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Seth J, Sharma S, Leong CJ, Rabkin SW. Eicosapentaenoic Acid (EPA) and Docosahexaenoic Acid (DHA) Ameliorate Heart Failure through Reductions in Oxidative Stress: A Systematic Review and Meta-Analysis. Antioxidants (Basel) 2024; 13:955. [PMID: 39199201 PMCID: PMC11351866 DOI: 10.3390/antiox13080955] [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: 06/17/2024] [Revised: 07/31/2024] [Accepted: 08/02/2024] [Indexed: 09/01/2024] Open
Abstract
The objectives of this study were to explore the role that eicosapentaenoic acid (EPA) and/or docosahexaenoic acid (DHA) plays in heart failure (HF), highlighting the potential connection to oxidative stress pathways. Following PRISMA guidelines, we conducted electronic searches of the literature in MEDLINE and EMBASE focusing on serum EPA and/or DHA and EPA and/or DHA supplementation in adult patients with heart failure or who had heart failure as an outcome of this study. We screened 254 studies, encompassing RCTs, observational studies, and cohort studies that examined HF outcomes in relation to either serum concentrations or dietary supplementation of EPA and/or DHA. The exclusion criteria were pediatric patients, non-HF studies, abstracts, editorials, case reports, and reviews. Eleven studies met our criteria. In meta-analyses, high serum concentrations of DHA were associated with a lower rate of heart failure with a hazard ratio of 0.74 (CI = 0.59-0.94). High serum concentrations of EPA also were associated with an overall reduction in major adverse cardiovascular events with a hazard ratio of 0.60 (CI = 0.46-0.77). EPA and DHA, or n3-PUFA administration, were associated with an increased LVEF with a mean difference of 1.55 (CI = 0.07-3.03)%. A potential explanation for these findings is the ability of EPA and DHA to inhibit pathways by which oxidative stress damages the heart or impairs cardiac systolic or diastolic function producing heart failure. Specifically, EPA may lower oxidative stress within the heart by reducing the concentration of reactive oxygen species (ROS) within cardiac tissue by (i) upregulating nuclear factor erythroid 2-related factor 2 (Nrf2), which increases the expression of antioxidant enzyme activity, including heme oxygenase-1, thioredoxin reductase 1, ferritin light chain, ferritin heavy chain, and manganese superoxide dismutase (SOD), (ii) increasing the expression of copper-zinc superoxide dismutase (MnSOD) and glutathione peroxidase, (iii) targeting Free Fatty Acid Receptor 4 (Ffar4), (iv) upregulating expression of heme-oxygenase-1, (v) lowering arachidonic acid levels, and (vi) inhibiting the RhoA/ROCK signaling pathway. DHA may lower oxidative stress within the heart by (i) reducing levels of mitochondrial-fission-related protein DRP-1(ser-63), (ii) promoting the incorporation of cardiolipin within the mitochondrial membrane, (iii) reducing myocardial fibrosis, which leads to diastolic heart failure, (iv) reducing the expression of genes such as Appa, Myh7, and Agtr1α, and (v) reducing inflammatory cytokines such as IL-6, TNF-α. In conclusion, EPA and/or DHA have the potential to improve heart failure, perhaps mediated by their ability to modulate oxidative stress.
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Affiliation(s)
- Jayant Seth
- Faculty of Medicine, University of British Columbia, 9th Floor 2775 Laurel St., Vancouver, BC V5Z 1M9, Canada; (J.S.); (S.S.); (C.J.L.)
| | - Sohat Sharma
- Faculty of Medicine, University of British Columbia, 9th Floor 2775 Laurel St., Vancouver, BC V5Z 1M9, Canada; (J.S.); (S.S.); (C.J.L.)
| | - Cameron J. Leong
- Faculty of Medicine, University of British Columbia, 9th Floor 2775 Laurel St., Vancouver, BC V5Z 1M9, Canada; (J.S.); (S.S.); (C.J.L.)
| | - Simon W. Rabkin
- Faculty of Medicine, University of British Columbia, 9th Floor 2775 Laurel St., Vancouver, BC V5Z 1M9, Canada; (J.S.); (S.S.); (C.J.L.)
- Department of Medicine, Division of Cardiology, University of British Columbia, 9th Floor 2775 Laurel St., Vancouver, BC V5Z 1M9, Canada
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Caturano A, Galiero R, Vetrano E, Sardu C, Rinaldi L, Russo V, Monda M, Marfella R, Sasso FC. Insulin-Heart Axis: Bridging Physiology to Insulin Resistance. Int J Mol Sci 2024; 25:8369. [PMID: 39125938 PMCID: PMC11313400 DOI: 10.3390/ijms25158369] [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: 07/01/2024] [Revised: 07/26/2024] [Accepted: 07/29/2024] [Indexed: 08/12/2024] Open
Abstract
Insulin signaling is vital for regulating cellular metabolism, growth, and survival pathways, particularly in tissues such as adipose, skeletal muscle, liver, and brain. Its role in the heart, however, is less well-explored. The heart, requiring significant ATP to fuel its contractile machinery, relies on insulin signaling to manage myocardial substrate supply and directly affect cardiac muscle metabolism. This review investigates the insulin-heart axis, focusing on insulin's multifaceted influence on cardiac function, from metabolic regulation to the development of physiological cardiac hypertrophy. A central theme of this review is the pathophysiology of insulin resistance and its profound implications for cardiac health. We discuss the intricate molecular mechanisms by which insulin signaling modulates glucose and fatty acid metabolism in cardiomyocytes, emphasizing its pivotal role in maintaining cardiac energy homeostasis. Insulin resistance disrupts these processes, leading to significant cardiac metabolic disturbances, autonomic dysfunction, subcellular signaling abnormalities, and activation of the renin-angiotensin-aldosterone system. These factors collectively contribute to the progression of diabetic cardiomyopathy and other cardiovascular diseases. Insulin resistance is linked to hypertrophy, fibrosis, diastolic dysfunction, and systolic heart failure, exacerbating the risk of coronary artery disease and heart failure. Understanding the insulin-heart axis is crucial for developing therapeutic strategies to mitigate the cardiovascular complications associated with insulin resistance and diabetes.
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Affiliation(s)
- Alfredo Caturano
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, 80138 Naples, Italy; (A.C.); (R.G.); (E.V.); (C.S.); (R.M.)
- Department of Experimental Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy;
| | - Raffaele Galiero
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, 80138 Naples, Italy; (A.C.); (R.G.); (E.V.); (C.S.); (R.M.)
| | - Erica Vetrano
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, 80138 Naples, Italy; (A.C.); (R.G.); (E.V.); (C.S.); (R.M.)
| | - Celestino Sardu
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, 80138 Naples, Italy; (A.C.); (R.G.); (E.V.); (C.S.); (R.M.)
| | - Luca Rinaldi
- Department of Medicine and Health Sciences “Vincenzo Tiberio”, Università degli Studi del Molise, 86100 Campobasso, Italy;
| | - Vincenzo Russo
- Department of Biology, College of Science and Technology, Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, Philadelphia, PA 19122, USA;
- Division of Cardiology, Department of Medical Translational Sciences, University of Campania Luigi Vanvitelli, 80138 Naples, Italy
| | - Marcellino Monda
- Department of Experimental Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy;
| | - Raffaele Marfella
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, 80138 Naples, Italy; (A.C.); (R.G.); (E.V.); (C.S.); (R.M.)
| | - Ferdinando Carlo Sasso
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, 80138 Naples, Italy; (A.C.); (R.G.); (E.V.); (C.S.); (R.M.)
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Sivalingam S, Hein Zobel E, Hansen CS, Ripa RS, von Scholten BJ, Rotbain Curovic V, Kjaer A, Jensen JK, Hansen TW, Rossing P. The effect of liraglutide on cardiac autonomic function in type 2 diabetes: A prespecified secondary analysis from the LIRAFLAME randomized, double-blinded, placebo-controlled trial. Diabetes Obes Metab 2022; 24:1638-1642. [PMID: 35415938 DOI: 10.1111/dom.14717] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 04/08/2022] [Accepted: 04/08/2022] [Indexed: 12/01/2022]
Affiliation(s)
| | | | | | - Rasmus S Ripa
- Department of Clinical Physiology and Nuclear Medicine and Cluster for Molecular Imaging, Copenhagen University Hospital - Rigshospitalet and Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Bernt J von Scholten
- Steno Diabetes Center Copenhagen, Copenhagen, Denmark
- Novo Nordisk A/S, Søborg, Denmark
| | | | - Andreas Kjaer
- Department of Clinical Physiology and Nuclear Medicine and Cluster for Molecular Imaging, Copenhagen University Hospital - Rigshospitalet and Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Jacob K Jensen
- Department of Clinical Physiology and Nuclear Medicine and Cluster for Molecular Imaging, Copenhagen University Hospital - Rigshospitalet and Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Tine W Hansen
- Steno Diabetes Center Copenhagen, Copenhagen, Denmark
| | - Peter Rossing
- Steno Diabetes Center Copenhagen, Copenhagen, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
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Salvatore T, Pafundi PC, Galiero R, Albanese G, Di Martino A, Caturano A, Vetrano E, Rinaldi L, Sasso FC. The Diabetic Cardiomyopathy: The Contributing Pathophysiological Mechanisms. Front Med (Lausanne) 2021; 8:695792. [PMID: 34277669 PMCID: PMC8279779 DOI: 10.3389/fmed.2021.695792] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 06/07/2021] [Indexed: 12/12/2022] Open
Abstract
Individuals with diabetes mellitus (DM) disclose a higher incidence and a poorer prognosis of heart failure (HF) than non-diabetic people, even in the absence of other HF risk factors. The adverse impact of diabetes on HF likely reflects an underlying “diabetic cardiomyopathy” (DM–CMP), which may by exacerbated by left ventricular hypertrophy and coronary artery disease (CAD). The pathogenesis of DM-CMP has been a hot topic of research since its first description and is still under active investigation, as a complex interplay among multiple mechanisms may play a role at systemic, myocardial, and cellular/molecular levels. Among these, metabolic abnormalities such as lipotoxicity and glucotoxicity, mitochondrial damage and dysfunction, oxidative stress, abnormal calcium signaling, inflammation, epigenetic factors, and others. These disturbances predispose the diabetic heart to extracellular remodeling and hypertrophy, thus leading to left ventricular diastolic and systolic dysfunction. This Review aims to outline the major pathophysiological changes and the underlying mechanisms leading to myocardial remodeling and cardiac functional derangement in DM-CMP.
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Affiliation(s)
- Teresa Salvatore
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Pia Clara Pafundi
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Raffaele Galiero
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Gaetana Albanese
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Anna Di Martino
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Alfredo Caturano
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Erica Vetrano
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Luca Rinaldi
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Ferdinando Carlo Sasso
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
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Kaze AD, Santhanam P, Erqou S, Ahima RS, Bertoni A, Echouffo-Tcheugui JB. Microvascular Disease and Incident Heart Failure Among Individuals With Type 2 Diabetes Mellitus. J Am Heart Assoc 2021; 10:e018998. [PMID: 34107742 PMCID: PMC8477890 DOI: 10.1161/jaha.120.018998] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Background Microvascular disease (MVD) is a potential contributor to the pathogenesis of diabetes mellitus-related cardiac dysfunction. However, there is a paucity of data on the link between MVD and incident heart failure (HF) in type 2 diabetes mellitus. We examined the association of MVD with incident HF in adults with type 2 diabetes mellitus. Methods and Results A total of 4095 participants with type 2 diabetes mellitus and free of HF were assessed for diabetes mellitus-related MVD including nephropathy, retinopathy, or neuropathy at baseline in the Look AHEAD (Action for Health in Diabetes) study. Incident HF events were prospectively assessed and adjudicated using hospital and death records. Cox models were used to generate hazard ratios and 95% CIs for HF. Of 4095 participants, 34.8% (n=1424) had MVD, defined as the presence of ≥1 of nephropathy, retinopathy, or neuropathy at baseline. Over a median of 9.7 years, there were 117 HF events. After adjusting for relevant confounders, participants with MVD had a 2.5-fold higher risk of incident HF than those without MVD (hazard ratio, 2.54; 95% CI, 1.73-3.75). This association remained significant after additional adjustment for interval development of coronary artery disease (hazard ratio, 2.42; 95% CI, 1.64-3.57). The hazard ratios for HF by type of MVD were 2.22 (95% CI, 1.51-3.27), 1.30 (95% CI, 0.72-2.36), and 1.33 (95% CI, 0.86-2.07) for nephropathy, retinopathy, and neuropathy, respectively. CONCLUSIONS MVD is associated with an excess HF risk in individuals with type 2 diabetes mellitus after adjusting for other known risk factors. Our findings underscore the contribution of MVD to the development of diabetes mellitus-related HF. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00017953.
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Affiliation(s)
- Arnaud D Kaze
- Department of Medicine University of Maryland Medical Center Baltimore MD
| | - Prasanna Santhanam
- Division of Endocrinology, Diabetes & Metabolism Johns Hopkins School of Medicine Baltimore MD
| | - Sebhat Erqou
- Department of Medicine Providence VA Medical Center and Alpert Medical School of Brown University Providence RI
| | - Rexford S Ahima
- Division of Endocrinology, Diabetes & Metabolism Johns Hopkins School of Medicine Baltimore MD
| | - Alain Bertoni
- Department of Epidemiology and Prevention Wake Forest University School of Medicine Winston-Salem NC
| | - Justin B Echouffo-Tcheugui
- Division of Endocrinology, Diabetes & Metabolism Johns Hopkins School of Medicine Baltimore MD.,Welch Prevention Center for Prevention, Epidemiology and Clinical Research Johns Hopkins University Baltimore MD
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Kaze AD, Santhanam P, Erqou S, Bertoni AG, Ahima RS, Echouffo-Tcheugui JB. Long-term variability of blood pressure and incidence of heart failure among individuals with Type 2 diabetes. ESC Heart Fail 2021; 8:2959-2967. [PMID: 34032375 PMCID: PMC8318432 DOI: 10.1002/ehf2.13385] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 04/08/2021] [Accepted: 04/12/2021] [Indexed: 01/01/2023] Open
Abstract
AIMS Data on the association of long-term variability of blood pressure (BP) with incident heart failure (HF) in individuals with Type 2 diabetes are scarce. We evaluated this association in a large community-based sample of adults with Type 2 diabetes. METHODS AND RESULTS A total of 4200 participants with Type 2 diabetes who had available BP measurements at four visits (baseline and 12, 24, and 36 months) in the Look AHEAD (Action for Health in Diabetes) study were included. Variability of systolic BP (SBP) and diastolic BP (DBP) across the four visits was assessed using four metrics. Participants free of HF during the first 36 months were followed for HF events. Cox regression was used to generate hazard ratios (HRs) and 95% confidence intervals (CIs) for HF. Of the 4200 participants, the average age was 59 years [standard deviation (SD): 6.8]; 58.5% were women. Over a median follow-up of 6.7 years, 129 developed HF events. After adjusting for relevant confounders, the HR of incident HF for the highest vs. lowest quartile of SD of SBP was 1.77 (95% CI 1.01-3.09); the HR for the highest (vs. lowest) quartile of variability independent of the mean of SBP was 1.29 (95% CI 0.78-2.14). The adjusted HR for participants in the highest (compared with the lowest) quartile of SD of DBP was 1.61 (95% CI 1.01-2.59), and the adjusted HR for variability independent of the mean of DBP was 1.65 (95% CI 1.03-2.65). CONCLUSIONS A greater variability in SBP and DBP is independently associated with greater risk of incident HF in individuals with Type 2 diabetes.
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Affiliation(s)
- Arnaud D Kaze
- Department of Medicine, University of Maryland Medical Center, Baltimore, MD, USA
| | - Prasanna Santhanam
- Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Johns Hopkins School of Medicine, Baltimore, MD, 21224, USA
| | - Sebhat Erqou
- Department of Medicine, Providence VA Medical Center and Alpert Medical School of Brown University, Providence, RI, USA
| | - Alain G Bertoni
- Department of Epidemiology and Prevention, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Rexford S Ahima
- Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Johns Hopkins School of Medicine, Baltimore, MD, 21224, USA
| | - Justin B Echouffo-Tcheugui
- Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Johns Hopkins School of Medicine, Baltimore, MD, 21224, USA
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Ponte CMM, Fernandes VO, Liberato CBR, Montenegro APDR, Batista LA, Gurgel MHC, de Azevedo Karbage LB, Vasconcelos ITGF, d’Alva CB, Montenegro Júnior RM. Association between cardiovascular autonomic neuropathy and left ventricular hypertrophy in young patients with congenital generalized lipodystrophy. Diabetol Metab Syndr 2019; 11:53. [PMID: 31303898 PMCID: PMC6604128 DOI: 10.1186/s13098-019-0444-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Accepted: 06/18/2019] [Indexed: 01/26/2023] Open
Abstract
BACKGROUND Congenital generalized lipodystrophy (CGL) is a rare disorder characterized by the absence of subcutaneous adipose tissue, severe insulin resistance, diabetes mellitus, and cardiovascular complications, including cardiac autonomic neuropathy (CAN), left ventricular hypertrophy (LVH), and atherosclerosis. The present study aimed to access the association between CAN parameters and cardiovascular abnormalities in CGL patients. METHODS A cross-sectional study was conducted with 10 CGL patients and 20 healthy controls matched for age, sex, BMI, and pubertal stage. We evaluated clinical, laboratory, and cardiovascular parameters-left ventricular mass index (LVMI), interventricular septum thickness (IVS), systolic and diastolic function determined by two-dimensional transthoracic echocardiography; carotid intimal media thickness (cIMT); and cQT interval. Heart rate variability (HRV) was evaluated by spectral analysis components-high frequency (HF), low frequency (LF), very low frequency (VLF), LF/HF ratio, and total amplitude spectrum (TAS)-and cardiovascular reflexes tests (postural hypotension test, respiratory, orthostatic and Valsalva coefficients). RESULTS In CGL group, four patients (40%) had LVH and diastolic dysfunction. HF component (parasympathetic control) was lower in LVH patients. CGL patients presented higher values of cIMT and cQT interval than heathy subjects. Inverse association between LVMI and LF (p = 0.011), IVS and LF (p = 0.007), and cIMT and leptin (p < 0.001) were observed, even after adjustments by HOMA-IR, A1c, and blood pressure. In CGL group, there were associations between LMVI and HF component (IC95%: - 1.000; - 00.553), LVMI and TAS (IC95%: - 1.000; - 0.012), and IVS and HF component (IC95%: - 1.000; - 0.371). CONCLUSION The association between increased LV mass and parameters of HRV provides possible speculations about the involvement of CAN in the pathophysiology of the cardiac complications, including LVH, in patients with CGL.
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Affiliation(s)
- Clarisse Mourão Melo Ponte
- Brazilian Group for the Study of Inherited and Acquired Lipodystrophies, Faculdade de Medicina, Universidade Federal do Ceará, Rua Professor Costa Mendes 1608, Fortaleza, Ceará 60416-200 Brazil
| | - Virgínia Oliveira Fernandes
- Brazilian Group for the Study of Inherited and Acquired Lipodystrophies, Faculdade de Medicina, Universidade Federal do Ceará, Rua Professor Costa Mendes 1608, Fortaleza, Ceará 60416-200 Brazil
| | - Christiane Bezerra Rocha Liberato
- Brazilian Group for the Study of Inherited and Acquired Lipodystrophies, Faculdade de Medicina, Universidade Federal do Ceará, Rua Professor Costa Mendes 1608, Fortaleza, Ceará 60416-200 Brazil
| | - Ana Paula Dias Rangel Montenegro
- Brazilian Group for the Study of Inherited and Acquired Lipodystrophies, Faculdade de Medicina, Universidade Federal do Ceará, Rua Professor Costa Mendes 1608, Fortaleza, Ceará 60416-200 Brazil
| | - Lívia Aline Batista
- Brazilian Group for the Study of Inherited and Acquired Lipodystrophies, Faculdade de Medicina, Universidade Federal do Ceará, Rua Professor Costa Mendes 1608, Fortaleza, Ceará 60416-200 Brazil
| | - Maria Helane Costa Gurgel
- Brazilian Group for the Study of Inherited and Acquired Lipodystrophies, Faculdade de Medicina, Universidade Federal do Ceará, Rua Professor Costa Mendes 1608, Fortaleza, Ceará 60416-200 Brazil
| | - Lia Beatriz de Azevedo Karbage
- Brazilian Group for the Study of Inherited and Acquired Lipodystrophies, Faculdade de Medicina, Universidade Federal do Ceará, Rua Professor Costa Mendes 1608, Fortaleza, Ceará 60416-200 Brazil
| | - Izabella Tamira Galdino Farias Vasconcelos
- Brazilian Group for the Study of Inherited and Acquired Lipodystrophies, Faculdade de Medicina, Universidade Federal do Ceará, Rua Professor Costa Mendes 1608, Fortaleza, Ceará 60416-200 Brazil
| | - Catarina Brasil d’Alva
- Brazilian Group for the Study of Inherited and Acquired Lipodystrophies, Faculdade de Medicina, Universidade Federal do Ceará, Rua Professor Costa Mendes 1608, Fortaleza, Ceará 60416-200 Brazil
| | - Renan Magalhães Montenegro Júnior
- Brazilian Group for the Study of Inherited and Acquired Lipodystrophies, Faculdade de Medicina, Universidade Federal do Ceará, Rua Professor Costa Mendes 1608, Fortaleza, Ceará 60416-200 Brazil
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Progression of cardiovascular autonomic neuropathy and cardiovascular disease in type 2 diabetes. Cardiovasc Diabetol 2018; 17:109. [PMID: 30071872 PMCID: PMC6071370 DOI: 10.1186/s12933-018-0752-6] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2018] [Accepted: 07/26/2018] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND To examine whether the progression rate of cardiovascular autonomic neuropathy (CAN) stage is an independent predictive factor for cardiovascular disease (CVD) in type 2 diabetes. METHODS Standardized cardiovascular autonomic reflex tests (CARTs) using traditional Ewing method were performed at baseline. The follow-up CARTs was recommended once every two years. We estimated the primary CVD endpoint, defined as coronary artery disease and ischemic stroke. The association between the progression rate of CAN stage and CVD was examined using time-dependent Cox proportional hazard models. RESULTS At baseline, 578 patients completed follow-up CARTs; the cohort comprised 329 women (56.9%) with a mean age of 58.3 ± 10.3 years and a mean diabetes duration of 10.1 ± 6.2 years. One hundred and seventy-six patients (30.4%) developed CAN progression between baseline and follow-up CARTs. In the multivariable Cox proportional hazards regression analysis, patients with CAN progression demonstrated a 3.32 times higher risk (95% confidence interval, CI 1.81-6.14, P < 0.001) of CVD than those without CAN progression. Patients who experienced CAN progression from the normal to definite stage had the greatest risk of CVD compared to other patients (hazard ratio 4.91, 95% CI 2.05-11.77, P for trend = 0.001). CONCLUSIONS CAN stage progression was associated with an increased risk of CVD in this type 2 diabetes cohort. Patients with rapid CAN progression had the greatest risk of CVD. Thus, regular screening and risk management of CAN progression is necessary to prevent CVD.
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Sakr S, Hassanien H, Bester MJ, Arbi S, Sobhy A, El Negris H, Steenkamp V. Beneficial effects of folic acid on the kidneys and testes of adult albino rats after exposure to methomyl. Toxicol Res (Camb) 2018; 7:480-491. [PMID: 30090598 PMCID: PMC6062218 DOI: 10.1039/c7tx00309a] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2017] [Accepted: 03/13/2018] [Indexed: 11/21/2022] Open
Abstract
The aim of this study was to evaluate the protective effect of folate against methomyl-induced toxicity on the kidneys and testes of male rats. Adult male albino rats were divided into four groups; Group I served as the control (vehicle), Group II received folic acid (1.1 mg per kg b.wt.), Group III methomyl (1 mg per kg b.wt.) and Group IV folic acid and methomyl. Treatments were administered via oral gavage on a daily basis for 14 weeks. Thereafter blood samples were collected and serum creatinine, testosterone and total antioxidant capacity (TAC) were determined. Animals were sacrificed and semen analysis was conducted. The kidneys and testes were excised and malondialdehyde (MDA) levels were determined. Histopathological and immunohistochemical analyses for caspase-3 were also undertaken. Methomyl treatment resulted in a significant (p < 0.001) elevation of creatinine and MDA levels and significant (p < 0.001) reduction in testosterone and TAC levels. Furthermore, methomyl caused a significant (p < 0.001) reduction in sperm quality. Histopathological examination indicated testicular and renal damage with strong immunoreactivity for caspase-3. Functional and tissue damage was prevented in rats treated with a combination of methomyl and folic acid. This is ascribed to the ability of folate to directly scavenge reactive oxygen species and indirectly enhance cellular redox homeostasis. This study identified that folic acid supplementation may have a beneficial effect in preventing or reducing the deleterious effects of methomyl exposure on kidney as well as testis structure and function. Future studies should focus on the fertility outcome/pregnancy index in rats.
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Affiliation(s)
- Samar Sakr
- Department of Forensic Medicine and Clinical Toxicology , Faculty of Medicine , University of Zagazig , Egypt . ; Tel: +201121114276
| | - Hanan Hassanien
- Department of Forensic Medicine and Clinical Toxicology , Faculty of Medicine , University of Zagazig , Egypt . ; Tel: +201121114276
| | - Megan Jean Bester
- Department of Anatomy , Faculty of Health Sciences , University of Pretoria , South Africa
| | - Sandra Arbi
- Department of Anatomy , Faculty of Health Sciences , University of Pretoria , South Africa
| | - Azza Sobhy
- Department of Forensic Medicine and Clinical Toxicology , Faculty of Medicine , University of Zagazig , Egypt . ; Tel: +201121114276
| | - Heba El Negris
- Department of Histology , Faculty of Medicine , University of Zagazig , Egypt
- Department of Basic Medical Science , School of Dentistry , University of Badr , Egypt
| | - Vanessa Steenkamp
- Department of Pharmacology , Faculty of Health Sciences , University of Pretoria , South Africa
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Duvernoy CS, Raffel DM, Swanson SD, Jaiswal M, Mueller G, Ibrahim ES, Pennathur S, Plunkett C, Stojanovska J, Brown MB, Pop-Busui R. Left ventricular metabolism, function, and sympathetic innervation in men and women with type 1 diabetes. J Nucl Cardiol 2016; 23:960-969. [PMID: 27146882 PMCID: PMC5103640 DOI: 10.1007/s12350-016-0434-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2015] [Revised: 01/29/2016] [Indexed: 01/09/2023]
Abstract
BACKGROUND In type I diabetes (T1DM), alterations in LV function may occur due to changes in innervation, metabolism, and efficiency. OBJECTIVES We evaluated the association between sympathetic nerve function, oxidative metabolism, resting blood flow, LV efficiency and function in healthy diabetics, and assessed gender differences. METHODS Cross-sectional study of 45 subjects with T1DM, 60% females, age 34 ± 13 years, and 10 age-matched controls. Positron emission tomography (PET) imaging with [(11)C]acetate and [(11)C]meta-hydroxyephedrine was performed, in addition to cardiac magnetic resonance imaging. RESULTS There were no significant differences in LV function, innervation, or oxidative metabolism between T1DM and controls. Cardiac oxidative metabolism was positively associated with higher levels of sympathetic activation, particularly in women. Diabetic women had significantly lower efficiency compared with diabetic men. Resting flow was significantly higher in diabetic women compared with diabetic men, and tended to be higher in female controls as well. CONCLUSIONS Measures of myocardial function, metabolism, blood flow, and sympathetic activation were preserved in young, otherwise healthy, T1DM patients. However, T1DM women presented with greater myocardial oxidative metabolism requirements than men. Ongoing studies are evaluating changes over time.
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Affiliation(s)
- Claire S Duvernoy
- Cardiology Section, VA Ann Arbor Healthcare System, Ann Arbor, MI, USA
- Division of Cardiology, University of Michigan, Ann Arbor, MI, USA
| | - David M Raffel
- Department of Radiology, University of Michigan, Ann Arbor, MI, USA
| | - Scott D Swanson
- Department of Radiology, University of Michigan, Ann Arbor, MI, USA
| | - Mamta Jaiswal
- Division of Metabolism, Endocrinology and Diabetes, University of Michigan, 5329 Brehm Tower, 1000 Wall Street, Ann Arbor, MI, 48105, USA
| | - Gisela Mueller
- Department of Radiology, University of Michigan, Ann Arbor, MI, USA
| | - El-Sayed Ibrahim
- Department of Radiology, University of Michigan, Ann Arbor, MI, USA
| | - Subramaniam Pennathur
- Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Cynthia Plunkett
- Division of Metabolism, Endocrinology and Diabetes, University of Michigan, 5329 Brehm Tower, 1000 Wall Street, Ann Arbor, MI, 48105, USA
| | | | - Morton B Brown
- Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA
| | - Rodica Pop-Busui
- Division of Metabolism, Endocrinology and Diabetes, University of Michigan, 5329 Brehm Tower, 1000 Wall Street, Ann Arbor, MI, 48105, USA.
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11
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Venkatesan B, Tumala A, Subramanian V, Vellaichamy E. Transient silencing of Npr3 gene expression improved the circulatory levels of atrial natriuretic peptides and attenuated β-adrenoceptor activation- induced cardiac hypertrophic growth in experimental rats. Eur J Pharmacol 2016; 782:44-58. [DOI: 10.1016/j.ejphar.2016.04.037] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Revised: 04/16/2016] [Accepted: 04/18/2016] [Indexed: 10/21/2022]
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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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Xiang L, Mittwede PN, Clemmer JS. Glucose Homeostasis and Cardiovascular Alterations in Diabetes. Compr Physiol 2015; 5:1815-39. [PMID: 26426468 DOI: 10.1002/cphy.c150001] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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14
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Balcıoğlu AS, Müderrisoğlu H. Diabetes and cardiac autonomic neuropathy: Clinical manifestations, cardiovascular consequences, diagnosis and treatment. World J Diabetes 2015; 6:80-91. [PMID: 25685280 PMCID: PMC4317320 DOI: 10.4239/wjd.v6.i1.80] [Citation(s) in RCA: 117] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2014] [Revised: 09/24/2014] [Accepted: 12/01/2014] [Indexed: 02/05/2023] Open
Abstract
Cardiac autonomic neuropathy (CAN) is a frequent chronic complication of diabetes mellitus with potentially life-threatening outcomes. CAN is caused by the impairment of the autonomic nerve fibers regulating heart rate, cardiac output, myocardial contractility, cardiac electrophysiology and blood vessel constriction and dilatation. It causes a wide range of cardiac disorders, including resting tachycardia, arrhythmias, intraoperative cardiovascular instability, asymptomatic myocardial ischemia and infarction and increased rate of mortality after myocardial infarction. Etiological factors associated with autonomic neuropathy include insufficient glycemic control, a longer period since the onset of diabetes, increased age, female sex and greater body mass index. The most commonly used methods for the diagnosis of CAN are based upon the assessment of heart rate variability (the physiological variation in the time interval between heartbeats), as it is one of the first findings in both clinically asymptomatic and symptomatic patients. Clinical symptoms associated with CAN generally occur late in the disease process and include early fatigue and exhaustion during exercise, orthostatic hypotension, dizziness, presyncope and syncope. Treatment is based on early diagnosis, life style changes, optimization of glycemic control and management of cardiovascular risk factors. Medical therapies, including aldose reductase inhibitors, angiotensin-converting enzyme inhibitors, prostoglandin analogs and alpha-lipoic acid, have been found to be effective in randomized controlled trials. The following article includes the epidemiology, clinical findings and cardiovascular consequences, diagnosis, and approaches to prevention and treatment of CAN.
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Parthasarathy A, Gopi V, Devi KM S, Balaji N, Vellaichamy E. Aminoguanidine inhibits ventricular fibrosis and remodeling process in isoproterenol-induced hypertrophied rat hearts by suppressing ROS and MMPs. Life Sci 2014; 118:15-26. [DOI: 10.1016/j.lfs.2014.09.030] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2014] [Revised: 09/24/2014] [Accepted: 09/30/2014] [Indexed: 12/11/2022]
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In vivo effects of propyl gallate, a novel Ca(2+) sensitizer, in a mouse model of dilated cardiomyopathy caused by cardiac troponin T mutation. Life Sci 2014; 109:15-9. [PMID: 24931907 DOI: 10.1016/j.lfs.2014.06.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2013] [Revised: 05/09/2014] [Accepted: 06/03/2014] [Indexed: 12/18/2022]
Abstract
AIMS We have previously demonstrated that propyl gallate has a Ca(2+) sensitizing effect on the force generation in membrane-permeabilized (skinned) cardiac muscle fibers. However, in vivo beneficial effects of propyl gallate as a novel Ca(2+) sensitizer remain uncertain. In the present study, we aim to explore in vivo effects of propyl gallate. MAIN METHODS We compared effects of propyl gallate on ex vivo intact cardiac muscle fibers and in vivo hearts in healthy mice with those of pimobendan, a clinically used Ca(2+) sensitizer. The therapeutic effect of propyl gallate was investigated using a mouse model of dilated cardiomyopathy (DCM) with reduced myofilament Ca(2+) sensitivity due to a deletion mutation ΔK210 in cardiac troponin T. KEY FINDINGS Propyl gallate, as well as pimobendan, showed a positive inotropic effect. Propyl gallate slightly increased the blood pressure without changing the heart rate in healthy mice, whereas pimobendan decreased the blood pressure probably through vasodilation via inhibition of phosphodiesterase and increased the heart rate. Propyl gallate prevented cardiac remodeling and systolic dysfunction and significantly improved the life-expectancy of knock-in mouse model of DCM with reduced myofilament Ca(2+) sensitivity due to a mutation in cardiac troponin T. On the other hand, gallate, a similarly strong antioxidant polyphenol lacking Ca(2+) sensitizing action, had no beneficial effects on the DCM mice. SIGNIFICANCE These results suggest that propyl gallate might be useful for the treatment of inherited DCM caused by a reduction in the myofilament Ca(2+) sensitivity.
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17
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Dimitropoulos G, Tahrani AA, Stevens MJ. Cardiac autonomic neuropathy in patients with diabetes mellitus. World J Diabetes 2014; 5:17-39. [PMID: 24567799 PMCID: PMC3932425 DOI: 10.4239/wjd.v5.i1.17] [Citation(s) in RCA: 188] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2013] [Revised: 12/02/2013] [Accepted: 12/12/2013] [Indexed: 02/05/2023] Open
Abstract
Cardiac autonomic neuropathy (CAN) is an often overlooked and common complication of diabetes mellitus. CAN is associated with increased cardiovascular morbidity and mortality. The pathogenesis of CAN is complex and involves a cascade of pathways activated by hyperglycaemia resulting in neuronal ischaemia and cellular death. In addition, autoimmune and genetic factors are involved in the development of CAN. CAN might be subclinical for several years until the patient develops resting tachycardia, exercise intolerance, postural hypotension, cardiac dysfunction and diabetic cardiomyopathy. During its sub-clinical phase, heart rate variability that is influenced by the balance between parasympathetic and sympathetic tones can help in detecting CAN before the disease is symptomatic. Newer imaging techniques (such as scintigraphy) have allowed earlier detection of CAN in the pre-clinical phase and allowed better assessment of the sympathetic nervous system. One of the main difficulties in CAN research is the lack of a universally accepted definition of CAN; however, the Toronto Consensus Panel on Diabetic Neuropathy has recently issued guidance for the diagnosis and staging of CAN, and also proposed screening for CAN in patients with diabetes mellitus. A major challenge, however, is the lack of specific treatment to slow the progression or prevent the development of CAN. Lifestyle changes, improved metabolic control might prevent or slow the progression of CAN. Reversal will require combination of these treatments with new targeted therapeutic approaches. The aim of this article is to review the latest evidence regarding the epidemiology, pathogenesis, manifestations, diagnosis and treatment for CAN.
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18
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Oxidative Stress and Cardiovascular Disease in Diabetes. OXIDATIVE STRESS IN APPLIED BASIC RESEARCH AND CLINICAL PRACTICE 2014. [DOI: 10.1007/978-1-4899-8035-9_11] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Pop-Busui R, Cleary PA, Braffett BH, Martin CL, Herman WH, Low PA, Lima JAC, Bluemke DA. Association between cardiovascular autonomic neuropathy and left ventricular dysfunction: DCCT/EDIC study (Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications). J Am Coll Cardiol 2012; 61:447-454. [PMID: 23265339 DOI: 10.1016/j.jacc.2012.10.028] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2012] [Accepted: 10/23/2012] [Indexed: 12/17/2022]
Abstract
OBJECTIVES The goal of these studies was to determine the association between cardiovascular autonomic neuropathy (CAN) and indices of left ventricle (LV) structure and function in patients with type 1 diabetes (T1DM) in the DCCT/EDIC (Diabetes Control and Complications Trial /Epidemiology of Diabetes Interventions and Complications) study. BACKGROUND The pathophysiology of LV dysfunction in T1DM remains unclear, especially when the LV ejection fraction (EF) is preserved. Whether CAN is associated with LV dysfunction is unclear. METHODS Indices of LV structure and function were obtained by cardiac magnetic resonance imaging (CMRI). CAN was assessed by cardiovascular reflex testing (R-R response to paced breathing, Valsalva ratio, and blood pressure response to standing). Analyses were performed in 966 DCCT/EDIC participants with valid CMRI and CAN data (mean age 51 years, 52% men, mean diabetes duration 29 years, and mean glycosylated hemoglobin 7.9%). RESULTS Systolic function (EF, end-systolic and end-diastolic volumes, stroke volumes) was not different in 371 subjects with CAN compared with 595 subjects without CAN. In multiple-adjusted analyses, participants with either abnormal R-R variation or a composite of abnormal R-R variation, abnormal Valsalva ratio, and postural blood pressure changes had significantly higher LV mass, mass-to-volume-ratio, and cardiac output compared with those with normal tests (p < 0.0001 for all). After further adjustment for traditional cardiovascular risk factors, subjects with abnormal R-R variation had higher LV mass and cardiac output compared with those with a normal R-R variation (p < 0.05). CONCLUSIONS In this large cohort of patients with T1DM, CAN is associated with increased LV mass and concentric remodeling as assessed by CMRI independent of age, sex, and other factors. (Diabetes Control and Complications Trial [DCCT]; NCT00360815) (Epidemiology of Diabetes Interventions and Complications [EDIC]; NCT00360893).
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Affiliation(s)
- Rodica Pop-Busui
- Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, Michigan.
| | - Patricia A Cleary
- Biostatistics Center, George Washington University, Rockville, Maryland
| | | | - Catherine L Martin
- Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, Michigan
| | - William H Herman
- Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, Michigan
| | - Phillip A Low
- Department of Neurology, Mayo Clinic, Rochester, Minnesota
| | - Joao A C Lima
- Division of Cardiology, Johns Hopkins University, Baltimore, Maryland
| | - David A Bluemke
- Radiology and Imaging Sciences, National Center for Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland
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20
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Pop-Busui R. What do we know and we do not know about cardiovascular autonomic neuropathy in diabetes. J Cardiovasc Transl Res 2012; 5:463-78. [PMID: 22644723 DOI: 10.1007/s12265-012-9367-6] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2012] [Accepted: 04/12/2012] [Indexed: 12/16/2022]
Abstract
Cardiovascular autonomic neuropathy (CAN) in diabetes is generally overlooked in practice, although awareness of its serious consequences is emerging. Challenges in understanding the complex, dynamic changes in the modulation of the sympathetic/parasympathetic systems' tone and their interactions with physiologic mechanisms regulating the control of heart rate, blood pressure, and other cardiovascular functions in the presence of acute hyper-or-hypoglycemic stress, other stressors or medication, and challenges with sensitive evaluations have contributed to lower CAN visibility compared with other diabetes complications. Yet, CAN is a significant cause of morbidity and mortality, due to a high-risk of cardiac arrhythmias, silent myocardial ischemia and sudden death. While striving for aggressive risk factor control in diabetes practice seemed intuitive, recent reports of major clinical trials undermine established thinking concerning glycemic control and cardiovascular risk. This review covers current understanding and gaps in that understanding of the clinical implications of CAN and prevention and treatment of CAN.
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Affiliation(s)
- Rodica Pop-Busui
- Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
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Abstract
Diabetic autonomic neuropathies are a heterogeneous and progressive disease entity and commonly complicate both type 1 and type 2 diabetes mellitus. Although the aetiology is not entirely understood, hyperglycaemia, insulin deficiency, metabolic derangements and potentially autoimmune mechanisms are thought to play an important role. A subgroup of diabetic autonomic neuropathy, cardiovascular autonomic neuropathy (CAN), is one of the most common diabetes-associated complications and is ultimately clinically important because of its correlation with increased mortality. The natural history of CAN is unclear, but is thought to progress from a subclinical stage characterized by impaired baroreflex sensitivity and abnormalities of spectral analysis of heart rate variability to a clinically apparent stage with diverse and disabling symptoms. Early diagnosis of CAN, using spectral analysis of heart rate variability or scintigraphic imaging techniques, might enable identification of patients at highest risk for the development of clinical CAN and, thereby, enable the targeting of intensive therapeutic approaches. This Review discusses methods for diagnosis, epidemiology, natural history and potential causes and consequences of CAN.
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Affiliation(s)
- Michael Kuehl
- Cardiovascular Research Department, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
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22
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Martín-Fernández B, de las Heras N, Miana M, Ballesteros S, Valero-Muñoz M, Vassallo D, Davel AP, Rossoni LV, Cachofeiro V, Lahera V. Spironolactone prevents alterations associated with cardiac hypertrophy produced by isoproterenol in rats: involvement of serum- and glucocorticoid-regulated kinase type 1. Exp Physiol 2012; 97:710-8. [PMID: 22327331 DOI: 10.1113/expphysiol.2011.063230] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Persistent β-adrenergic receptor stimulation with isoproterenol is associated with cardiac hypertrophy as well as cardiac synthesis of angiotensin II. Serum- and glucocorticoid-regulated kinase type 1 (SGK-1) is a key mediator in structural, functional and molecular cardiac effects of aldosterone in rats. This study was designed to investigate the cardiac effects of the mineralocorticoid receptor antagonist spironolactone on the response to isoproterenol treatment in rats, as well as the involvement of the main mediator of cellular aldosterone action, SGK-1, in the heart. Male Wistar rats received isoproterenol (3 mg kg(-1) day(-1)) or vehicle for 15 days. Half of the animals in each group were simultaneously treated with spironolactone (200 mg kg(-1) day(-1)). Systolic and diastolic blood pressures were not significantly different among groups. Treatment with spironolactone normalized the increased left ventricular end-diastolic pressure observed in isoproterenol-treated rats. Isoproterenol treatment induced cardiac hypertrophy and increased collagen content, both of which were normalized by spironolactone treatment. The mRNA levels of transforming growth factor β, connective tissue growth factor, matrix metalloprotease 2, matrix metalloprotease inhibitor 2, tumour necrosis factor α, interleukin 1β, p22phox and xanthine dehydrogenase were increased (P < 0.05) in isoproterenol-treated rats, and this effect was prevented by spironolactone (P < 0.05). Spironolactone also reduced the elevated SGK-1 expression in isoproterenol-treated rats. The observed reduction of the principal mediator of aldosterone cellular actions, SGK-1, by spironolactone in hearts from isoproterenol-treated rats suggests a role of mineralocorticoids in the cardiac hypertrophy, fibrosis, inflammation, oxidation and diastolic dysfunction induced by isoproterenol treatment in rats.
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Kao MPC, Ang DSC, Pall A, Struthers AD. Oxidative stress in renal dysfunction: mechanisms, clinical sequelae and therapeutic options. J Hum Hypertens 2010; 24:1-8. [PMID: 19727125 DOI: 10.1038/jhh.2009.70] [Citation(s) in RCA: 140] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Oxidative stress has been increasingly linked to the high incidence of cardiovascular events in patients with chronic kidney disease (CKD), especially as traditional cardiovascular risk factors seem to not be able to account for the huge cardiovascular morbidity and mortality in this population group. Oxidative stress is increased in patients with renal impairment as a result of increased oxidant activity and reduced antioxidant capacity, and this is increased in a graded manner with increasing renal dysfunction. Inflammation, which is also present in CKD, further amplifies the oxidant generation process. The two clinical sequelae of oxidative stress are endothelial dysfunction and left ventricular hypertrophy, which have adverse cardiovascular consequences. With our new understanding of oxidative stress, it is now important to assess treatment options that reduce it in the hope that they reverse endothelial dysfunction and left ventricular hypertrophy and the clinical sequelae of these abnormalities.
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Affiliation(s)
- M P C Kao
- Division of Medical Sciences, Centre for Cardiovascular and Lung Biology, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
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Pop-Busui R, Roberts L, Pennathur S, Kretzler M, Brosius FC, Feldman EL. The management of diabetic neuropathy in CKD. Am J Kidney Dis 2010; 55:365-85. [PMID: 20042258 PMCID: PMC4007054 DOI: 10.1053/j.ajkd.2009.10.050] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2009] [Accepted: 10/29/2009] [Indexed: 02/07/2023]
Abstract
A 64-year-old male with a 15-year history of poorly controlled type 2 diabetes and a 10-year history of hypertension and hyperlipidemia had developed multiple diabetes-related complications within the last 5 years. He first developed albuminuria 5 years ago, and over the next several years experienced fairly rapid decline in kidney function, with eGFR of 55 mL/min/1.73m2 noted 2 years ago. He was diagnosed with proliferative retinopathy 5 years ago and underwent laser photocoagulation. Four years ago, he noted symptoms of peripheral neuropathy manifested as shooting pain and numbness with loss of light touch, thermal and vibratory sensation in a stocking distribution. Last year he developed a non-healing ulcer on the plantar aspect of his left foot which was complicated with gangrene and resulted in a below-the-knee amputation of the left leg one year ago. He now reports a new onset of weakness, lightheadedness and dizziness on standing that affects his daily activities. He reports lancinating pain in his right lower extremity, worse in the evening. Medications include: neutral protamine Hagedorn insulin twice daily and regular insulin on a sliding scale, metoprolol 50 mg/d, lisinopril 40 mg/d, atorvastatin 80 mg/d, furosemide 40 mg/d and aspirin 81 mg/d. Blood pressure is 127/69 mm Hg with a pulse rate of 96 bpm while supine and 94/50 mmHg with a pulse rate of 102 bpm while standing. Strength is normal but with a complete loss of all sensory modalities to the knee in his remaining limb and up to the wrists in both upper extremities, and he is areflexic. Today's laboratory evaluations show a serum creatinine of 2.8 mg/dl, an estimated GFR (eGFR) of 24 ml/min/1.73m2, a hemoglobin A1c (HbA1c) of 7.9 % and 2.1 g of urine protein per gram of creatinine. What would be the most appropriate management for this patient?
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Affiliation(s)
- Rodica Pop-Busui
- University of Michigan Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes
| | | | | | - Mathias Kretzler
- University of Michigan Department of Internal Medicine, Division of Nephrology
| | - Frank C. Brosius
- University of Michigan Department of Internal Medicine, Division of Nephrology
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Affiliation(s)
- Rodica Pop-Busui
- Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, Michigan, USA.
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Tadano N, Morimoto S, Takahashi-Yanaga F, Miwa Y, Ohtsuki I, Sasaguri T. Propyl gallate, a strong antioxidant, increases the Ca2+ sensitivity of cardiac myofilament. J Pharmacol Sci 2009; 109:456-8. [PMID: 19305124 DOI: 10.1254/jphs.08266sc] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
Abstract
Ca(2+) sensitizers are cardiotonic agents that directly increase the Ca(2+) sensitivity of cardiac myofilament. To find a novel Ca(2+) sensitizer, we have screened a group of phenolic compounds by examining their effects on the Ca(2+)-dependent force generation in cardiac muscle fibers. We found that propyl gallate, a strong antioxidant, increased the Ca(2+) sensitivity of cardiac myofilament in a dose-dependent and reversible manner. The present study indicates that propyl gallate is a novel type of Ca(2+) sensitizer with antioxidant activity, which might be more beneficial for the treatment of congestive heart failure associated with oxidative stress than existing Ca(2+) sensitizers.
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Affiliation(s)
- Naoto Tadano
- Depertment of Clinical Pharmacology, Graduate School of Medical Sciences, Kyushu University, Japan
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27
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Shinke T, Shite J, Takaoka H, Hata K, Inoue N, Yoshikawa R, Matsumoto H, Masai H, Watanabe S, Ozawa T, Otake H, Matsumoto D, Hirata KI, Yokoyama M. Vitamin C restores the contractile response to dobutamine and improves myocardial efficiency in patients with heart failure after anterior myocardial infarction. Am Heart J 2007; 154:645.e1-8. [PMID: 17892985 DOI: 10.1016/j.ahj.2007.07.005] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2006] [Accepted: 07/04/2007] [Indexed: 10/22/2022]
Abstract
BACKGROUND Excessive oxidative stress is considered one of the mechanisms of a decrease in contractile force without concomitant reduction in oxygen cost in failing myocardium. We hypothesized that the antioxidant vitamin C may help reverse hyporesponsiveness to beta-adrenergic stimulation and improve myocardial efficiency in patients with heart failure (HF) after myocardial infarction (MI). METHODS AND RESULTS Nineteen patients with mild to moderate HF due to previous MI (mean left ventricular [LV] ejection fraction 39%) were instrumented with conductance and coronary sinus thermodilution catheters. Left ventricular contractility, expressed as E(es), the slope of end-systolic pressure-volume relationship, and mechanical efficiency, expressed as the ratio of LV stroke work (SW) to myocardial oxygen consumption (MVO2), were measured in response to the intravenous infusion of dobutamine (4 microg/kg per min) before (Dob) and during (Dob + Vit C) the infusion of vitamin C (2.0-g bolus injection and subsequent 50-mg/min infusion through the jugular vein) (vitamin C group, n = 10). The infusion of vitamin C augmented the E(es) response to dobutamine by 20% +/- 8% (Dob 2.1 +/- 0.3, Dob + Vit C 2.5 +/- 0.4 mm Hg/mL, P < .01) and the SW/MVO2 response by 21% +/- 5% (Dob 36% +/- 3%, Dob + Vit C 43% +/- 4%, P < .01). In the control group (n = 9), E(es) and SW/MVO2 were measured in response to dobutamine before (Dob) and during (Dob + vehicle) the infusion of saline. No difference in E(es) or SW/MVO2 was observed between Dob and Dob + vehicle (E(es): Dob 2.1 +/- 0.2, Dob + vehicle 2.1 +/- 0.2 mm Hg/mL per square meter, P = nonsignificant) (SW/MVO2: Dob 35% +/- 4%, Dob + vehicle 33% +/- 4%, P = nonsignificant). CONCLUSION The administration of the antioxidant vitamin C enhances the contractile response to dobutamine and improves myocardial efficiency in patients with HF.
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Affiliation(s)
- Toshiro Shinke
- Division of Cardiovascular and Respiratory Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
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28
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Esper RJ, Nordaby RA, Vilariño JO, Paragano A, Cacharrón JL, Machado RA. Endothelial dysfunction: a comprehensive appraisal. Cardiovasc Diabetol 2006; 5:4. [PMID: 16504104 PMCID: PMC1434727 DOI: 10.1186/1475-2840-5-4] [Citation(s) in RCA: 300] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2006] [Accepted: 02/23/2006] [Indexed: 12/20/2022] Open
Abstract
The endothelium is a thin monocelular layer that covers all the inner surface of the blood vessels, separating the circulating blood from the tissues. It is not an inactive organ, quite the opposite. It works as a receptor-efector organ and responds to each physical or chemical stimulus with the release of the correct substance with which it may maintain vasomotor balance and vascular-tissue homeostasis. It has the property of producing, independently, both agonistic and antagonistic substances that help to keep homeostasis and its function is not only autocrine, but also paracrine and endocrine. In this way it modulates the vascular smooth muscle cells producing relaxation or contraction, and therefore vasodilatation or vasoconstriction. The endothelium regulating homeostasis by controlling the production of prothrombotic and antithrombotic components, and fibrynolitics and antifibrynolitics. Also intervenes in cell proliferation and migration, in leukocyte adhesion and activation and in immunological and inflammatory processes. Cardiovascular risk factors cause oxidative stress that alters the endothelial cells capacity and leads to the so called endothelial "dysfunction" reducing its capacity to maintain homeostasis and leads to the development of pathological inflammatory processes and vascular disease. There are different techniques to evaluate the endothelium functional capacity, that depend on the amount of NO produced and the vasodilatation effect. The percentage of vasodilatation with respect to the basal value represents the endothelial functional capacity. Taking into account that shear stress is one of the most important stimulants for the synthesis and release of NO, the non-invasive technique most often used is the transient flow-modulate "endothelium-dependent" post-ischemic vasodilatation, performed on conductance arteries such as the brachial, radial or femoral arteries. This vasodilatation is compared with the vasodilatation produced by drugs that are NO donors, such as nitroglycerine, called "endothelium independent". The vasodilatation is quantified by measuring the arterial diameter with high resolution ultrasonography. Laser-Doppler techniques are now starting to be used that also consider tissue perfusion. There is so much proof about endothelial dysfunction that it is reasonable to believe that there is diagnostic and prognostic value in its evaluation for the late outcome. There is no doubt that endothelial dysfunction contributes to the initiation and progression of atherosclerotic disease and could be considered an independent vascular risk factor. Although prolonged randomized clinical trials are needed for unequivocal evidence, the data already obtained allows the methods of evaluation of endothelial dysfunction to be considered useful in clinical practice and have overcome the experimental step, being non-invasive increases its value making it use full for follow-up of the progression of the disease and the effects of different treatments.
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Affiliation(s)
- Ricardo J Esper
- Hospital Militar Central, Departamento Cardiovascular, Servicio de Cardiología, Buenos Aires, Argentina
- Universidad del Salvador, Escuela de Posgrado, Carrera de Cardiología, Buenos Aires, Argentina
- Universidad de Buenos Aires, Escuela de Medicina, Buenos Aires, Argentina
- Virrey Loreto 2111, C1426DXM Buenos Aires, Argentina
| | - Roberto A Nordaby
- Hospital Francés, Servicio de Cardiología, Buenos Aires, Argentina
- Universidad del Salvador, Escuela de Posgrado, Carrera de Cardiología, Buenos Aires, Argentina
| | - Jorge O Vilariño
- Hospital Militar Central, Departamento Cardiovascular, Servicio de Cardiología, Buenos Aires, Argentina
- Universidad del Salvador, Escuela de Posgrado, Carrera de Cardiología, Buenos Aires, Argentina
| | - Antonio Paragano
- Hospital Militar Central, Departamento Cardiovascular, Servicio de Cardiología, Buenos Aires, Argentina
| | - José L Cacharrón
- Universidad del Salvador, Escuela de Posgrado, Carrera de Cardiología, Buenos Aires, Argentina
- Universidad de Buenos Aires, Escuela de Medicina, Buenos Aires, Argentina
| | - Rogelio A Machado
- Hospital Militar Central, Departamento Cardiovascular, Servicio de Cardiología, Buenos Aires, Argentina
- Hospital Francés, Servicio de Cardiología, Buenos Aires, Argentina
- Universidad del Salvador, Escuela de Posgrado, Carrera de Cardiología, Buenos Aires, Argentina
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29
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Mak S, Overgaard CB, Newton GE. Effect of vitamin C and L-NMMA on the inotropic response to dobutamine in patients with heart failure. Am J Physiol Heart Circ Physiol 2005; 289:H2424-8. [PMID: 16040714 DOI: 10.1152/ajpheart.00453.2005] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The positive effect of vitamin C on left ventricular (LV) inotropic responses to dobutamine, observed in patients with preserved LV function, is lost in heart failure (HF). We tested the hypothesis that in HF, endogenous nitric oxide (NO) opposes the positive effect of vitamin C on adrenergically stimulated contractility by examining the effects of vitamin C on dobutamine responses during NO synthase inhibition. In 11 HF patients, a micromanometer-tipped catheter was inserted into the LV and an infusion catheter was positioned in the left main coronary artery. The peak positive rate of change of LV pressure (LV +dP/dt) was measured in response to intravenous dobutamine (Dob-1). After recontrol, intracoronary N(G)-monomethyl-L-arginine (l-NMMA) was infused before reinfusion of dobutamine (L-NMMA + Dob-2). Finally, intracoronary vitamin C was infused in addition to intracoronary L-NMMA and dobutamine (L-NMMA + Dob-2 + vitamin C). Intracoronary L-NMMA alone had no effect on LV +dP/dt. After a stable inotropic response to intracoronary L-NMMA and dobutamine was established, the addition of intracoronary vitamin C resulted in a modest but significant increase in LV +dP/dt. The change in LV +dP/dt in response to dobutamine alone was 25 +/- 5%, with intracoronary L-NMMA, 27 +/- 6%, and with intracoronary L-NMMA plus vitamin C, 37 +/- 5% (P < 0.05 vs. Dob-1 and L-NMMA + Dob-2). These findings demonstrate that an interaction between endogenous NO and redox environment exists and exerts some influence on stimulated contractility in HF.
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Affiliation(s)
- Susanna Mak
- Cardiovascular Clinical Research Laboratory, Div. of Cardiology, Mount Sinai Hospital, 600 University Ave., Rm. 1543, Toronto, Ontario, Canada M5G 1X5
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30
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Pop-Busui R, Kirkwood I, Schmid H, Marinescu V, Schroeder J, Larkin D, Yamada E, Raffel DM, Stevens MJ. Sympathetic dysfunction in type 1 diabetes: association with impaired myocardial blood flow reserve and diastolic dysfunction. J Am Coll Cardiol 2005; 44:2368-74. [PMID: 15607400 DOI: 10.1016/j.jacc.2004.09.033] [Citation(s) in RCA: 121] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2003] [Revised: 07/02/2004] [Accepted: 09/14/2004] [Indexed: 12/15/2022]
Abstract
OBJECTIVES This study was designed to explore the relationships of early diabetic microangiopathy to alterations of cardiac sympathetic tone and myocardial blood flow (MBF) regulation in subjects with stable type 1 diabetes. BACKGROUND In diabetes, augmented cardiac sympathetic tone and abnormal MBF regulation may predispose to myocardial injury and enhanced cardiac risk. METHODS Subject groups comprised healthy controls (C) (n = 10), healthy diabetic subjects (DC) (n = 12), and diabetic subjects with very early diabetic microangiopathy (DMA+) (n = 16). [(11)C]meta-hydroxyephedrine ([(11)C]HED) and positron emission tomography (PET) were used to explore left ventricular (LV) sympathetic integrity and [(13)N]ammonia-PET to assess MBF regulation in response to cold pressor testing (CPT) and adenosine infusion. RESULTS Deficits of LV [(11)C]HED retention were extensive and global in the DMA+ subjects (36 +/- 31% vs. 1 +/- 1% in DC subjects; p < 0.01) despite preserved autonomic reflex tests. On CPT, plasma norepinephrine excursions were two-fold greater than in C and DC subjects (p < 0.05), and basal LV blood flow decreased (-12%, p < 0.05) in DMA+ but not in C or DC subjects (+45% and +51%, respectively). On adenosine infusion, compared with C subjects, MBF reserve decreased by approximately 45% (p < 0.05) in DMA+ subjects. Diastolic dysfunction was detected by two-dimensional echocardiography in 5 of 8 and 0 of 8 consecutively tested DMA+ and DC subjects, respectively. CONCLUSIONS Augmented cardiac sympathetic tone and responsiveness and impaired myocardial perfusion may contribute to myocardial injury in diabetes.
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Affiliation(s)
- Rodica Pop-Busui
- Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Michigan, 1150 West Medical Center Drive, Ann Arbor, MI 48109-0678, USA
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31
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Singh K, Xiao L, Remondino A, Sawyer DB, Colucci WS. Adrenergic regulation of cardiac myocyte apoptosis. J Cell Physiol 2001; 189:257-65. [PMID: 11748583 DOI: 10.1002/jcp.10024] [Citation(s) in RCA: 149] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
The direct effects of catecholamines on cardiac myocytes may contribute to both normal physiologic adaptation and pathologic remodeling, and may be associated with cellular hypertrophy, apoptosis, and alterations in contractile function. Norepinephrine (NE) signals via alpha- and beta-adrenergic receptors (AR) that are coupled to G-proteins. Pharmacologic studies of cardiac myocytes in vitro demonstrate that stimulation of beta1-AR induces apoptosis which is cAMP-dependent and involves the voltage-dependent calcium influx channel. In contrast, stimulation of beta2-AR exerts an anti-apoptotic effect which appears to be mediated by a pertussis toxin-sensitive G protein. Stimulation of alpha1-AR causes myocyte hypertrophy and may exert an anti-apoptotic action. In transgenic mice, myocardial overexpression of either beta1-AR or G(alpha)s is associated with myocyte apoptosis and the development of dilated cardiomyopathy. Myocardial overexpression of beta2-AR at low levels results in improved cardiac function, whereas expression at high levels leads to dilated cardiomyopathy. Overexpression of wildtype alpha1B-AR does not result in apoptosis, whereas overexpression of G(alpha)q results in myocyte hypertrophy and/or apoptosis depending on the level of expression. Differential activation of the members of the mitogen-activated protein kinase (MAPK) superfamily and production of reactive oxygen species appear to play a key role in mediating the actions of adrenergic pathways on myocyte apoptosis and hypertrophy. This review summarizes current knowledge about the molecular and cellular mechanisms involved in the regulation of cardiac myocyte apoptosis via stimulation of adrenergic receptors and their coupled effector pathways.
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MESH Headings
- Adrenergic alpha-Agonists/pharmacology
- Animals
- Apoptosis
- Cardiomyopathy, Dilated/etiology
- Heterotrimeric GTP-Binding Proteins/genetics
- Heterotrimeric GTP-Binding Proteins/physiology
- Mice
- Mice, Transgenic
- Mitogen-Activated Protein Kinases/metabolism
- Models, Biological
- Myocardium/cytology
- Myocardium/metabolism
- Norepinephrine/pharmacology
- Reactive Oxygen Species/metabolism
- Receptors, Adrenergic, alpha/genetics
- Receptors, Adrenergic, alpha/metabolism
- Receptors, Adrenergic, beta/genetics
- Receptors, Adrenergic, beta/metabolism
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Affiliation(s)
- K Singh
- Cardiovascular Medicine Section, Boston University Medical Center, Boston, Massachussetts 02118, USA
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