await to be tested in diabetic cardiomyopathy.
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18
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Mittal A, Garg R, Bahl A, Khullar M. Molecular Mechanisms and Epigenetic Regulation in Diabetic Cardiomyopathy. Front Cardiovasc Med 2022; 8:725532. [PMID: 34977165 PMCID: PMC8716459 DOI: 10.3389/fcvm.2021.725532] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 11/15/2021] [Indexed: 12/25/2022] Open
Abstract
Diabetes mellitus (DM) is an important lifestyle disease. Type 2 diabetes is one of the prime contributors to cardiovascular diseases (CVD) and diabetic cardiomyopathy (DbCM) and leads to increased morbidity and mortality in patients with DM. DbCM is a typical cardiac disease, characterized by cardiac remodeling in the presence of DM and in the absence of other comorbidities such as hypertension, valvular diseases, and coronary artery disease. DbCM is associated with defective cardiac metabolism, altered mitochondrial structure and function, and other physiological and pathophysiological signaling mechanisms such as oxidative stress, inflammation, myocardial apoptosis, and autophagy. Epigenetic modifiers are crucial players in the pathogenesis of DbCM. Thus, it is important to explore the role of epigenetic modifiers or modifications in regulating molecular pathways associated with DbCM. In this review, we have discussed the role of various epigenetic mechanisms such as histone modifications (acetylation and methylation), DNA methylation and non-coding RNAs in modulating molecular pathways involved in the pathophysiology of the DbCM.
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Affiliation(s)
- Anupam Mittal
- Department of Translational and Regenerative Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Rajni Garg
- Council of Scientific and Industrial Research - Institute of Microbial Technology, Chandigarh, India
| | - Ajay Bahl
- Department of Cardiology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Madhu Khullar
- Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
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19
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Kobayashi M, Voors AA, Ouwerkerk W, Duarte K, Girerd N, Rossignol P, Metra M, Lang CC, Ng LL, Filippatos G, Dickstein K, van Veldhuisen DJ, Zannad F, Ferreira JP. Perceived risk profile and treatment optimization in heart failure: an analysis from BIOlogy Study to TAilored Treatment in chronic heart failure. Clin Cardiol 2021; 44:780-788. [PMID: 33960439 PMCID: PMC8207977 DOI: 10.1002/clc.23576] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 01/07/2021] [Accepted: 02/08/2021] [Indexed: 12/21/2022] Open
Abstract
Background Achieving target doses of angiotensin‐converting‐enzyme inhibitor/angiotensin‐receptor blockers (ACEi/ARB) and beta‐blockers in heart failure with reduced ejection fraction (HFrEF) is often underperformed. In BIOlogy Study to TAilored Treatment in chronic heart failure (BIOSTAT‐CHF) study, many patients were not up‐titrated for which no clear reason was reported. Therefore, we hypothesized that perceived‐risk profile might influence treatment optimization. Methods We studied 2100 patients with HFrEF (LVEF≤40%) to compare the clinical characteristics and adverse events associated with treatment up‐titration (after a 3‐month titration protocol) between; a) patients not reaching target doses for unclear reason; b) patients not reaching target doses due to symptoms and/or side effects; c) patients reaching target doses. Results For ACEi/ARB, (a), (b) and (c) was observed in 51.3%, 25.9% and 22.7% of patients, respectively. For beta‐blockers, (a), (b) and (c) was observed in 67.5%, 20.2% and 12.3% of patients, respectively. By multinomial logistic regression analysis for ACEi/ARB, patients in group (a) and (b) had lower blood pressure and poorer renal function, and patients in group (a) were older and had lower ejection fraction. For beta‐blockers, patients in group (a) and (b) had more severe congestion and lower heart rate. At 9 months, adverse events (i.e., hypotension, bradycardia, renal impairment, and hyperkalemia) occurred similarly among the three groups. Conclusions Patients in whom clinicians did not give a reason why up‐titration was missed were older and had more co‐morbidities. Patients in whom up‐titration was achieved did not have excess adverse events. However, from these observational findings, the pattern of subsequent adverse events among patients in whom up‐titration was missed cannot be determined.
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Affiliation(s)
- Masatake Kobayashi
- Université de Lorraine, INSERM, Centre d'Investigations Cliniques Plurithématique 1433, Inserm U1116, CHRU de Nancy and F-CRIN INI-CRCT, Nancy, France
| | - Adriaan A Voors
- Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Wouter Ouwerkerk
- National Heart Centre Singapore, Hospital Drive, Singapore.,Department of Dermatology, Amsterdam UMC, Amsterdam Infection & Immunity Institute, University of Amsterdam, Amsterdam, Netherlands
| | - Kevin Duarte
- Université de Lorraine, INSERM, Centre d'Investigations Cliniques Plurithématique 1433, Inserm U1116, CHRU de Nancy and F-CRIN INI-CRCT, Nancy, France
| | - Nicolas Girerd
- Université de Lorraine, INSERM, Centre d'Investigations Cliniques Plurithématique 1433, Inserm U1116, CHRU de Nancy and F-CRIN INI-CRCT, Nancy, France
| | - Patrick Rossignol
- Université de Lorraine, INSERM, Centre d'Investigations Cliniques Plurithématique 1433, Inserm U1116, CHRU de Nancy and F-CRIN INI-CRCT, Nancy, France
| | - Marco Metra
- Cardiology. University and Civil hospitals of Brescia, Brescia, Italy
| | - Chim C Lang
- Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee, Ninewells Hospital & Medical School, Dundee, UK
| | - Leong L Ng
- Department of Cardiovascular Sciences, University of Leicester, NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK
| | | | - Kenneth Dickstein
- Department of Internal Medicine, University of Bergen, Bergen, Norway.,Department of Cardiology, Stavanger University Hospital, Stavanger, Norway
| | - Dirk J van Veldhuisen
- Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Faiez Zannad
- Université de Lorraine, INSERM, Centre d'Investigations Cliniques Plurithématique 1433, Inserm U1116, CHRU de Nancy and F-CRIN INI-CRCT, Nancy, France
| | - João Pedro Ferreira
- Université de Lorraine, INSERM, Centre d'Investigations Cliniques Plurithématique 1433, Inserm U1116, CHRU de Nancy and F-CRIN INI-CRCT, Nancy, France
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Ifuku M, Takahashi K, Hosono Y, Iso T, Ishikawa A, Haruna H, Takubo N, Komiya K, Kurita M, Ikeda F, Watada H, Shimizu T. Left atrial dysfunction and stiffness in pediatric and adult patients with Type 1 diabetes mellitus assessed with speckle tracking echocardiography. Pediatr Diabetes 2021; 22:303-319. [PMID: 33094524 DOI: 10.1111/pedi.13141] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2020] [Revised: 10/05/2020] [Accepted: 10/15/2020] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Subclinical diastolic dysfunction in patients with Type 1 diabetes mellitus (T1DM) caused by myocardial injury due to diabetic cardiomyopathy leads to a high risk of death and heart failure. This myocardial injury extends not only to the left ventricle (LV) but also to the left atrium (LA). However, LA function in children and young adults with T1DM has not been extensively studied. OBJECTIVE Therefore, the aim of this study was to assess LA dysfunction in pediatric and adult patients with T1DM using LA strain analysis with echocardiography. SUBJECTS Fifty-three patients (median age: 23 [range: 5-41] years) with T1DM. METHODS We divided the patients into three age groups (D1: 5-14 years, D2: 15-24 years, D3: 25-41 years); 53 age- and sex-matched controls were divided into three corresponding groups (C1, C2, and C3). LA and LV functions were evaluated using echocardiography. RESULTS LA reservoir strain was lower in the D2 and D3 groups than in the C2 and C3 groups (P = 0.001, P = 0.004, respectively). LA conduit strain was lower in the D2 group than in the C2 group (P = 0.002). LA stiffness was significantly greater in the D3 group than in the C3 group (P < 0.001). CONCLUSIONS In patients with T1DM, LA phasic function decreased in adolescents and young adults, and LA stiffness increased in adult patients aged >30 years. LA phasic function and LA stiffness can be potentially used as early markers for diastolic dysfunction.
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Affiliation(s)
- Mayumi Ifuku
- Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan
| | - Ken Takahashi
- Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan
| | - Yu Hosono
- Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan
| | - Takeshi Iso
- Department of Pediatrics, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo, Japan
| | - Akimi Ishikawa
- Department of Pediatrics, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo, Japan
| | - Hidenori Haruna
- Department of Pediatrics, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo, Japan
| | - Noriyuki Takubo
- Department of Pediatrics, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo, Japan
| | - Kouji Komiya
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan
| | - Mika Kurita
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan
| | - Fuki Ikeda
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan
| | - Hirotaka Watada
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan
| | - Toshiaki Shimizu
- Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan.,Department of Pediatrics, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo, Japan
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Cosentino F, Grant PJ, Aboyans V, Bailey CJ, Ceriello A, Delgado V, Federici M, Filippatos G, Grobbee DE, Hansen TB, Huikuri HV, Johansson I, Jüni P, Lettino M, Marx N, Mellbin LG, Östgren CJ, Rocca B, Roffi M, Sattar N, Seferović PM, Sousa-Uva M, Valensi P, Wheeler DC. 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J 2021; 41:255-323. [PMID: 31497854 DOI: 10.1093/eurheartj/ehz486] [Citation(s) in RCA: 2588] [Impact Index Per Article: 647.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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Wang L, Cai Y, Jian L, Cheung CW, Zhang L, Xia Z. Impact of peroxisome proliferator-activated receptor-α on diabetic cardiomyopathy. Cardiovasc Diabetol 2021; 20:2. [PMID: 33397369 PMCID: PMC7783984 DOI: 10.1186/s12933-020-01188-0] [Citation(s) in RCA: 77] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Accepted: 12/02/2020] [Indexed: 12/21/2022] Open
Abstract
The prevalence of cardiomyopathy is higher in diabetic patients than those without diabetes. Diabetic cardiomyopathy (DCM) is defined as a clinical condition of abnormal myocardial structure and performance in diabetic patients without other cardiac risk factors, such as coronary artery disease, hypertension, and significant valvular disease. Multiple molecular events contribute to the development of DCM, which include the alterations in energy metabolism (fatty acid, glucose, ketone and branched chain amino acids) and the abnormalities of subcellular components in the heart, such as impaired insulin signaling, increased oxidative stress, calcium mishandling and inflammation. There are no specific drugs in treating DCM despite of decades of basic and clinical investigations. This is, in part, due to the lack of our understanding as to how heart failure initiates and develops, especially in diabetic patients without an underlying ischemic cause. Some of the traditional anti-diabetic or lipid-lowering agents aimed at shifting the balance of cardiac metabolism from utilizing fat to glucose have been shown inadequately targeting multiple aspects of the conditions. Peroxisome proliferator-activated receptor α (PPARα), a transcription factor, plays an important role in mediating DCM-related molecular events. Pharmacological targeting of PPARα activation has been demonstrated to be one of the important strategies for patients with diabetes, metabolic syndrome, and atherosclerotic cardiovascular diseases. The aim of this review is to provide a contemporary view of PPARα in association with the underlying pathophysiological changes in DCM. We discuss the PPARα-related drugs in clinical applications and facts related to the drugs that may be considered as risky (such as fenofibrate, bezafibrate, clofibrate) or safe (pemafibrate, metformin and glucagon-like peptide 1-receptor agonists) or having the potential (sodium-glucose co-transporter 2 inhibitor) in treating DCM.
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Affiliation(s)
- Lin Wang
- Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
- Department of Anaesthesiology, The University of Hong Kong, Hong Kong, SAR, China
| | - Yin Cai
- Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
- Department of Anaesthesiology, The University of Hong Kong, Hong Kong, SAR, China
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong, SAR, China
| | - Liguo Jian
- Department of Cardiology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Chi Wai Cheung
- Department of Anaesthesiology, The University of Hong Kong, Hong Kong, SAR, China
| | - Liangqing Zhang
- Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China.
| | - Zhengyuan Xia
- Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China.
- Department of Anaesthesiology, The University of Hong Kong, Hong Kong, SAR, China.
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23
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Haye A, Ansari MA, Rahman SO, Shamsi Y, Ahmed D, Sharma M. Role of AMP-activated protein kinase on cardio-metabolic abnormalities in the development of diabetic cardiomyopathy: A molecular landscape. Eur J Pharmacol 2020; 888:173376. [PMID: 32810493 DOI: 10.1016/j.ejphar.2020.173376] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Revised: 07/10/2020] [Accepted: 07/13/2020] [Indexed: 12/13/2022]
Abstract
Cardiovascular complications associated with diabetes mellitus remains a leading cause of morbidity and mortality across the world. Diabetic cardiomyopathy is a descriptive pathology that in absence of co-morbidities such as hypertension, dyslipidemia initially characterized by cardiac stiffness, myocardial fibrosis, ventricular hypertrophy, and remodeling. These abnormalities further contribute to diastolic dysfunctions followed by systolic dysfunctions and eventually results in clinical heart failure (HF). The clinical outcomes associated with HF are considerably worse in patients with diabetes. The complexity of the pathogenesis and clinical features of diabetic cardiomyopathy raises serious questions in developing a therapeutic strategy to manage cardio-metabolic abnormalities. Despite extensive research in the past decade the compelling approaches to manage and treat diabetic cardiomyopathy are limited. AMP-Activated Protein Kinase (AMPK), a serine-threonine kinase, often referred to as cellular "metabolic master switch". During the development and progression of diabetic cardiomyopathy, a plethora of evidence demonstrate the beneficial role of AMPK on cardio-metabolic abnormalities including altered substrate utilization, impaired cardiac insulin metabolic signaling, mitochondrial dysfunction and oxidative stress, myocardial inflammation, increased accumulation of advanced glycation end-products, impaired cardiac calcium handling, maladaptive activation of the renin-angiotensin-aldosterone system, endoplasmic reticulum stress, myocardial fibrosis, ventricular hypertrophy, cardiac apoptosis, and impaired autophagy. Therefore, in this review, we have summarized the findings from pre-clinical and clinical studies and provided a collective overview of the pathophysiological mechanism and the regulatory role of AMPK on cardio-metabolic abnormalities during the development of diabetic cardiomyopathy.
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Affiliation(s)
- Abdul Haye
- Pharmaceutical Medicine, Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India
| | - Mohd Asif Ansari
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India
| | - Syed Obaidur Rahman
- Pharmaceutical Medicine, Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India
| | - Yasmeen Shamsi
- Department of Moalejat, School of Unani Medical Education and Research, Jamia Hamdard, New Delhi, 110062, India
| | - Danish Ahmed
- Department of Pharmaceutical Sciences, Faculty of Health Sciences, Sam Higginbottom University of Agriculture Technology and Sciences, Allahabad, Uttar Pradesh, India
| | - Manju Sharma
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India.
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Li N, Zhou H. SGLT2 Inhibitors: A Novel Player in the Treatment and Prevention of Diabetic Cardiomyopathy. DRUG DESIGN DEVELOPMENT AND THERAPY 2020; 14:4775-4788. [PMID: 33192053 PMCID: PMC7654518 DOI: 10.2147/dddt.s269514] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Accepted: 09/23/2020] [Indexed: 12/16/2022]
Abstract
Diabetic cardiomyopathy (DCM) characterized by diastolic and systolic dysfunction independently of hypertension and coronary heart disease, eventually develops into heart failure, which is strongly linked to a high prevalence of mortality in people with diabetes mellitus (DM). Sodium-glucose cotransporter type2 inhibitors (SGLT2Is) are a novel type of hypoglycemic agent in increasing urinary glucose and sodium excretion. Excitingly, the EMPA-REG clinical trial proved that empagliflozin significantly reduced the relative risk of cardiovascular (CV) death and hospitalization for heart failure (HHF) in patients with type 2 DM (T2DM) plus CV disease (CVD). The EMPRISE trial showed that empagliflozin decreased the risk of HHF in T2DM patients with and without a CVD history in routine care. These beneficial effects of SGLT2Is could not be entirely attributed to glucose-lowering or natriuretic action. There could be potential direct mechanisms of SGLT2Is in cardioprotection. Recent studies have shown the effects of SGLT2Is on cardiac iron homeostasis, mitochondrial function, anti-inflammation, anti-fibrosis, antioxidative stress, and renin-angiotensin-aldosterone system activity, as well as GlcNAcylation in the heart. This article reviews the current literature on the effects of SGLT2Is on DCM in preclinical studies. Possible molecular mechanisms regarding potential benefits of SGLT2Is for DCM are highlighted, with the purpose of providing a novel strategy for preventing DCM.
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Affiliation(s)
- Na Li
- Department of Endocrinology, Second Hospital of Hebei Medical University, Shijiazhuang, People's Republic of China
| | - Hong Zhou
- Department of Endocrinology, Second Hospital of Hebei Medical University, Shijiazhuang, People's Republic of China
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25
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Hyperkalemia and management of renin-angiotensin-aldosterone system inhibitors in chronic heart failure with reduced ejection fraction: A systematic review. REVISTA PORTUGUESA DE CARDIOLOGIA (ENGLISH EDITION) 2020. [DOI: 10.1016/j.repce.2020.03.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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26
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Fonseca C, Brito D, Branco P, Frazão JM, Silva-Cardoso J, Bettencourt P. Hyperkalemia and management of renin-angiotensin-aldosterone system inhibitors in chronic heart failure with reduced ejection fraction: A systematic review. Rev Port Cardiol 2020; 39:517-541. [PMID: 32868174 DOI: 10.1016/j.repc.2020.03.015] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 01/17/2020] [Accepted: 03/23/2020] [Indexed: 11/17/2022] Open
Abstract
INTRODUCTION AND OBJECTIVES Renin-angiotensin-aldosterone system inhibitors (RAASi) are the cornerstone of treatment of heart failure with reduced ejection fraction (HFrEF). RAASi optimization in real-life care is challenged by hyperkalemia, a potentially fatal adverse event, which can necessitate downtitration or discontinuation of RAASi and negatively impact survival in HFrEF. The literature on this problem is sparse. We performed a systematic review of studies on HFrEF to investigate the prevalence, incidence, and risk factors of hyperkalemia, RAASi prescription rates, frequency of RAASi downtitration or discontinuation due to hyperkalemia, and the potential negative effect of the latter on prognosis. METHODS We conducted a MEDLINE (PubMed) search including observational and interventional studies published between January 1987 and May 2018. RESULTS A total of 30 observational and 18 interventional studies were included in the review. The incidence of hyperkalemia reported was between 0% and 63% in observational studies and was between 0% and 30% in clinical trials. Risk factors for hyperkalemia included RAASi prescription, older age, diabetes, and chronic kidney disease. In real-life studies, RAASi were downtitrated or discontinued in 3-22% of HFrEF patients; hyperkalemia was the reported cause in 5% of cases. No reports were found on the impact on prognosis of RAASi downtitration or discontinuation due to hyperkalemia. CONCLUSIONS Hyperkalemia and RAASi downtitration or discontinuation are frequent, particularly in real-life HFrEF studies. Further research is needed to clarify the role of RAASi downtitration or discontinuation due to hyperkalemia and to assess its long-term prognostic impact in HFrEF patients.
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Affiliation(s)
- Cândida Fonseca
- Heart Failure Clinic, São Francisco Xavier Hospital, Centro Hospitalar de Lisboa Ocidental (CHLO), Lisboa, Portugal; NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal.
| | - Dulce Brito
- Cardiology Department, Centro Hospitalar Universitário Lisboa Norte (CHLN), Lisboa, Portugal; CCUL, Faculty of Medicine, Universidade de Lisboa, Lisboa, Portugal
| | - Patrícia Branco
- Nephrology Department, Santa Cruz Hospital, Centro Hospitalar de Lisboa Ocidental (CHLO), Carnaxide, Portugal
| | - João Miguel Frazão
- Institute for Research and Innovation in Health Sciences (i3S) and Institute for Biomedical Engineering (INEB), Universidade do Porto, Porto, Portugal; Nephrology Department, Centro Hospitalar Universitário de São João (CHUSJ) and Faculty of Medicine, Universidade do Porto, Porto, Portugal
| | - José Silva-Cardoso
- Center for Health Technology and Services Research (CINTESIS), Porto, Portugal; Cardiology Department, Centro Hospitalar Universitário de São João (CHUSJ), Porto, Portugal
| | - Paulo Bettencourt
- Internal Medicine Department, CUF Porto Hospital, Porto, Portugal; Faculty of Medicine, University of Porto, Porto, Portugal
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27
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Butler J, Januzzi JL, Rosenstock J. Management of heart failure and type 2 diabetes mellitus: Maximizing complementary drug therapy. Diabetes Obes Metab 2020; 22:1243-1262. [PMID: 32243706 DOI: 10.1111/dom.14042] [Citation(s) in RCA: 10] [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: 01/06/2020] [Revised: 03/19/2020] [Accepted: 03/27/2020] [Indexed: 12/11/2022]
Abstract
Type 2 diabetes mellitus (T2DM) is a major risk factor for cardiovascular disease and occurs in ~25% of patients with heart failure (HF). Patients with co-morbid HF and T2DM are at elevated risk of adverse outcomes, making optimization of complementary drug therapies essential. While research is ongoing, recent advances in drug therapy, including the introduction of sacubitril/valsartan for HF with reduced ejection fraction and the finding of positive cardiovascular effects of glucose-lowering agents (particularly sodium-glucose co-transporter-2 [SGLT2] inhibitors) have the potential to transform pharmacologic management of co-morbid HF and T2DM. In this review, we provide a comprehensive overview of cardiovascular clinical trials of therapies for HF and diabetes mellitus to date and identify areas requiring further investigation. We also discuss the pathophysiologic overlap of the two diseases and explore the complementary therapeutic effects of HF and T2DM drugs, with a particular focus on sacubitril/valsartan and SGLT2 inhibitors.
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28
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Meindl C, Hochadel M, Frankenstein L, Bruder O, Pauschinger M, Hambrecht R, von Scheidt W, Pfister O, Hartmann A, Maier LS, Senges J, Unsöld B. The role of diabetes in cardiomyopathies of different etiologies-Characteristics and 1-year follow-up results of the EVITA-HF registry. PLoS One 2020; 15:e0234260. [PMID: 32525964 PMCID: PMC7289353 DOI: 10.1371/journal.pone.0234260] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 05/21/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Type 2 diabetes is a major risk factor for cardiovascular diseases, e.g. coronary artery disease (CAD). But it has also been shown that diabetes can cause heart failure independently of ischemic heart disease (IHD) by causing diabetic cardiomyopathy. In contrast to diabetes and IHD, limited data exist regarding patients with diabetes and dilated cardiomyopathy (DCM). METHODS EVIdence based TreAtment in Heart Failure (EVITA-HF) comprises web-based case report data on demography, diagnostic measures, adverse events and 1-year follow-up of patients hospitalized for chronic heart failure and an ejection fraction ≤40%. In the present study we focused on the results of patients with diabetes and heart failure. RESULTS Between February 2009 and November 2015, 4101 patients with chronic heart failure were included in 16 tertiary care centers in Germany. The mortality in patients with diabetes and DCM (n = 323) was more than double (15.2%) than that of DCM patients without diabetes (6.5%, p<0.001, n = 885). In contrast the mortality rate of patients with IHD was not influenced by the presence of diabetes (17.6% in patients with IHD and diabetes n = 945, vs. 14.7% in patients with IHD and no diabetes, n = 1236, p = 0.061). The results also remained stable after performing a multivariable analysis (unadjusted p-value for interaction = 0.002, adjusted p = 0.046). CONCLUSION The influence of diabetes on the mortality rate is only significant in patients with DCM not in patients with CAD. Therefore, the underlying mechanisms of this effect should be studied in greater detail to improve patient care and outcome.
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Affiliation(s)
- Christine Meindl
- Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
| | - Matthias Hochadel
- Stiftung Institut für Herzinfarktforschung Ludwigshafen, Ludwigshafen, Germany
| | - Lutz Frankenstein
- Department of Internal Medicine III, University Hospital Heidelberg, Heidelberg, Germany
| | - Oliver Bruder
- Department of Cardiology and Angiology, Elisabeth-Hospital Essen, Essen, Germany
| | | | - Rainer Hambrecht
- Department of Internal Medicine II, Hospital Links der Weser, Bremen, Germany
| | - Wolfgang von Scheidt
- Department of Internal Medicine I, University Hospital Augsburg, Augsburg, Germany
| | - Otmar Pfister
- Department of Cardiology, University Hospital Basel, Basel, Switzerland
| | - Andreas Hartmann
- Department of Cardiology and Internal Intensive Care, St. Georg Hospital Leipzig, Leipzig, Germany
| | - Lars S. Maier
- Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
| | - Jochen Senges
- Stiftung Institut für Herzinfarktforschung Ludwigshafen, Ludwigshafen, Germany
| | - Bernhard Unsöld
- Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
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Abstract
The term diabetic cardiomyopathy is defined as the presence of abnormalities in myocardial structure and function that occur in the absence of, or in addition to, well-established cardiovascular risk factors. A key contributor to this abnormal structural-functional relation is the complex interplay of myocardial metabolic remodeling, defined as the loss the flexibility in myocardial substrate metabolism and its downstream detrimental effects, such as mitochondrial dysfunction, inflammation, and fibrosis. In parallel with the growth in understanding of these biological underpinnings has been developmental advances in imaging tools such as positron emission tomography and magnetic resonance imaging and spectroscopy that permit the detection and in many cases quantification, of the processes that typifies the myocardial metabolic remodeling in diabetic cardiomyopathy. The imaging readouts can be obtained in both preclinical models of diabetes mellitus and patients with diabetes mellitus facilitating the bi-directional movement of information between bench and bedside. Moreover, imaging biomarkers provided by these tools are now being used to enhance discovery and development of therapies designed to reduce the myocardial effects of diabetes mellitus through metabolic modulation. In this review, the use of these imaging tools in the patient with diabetes mellitus from a mechanistic, therapeutic effect, and clinical management perspective will be discussed.
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Affiliation(s)
- Linda R Peterson
- From the Cardiovascular Division, Department of Medicine (L.R.P.), Washington University School of Medicine, St Louis, MO
| | - Robert J Gropler
- Division of Radiological Sciences, Edward Mallinckrodt Institute of Radiology (R.J.G.), Washington University School of Medicine, St Louis, MO
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Lunney M, Ruospo M, Natale P, Quinn RR, Ronksley PE, Konstantinidis I, Palmer SC, Tonelli M, Strippoli GF, Ravani P. Pharmacological interventions for heart failure in people with chronic kidney disease. Cochrane Database Syst Rev 2020; 2:CD012466. [PMID: 32103487 PMCID: PMC7044419 DOI: 10.1002/14651858.cd012466.pub2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Approximately half of people with heart failure have chronic kidney disease (CKD). Pharmacological interventions for heart failure in people with CKD have the potential to reduce death (any cause) or hospitalisations for decompensated heart failure. However, these interventions are of uncertain benefit and may increase the risk of harm, such as hypotension and electrolyte abnormalities, in those with CKD. OBJECTIVES This review aims to look at the benefits and harms of pharmacological interventions for HF (i.e., antihypertensive agents, inotropes, and agents that may improve the heart performance indirectly) in people with HF and CKD. SEARCH METHODS We searched the Cochrane Kidney and Transplant Register of Studies through 12 September 2019 in consultation with an Information Specialist and using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA We included randomised controlled trials of any pharmacological intervention for acute or chronic heart failure, among people of any age with chronic kidney disease of at least three months duration. DATA COLLECTION AND ANALYSIS Two authors independently screened the records to identify eligible studies and extracted data on the following dichotomous outcomes: death, hospitalisations, worsening heart failure, worsening kidney function, hyperkalaemia, and hypotension. We used random effects meta-analysis to estimate treatment effects, which we expressed as a risk ratio (RR) with 95% confidence intervals (CI). We assessed the risk of bias using the Cochrane tool. We applied the GRADE methodology to rate the certainty of evidence. MAIN RESULTS One hundred and twelve studies met our selection criteria: 15 were studies of adults with CKD; 16 studies were conducted in the general population but provided subgroup data for people with CKD; and 81 studies included individuals with CKD, however, data for this subgroup were not provided. The risk of bias in all 112 studies was frequently high or unclear. Of the 31 studies (23,762 participants) with data on CKD patients, follow-up ranged from three months to five years, and study size ranged from 16 to 2916 participants. In total, 26 studies (19,612 participants) reported disaggregated and extractable data on at least one outcome of interest for our review and were included in our meta-analyses. In acute heart failure, the effects of adenosine A1-receptor antagonists, dopamine, nesiritide, or serelaxin on death, hospitalisations, worsening heart failure or kidney function, hyperkalaemia, hypotension or quality of life were uncertain due to sparse data or were not reported. In chronic heart failure, the effects of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) (4 studies, 5003 participants: RR 0.85, 95% CI 0.70 to 1.02; I2 = 78%; low certainty evidence), aldosterone antagonists (2 studies, 34 participants: RR 0.61 95% CI 0.06 to 6.59; very low certainty evidence), and vasopressin receptor antagonists (RR 1.26, 95% CI 0.55 to 2.89; 2 studies, 1840 participants; low certainty evidence) on death (any cause) were uncertain. Treatment with beta-blockers may reduce the risk of death (any cause) (4 studies, 3136 participants: RR 0.69, 95% CI 0.60 to 0.79; I2 = 0%; moderate certainty evidence). Treatment with ACEi or ARB (2 studies, 1368 participants: RR 0.90, 95% CI 0.43 to 1.90; I2 = 97%; very low certainty evidence) had uncertain effects on hospitalisation for heart failure, as treatment estimates were consistent with either benefit or harm. Treatment with beta-blockers may decrease hospitalisation for heart failure (3 studies, 2287 participants: RR 0.67, 95% CI 0.43 to 1.05; I2 = 87%; low certainty evidence). Aldosterone antagonists may increase the risk of hyperkalaemia compared to placebo or no treatment (3 studies, 826 participants: RR 2.91, 95% CI 2.03 to 4.17; I2 = 0%; low certainty evidence). Renin inhibitors had uncertain risks of hyperkalaemia (2 studies, 142 participants: RR 0.86, 95% CI 0.49 to 1.49; I2 = 0%; very low certainty). We were unable to estimate whether treatment with sinus node inhibitors affects the risk of hyperkalaemia, as there were few studies and meta-analysis was not possible. Hyperkalaemia was not reported for the CKD subgroup in studies investigating other therapies. The effects of ACEi or ARB, or aldosterone antagonists on worsening heart failure or kidney function, hypotension, or quality of life were uncertain due to sparse data or were not reported. Effects of anti-arrhythmic agents, digoxin, phosphodiesterase inhibitors, renin inhibitors, sinus node inhibitors, vasodilators, and vasopressin receptor antagonists were very uncertain due to the paucity of studies. AUTHORS' CONCLUSIONS The effects of pharmacological interventions for heart failure in people with CKD are uncertain and there is insufficient evidence to inform clinical practice. Study data for treatment outcomes in patients with heart failure and CKD are sparse despite the potential impact of kidney impairment on the benefits and harms of treatment. Future research aimed at analysing existing data in general population HF studies to explore the effect in subgroups of patients with CKD, considering stage of disease, may yield valuable insights for the management of people with HF and CKD.
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Affiliation(s)
- Meaghan Lunney
- University of Calgary, Department of Community Health Sciences, 3330 Hospital Drive NW, Calgary, Alberta, Canada, T2N 4N1
| | - Marinella Ruospo
- The University of Sydney, Sydney School of Public Health, Sydney, Australia
- University of Bari, Department of Emergency and Organ Transplantation, Bari, Italy
| | - Patrizia Natale
- The University of Sydney, Sydney School of Public Health, Sydney, Australia
- University of Bari, Department of Emergency and Organ Transplantation, Bari, Italy
| | - Robert R Quinn
- University of Calgary, Department of Community Health Sciences, 3330 Hospital Drive NW, Calgary, Alberta, Canada, T2N 4N1
- Cumming School of Medicine, University of Calgary, Department of Medicine, Calgary, Canada
| | - Paul E Ronksley
- University of Calgary, Department of Community Health Sciences, 3330 Hospital Drive NW, Calgary, Alberta, Canada, T2N 4N1
| | - Ioannis Konstantinidis
- University of Pittsburgh Medical Center, Department of Medicine, 3459 Fifth Avenue, Pittsburgh, PA, USA, 15213
| | - Suetonia C Palmer
- Christchurch Hospital, University of Otago, Department of Medicine, Nephrologist, Christchurch, New Zealand
| | - Marcello Tonelli
- Cumming School of Medicine, University of Calgary, Department of Medicine, Calgary, Canada
| | - Giovanni Fm Strippoli
- The University of Sydney, Sydney School of Public Health, Sydney, Australia
- University of Bari, Department of Emergency and Organ Transplantation, Bari, Italy
- The Children's Hospital at Westmead, Cochrane Kidney and Transplant, Centre for Kidney Research, Westmead, NSW, Australia, 2145
| | - Pietro Ravani
- University of Calgary, Department of Community Health Sciences, 3330 Hospital Drive NW, Calgary, Alberta, Canada, T2N 4N1
- Cumming School of Medicine, University of Calgary, Department of Medicine, Calgary, Canada
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31
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Kaludercic N, Di Lisa F. Mitochondrial ROS Formation in the Pathogenesis of Diabetic Cardiomyopathy. Front Cardiovasc Med 2020; 7:12. [PMID: 32133373 PMCID: PMC7040199 DOI: 10.3389/fcvm.2020.00012] [Citation(s) in RCA: 175] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Accepted: 01/28/2020] [Indexed: 12/20/2022] Open
Abstract
Diabetic cardiomyopathy is a result of diabetes-induced changes in the structure and function of the heart. Hyperglycemia affects multiple pathways in the diabetic heart, but excessive reactive oxygen species (ROS) generation and oxidative stress represent common denominators associated with adverse tissue remodeling. Indeed, key processes underlying cardiac remodeling in diabetes are redox sensitive, including inflammation, organelle dysfunction, alteration in ion homeostasis, cardiomyocyte hypertrophy, apoptosis, fibrosis, and contractile dysfunction. Extensive experimental evidence supports the involvement of mitochondrial ROS formation in the alterations characterizing the diabetic heart. In this review we will outline the central role of mitochondrial ROS and alterations in the redox status contributing to the development of diabetic cardiomyopathy. We will discuss the role of different sources of ROS involved in this process, with a specific emphasis on mitochondrial ROS producing enzymes within cardiomyocytes. Finally, the therapeutic potential of pharmacological inhibitors of ROS sources within the mitochondria will be discussed.
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Affiliation(s)
- Nina Kaludercic
- Neuroscience Institute, National Research Council of Italy (CNR), Padua, Italy
| | - Fabio Di Lisa
- Neuroscience Institute, National Research Council of Italy (CNR), Padua, Italy.,Department of Biomedical Sciences, University of Padua, Padua, Italy
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32
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Seferovic JP, Solomon SD, Seely EW. Potential mechanisms of beneficial effect of sacubitril/valsartan on glycemic control. Ther Adv Endocrinol Metab 2020; 11:2042018820970444. [PMID: 33489085 PMCID: PMC7768573 DOI: 10.1177/2042018820970444] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Accepted: 10/12/2020] [Indexed: 12/11/2022] Open
Abstract
Heart failure (HF) and diabetes mellitus (DM) frequently coexist, with a prevalence of DM of 35-40% in patients with HF, independent of the level of impairment of the ejection fraction (EF). Furthermore, DM is considered a strong independent risk factor for the progression of HF with either preserved or reduced EF and is associated with poor prognosis. The ability of neprilysin inhibitors to elevate levels of biologically active natriuretic peptides has made them a potential therapeutic approach in HF. In the Prospective comparison of ARNi with ACEi to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM-HF) trial, a dual-acting angiotensin-receptor-neprilysin inhibitor, sacubitril/valsartan was superior to enalapril in reducing the risks of death and HF hospitalization in patients with HF with reduced EF. In addition, in a post-hoc analysis of this trial, among patients with DM, treatment with sacubitril/valsartan resulted in improved glycemic control compared with enalapril. Also, there are additional studies suggesting beneficial metabolic effects of this class of drugs. In this review we discuss potential mechanisms of sacubitril/valsartan effect on glycemic control. Sacubitril/valsartan concomitantly blocks the renin-angiotensin system and inhibits neprilysin, a ubiquitous enzyme responsible for the breakdown of more than 50 vasoactive peptides, including the biologically active natriuretic peptides, bradykinin, angiotensin I and II, endothelin 1, glucagon, glucagon-like peptide-1, insulin-B chain, and others. There are a number of potential mechanisms by which inhibition of neprilysin may lead to improvement in glycemic control, with most evidence suggesting modulation of neprilysin circulating substrates. Although there is some evidence suggesting the improvement of glucose metabolism by renin-angiotensin system inhibition, this effect is most likely modest. As these mechanisms are not fully understood, detailed mechanistic studies, as well as large randomized clinical trials in patients with DM, are needed to further clarify beneficial metabolic properties of sacubitril/valsartan.
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Affiliation(s)
| | - Scott D. Solomon
- Cardiovascular Division, Brigham and Women’s
Hospital, Harvard Medical School, Boston, MA, USA
| | - Ellen W. Seely
- Endocrinology, Diabetes, and Hypertension
Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA,
USA
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33
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Athithan L, Gulsin GS, McCann GP, Levelt E. Diabetic cardiomyopathy: Pathophysiology, theories and evidence to date. World J Diabetes 2019; 10:490-510. [PMID: 31641426 PMCID: PMC6801309 DOI: 10.4239/wjd.v10.i10.490] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Revised: 09/25/2019] [Accepted: 09/25/2019] [Indexed: 02/05/2023] Open
Abstract
The prevalence of type 2 diabetes (T2D) has increased worldwide and doubled over the last two decades. It features among the top 10 causes of mortality and morbidity in the world. Cardiovascular disease is the leading cause of complications in diabetes and within this, heart failure has been shown to be the leading cause of emergency admissions in the United Kingdom. There are many hypotheses and well-evidenced mechanisms by which diabetic cardiomyopathy as an entity develops. This review aims to give an overview of these mechanisms, with particular emphasis on metabolic inflexibility. T2D is associated with inefficient substrate utilisation, an inability to increase glucose metabolism and dependence on fatty acid oxidation within the diabetic heart resulting in mitochondrial uncoupling, glucotoxicity, lipotoxicity and initially subclinical cardiac dysfunction and finally in overt heart failure. The review also gives a concise update on developments within clinical imaging, specifically cardiac magnetic resonance studies to characterise and phenotype early cardiac dysfunction in T2D. A better understanding of the pathophysiology involved provides a platform for targeted therapy in diabetes to prevent the development of early heart failure with preserved ejection fraction.
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Affiliation(s)
- Lavanya Athithan
- Department of Cardiovascular Sciences, University of Leicester and NIHR Leicester Cardiovascular Biomedical Research Centre, Glenfield Hospital, Leicester LE3 9QP, United Kingdom
| | - Gaurav S Gulsin
- Department of Cardiovascular Sciences, University of Leicester and NIHR Leicester Cardiovascular Biomedical Research Centre, Glenfield Hospital, Leicester LE3 9QP, United Kingdom
| | - Gerald P McCann
- Department of Cardiovascular Sciences, University of Leicester and NIHR Leicester Cardiovascular Biomedical Research Centre, Glenfield Hospital, Leicester LE3 9QP, United Kingdom
| | - Eylem Levelt
- Multidisciplinary Cardiovascular Research Centre and Biomedical Imaging Science Department, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds LF9 7TF, United Kingdom
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34
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Abstract
Heart failure and related morbidity and mortality are increasing at an alarming rate, in large part, because of increases in aging, obesity, and diabetes mellitus. The clinical outcomes associated with heart failure are considerably worse for patients with diabetes mellitus than for those without diabetes mellitus. In people with diabetes mellitus, the presence of myocardial dysfunction in the absence of overt clinical coronary artery disease, valvular disease, and other conventional cardiovascular risk factors, such as hypertension and dyslipidemia, has led to the descriptive terminology, diabetic cardiomyopathy. The prevalence of diabetic cardiomyopathy is increasing in parallel with the increase in diabetes mellitus. Diabetic cardiomyopathy is initially characterized by myocardial fibrosis, dysfunctional remodeling, and associated diastolic dysfunction, later by systolic dysfunction, and eventually by clinical heart failure. Impaired cardiac insulin metabolic signaling, mitochondrial dysfunction, increases in oxidative stress, reduced nitric oxide bioavailability, elevations in advanced glycation end products and collagen-based cardiomyocyte and extracellular matrix stiffness, impaired mitochondrial and cardiomyocyte calcium handling, inflammation, renin-angiotensin-aldosterone system activation, cardiac autonomic neuropathy, endoplasmic reticulum stress, microvascular dysfunction, and a myriad of cardiac metabolic abnormalities have all been implicated in the development and progression of diabetic cardiomyopathy. Molecular mechanisms linked to the underlying pathophysiological changes include abnormalities in AMP-activated protein kinase, peroxisome proliferator-activated receptors, O-linked N-acetylglucosamine, protein kinase C, microRNA, and exosome pathways. The aim of this review is to provide a contemporary view of these instigators of diabetic cardiomyopathy, as well as mechanistically based strategies for the prevention and treatment of diabetic cardiomyopathy.
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Affiliation(s)
- Guanghong Jia
- From the Diabetes and Cardiovascular Research Center (G.J., J.R.S.) and Department of Medical Pharmacology and Physiology (M.A.H., J.R.S.), University of Missouri School of Medicine, Columbia; Dalton Cardiovascular Research Center, University of Missouri, Columbia (M.A.H., J.R.S.); and Research Service, Truman Memorial Veterans Hospital, Columbia, MO (G.J., J.R.S.)
| | - Michael A Hill
- From the Diabetes and Cardiovascular Research Center (G.J., J.R.S.) and Department of Medical Pharmacology and Physiology (M.A.H., J.R.S.), University of Missouri School of Medicine, Columbia; Dalton Cardiovascular Research Center, University of Missouri, Columbia (M.A.H., J.R.S.); and Research Service, Truman Memorial Veterans Hospital, Columbia, MO (G.J., J.R.S.)
| | - James R Sowers
- From the Diabetes and Cardiovascular Research Center (G.J., J.R.S.) and Department of Medical Pharmacology and Physiology (M.A.H., J.R.S.), University of Missouri School of Medicine, Columbia; Dalton Cardiovascular Research Center, University of Missouri, Columbia (M.A.H., J.R.S.); and Research Service, Truman Memorial Veterans Hospital, Columbia, MO (G.J., J.R.S.).
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35
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Quinaglia T, Oliveira DC, Matos-Souza JR, Sposito AC. Diabetic cardiomyopathy: factual or factoid? ACTA ACUST UNITED AC 2019; 65:61-69. [PMID: 30758422 DOI: 10.1590/1806-9282.65.1.69] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Accepted: 10/26/2018] [Indexed: 02/08/2023]
Abstract
Although long ago described, there is no established consensus regarding the real existence of Diabetic Cardiomyopathy (CMPDM). Due to its complex pathophysiology, it has been difficult for clinical and experimental research to establish clear connections between diabetes mellitus (DM) and heart failure (HF), as well as to solve the mechanisms of the underlying myocardial disease. However, the epidemiological evidence of the relationship of these conditions is undisputed. The interest in understanding this disease has intensified due to the recent results of clinical trials evaluating new glucose-lowering drugs, such as sodium-glucose transporter inhibitors 2, which demonstrated favorable responses considering the prevention and treatment of HF in patients with DM. In this review we cover aspects of the epidemiology of CMPDM and its possible pathogenic mechanisms, as well as, present the main cardiac phenotypes of CMPDM (HF with preserved and reduced ejection fraction) and implications of the therapeutic management of this disease.
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Affiliation(s)
- Thiago Quinaglia
- Subject of Cardiology, Faculty of Medical Sciences - State University of Campinas (Unicamp), Campinas, SP, Brasil
| | - Daniela C Oliveira
- Subject of Cardiology, Faculty of Medical Sciences - State University of Campinas (Unicamp), Campinas, SP, Brasil
| | - José Roberto Matos-Souza
- Subject of Cardiology, Faculty of Medical Sciences - State University of Campinas (Unicamp), Campinas, SP, Brasil
| | - Andrei C Sposito
- Subject of Cardiology, Faculty of Medical Sciences - State University of Campinas (Unicamp), Campinas, SP, Brasil
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36
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Ofstad AP, Atar D, Gullestad L, Langslet G, Johansen OE. The heart failure burden of type 2 diabetes mellitus-a review of pathophysiology and interventions. Heart Fail Rev 2018; 23:303-323. [PMID: 29516230 PMCID: PMC5937871 DOI: 10.1007/s10741-018-9685-0] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Diabetes and heart failure (HF) are both global epidemics with tremendous costs on society with increased rates of HF hospitalizations and worsened prognosis when co-existing, making it a significant "deadly duo." The evidence for pharmacological treatment of HF in patients with type 2 diabetes mellitus (T2DM) stems typically from either subgroup analyses of patients that were recruited to randomized controlled trials of HF interventions, usually in patients with reduced ejection fraction (EF), or from subgroup analyses of HF patients recruited to cardiovascular (CV) outcome trials (CVOT) of glucose lowering agents involving patients with T2DM. Studies in patients with HF with preserved EF are sparse. This review summarizes the literature on pathophysiology and interventions aiming to reduce the HF burden in T2DM and includes HF trials of ACEi, digoxin, β-blocker, ARB, If-blocker, MRA, and ARNI involving 38,600 patients, with or without prevalent diabetes, and CV outcome trials in T2DM involving 74,351 patients, with or without prevalent HF. In all HF trials, HF outcomes by prevalent diabetes were reported with an incremental risk of HF and death confessed by prevalent diabetes and a treatment effect similar to those without diabetes. All T2DM CVOTs reported on HF outcomes with heterogeneity between trials with two reporting benefits (empagliflozin and canagliflozin) and two reporting increased risk (saxagliptin, pioglitazone). In vulnerable T2DM patients with concomitant HF, guideline-recommended HF drugs are effective. When choosing glucose-lowering therapy, outcomes from available CVOTs should be considered.
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Affiliation(s)
- Anne Pernille Ofstad
- Bærum Hospital, Vestre Viken HF, Rud, Norway.
- Medical Department, Boehringer Ingelheim, Asker, Norway.
| | - Dan Atar
- Department of Cardiology B, Oslo University Hospital, Ullevål, Oslo, Norway
- Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Lars Gullestad
- Faculty of Medicine, University of Oslo, Oslo, Norway
- Department of Cardiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Gisle Langslet
- Rikshospitalet, Lipid Clinic, Oslo University Hospital, Oslo, Norway
| | - Odd Erik Johansen
- Bærum Hospital, Vestre Viken HF, Rud, Norway
- Medical Department, Boehringer Ingelheim, Asker, Norway
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37
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Seferović PM, Petrie MC, Filippatos GS, Anker SD, Rosano G, Bauersachs J, Paulus WJ, Komajda M, Cosentino F, de Boer RA, Farmakis D, Doehner W, Lambrinou E, Lopatin Y, Piepoli MF, Theodorakis MJ, Wiggers H, Lekakis J, Mebazaa A, Mamas MA, Tschöpe C, Hoes AW, Seferović JP, Logue J, McDonagh T, Riley JP, Milinković I, Polovina M, van Veldhuisen DJ, Lainscak M, Maggioni AP, Ruschitzka F, McMurray JJV. Type 2 diabetes mellitus and heart failure: a position statement from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2018. [PMID: 29520964 DOI: 10.1002/ejhf.1170] [Citation(s) in RCA: 431] [Impact Index Per Article: 61.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The coexistence of type 2 diabetes mellitus (T2DM) and heart failure (HF), either with reduced (HFrEF) or preserved ejection fraction (HFpEF), is frequent (30-40% of patients) and associated with a higher risk of HF hospitalization, all-cause and cardiovascular (CV) mortality. The most important causes of HF in T2DM are coronary artery disease, arterial hypertension and a direct detrimental effect of T2DM on the myocardium. T2DM is often unrecognized in HF patients, and vice versa, which emphasizes the importance of an active search for both disorders in the clinical practice. There are no specific limitations to HF treatment in T2DM. Subanalyses of trials addressing HF treatment in the general population have shown that all HF therapies are similarly effective regardless of T2DM. Concerning T2DM treatment in HF patients, most guidelines currently recommend metformin as the first-line choice. Sulphonylureas and insulin have been the traditional second- and third-line therapies although their safety in HF is equivocal. Neither glucagon-like preptide-1 (GLP-1) receptor agonists, nor dipeptidyl peptidase-4 (DPP4) inhibitors reduce the risk for HF hospitalization. Indeed, a DPP4 inhibitor, saxagliptin, has been associated with a higher risk of HF hospitalization. Thiazolidinediones (pioglitazone and rosiglitazone) are contraindicated in patients with (or at risk of) HF. In recent trials, sodium-glucose co-transporter-2 (SGLT2) inhibitors, empagliflozin and canagliflozin, have both shown a significant reduction in HF hospitalization in patients with established CV disease or at risk of CV disease. Several ongoing trials should provide an insight into the effectiveness of SGLT2 inhibitors in patients with HFrEF and HFpEF in the absence of T2DM.
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Affiliation(s)
- Petar M Seferović
- University of Belgrade School of Medicine, Belgrade University Medical Center, Belgrade, Serbia
| | - Mark C Petrie
- Institute of Cardiovascular and Medical Sciences, British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK
| | - Gerasimos S Filippatos
- Department of Cardiology, National and Kapodistrian University of Athens Medical School, Athens University Hospital "Attikon", Athens, Greece
| | - Stefan D Anker
- Division of Cardiology and Metabolism - Heart Failure, Cachexia & Sarcopenia, Department of Cardiology (CVK); and Berlin-Brandenburg Center for Regenerative Therapies (BCRT); Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK) Berlin; Charité Universitätsmedizin Berlin, Germany; Department of Cardiology and Pneumology, University Medicine Göttingen, Göttingen, Germany
| | - Giuseppe Rosano
- Department of Medical Sciences, IRCCS San Raffaele Pisana, Roma, Italy and Cardiovascular and Cell Science Institute, St George's University of London, London, UK
| | - Johann Bauersachs
- NIHR Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, London, UK
| | - Walter J Paulus
- Department of Physiology and Institute for Cardiovascular Research VU, VU University Medical Center, Amsterdam, The Netherlands
| | - Michel Komajda
- Institute of Cardiometabolism and Nutrition (ICAN), Pierre et Marie Curie University, Paris VI, La Pitié-Salpétrière Hospital, Paris, France
| | - Francesco Cosentino
- Cardiology Unit, Department of Medicine, Karolinska University Hospital, Stockholm, Sweden
| | - Rudolf A de Boer
- University of Groningen, University Medical Centre Groningen, Department of Cardiology, Hanzeplein Groningen, The Netherlands
| | - Dimitrios Farmakis
- Institute of Cardiovascular and Medical Sciences, British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK
| | - Wolfram Doehner
- Charité - Campus Virchow (CVK), Center for Stroke Research, Berlin, Germany
| | | | - Yuri Lopatin
- Volgograd Medical University, Cardiology Centre, Volgograd, Russian Federation
| | - Massimo F Piepoli
- Heart Failure Unit, Cardiac Department, Guglielmo da Saliceto Hospital, AUSL, Piacenza, Italy
| | - Michael J Theodorakis
- Endocrinology, Metabolism and Diabetes Unit, Evgenideion Hospital, University of Athens, Athens, Greece
| | - Henrik Wiggers
- Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark
| | - John Lekakis
- Institute of Cardiovascular and Medical Sciences, British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK
| | - Alexandre Mebazaa
- University Paris Diderot, Paris, France; and Department of Anaesthesia and Critical Care, University Hospitals Saint Louis-Lariboisière, Paris, France
| | - Mamas A Mamas
- Cardiovascular Research Group, Keele University, Stoke-on-Trent, UK
| | - Carsten Tschöpe
- Department of Cardiology, Campus Virchow Klinikum, Charite - Universitaetsmedizin Berlin, Berlin, Germany
| | - Arno W Hoes
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Jelena P Seferović
- Clinic of Endocrinology, Diabetes and Metabolic Diseases, Belgrade University Medical Center, Belgrade, Serbia
| | - Jennifer Logue
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
| | - Theresa McDonagh
- Department of Cardiology, King's College Hospital, Denmark Hill, London, UK
| | - Jillian P Riley
- National Heart and Lung Institute Imperial College London, London, UK
| | - Ivan Milinković
- University of Belgrade School of Medicine, Belgrade University Medical Center, Belgrade, Serbia
| | - Marija Polovina
- University of Belgrade School of Medicine, Belgrade University Medical Center, Belgrade, Serbia
| | - Dirk J van Veldhuisen
- Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Mitja Lainscak
- Department of Internal Medicine, and Department of Research and Education, General Hospital Murska Sobota, Murska Sobota, Slovenia
| | - Aldo P Maggioni
- Research Center of the Italian Association of Hospital Cardiologists, Florence, Italy
| | - Frank Ruschitzka
- University Heart Centre, University Hospital Zurich, Zurich, Switzerland
| | - John J V McMurray
- British Heart Foundation, Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
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38
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Packer M. Heart Failure: The Most Important, Preventable, and Treatable Cardiovascular Complication of Type 2 Diabetes. Diabetes Care 2018; 41:11-13. [PMID: 29263193 DOI: 10.2337/dci17-0052] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Affiliation(s)
- Milton Packer
- Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX
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39
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Gustafson D, Veitch S, Fish JE. Extracellular Vesicles as Protagonists of Diabetic Cardiovascular Pathology. Front Cardiovasc Med 2017; 4:71. [PMID: 29209616 PMCID: PMC5701646 DOI: 10.3389/fcvm.2017.00071] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Accepted: 10/26/2017] [Indexed: 12/21/2022] Open
Abstract
Extracellular vesicles (EVs) represent an emerging mechanism of cell–cell communication in the cardiovascular system. Recent data suggest that EVs are produced and taken up by multiple cardiovascular cell types, influencing target cells through signaling or transfer of cargo (including proteins, lipids, messenger RNA, and non-coding RNA). The concentration and contents of circulating EVs are altered in several diseases and represent explicit signatures of cellular activation, making them of particular interest as circulating biomarkers. EVs also actively contribute to the progression of various cardiovascular diseases, including diabetes-related vascular disease. Understanding the relationships between circulating EVs, diabetes, and cardiovascular disease is of importance as diabetic patients are at elevated risk for developing several debilitating cardiovascular pathologies, including diabetic cardiomyopathy (DCM), a disease that remains an enigma at the molecular level. Enhancing and exploiting our understanding of EV biology could facilitate the development of effective non-invasive diagnostics, prognostics, and therapeutics. This review will focus on EV biology in diabetic cardiovascular diseases, including atherosclerosis and DCM. We will review EV biogenesis and functional properties, as well as provide insight into their emerging role in cell–cell communication. Finally, we will address the utility of EVs as clinical biomarkers and outline their impact as a biomedical tool in the development of therapeutics.
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Affiliation(s)
- Dakota Gustafson
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Shawn Veitch
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Jason E Fish
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.,Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada.,Heart & Stroke Richard Lewar Center of Excellence in Cardiovascular Research, University of Toronto, Toronto, ON, Canada
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40
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Dauriz M, Mantovani A, Bonapace S, Verlato G, Zoppini G, Bonora E, Targher G. Prognostic Impact of Diabetes on Long-term Survival Outcomes in Patients With Heart Failure: A Meta-analysis. Diabetes Care 2017; 40:1597-1605. [PMID: 29061587 DOI: 10.2337/dc17-0697] [Citation(s) in RCA: 79] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2017] [Accepted: 07/28/2017] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Several studies have explored the impact of diabetes on mortality in patients with heart failure (HF). However, the extent to which diabetes may confer risk of mortality and hospitalization in this patient population remains imperfectly known. Here we examine the independent prognostic impact of diabetes on the long-term risk of mortality and hospitalization in patients with HF. RESEARCH DESIGN AND METHODS PubMed, Scopus, and Web of Science from January 1990 to October 2016 were the data sources used. We included large (n ≥1,000) observational registries and randomized controlled trials with a follow-up duration of at least 1 year. Eligible studies were selected according to predefined keywords and clinical outcomes. Data from selected studies were extracted, and meta-analysis was performed using random-effects modeling. RESULTS A total of 31 registries and 12 clinical trials with 381,725 patients with acute and chronic HF and 102,036 all-cause deaths over a median follow-up of 3 years were included in the final analysis. Diabetes was associated with a higher risk of all-cause death (random-effects hazard ratio [HR] 1.28 [95% CI 1.21, 1.35]), cardiovascular death (1.34 [1.20, 1.49]), hospitalization (1.35 [1.20, 1.50]), and the combined end point of all-cause death or hospitalization (1.41 [1.29, 1.53]). The impact of diabetes on mortality and hospitalization was greater in patients with chronic HF than in those with acute HF. Limitations included high heterogeneity and varying degrees of confounder adjustment across individual studies. CONCLUSIONS This updated meta-analysis shows that the presence of diabetes per se adversely affects long-term survival and risk of hospitalization in patients with acute and chronic HF.
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Affiliation(s)
- Marco Dauriz
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Verona and Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy
| | - Alessandro Mantovani
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Verona and Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy
| | - Stefano Bonapace
- Division of Cardiology, ''Sacro Cuore'' Hospital, Negrar, Verona, Italy
| | - Giuseppe Verlato
- Unit of Epidemiology and Medical Statistics, Department of Medicine and Public Health, University of Verona, Verona, Italy
| | - Giacomo Zoppini
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Verona and Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy
| | - Enzo Bonora
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Verona and Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy
| | - Giovanni Targher
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Verona and Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy
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41
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Kim MS, Lee JH, Kim EJ, Park DG, Park SJ, Park JJ, Shin MS, Yoo BS, Youn JC, Lee SE, Ihm SH, Jang SY, Jo SH, Cho JY, Cho HJ, Choi S, Choi JO, Han SW, Hwang KK, Jeon ES, Cho MC, Chae SC, Choi DJ. Korean Guidelines for Diagnosis and Management of Chronic Heart Failure. Korean Circ J 2017; 47:555-643. [PMID: 28955381 PMCID: PMC5614939 DOI: 10.4070/kcj.2017.0009] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2017] [Revised: 06/19/2017] [Accepted: 06/23/2017] [Indexed: 11/11/2022] Open
Abstract
The prevalence of heart failure (HF) is skyrocketing worldwide, and is closely associated with serious morbidity and mortality. In particular, HF is one of the main causes for the hospitalization and mortality in elderly individuals. Korea also has these epidemiological problems, and HF is responsible for huge socioeconomic burden. However, there has been no clinical guideline for HF management in Korea.
The present guideline provides the first set of practical guidelines for the management of HF in Korea and was developed using the guideline adaptation process while including as many data from Korean studies as possible. The scope of the present guideline includes the definition, diagnosis, and treatment of chronic HF with reduced/preserved ejection fraction of various etiologies.
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Affiliation(s)
- Min-Seok Kim
- Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Ju-Hee Lee
- Division of Cardiology, Department of Internal Medicine, Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, Korea
| | - Eung Ju Kim
- Department of Cardiology, Cardiovascular Center, Korea University Guro Hospital, Seoul, Korea
| | - Dae-Gyun Park
- Division of Cardiology, Hallym University Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea
| | - Sung-Ji Park
- Division of Cardiology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jin Joo Park
- Department of Internal Medicine, Cardiovascular Center, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Mi-Seung Shin
- Division of Cardiology, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea
| | - Byung Su Yoo
- Division of Cardiology, Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Jong-Chan Youn
- Division of Cardiology, Hallym University Dongtan Sacred Heart Hospital, Hallym University College of Medicine, Hwaseong, Korea
| | - Sang Eun Lee
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
| | - Sang Hyun Ihm
- Department of Cardiology, Bucheon St. Mary's Hospital, The Catholic University of Korea, Bucheon, Korea
| | - Se Yong Jang
- Division of Cardiology, Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Korea
| | - Sang-Ho Jo
- Division of Cardiology, Hallym University Pyeongchon Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Korea
| | - Jae Yeong Cho
- Department of Cardiovascular Medicine, Chonnam National University Hospital, Gwangju, Korea
| | - Hyun-Jai Cho
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
| | - Seonghoon Choi
- Division of Cardiology, Hallym University Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea
| | - Jin-Oh Choi
- Division of Cardiology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Seong Woo Han
- Division of Cardiology, Hallym University Dongtan Sacred Heart Hospital, Hallym University College of Medicine, Hwaseong, Korea
| | - Kyung Kuk Hwang
- Division of Cardiology, Department of Internal Medicine, Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, Korea
| | - Eun Seok Jeon
- Division of Cardiology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Myeong-Chan Cho
- Division of Cardiology, Department of Internal Medicine, Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, Korea
| | - Shung Chull Chae
- Division of Cardiology, Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Korea
| | - Dong-Ju Choi
- Department of Internal Medicine, Cardiovascular Center, Seoul National University Bundang Hospital, Seongnam, Korea
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Novel Cardiac Intracrine Mechanisms Based on Ang-(1-12)/Chymase Axis Require a Revision of Therapeutic Approaches in Human Heart Disease. Curr Hypertens Rep 2017; 19:16. [PMID: 28233239 DOI: 10.1007/s11906-017-0708-3] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
PURPOSE OF THE REVIEW Drugs targeting the renin-angiotensin system (RAS), namely angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers, are the most commonly prescribed drugs for patients with or at risk for cardiovascular events. However, new treatment strategies aimed at mitigating the rise of the heart failure pandemic are warranted because clinical trials show that RAS blockers have limited benefits in halting disease progression. The main goal of this review is to put forward the concept of an intracrine RAS signaling through the novel angiotensin-(1-12)/chymase axis as the main source of deleterious angiotensin II (Ang II) in cardiac maladaptive remodeling leading to heart failure (HF). RECENT FINDINGS Expanding traditional knowledge, Ang II can be produced in tissues independently from the circulatory renin-angiotensin system. In the heart, angiotensin-(1-12) [Ang-(1-12)], a recently discovered derivative of angiotensinogen, is a precursor of Ang II, and chymase rather than ACE is the main enzyme contributing to the direct production of Ang II from Ang-(1-12). The Ang-(1-12)/chymase axis is an independent intracrine pathway accounting for the trophic, contractile, and pro-arrhythmic Ang II actions in the human heart. Ang-(1-12) expression and chymase activity have been found elevated in the left atrial appendage of heart disease subjects, suggesting a pivotal role of this axis in the progression of HF. Recent meta-analysis of large clinical trials on the use of ACE inhibitors and angiotensin receptor blockers in cardiovascular disease has demonstrated an imbalance between patients that significantly benefit from these therapeutic agents and those that remain at risk for heart disease progression. Looking to find an explanation, detailed investigation on the RAS has unveiled a previously unrecognized complexity of substrates and enzymes in tissues ultimately associated with the production of Ang II that may explain the shortcomings of ACE inhibition and angiotensin receptor blockade. Discovery of the Ang-(1-12)/chymase axis in human hearts, capable of producing Ang II independently from the circulatory RAS, has led to the notion that a tissue-delimited RAS signaling in an intracrine fashion may account for the deleterious effects of Ang II in the heart, contributing to the transition from maladaptive cardiac remodeling to heart failure. Targeting intracellular RAS signaling may improve current therapies aimed at reducing the burden of heart failure.
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Lee WS, Kim J. Diabetic cardiomyopathy: where we are and where we are going. Korean J Intern Med 2017; 32:404-421. [PMID: 28415836 PMCID: PMC5432803 DOI: 10.3904/kjim.2016.208] [Citation(s) in RCA: 112] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2016] [Accepted: 01/08/2017] [Indexed: 12/15/2022] Open
Abstract
The global burden of diabetes mellitus and its related complications are currently increasing. Diabetes mellitus affects the heart through various mechanisms including microvascular impairment, metabolic disturbance, subcellular component abnormalities, cardiac autonomic dysfunction, and a maladaptive immune response. Eventually, diabetes mellitus can cause functional and structural changes in the myocardium without coronary artery disease, a disorder known as diabetic cardiomyopathy (DCM). There are many diagnostic tools and management options for DCM, although it is difficult to detect its development and effectively prevent its progression. In this review, we summarize the current research regarding the pathophysiology and pathogenesis of DCM. Moreover, we discuss emerging diagnostic evaluation methods and treatment strategies for DCM, which may help our understanding of its underlying mechanisms and facilitate the identification of possible new therapeutic targets.
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Affiliation(s)
- Wang-Soo Lee
- Division of Cardiology, Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea
| | - Jaetaek Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea
- Correspondence to Jaetaek Kim, M.D. Division of Endocrinology and Metabolism, Department of Internal Medicine, Chung-Ang University Hospital, 102 Heukseok-ro, Dongjak-gu, Seoul 06973, Korea Tel: +82-2-6299-1397 Fax: +82-2-6299-1390 E-mail:
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Abstract
Following extensive clinical research, drugs affecting the renin-angiotensin system have been used for the treatment of patients with congestive heart failure, myocardial infarction, hypertension, diabetic nephropathy, chronic renal failure and for reducing the risk of developing major cardiovascular (CV) events. This review examines all mega trials (those involving >1000 patients) and smaller pivotal trials involving angiotensin-converting enzyme inhibitors (ACE-Is; 25 mega trials) and angiotensin receptor blockers (ARBs; 27 mega trials) to provide perspective on the huge database of evidence that has accumulated on the use of these drugs. Our review demonstrates that ACE-Is and ARBs are generally as effective as conventional therapies in the treatment of hypertension, but offer additional cardioprotective benefits in patients with heart failure, and in those who have experienced myocardial infarction. Also, both ACE-Is and ARBs are capable of renal protection in addition to their blood-pressure-lowering effects. Although ACE-Is and ARBs provide major benefits to CV patients, doubts remain over the concept of blood-pressure-independent CV protection offered by both classes of drugs. ACE-Is and ARBs appear to be equally effective with respect to morbidity and mortality endpoints, but ARBs are better tolerated. Considering the available evidence, the combined use of an ACE-I and ARB should be avoided and full doses of either ACE-I or ARB should be aimed for as evidence suggests they provide a greater prognostic benefit.
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Affiliation(s)
- Rainer Düsing
- Hypertoniezentrum Bonn, Am Burgweiher 52-54, 53123 Bonn, Germany
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Lombardi C, Spigoni V, Gorga E, Dei Cas A. Novel insight into the dangerous connection between diabetes and heart failure. Herz 2017; 41:201-7. [PMID: 27071966 DOI: 10.1007/s00059-016-4415-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Heart failure (HF) affects approximately 1-2 % of the adult population. Diabetes mellitus (DM) is one of the most frequent comorbidities in HF, portending a worse prognosis. DM is associated with an increased risk of artery disease, and consequently of post-ischemic HF, but it may also alter directly the myocardial structure and function. Insights into the pathophysiological mechanisms of diabetic cardiomyopathy have been provided by both experimental and clinical investigations. In recent years, it has emerged that the fibrotic process is a result of the convergence of multiple neurohormonal alterations in diabetic cardiomyopathy at the basis of disease progression and phenotype determination: HF with reduced or preserved ejection fraction. Therapies for HF and DM should demonstrate an improved prognosis and have a neutral effect on glucose homeostasis and the risk of HF development.
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Affiliation(s)
- C Lombardi
- Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Parma and AOU of Parma, Parma, Italy
| | - V Spigoni
- Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, Cardiology, University of Brescia, Brescia, Italy
| | - E Gorga
- Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, Cardiology, University of Brescia, Brescia, Italy
| | - A Dei Cas
- , Via Gramsci 14, 43126, Parma, Italy.
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46
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Dei Cas A, Khan SS, Butler J, Mentz RJ, Bonow RO, Avogaro A, Tschoepe D, Doehner W, Greene SJ, Senni M, Gheorghiade M, Fonarow GC. Impact of diabetes on epidemiology, treatment, and outcomes of patients with heart failure. JACC-HEART FAILURE 2016; 3:136-45. [PMID: 25660838 DOI: 10.1016/j.jchf.2014.08.004] [Citation(s) in RCA: 245] [Impact Index Per Article: 27.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/25/2014] [Revised: 08/18/2014] [Accepted: 08/22/2014] [Indexed: 12/11/2022]
Abstract
The prevalence of patients with concomitant heart failure (HF) and diabetes mellitus (DM) continues to increase with the general aging of the population. In patients with chronic HF, prevalence of DM is 24% compared with 40% in those hospitalized with worsening HF. Patients with concomitant HF and DM have diverse pathophysiologic, metabolic, and neurohormonal abnormalities that potentially contribute to worse outcomes than those without comorbid DM. In addition, although stable HF outpatients with DM show responses that are similar to those of patients without DM undergoing evidence-based therapies, it is unclear whether hospitalized HF patients with DM will respond similarly to novel investigational therapies. These data support the need to re-evaluate the epidemiology, pathophysiology, and therapy of HF patients with concomitant DM. This paper discusses the role of DM in HF patients and underscores the potential need for the development of targeted therapies.
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Affiliation(s)
- Alessandra Dei Cas
- Unit of Diabetes and Prevention of Associated Diseases, Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy
| | - Sadiya S Khan
- Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Javed Butler
- Cardiology Division, Stony Brook University, Stony Brook, New York
| | - Robert J Mentz
- Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, North Carolina
| | - Robert O Bonow
- Center for Cardiovascular Innovation, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Angelo Avogaro
- Department of Medicine, University of Padova, Padova, Italy
| | - Diethelm Tschoepe
- Heart and Diabetes Center North Rhine Westfalia, University Clinic of the Ruhr University, Bochum, Germany
| | - Wolfram Doehner
- Center for Stroke Research, Charite Universitätsmedizin, Berlin, Germany
| | - Stephen J Greene
- Center for Cardiovascular Innovation, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Michele Senni
- Cardiovascular Department, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy
| | - Mihai Gheorghiade
- Center for Cardiovascular Innovation, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Gregg C Fonarow
- Ahmanson-UCLA Cardiomyopathy Center, Ronald Reagan-University of California Medical Center Los Angeles, Los Angeles, California.
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Felício JS, Koury CC, Carvalho CT, Abrahão Neto JF, Miléo KB, Arbage TP, Silva DD, de Oliveira AF, Peixoto AS, Figueiredo AB, Ribeiro Dos Santos ÂKC, Yamada ES, Zanella MT. Present Insights on Cardiomyopathy in Diabetic Patients. Curr Diabetes Rev 2016; 12:384-395. [PMID: 26364799 PMCID: PMC5101638 DOI: 10.2174/1573399812666150914120529] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2015] [Revised: 08/27/2015] [Accepted: 09/14/2015] [Indexed: 12/22/2022]
Abstract
The pathogenesis of diabetic cardiomyopathy (DCM) is partially understood and is likely to be multifactorial, involving metabolic disturbances, hypertension and cardiovascular autonomic neuropathy (CAN). Therefore, an important need remains to further delineate the basic mechanisms of diabetic cardiomyopathy and to apply them to daily clinical practice. We attempt to detail some of these underlying mechanisms, focusing in the clinical features and management. The novelty of this review is the role of CAN and reduction of blood pressure descent during sleep in the development of DCM. Evidence has suggested that CAN might precede left ventricular hypertrophy and diastolic dysfunction in normotensive patients with type 2 diabetes, serving as an early marker for the evaluation of preclinical cardiac abnormalities. Additionally, a prospective study demonstrated that an elevation of nocturnal systolic blood pressure and a loss of nocturnal blood pressure fall might precede the onset of abnormal albuminuria and cardiovascular events in hypertensive normoalbuminuric patients with type 2 diabetes. Therefore, existing microalbuminuria could imply the presence of myocardium abnormalities. Considering that DCM could be asymptomatic for a long period and progress to irreversible cardiac damage, early recognition and treatment of the preclinical cardiac abnormalities are essential to avoid severe cardiovascular outcomes. In this sense, we recommend that all type 2 diabetic patients, especially those with microalbuminuria, should be regularly submitted to CAN tests, Ambulatory Blood Pressure Monitoring and echocardiography, and treated for any abnormalities in these tests in the attempt of reducing cardiovascular morbidity and mortality.
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Affiliation(s)
- João Soares Felício
- Hospital Universitário João de Barros Barreto - Universidade Federal do Pará, Mundurucus Street, 4487 - Postal Code: 66073-000 - Guamá - Belém - PA - Brazil.
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Paneni F. DPP-4 inhibitors, heart failure and type 2 diabetes: all eyes on safety. Cardiovasc Diagn Ther 2015; 5:471-8. [PMID: 26672798 PMCID: PMC4666697 DOI: 10.3978/j.issn.2223-3652.2015.09.06] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Accepted: 09/23/2015] [Indexed: 12/12/2022]
Abstract
Epidemiological analyses have clearly outlined the association between heart failure (HF) and diabetes (DM). HF patients with concomitant DM show a further increase in morbidity and mortality due to coexistence of several mechanisms including disturbed neurohormonal axis as well as structural and functional abnormalities occurring in the diabetic myocardium. Although several studies have shown that poor glycemic control-as indicated by HbA1c levels-may be associated with an increased risk of HF, this issue remains poorly understood and further evidence is required to show unequivocal benefits of this approach. In the attempt to explore the effects of new anti-hyperglycemic therapies, randomized trials have shown that some glucose-lowering drugs-thought not affecting cardiovascular (CV) death or ischemic complications-might significantly increase the risk of HF-hospitalizations in DM patients. Specifically, the use of dipeptidyl-peptidase-4 (DDP-4) inhibitors (DPP-4i) has recently raised a major safety concern owing to an increase of HF hospitalizations in SAVOR-TIMI 53 trial. In contrast with these findings, the more recent TECOS study as well as new TECOS sub-analyses presented at the last ESC Congress-have yielded to the conclusion that the DPP-4i sitagliptin is not associated with any sort of HF risk. Therefore, increased risk of HF hospitalizations does not seem to be a class effect of DPP-4i. The present article critically discusses available evidence concerning DPP-4i and risk of HF in patients with type 2 diabetes (T2D). The use of DPP-4i in combination therapy is also discussed, in light of the recent EMPA-REG trial.
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Affiliation(s)
- Francesco Paneni
- Cardiology Unit, Department of Medicine, Karolinska University Hospital, Solna, Stockholm, Sweden
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Jiang M, Huang CR, Wang Q, Zhu YY, Wang J, Chen J, Shi JH. Combined spectroscopies and molecular docking approach to characterizing the binding interaction between lisinopril and bovine serum albumin. LUMINESCENCE 2015; 31:468-477. [DOI: 10.1002/bio.2984] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2015] [Revised: 06/26/2015] [Accepted: 06/28/2015] [Indexed: 11/10/2022]
Affiliation(s)
- Min Jiang
- College of Pharmaceutical Science; Zhejiang University of Technology; Hangzhou 310032 China
| | - Chuan-ren Huang
- College of Pharmaceutical Science; Zhejiang University of Technology; Hangzhou 310032 China
| | - Qi Wang
- College of Pharmaceutical Science; Zhejiang University of Technology; Hangzhou 310032 China
| | - Ying-yao Zhu
- College of Pharmaceutical Science; Zhejiang University of Technology; Hangzhou 310032 China
| | - Jing Wang
- College of Pharmaceutical Science; Zhejiang University of Technology; Hangzhou 310032 China
| | - Jun Chen
- College of Pharmaceutical Science; Zhejiang University of Technology; Hangzhou 310032 China
| | - Jie-hua Shi
- College of Pharmaceutical Science; Zhejiang University of Technology; Hangzhou 310032 China
- State Key Laboratory Breeding Base of Green Chemistry Synthesis Technology; Zhejiang University of Technology; Hangzhou 310032 China
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50
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Fried TR, O’Leary J, Towle V, Goldstein MK, Trentelange M, Martin DK. The effects of comorbidity on the benefits and harms of treatment for chronic disease: a systematic review. PLoS One 2014; 9:e112593. [PMID: 25402463 PMCID: PMC4234418 DOI: 10.1371/journal.pone.0112593] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2014] [Accepted: 10/10/2014] [Indexed: 01/13/2023] Open
Abstract
Background There are concerns about the potential for unintentional harms when clinical practice guidelines are applied to patients with multimorbidity. The objective was to summarize the evidence regarding the effect(s) of comorbidity on the outcomes of medication for an index chronic condition. Methods A systematic review was conducted of studies published in MEDLINE and Cochrane Trials before May 2012. The search strategy was constructed to identify articles indexed with “comorbidity” or a related term or by a given condition and one or more additional specified comorbid conditions. The search yielded 3252 articles, of which 37 passed the title/abstract screening process, and 22 were included after full-text review. An additional 23 articles were identified by screening the reference lists for included articles. Information was extracted on study design; population; therapy; comparison groups; outcome(s); main findings. Findings Indexing of articles was inconsistent, with no term for “multimorbidity,” and rare use of “comorbidity”. Only one article examined the effects of comorbidity per se, finding no benefit of tight control of DM among persons with high comorbidity, defined using a comorbidity index. The remainder examined pairs of conditions, the majority of which were post-hoc analyses of randomized controlled trials and which found no difference in outcomes according to whether a comorbid condition was present. Several demonstrated no difference or an increased risk of adverse outcome among persons with DM and tight control of HTN as compared to usual control. Several demonstrated lack of benefit of statins among persons with end-stage renal disease. Conclusions There is limited evidence regarding the effects of multiple comorbidities on treatment outcomes. The majority of studies demonstrated no effect of a single comorbid condition on outcomes. Additional studies examining a broad range of comorbidity are required, along with clear and consistent indexing to allow for improved synthesis of the evidence.
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Affiliation(s)
- Terri R. Fried
- Clinical Epidemiology Research Center, VA Connecticut Healthcare System, West Haven, Connecticut, United States of America
- Department of Medicine, Yale School of Medicine, New Haven, Connecticut, United States of America
- * E-mail:
| | - John O’Leary
- Clinical Epidemiology Research Center, VA Connecticut Healthcare System, West Haven, Connecticut, United States of America
- Program on Aging, Yale School of Medicine, New Haven, Connecticut, United States of America
| | - Virginia Towle
- Program on Aging, Yale School of Medicine, New Haven, Connecticut, United States of America
| | - Mary K. Goldstein
- Palo Alto Geriatrics Research Education and Clinical Center (GRECC), VA Palo Alto Health Care System, Palo Alto, Connecticut, 94304, United States of America
- Center for Primary Care and Outcomes Research, Stanford University School of Medicine, Stanford, California, 94305, United States of America
| | - Mark Trentelange
- Program on Aging, Yale School of Medicine, New Haven, Connecticut, United States of America
| | - Deanna K. Martin
- Clinical Epidemiology Research Center, VA Connecticut Healthcare System, West Haven, Connecticut, United States of America
- Program on Aging, Yale School of Medicine, New Haven, Connecticut, United States of America
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