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de Paula LJC, Uchida AH, Rezende PC, Soares P, Scudeler TL. Protective or Inhibitory Effect of Pharmacological Therapy on Cardiac Ischemic Preconditioning: A Literature Review. Curr Vasc Pharmacol 2022; 20:409-428. [PMID: 35986546 DOI: 10.2174/1570161120666220819163025] [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] [Received: 03/21/2022] [Revised: 05/23/2022] [Accepted: 05/31/2022] [Indexed: 01/25/2023]
Abstract
Ischemic preconditioning (IP) is an innate phenomenon, triggered by brief, non-lethal cycles of ischemia/reperfusion applied to a tissue or organ that confers tolerance to a subsequent more prolonged ischemic event. Once started, it can reduce the severity of myocardial ischemia associated with some clinical situations, such as percutaneous coronary intervention (PCI) and intermittent aortic clamping during coronary artery bypass graft surgery (CABG). Although the mechanisms underlying IP have not been completely elucidated, several studies have shown that this phenomenon involves the participation of cell triggers, intracellular signaling pathways, and end-effectors. Understanding this mechanism enables the development of preconditioning mimetic agents. It is known that a range of medications that activate the signaling cascades at different cellular levels can interfere with both the stimulation and the blockade of IP. Investigations of signaling pathways underlying ischemic conditioning have identified a number of therapeutic targets for pharmacological manipulation. This review aims to present and discuss the effects of several medications on myocardial IP.
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Affiliation(s)
| | | | - Paulo Cury Rezende
- Instituto do Coração (InCor), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Paulo Soares
- Instituto do Coração (InCor), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Thiago Luis Scudeler
- Instituto do Coração (InCor), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
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Buckley JP, Riddell M, Mellor D, Bracken RM, Ross MK, LaGerche A, Poirier P. Acute glycaemic management before, during and after exercise for cardiac rehabilitation participants with diabetes mellitus: a joint statement of the British and Canadian Associations of Cardiovascular Prevention and Rehabilitation, the International Council for Cardiovascular Prevention and Rehabilitation and the British Association of Sport and Exercise Sciences. Br J Sports Med 2020; 55:bjsports-2020-102446. [PMID: 33361136 DOI: 10.1136/bjsports-2020-102446] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/19/2020] [Indexed: 12/12/2022]
Abstract
Type 1 (T1) and type 2 (T2) diabetes mellitus (DM) are significant precursors and comorbidities to cardiovascular disease and prevalence of both types is still rising globally. Currently,~25% of participants (and rising) attending cardiac rehabilitation in Europe, North America and Australia have been reported to have DM (>90% have T2DM). While there is some debate over whether improving glycaemic control in those with heart disease can independently improve future cardiovascular health-related outcomes, for the individual patient whose blood glucose is well controlled, it can aid the exercise programme in being more efficacious. Good glycaemic management not only helps to mitigate the risk of acute glycaemic events during exercising, it also aids in achieving the requisite physiological and psycho-social aims of the exercise component of cardiac rehabilitation (CR). These benefits are strongly associated with effective behaviour change, including increased enjoyment, adherence and self-efficacy. It is known that CR participants with DM have lower uptake and adherence rates compared with those without DM. This expert statement provides CR practitioners with nine recommendations aimed to aid in the participant's improved blood glucose control before, during and after exercise so as to prevent the risk of glycaemic events that could mitigate their beneficial participation.
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Affiliation(s)
- John P Buckley
- Shrewsbury Centre for Active Living, University of Chester Faculty of Medicine and Life Sciences, Chester, Cheshire West and Chester, UK
- Institute of Sport Exercise and Health, University College London, London, UK
| | - Michael Riddell
- School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada
- LMC Healthcare, Diabetes and Endocrinology, Toronto, Ontario, Canada
| | - Duane Mellor
- Aston Medical School, Aston University, Birmingham, West Midlands, UK
- Sport and Exercise Science, Swansea University College of Engineering, Swansea, Wales, UK
| | - Richard M Bracken
- Sport and Exercise Science, Swansea University College of Engineering, Swansea, Wales, UK
| | - Marie-Kristelle Ross
- Hotel-Dieu de Levis, Laval University Faculty of Medicine, Quebec city, Quebec, Canada
| | - Andre LaGerche
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
- St Vincent's Hospital Melbourne Pty Ltd, Fitzroy, Victoria, Australia
| | - Paul Poirier
- Cardiology, Institut universitaire de cardiologie et de pneumologie de Québec, Quebec City, Quebec, Canada
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Effect of ischemic preconditioning on cardiovascular outcomes in patients with symptomatic coronary artery disease: a cohort study. Coron Artery Dis 2019; 30:536-541. [PMID: 30994494 DOI: 10.1097/mca.0000000000000748] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Despite the powerful myocardial protection of ischemic preconditioning (IP) observed in experimental studies, it remains a challenge to observe such protection in humans. Thus, the aim of this study was to evaluate the possible effects of IP on clinical outcomes in patients with coronary artery disease (CAD). PATIENTS AND METHODS In this cohort study, patients with multivessel CAD, preserved systolic ventricular function, and stable angina were prospectively selected. They underwent two sequential exercise stress tests (EST) to evaluate IP presence. IP was considered present if patients had an improvement in the time to the onset of 1.0-mm STsegment deviation in the second EST. The primary end point was the composite rate of cardiac death, nonfatal myocardial infarction, or revascularization during 1-year follow-up. Patients with (IP+) and without (IP-) the cardioprotective mechanism were compared regarding clinical end points. RESULTS A total of 229 patients completed EST and had IP evaluated: 165 (72%) were IP+ and 64 (28%) were IP - patients. Of these, 218 patients had complete follow-up. At 1-year, event-free survival regarding the primary end point was 95.5 versus 83.6% (P = 0.0024) and event-free survival regarding cardiac death or myocardial infarction was 99.4 versus 91.7% (P=0.0020), respectively, in IP + and IP - groups. The unadjusted hazard ratio (IP + /IP-) for the primary end point was 4.63 (1.52-14.08). After multivariate analysis, IP was still significantly associated with better clinical outcomes (P = 0.0025). CONCLUSION This data suggest that IP may contribute to better clinical outcomes in patients with ischemic heart disease.
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Leonard CE, Hennessy S, Han X, Siscovick DS, Flory JH, Deo R. Pro- and Antiarrhythmic Actions of Sulfonylureas: Mechanistic and Clinical Evidence. Trends Endocrinol Metab 2017; 28:561-586. [PMID: 28545784 PMCID: PMC5522643 DOI: 10.1016/j.tem.2017.04.003] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Revised: 04/18/2017] [Accepted: 04/19/2017] [Indexed: 12/19/2022]
Abstract
Sulfonylureas are the most commonly used second-line drug class for treating type 2 diabetes mellitus (T2DM). While the cardiovascular safety of sulfonylureas has been examined in several trials and nonrandomized studies, little is known of their specific effects on sudden cardiac arrest (SCA) and related serious arrhythmic outcomes. This knowledge gap is striking, because persons with DM are at increased risk of SCA. In this review, we explore the influence of sulfonylureas on the risk of serious arrhythmias, with specific foci on ischemic preconditioning, cardiac excitability, and serious hypoglycemia as putative mechanisms. Elucidating the relationship between individual sulfonylureas and serious arrhythmias is critical, especially as the diabetes epidemic intensifies and SCA incidence increases in persons with diabetes.
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Affiliation(s)
- Charles E Leonard
- Center for Pharmacoepidemiology Research and Training, Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
| | - Sean Hennessy
- Center for Pharmacoepidemiology Research and Training, Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Xu Han
- Center for Pharmacoepidemiology Research and Training, Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - David S Siscovick
- The New York Academy of Medicine, New York, NY 10029, USA; Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA 98195, USA
| | - James H Flory
- Center for Pharmacoepidemiology Research and Training, Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Healthcare Policy and Research, Division of Comparative Effectiveness, Weill Cornell Medicine, Cornell University, New York, NY 10065, USA; Memorial Sloan Kettering Cancer Center, New York, NY 10022, USA
| | - Rajat Deo
- Center for Pharmacoepidemiology Research and Training, Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Cardiovascular Medicine, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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Rezende PC, Rahmi RM, Hueb W. The Influence of Diabetes Mellitus in Myocardial Ischemic Preconditioning. J Diabetes Res 2016; 2016:8963403. [PMID: 27656659 PMCID: PMC5021496 DOI: 10.1155/2016/8963403] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Accepted: 08/14/2016] [Indexed: 11/24/2022] Open
Abstract
Ischemic preconditioning (IP) is a powerful mechanism of protection discovered in the heart in which ischemia paradoxically protects the myocardium against other ischemic insults. Many factors such as diseases and medications may influence IP expression. Although diabetes poses higher cardiovascular risk, the physiopathology underlying this condition is uncertain. Moreover, although diabetes is believed to alter intracellular pathways related to myocardial protective mechanisms, it is still controversial whether diabetes may interfere with ischemic preconditioning and whether this might influence clinical outcomes. This review article looks at published reports with animal models and humans that tried to evaluate the possible influence of diabetes in myocardial ischemic preconditioning.
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Affiliation(s)
- Paulo Cury Rezende
- Department of Atherosclerosis, Heart Institute of the University of São Paulo Medical School, São Paulo, SP, Brazil
| | - Rosa Maria Rahmi
- Department of Atherosclerosis, Heart Institute of the University of São Paulo Medical School, São Paulo, SP, Brazil
| | - Whady Hueb
- Department of Atherosclerosis, Heart Institute of the University of São Paulo Medical School, São Paulo, SP, Brazil
- *Whady Hueb:
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Exercise-induced ischemic preconditioning and the potential application to cardiac rehabilitation: a systematic review. J Cardiopulm Rehabil Prev 2015; 35:93-102. [PMID: 25622217 DOI: 10.1097/hcr.0000000000000099] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Exercise-induced ischemic preconditioning (IPC) can be assessed by the results of the second of sequential exercise tests. Exercise-induced IPC is quantified by using the time to 1-mm ST-segment depression, the rate-pressure product at 1-mm ST-segment depression, the maximal ST-segment depression, and the rate-pressure product at the peak of exercise. Few studies reported whether exercise-induced IPC could be used in cardiovascular rehabilitation. A systematic review of the literature limited to human studies was performed using electronic databases, and the main key words were ischemic preconditioning, warm-up phenomenon, and exercise. After careful review, 38 articles were included in the systematic review. This review summarizes the molecular pathways of IPC and describes the first window of protection induced by sequential exercise tests, as well as the effect of medication on exercise-induced IPC. A section on the exercise protocol, mode of exercise, and intensity provides understanding as to what is needed for clinicians to induce IPC with sequential stress tests. The final section of the review is a discussion of the potential use of exercise-induced IPC in a cardiovascular rehabilitation setting. Even if exercise-induced IPC is a well-documented phenomenon, additional studies are needed in order to more fully understand its use in rehabilitation.
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Rezende PC, Rahmi RM, Uchida AH, da Costa LMA, Scudeler TL, Garzillo CL, Lima EG, Segre CAW, Girardi P, Takiuti M, Silva MF, Hueb W, Ramires JAF, Kalil Filho R. Type 2 diabetes mellitus and myocardial ischemic preconditioning in symptomatic coronary artery disease patients. Cardiovasc Diabetol 2015; 14:66. [PMID: 26025451 PMCID: PMC4451743 DOI: 10.1186/s12933-015-0228-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2015] [Accepted: 05/21/2015] [Indexed: 01/10/2023] Open
Abstract
Background The influence of diabetes mellitus on myocardial ischemic preconditioning is not clearly defined. Experimental studies are conflicting and human studies are scarce and inconclusive. Objectives Identify whether diabetes mellitus intervenes on ischemic preconditioning in symptomatic coronary artery disease patients. Methods Symptomatic multivessel coronary artery disease patients with preserved systolic ventricular function and a positive exercise test underwent two sequential exercise tests to demonstrate ischemic preconditioning. Ischemic parameters were compared among patients with and without type 2 diabetes mellitus. Ischemic preconditioning was considered present when the time to 1.0 mm ST deviation and rate pressure-product were greater in the second of 2 exercise tests. Sequential exercise tests were analyzed by 2 independent cardiologists. Results Of the 2,140 consecutive coronary artery disease patients screened, 361 met inclusion criteria, and 174 patients (64.2 ± 7.6 years) completed the study protocol. Of these, 86 had the diagnosis of type 2 diabetes. Among diabetic patients, 62 (72 %) manifested an improvement in ischemic parameters consistent with ischemic preconditioning, whereas among nondiabetic patients, 60 (68 %) manifested ischemic preconditioning (p = 0.62). The analysis of patients who demonstrated ischemic preconditioning showed similar improvement in the time to 1.0 mm ST deviation between diabetic and nondiabetic groups (79.4 ± 47.6 vs 65.5 ± 36.4 s, respectively, p = 0.12). Regarding rate pressure-product, the improvement was greater in diabetic compared to nondiabetic patients (3011 ± 2430 vs 2081 ± 2139 bpm x mmHg, respectively, p = 0.01). Conclusions In this study, diabetes mellitus was not associated with impairment in ischemic preconditioning in symptomatic coronary artery disease patients. Furthermore, diabetic patients experienced an improvement in this significant mechanism of myocardial protection.
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Affiliation(s)
- Paulo Cury Rezende
- Department of Atherosclerosis, Heart Institute (InCor) of the University of São Paulo, Av. Dr. Eneas de Carvalho Aguiar 44, AB, Sala 114, 05403-000, Cerqueira César, São Paulo, Brazil.
| | - Rosa Maria Rahmi
- Department of Atherosclerosis, Heart Institute (InCor) of the University of São Paulo, Av. Dr. Eneas de Carvalho Aguiar 44, AB, Sala 114, 05403-000, Cerqueira César, São Paulo, Brazil.
| | - Augusto Hiroshi Uchida
- Department of Atherosclerosis, Heart Institute (InCor) of the University of São Paulo, Av. Dr. Eneas de Carvalho Aguiar 44, AB, Sala 114, 05403-000, Cerqueira César, São Paulo, Brazil.
| | - Leandro Menezes Alves da Costa
- Department of Atherosclerosis, Heart Institute (InCor) of the University of São Paulo, Av. Dr. Eneas de Carvalho Aguiar 44, AB, Sala 114, 05403-000, Cerqueira César, São Paulo, Brazil.
| | - Thiago Luis Scudeler
- Department of Atherosclerosis, Heart Institute (InCor) of the University of São Paulo, Av. Dr. Eneas de Carvalho Aguiar 44, AB, Sala 114, 05403-000, Cerqueira César, São Paulo, Brazil.
| | - Cibele Larrosa Garzillo
- Department of Atherosclerosis, Heart Institute (InCor) of the University of São Paulo, Av. Dr. Eneas de Carvalho Aguiar 44, AB, Sala 114, 05403-000, Cerqueira César, São Paulo, Brazil.
| | - Eduardo Gomes Lima
- Department of Atherosclerosis, Heart Institute (InCor) of the University of São Paulo, Av. Dr. Eneas de Carvalho Aguiar 44, AB, Sala 114, 05403-000, Cerqueira César, São Paulo, Brazil.
| | - Carlos Alexandre Wainrober Segre
- Department of Atherosclerosis, Heart Institute (InCor) of the University of São Paulo, Av. Dr. Eneas de Carvalho Aguiar 44, AB, Sala 114, 05403-000, Cerqueira César, São Paulo, Brazil.
| | - Priscyla Girardi
- Department of Atherosclerosis, Heart Institute (InCor) of the University of São Paulo, Av. Dr. Eneas de Carvalho Aguiar 44, AB, Sala 114, 05403-000, Cerqueira César, São Paulo, Brazil.
| | - Myrthes Takiuti
- Department of Atherosclerosis, Heart Institute (InCor) of the University of São Paulo, Av. Dr. Eneas de Carvalho Aguiar 44, AB, Sala 114, 05403-000, Cerqueira César, São Paulo, Brazil.
| | - Marcela Francisca Silva
- Department of Atherosclerosis, Heart Institute (InCor) of the University of São Paulo, Av. Dr. Eneas de Carvalho Aguiar 44, AB, Sala 114, 05403-000, Cerqueira César, São Paulo, Brazil.
| | - Whady Hueb
- Department of Atherosclerosis, Heart Institute (InCor) of the University of São Paulo, Av. Dr. Eneas de Carvalho Aguiar 44, AB, Sala 114, 05403-000, Cerqueira César, São Paulo, Brazil.
| | - Jose Antonio Franchini Ramires
- Department of Atherosclerosis, Heart Institute (InCor) of the University of São Paulo, Av. Dr. Eneas de Carvalho Aguiar 44, AB, Sala 114, 05403-000, Cerqueira César, São Paulo, Brazil.
| | - Roberto Kalil Filho
- Department of Atherosclerosis, Heart Institute (InCor) of the University of São Paulo, Av. Dr. Eneas de Carvalho Aguiar 44, AB, Sala 114, 05403-000, Cerqueira César, São Paulo, Brazil.
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Rahmi Garcia RM, Rezende PC, Hueb W. Impact of hypoglycemic agents on myocardial ischemic preconditioning. World J Diabetes 2014; 5:258-266. [PMID: 24936247 PMCID: PMC4058730 DOI: 10.4239/wjd.v5.i3.258] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2013] [Accepted: 03/18/2014] [Indexed: 02/05/2023] Open
Abstract
Murry et al in 1986 discovered the intrinsic mechanism of profound protection called ischemic preconditioning. The complex cellular signaling cascades underlying this phenomenon remain controversial and are only partially understood. However, evidence suggests that adenosine, released during the initial ischemic insult, activates a variety of G protein-coupled agonists, such as opioids, bradykinin, and catecholamines, resulting in the activation of protein kinases, especially protein kinase C (PKC). This leads to the translocation of PKC from the cytoplasm to the sarcolemma, where it stimulates the opening of the ATP-sensitive K+ channel, which confers resistance to ischemia. It is known that a range of different hypoglycemic agents that activate the same signaling cascades at various cellular levels can interfere with protection from ischemic preconditioning. This review examines the effects of several hypoglycemic agents on myocardial ischemic preconditioning in animal studies and clinical trials.
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Lalonde F, Poirier P, Sylvestre MP, Arvisais D, Curnier D. Exercise-induced ischemic preconditioning detected by sequential exercise stress tests: A meta-analysis. Eur J Prev Cardiol 2013; 22:100-12. [DOI: 10.1177/2047487313502447] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Affiliation(s)
- François Lalonde
- Laboratoire de Physiopathologie de l'Exercice, Département de Kinésiologie, Université de Montréal, Canada
- Centre de Recherche du Centre Hospitalier Universitaire de Montréal, Canada
| | - Paul Poirier
- Faculté de Pharmacie, Université Laval, Canada; Institut universitaire de cardiologie et de pneumologie de Québec, Université Laval, Canada
| | - Marie-Pierre Sylvestre
- Centre de Recherche du Centre Hospitalier Universitaire de Montréal, Canada
- Département de Médecine Préventive et Sociale, Université de Montréal, Canada
| | - Denis Arvisais
- Direction des bibliothéques, Universitéde Montréal, Canada
| | - Daniel Curnier
- Laboratoire de Physiopathologie de l'Exercice, Département de Kinésiologie, Université de Montréal, Canada
- Centre de Recherche du Centre Hospitalier Universitaire de Montréal, Canada
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Williams RP, Manou-Stathopoulou V, Redwood SR, Marber MS. ‘Warm-up Angina’: harnessing the benefits of exercise and myocardial ischaemia. Heart 2013; 100:106-14. [DOI: 10.1136/heartjnl-2013-304187] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
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Rahmi RM, Uchida AH, Rezende PC, Lima EG, Garzillo CL, Favarato D, Strunz CMC, Takiuti M, Girardi P, Hueb W, Kalil Filho R, Ramires JAF. Effect of hypoglycemic agents on ischemic preconditioning in patients with type 2 diabetes and symptomatic coronary artery disease. Diabetes Care 2013; 36:1654-9. [PMID: 23250803 PMCID: PMC3661846 DOI: 10.2337/dc12-1495] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE To assess the effect of two hypoglycemic drugs on ischemic preconditioning (IPC) patients with type 2 diabetes and coronary artery disease (CAD). RESEARCH DESIGN AND METHODS We performed a prospective study of 96 consecutive patients allocated into two groups: 42 to group repaglinide (R) and 54 to group vildagliptin (V). All patients underwent two consecutive exercise tests (ET1 and ET2) in phase 1 without drugs. In phase 2, 1 day after ET1 and -2, 2 mg repaglinide three times daily or 50 mg vildagliptin twice daily was given orally to patients in the respective group for 6 days. On the seventh day, 60 min after 6 mg repaglinide or 100 mg vildagliptin, all patients underwent two consecutive exercise tests (ET3 and ET4). RESULTS In phase 1, IPC was demonstrated by improvement in the time to 1.0 mm ST-segment depression and rate pressure product (RPP). All patients developed ischemia in ET3; however, 83.3% of patients in group R experienced ischemia earlier in ET4, without significant improvement in RPP, indicating the cessation of IPC (P < 0.0001). In group V, only 28% of patients demonstrated IPC cessation, with 72% still having the protective effect (P < 0.0069). CONCLUSIONS Repaglinide eliminated myocardial IPC, probably by its effect on the KATP channel. Vildagliptin did not damage this protective mechanism in a relevant way in patients with type 2 diabetes and CAD, suggesting a good alternative treatment in this population.
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Affiliation(s)
- Rosa Maria Rahmi
- Department of Atherosclerosis, Heart Institute of the University of São Paulo, São Paulo, Brazil
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Engoren M, Schwann TA, Arslanian-Engoren C, Maile M, Habib RH. U-shape association between hemoglobin A1c and late mortality in patients with heart failure after cardiac surgery. Am J Cardiol 2013; 111:1209-13. [PMID: 23391105 DOI: 10.1016/j.amjcard.2012.12.054] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2012] [Revised: 12/23/2012] [Accepted: 12/23/2012] [Indexed: 11/24/2022]
Abstract
Hemoglobin A1c (HbA1c) levels are used as a measure of glycemic control, with greater levels indicating poorer control and a greater risk of death. However, recent studies have found a U-shaped association between the HbA1c levels and mortality in patients with heart failure, with the lowest risk of death associated with elevated HbA1c levels, usually >7%. Cardiac surgery is frequently used to mitigate the signs and symptoms of heart failure. The purpose of the present study was to determine the association between HbA1c levels and late mortality in cardiac surgery patients with and without heart failure. Patients with and without New York Heart Association class III or IV heart failure were divided into quartiles according to the preoperative HbA1c level. Mortality was determined for each group and compared using chi-square tests and Cox modeling. Of the 311 patients with heart failure, 65 (21%) were dead at follow-up compared to 57 of 669 patients (9%) without heart failure (p <0.001). After adjusting for confounders, the patients without heart failure and with HbA1c ≤5.7% had the lowest risk of death. In patients with preoperative heart failure, we found a U-shaped association between HbA1c levels and late mortality, with those patients with HbA1c levels of 5.8% to 6.2% having the lowest risk of death. HbA1c levels ≤5.7% and ≥7.2% were associated with statistically significant greater risks of death. In conclusion, we found in patients with heart failure that the lowest risk of death was associated with HbA1c levels of 5.8% to 6.2%.
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Home P. Cardiovascular disease and oral agent glucose-lowering therapies in the management of type 2 diabetes. Diabetes Technol Ther 2012; 14 Suppl 1:S33-42. [PMID: 22650223 DOI: 10.1089/dia.2012.0007] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Although glucose-lowering oral agents have been available for clinical use for over 60 years, the formal evidence base supporting their advantage and safety in regard of cardiovascular (CV) outcomes remains less than optimal. However, a synthesis of the evidence results in a high probability of benefit. For metformin, the United Kingdom Prospective Diabetes Study (UKPDS) substudy is convincing for a definite effect in reducing myocardial infarction (MI), but the quantitative extent of that is uncertain. For sulfonylureas, support for reduction in MI comes from the UKPDS extension study, where the central estimate for risk reduction remains the same as in the original planned end to the study, but the greater number of events was statistically significant for the sulfonylurea/insulin arm. Other studies do not support the view that metformin and sulfonylureas differ with respect to MI or indeed CV outcomes more generally. The data available for acarbose, an α-glucosidase inhibitor, are weak but not of concern, although some positive substudy data are available for people with impaired glucose tolerance. For peroxisome proliferator-activated receptor-γ agonists the CV data are more controversial, but the purpose-designed randomized controlled trials are clear that pioglitazone is advantageous to placebo (except for heart failure [HF]), whereas rosiglitazone is indistinguishable from metformin/sulfonylureas (even when including HF data). Lower-quality data do, however, lead to significant concerns for MI with rosiglitazone. Early and somewhat low-quality data for the dipeptidyl peptidase inhibitors show they are safe and hold promise for cardiovascular advantage, with major randomized controlled trials being underway. Preliminary CV data are available for one sodium/glucose cotransporter 2 inhibitor and look reassuring.
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Affiliation(s)
- Philip Home
- The Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom.
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Abstract
Type 2 diabetes mellitus (T2DM) is a progressive disease characterized by worsening hyperglycaemia. Lowering haemoglobin A1c to below or around 7% has been shown to reduce microvascular and neuropathic complications of diabetes. The ongoing uncertainty regarding whether intensive glycaemic control can reduce the increased risk of cardiovascular disease (CVD) in people with T2DM stirred the launch of the recent long-term megatrials. These trials compared the effects of intensive vs. standard control on vascular complications in relatively high CV risk participants with T2DM. While in Veterans Affairs Diabetes Trial, and Action to Control Cardiovascular Risk in Diabetes, the effect of glucose optimization resulted either in no protection or in an excessive CVD death, the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation trial showed that intensive glycaemic control reduced the risk of combined major macrovascular and microvascular events. In this trial, the glucose control strategy was based on gliclazide MR at randomization in all patients and then further sequential addition of other glucose-lowering drugs. Several studies showed that gliclazide has antioxidant properties, reduces markers of endothelial inflammation, and prevents glucose-induced apoptosis of endothelial cells. These positive antioxidant effects are not confined to the vascular wall but they are effective also in the β cells. These properties are important because (i) in patients with atherosclerotic process, microvascular abnormalities may hasten disease progression and (ii) slowing the microvascular complications may have a potentially remarkable effect on the natural history of macrovascular disease.
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Affiliation(s)
- A Avogaro
- Department of Clinical and Experimental Medicine, University of Padova, Venetian Institute of Molecular Medicine, Padova, Italy.
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15
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Ye Y, Perez-Polo JR, Aguilar D, Birnbaum Y. The potential effects of anti-diabetic medications on myocardial ischemia-reperfusion injury. Basic Res Cardiol 2011; 106:925-52. [PMID: 21892746 DOI: 10.1007/s00395-011-0216-6] [Citation(s) in RCA: 80] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2011] [Revised: 08/04/2011] [Accepted: 08/16/2011] [Indexed: 12/15/2022]
Abstract
Heart disease and stroke account for 65% of the deaths in people with diabetes mellitus (DM). DM and hyperglycemia cause systemic inflammation, endothelial dysfunction, a hypercoagulable state with impaired fibrinolysis and increased platelet degranulation, and reduced coronary collateral blood flow. DM also interferes with myocardial protection afforded by preconditioning and postconditioning. Newer anti-diabetic agents should not only reduce serum glucose and HbA1c levels, but also improve cardiovascular outcomes. The older sulfonylurea agent, glyburide, abolishes the benefits of ischemic and pharmacologic preconditioning, but newer sulfonylurea agents, such as glimepiride, may not interfere with preconditioning. GLP-1 analogs and sitagliptin, an oral dipeptidyl peptidase IV inhibitor, limit myocardial infarct size in animal models by increasing intracellular cAMP levels and activating protein kinase A, whereas metformin protects the heart by activating AMP-activated protein kinase. Both thiazolidinediones (rosiglitazone and pioglitazone) limit infarct size in animal models. The protective effect of pioglitazone is dependent on downstream activation of cytosolic phospholipase A(2) and cyclooxygenase-2 with subsequent increased production of 15-epi-lipoxin A(4), prostacyclin and 15-d-PGJ(2). We conclude that agents used to treat DM have additional actions that have been shown to affect the ability of the heart to protect itself against ischemia-reperfusion injury in preclinical models. However, the effects of these agents in doses used in the clinical setting to minimize ischemia-reperfusion injury and to affect clinical outcomes in patients with DM have yet to be shown. The clinical implications as well as the mechanisms of protection should be further studied.
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Affiliation(s)
- Yumei Ye
- Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA
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16
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Schramm TK, Gislason GH, Vaag A, Rasmussen JN, Folke F, Hansen ML, Fosbøl EL, Køber L, Norgaard ML, Madsen M, Hansen PR, Torp-Pedersen C. Mortality and cardiovascular risk associated with different insulin secretagogues compared with metformin in type 2 diabetes, with or without a previous myocardial infarction: a nationwide study. Eur Heart J 2011; 32:1900-8. [PMID: 21471135 DOI: 10.1093/eurheartj/ehr077] [Citation(s) in RCA: 284] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
AIMS The impact of insulin secretagogues (ISs) on long-term major clinical outcomes in type 2 diabetes remains unclear. We examined mortality and cardiovascular risk associated with all available ISs compared with metformin in a nationwide study. METHODS AND RESULTS All Danish residents >20 years, initiating single-agent ISs or metformin between 1997 and 2006 were followed for up to 9 years (median 3.3 years) by individual-level linkage of nationwide registers. All-cause mortality, cardiovascular mortality, and the composite of myocardial infarction (MI), stroke, and cardiovascular mortality associated with individual ISs were investigated in patients with or without previous MI by multivariable Cox proportional-hazard analyses including propensity analyses. A total of 107 806 subjects were included, of whom 9607 had previous MI. Compared with metformin, glimepiride (hazard ratios and 95% confidence intervals): 1.32 (1.24-1.40), glibenclamide: 1.19 (1.11-1.28), glipizide: 1.27 (1.17-1.38), and tolbutamide: 1.28 (1.17-1.39) were associated with increased all-cause mortality in patients without previous MI. The corresponding results for patients with previous MI were as follows: glimepiride: 1.30 (1.11-1.44), glibenclamide: 1.47 (1.22-1.76), glipizide: 1.53 (1.23-1.89), and tolbutamide: 1.47 (1.17-1.84). Results for gliclazide [1.05 (0.94-1.16) and 0.90 (0.68-1.20)] and repaglinide and [0.97 (0.81-1.15) and 1.29 (0.86-1.94)] were not statistically different from metformin in both patients without and with previous MI, respectively. Results were similar for cardiovascular mortality and for the composite endpoint. CONCLUSION Monotherapy with the most used ISs, including glimepiride, glibenclamide, glipizide, and tolbutamide, seems to be associated with increased mortality and cardiovascular risk compared with metformin. Gliclazide and repaglinide appear to be associated with a lower risk than other ISs.
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Affiliation(s)
- Tina Ken Schramm
- Department of Cardiology B, section 2141, Rigshospitalet, The Heart Center, Copenhagen University Hospital, Blegdamsvej 9, 2100 Copenhagen, Denmark.
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17
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Jørgensen CH, Gislason GH, Andersson C, Ahlehoff O, Charlot M, Schramm TK, Vaag A, Abildstrøm SZ, Torp-Pedersen C, Hansen PR. Effects of oral glucose-lowering drugs on long term outcomes in patients with diabetes mellitus following myocardial infarction not treated with emergent percutaneous coronary intervention--a retrospective nationwide cohort study. Cardiovasc Diabetol 2010; 9:54. [PMID: 20843380 PMCID: PMC2946277 DOI: 10.1186/1475-2840-9-54] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2010] [Accepted: 09/16/2010] [Indexed: 12/13/2022] Open
Abstract
Background The optimum oral pharmacological treatment of diabetes mellitus to reduce cardiovascular disease and mortality following myocardial infarction has not been established. We therefore set out to investigate the association between individual oral glucose-lowering drugs and cardiovascular outcomes following myocardial infarction in patients with diabetes mellitus not treated with emergent percutaneous coronary intervention. Materials and methods All patients aged 30 years or older receiving glucose-lowering drugs (GLDs) and admitted with myocardial infarction (MI) not treated with emergent percutaneous coronary intervention in Denmark during 1997-2006 were identified by individual-level linkage of nationwide registries of hospitalizations and drug dispensing from pharmacies. Multivariable Cox regression models adjusted for age, sex, calendar year, comorbidity, and concomitant pharmacotherapy were used to assess differences in the composite endpoint of non-fatal MI and cardiovascular mortality between individual GLDs, using metformin monotherapy as reference. Results The study comprised 9876 users of GLDs admitted with MI. The mean age was 72.3 years and 56.5% of patients were men. A total of 3649 received sulfonylureas and 711 received metformin at admission. The average length of follow-up was 2.2 (SD 2.6) years. A total of 6,171 patients experienced the composite study endpoint. The sulfonylureas glibenclamide, glimepiride, glipizide, and tolbutamide were associated with increased risk of cardiovascular mortality and/or nonfatal MI with hazard ratios [HRs] of 1.31 (95% confidence interval [CI] 1.17-1.46), 1.19 (1.06-1.32), 1.25 (1.11-1.42), and 1.18 (1.03-1.34), respectively, compared with metformin. Gliclazide was the only sulfonylurea not associated with increased risk compared with metformin (HR 1.03 [0.88-1.22]). Conclusions In patients with diabetes mellitus admitted with MI not treated with emergent percutaneous coronary intervention, monotherapy treatment with the sulfonylureas glibenclamide, glimepiride, glipizide, and tolbutamide was associated with increased cardiovascular risk compared with metformin monotherapy.
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Affiliation(s)
- Casper H Jørgensen
- Department of Cardiology, Copenhagen University Hospital Gentofte, Hellerup, Denmark.
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Golomb E, Nyska A, Schwalb H. Occult Cardiotoxicity—Toxic Effects on Cardiac Ischemic Tolerance. Toxicol Pathol 2009; 37:572-93. [DOI: 10.1177/0192623309339503] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The outcome of cardiac ischemic events depends not only on the extent and duration of the ischemic stimulus but also on the myocardial intrinsic tolerance to ischemic injury. Cardiac ischemic tolerance reflects myocardial functional reserves that are not always used when the tissue is appropriately oxygenated. Ischemic tolerance is modulated by ubiquitous signal transduction pathways, transcription factors and cellular enzymes, converging on the mitochondria as the main end effector. Therefore, drugs and toxins affecting these pathways may impair cardiac ischemic tolerance without affecting myocardial integrity or function in oxygenated conditions. Such effect would not be detected by current toxicological studies but would considerably influence the outcome of ischemic events. The authors refer to such effect as “occult cardiotoxicity.” In this review, the authors summarize current knowledge about main mechanisms that determine cardiac ischemic tolerance, methods to assess it, and the effects of drugs and toxins on it. The authors offer a view that low cardiac ischemic tolerance is a premorbid status and, therefore, that occult cardiotoxicity is a significant potential source of cardiac morbidity. The authors propose that toxicologic assessment of compounds would include the assessment of their effect on cardiac ischemic tolerance.
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Affiliation(s)
- Eliahu Golomb
- Department of Pathology, Shaare Zedek Medical Center, Jerusalem 91031, Israel
| | - Abraham Nyska
- Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel-Aviv 69978, Israel
| | - Herzl Schwalb
- The Joseph Lunenfeld Cardiac Surgery Research Center, Department of Cardiothoracic Surgery, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel
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