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Modulation of circulating vasoactive peptides and extracellular matrix proteins are two novel mechanisms in the cardioprotective action of acarbose.
Rudovich, N, Pivovarova, O, Bernigau, W, Sparwasser, A, Tacke, C, Murahovshi, V, Mertes, G, Birkenfeld, AL, Bergmann, A, Weickert, MO, et al
Minerva endocrinologica. 2016;(4):456-68
Abstract
BACKGROUND Acarbose, an alpha-glucosidase inhibitor, unexpectedly reduced the incidence of hypertension and cardiovascular endpoints in the STOP-NIDDM study. Based on the growing evidence of a link between vasoregulatory peptides and metabolic traits, we hypothesized that changes of the Glycemic Index by acarbose may modulate vasoregulatory peptide levels via regulation of postprandial metabolism. METHODS Subjects with type 2 diabetes and with metabolic syndrome were treated with acarbose (12 weeks, 300mg/d) in a double-blind, placebo-controlled, cross-over intervention. Changes in fasting and postprandial levels of midregional pro-atrial natriuretic peptide (MR-proANP), C-terminal pro-endothelin-1 (CT-proET-1) and midregional pro-adrenomedullin (MR-proADM), WNT1 Inducible Signaling Pathway Protein 1 (WISP1) as well as fasting and postprandial glucose/insulin levels in the liquid meal test were assessed. RESULTS Acarbose strongly decreased postprandial insulin concentrations in subjects with metabolic syndrome (P=0.004), and postprandial glucose excursions in both groups. Postprandial MR-proANP and CT-proET-1 levels increased after acarbose treatment (P<0.01 and P<0.05, respectively) in subjects with metabolic syndrome only. No effect of acarbose treatment on MR-prADM was observed in both groups. All three peptides were correlated with each over, but neither with insulin sensitivity in euglycemic clamps, nor with adiponectin levels. WISP1 decreased after acarbose treatment in subjects with metabolic syndrome. CONCLUSIONS Plasma MR- proANP and CT-proET-1 concentrations, but not MR-prADM concentrations, were affected by treatment with acarbose over 12 weeks. Our findings provide new possible mechanisms of acarbose action in diabetes and metabolic syndrome.
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Protective effect of metformin on myocardial injury in metabolic syndrome patients following percutaneous coronary intervention.
Li, J, Xu, JP, Zhao, XZ, Sun, XJ, Xu, ZW, Song, SJ
Cardiology. 2014;(2):133-9
Abstract
OBJECTIVES The present study tested the hypothesis that pretreatment with metformin decreases postprocedural myocardial injury and improves clinical outcomes in metabolic syndrome patients following percutaneous coronary intervention (PCI). METHODS We enrolled 152 metabolic syndrome patients with no prior history of metformin treatment. Patients scheduled for elective coronary intervention were randomized to the metformin or control group 7 days before the procedure. Creatine kinase-MB (CK-MB) and troponin I levels were measured at baseline and 8 and 24 h after the procedure, and clinical outcomes were monitored for 1 year. RESULTS Post-PCI myocardial injury as indicated by CK-MB elevation (14.5 vs. 32.9%, p = 0.008) and troponin I elevation (14.5 vs. 34.2%, p = 0.005) was significantly lower in the metformin group than in the control group. Postprocedural peak values of CK-MB (2.70 ± 4.30 vs. 6.29 ± 8.03 ng/ml, p < 0.001) and troponin I (0.02 ± 0.05 vs. 0.07 ± 0.10 ng/ml, p = 0.001) were also significantly lower in the metformin group than in the control group. At 1 year, the composite endpoint of death from any cause, post-PCI myocardial infarction (MI), MI after PCI hospitalization or ischemia-driven target lesion revascularization occurred in 7.9% of metformin-treated patients and 28.9% of controls (hazard ratio 0.25, 95% CI 0.10-0.62, log rank p = 0.001). CONCLUSIONS A 7-day metformin pretreatment regimen (250 mg 3 times a day) significantly reduces postprocedural myocardial injury and improves 1-year clinical outcomes in metabolic syndrome patients undergoing PCI.
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Effects of a nutraceutical combination on left ventricular remodeling and vasoreactivity in subjects with the metabolic syndrome.
Carlomagno, G, Pirozzi, C, Mercurio, V, Ruvolo, A, Fazio, S
Nutrition, metabolism, and cardiovascular diseases : NMCD. 2012;(5):e13-4
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New pharmacologic options in the treatment of acute coronary syndromes and myocardial ischemia-reperfusion injury: potential role of levosimendan.
Garcia-Gonzalez, MJ, Dominguez-Rodriguez, A, Abreu-Gonzalez, P
Minerva cardioangiologica. 2007;(5):625-35
Abstract
Modern and effective therapeutic possibilities have improved the management and outcomes in acute coronary syndromes and acute myocardial infarction. However, substantial morbidity and mortality still remain. Myocardial ischemia-reperfusion injury may contribute to additional damage to myocardial necrosis and apoptosis. Therefore, it has been focused on attention and field of therapeutic actions in the last years. The main mechanisms involved in the pathogenesis of ischemia-reperfusion injury are depressed energy metabolism, elevated oxidative damage, and altered calcium homeostasis. In experimental trials, a variety of drugs have proved effectiveness for the prevention and treatment of the ischemia-reperfusion injury. However, its efficacy, not always confirmed, has not yet been established in clinical practice. On the basis of the strong evidence linking potassium ATP dependent channels opening in the myocardium and its proved cardioprotective role during ischemia, these channels have been pointed out as possible and promising pharmacological targets in this setting. Some evidences suggest that the calcium sensitizing agent levosimendan may have of beneficial and exerts cardioprotective effects on myocardial ischemia and ischemia-reperfusion injury. Further investigation is warranted on this novel application of levosimendan.
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5.
Emerging therapies for the management of decompensated heart failure: from bench to bedside.
deGoma, EM, Vagelos, RH, Fowler, MB, Ashley, EA
Journal of the American College of Cardiology. 2006;(12):2397-409
Abstract
While pharmaceutical innovation has been highly successful in reducing mortality in chronic heart failure, this has not been matched by similar success in decompensated heart failure syndromes. Despite outstanding issues over definitions and end points, we argue in this paper that an unprecedented wealth of pharmacologic innovation may soon transform the management of these challenging patients. Agents that target contractility, such as cardiac myosin activators and novel adenosine triphosphate-dependent transmembrane sodium-potassium pump inhibitors, provide inotropic support without arrhythmogenic increases in cytosolic calcium or side effects of more traditional agents. Adenosine receptor blockade may improve glomerular filtration and diuresis by exerting a direct beneficial effect on glomerular blood flow while vasopressin antagonists promote free water excretion without compromising renal function and may simultaneously inhibit myocardial remodeling. Urodilatin, the renally synthesized isoform of atrial natriuretic peptide, may improve pulmonary congestion via vasodilation and enhanced diuresis. Finally, metabolic modulators such as perhexiline may optimize myocardial energy utilization by shifting adenosine triphosphate production from free fatty acids to glucose, a unique and conceptually appealing approach to the management of heart failure. These advances allow optimism not only for the advancement of our understanding and management of decompensated heart failure syndromes but for the translational research effort in heart failure biology in general.
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6.
Insulin therapy as an adjunct to reperfusion after acute coronary ischemia: a proposed direct myocardial cell survival effect independent of metabolic modulation.
Sack, MN, Yellon, DM
Journal of the American College of Cardiology. 2003;(8):1404-7
Abstract
Reperfusion therapy has become a practical and effective strategy in the salvage of ischemic myocardium. The direct enhancement of cardiac cellular tolerance against ischemic and reperfusion injury should further improve patient outcome in acute coronary syndromes (ACS). This approach has been explored for many decades, and although we await mortality-weighted randomized clinical trials, the infusion of glucose-insulin-potassium (GIK) has shown promise in protecting post-infarct myocardium. The current dogma is that this cardioprotective effect of GIK acts via the modulation of cardiac and circulating metabolites to provide the heart with an optimal metabolic milieu to resist ischemia and reperfusion injury. This concept of metabolic modulation has gained favor in coronary heart disease, and its efficacy currently is being investigated in stable angina using the new class of partial fatty acid oxidation inhibitors, including trimetazidine and ranolazine. We contend that the mitogen insulin, itself, promotes tolerance against ischemic cell death via the activation of innate cell-survival pathways in the heart. To advance this viewpoint, we will present clinical data that support a dose-dependent effect of insulin's beneficial action in the management of acute myocardial infarction. Furthermore, we present experimental data that identify cell-survival programs that are directly activated by the administration of insulin. Finally, as intravenous insulin therapy is both labor intensive and associated with metabolic perturbations, we propose that the development of pharmaco-therapeutic agents that target downstream cell-survival insulin-activated signaling molecules may be an alternate approach to promote cardioprotection during ACS.
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Inotropic therapy is unsuccessful: wrong conceptual target or wrong therapeutic tools?
Rapezzi, C, Perugini, E, Santi, M, Bracchetti, G, Branzi, A
Italian heart journal : official journal of the Italian Federation of Cardiology. 2003;:22S-26S
Abstract
Since a depressed contractility has long been considered the primary defect in patients with heart failure, the use of inotropic agents has been regarded as a logical approach to treat this syndrome. Despite this conceptual framework, these drugs have not yet established themselves in the treatment of chronic heart failure and their long-term use was associated with an excessive mortality while the short-term intravenous administration in critically ill patients produced only acute hemodynamic results without a stable clinical improvement. At least four mechanisms could explain this discrepancy: their arrhythmogenicity, their direct cardiotoxic effects, the downregulation of the beta-adrenoreceptors, and the energetic cost of inotropic intervention. Moreover, in many patients with ischemic cardiomyopathy the reduction in contractility could be considered as a compensatory mechanism since hibernation is able to decrease the metabolic requirements of the heart. The contractile force of the heart can be augmented not only by an increased availability of intracellular calcium for troponin C but also by an increased sensitivity of the contractile proteins to calcium. A new class of inotropes working with this mechanism is now available and could represent a real improvement in this challenging therapeutic area.