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      Mineralocorticoid receptor antagonist pre-treatment and early post-treatment to minimize reperfusion injury after ST-elevation myocardial infarction: The MINIMIZE STEMI trial

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          Abstract

          Background

          Mineralocorticoid receptor antagonist (MRA) therapy has been shown to prevent adverse left ventricular (LV) remodeling in ST-segment elevation myocardial infarction (STEMI) patients with heart failure. Whether initiating MRA therapy prior to primary percutaneous coronary intervention (PPCI) accrues additional benefit of reducing myocardial infarct size and preventing adverse LV remodeling is not known. We aimed to investigate whether MRA therapy initiated prior to reperfusion reduces myocardial infarct (MI) size and prevents adverse LV remodeling in STEMI patients.

          Methods

          STEMI patients presenting within 12 hours and with a proximal coronary artery occlusion with Thrombolysis In Myocardial Infarction flow grade 0 were consented and randomized to either an intravenous bolus of potassium canrenoate, followed by oral spironolactone for 3 months or matching placebo. The primary endpoint was MI size by cardiovascular magnetic resonance at 3 months.

          Results

          Sixty-seven patients completed the study. There was no significant difference in the final MI size at 3 months between the 2 groups (placebo: 17 ± 11%, MRA: 16 ± 10%, P = .574). There was also no difference in acute MI size (26 ± 16% versus 23 ± 14%, P = .425) or myocardial salvage (26 ± 12% versus 24 ± 8%, P = .456). At follow-up, there was a trend towards an improvement in LVEF (placebo: 49 ± 8%, MRA: 54 ± 11%, P = .053), and the MRA group had significantly greater percentage decrease in LVEDV (mean difference: −12.2 (95% CI −20.3 to −4.4)%, P = .003) and LVESV (mean difference: −18.2 (95% CI −30.1 to −6.3)%, P = .003).

          Conclusion

          This pilot study showed no benefit of MRA therapy in reducing MI size in STEMI patients when initiated prior to reperfusion, but there was an improvement in LV remodeling at 3 months. Adequately powered studies are warranted to confirm these findings.

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          Most cited references16

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          2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation

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            Myocardial reperfusion injury: looking beyond primary PCI.

            Coronary heart disease (CHD) is the leading cause of death and disability in Europe. For patients presenting with an acute ST-segment elevation myocardial infarction (STEMI), timely myocardial reperfusion using either thrombolytic therapy or primary percutaneous coronary intervention (PPCI) is the most effective therapy for limiting myocardial infarct (MI) size, preserving left-ventricular systolic function and reducing the onset of heart failure. Despite this, the morbidity and mortality of STEMI patients remain significant, and novel therapeutic interventions are required to improve clinical outcomes in this patient group. Paradoxically, the process of myocardial reperfusion can itself induce cardiomyocyte death-a phenomenon which has been termed 'myocardial reperfusion injury' (RI), the irreversible consequences of which include microvascular obstruction and myocardial infarction. Unfortunately, there is currently no effective therapy for preventing myocardial RI in STEMI patients making it an important residual target for cardioprotection. Previous attempts to translate cardioprotective therapies (antioxidants, calcium-channel blockers, and anti-inflammatory agents) for reducing RI into the clinic, have been unsuccessful. An improved understanding of the pathophysiological mechanisms underlying RI has resulted in the identification of several promising mechanical (ischaemic post-conditioning, remote ischaemic pre-conditioning, therapeutic hypothermia, and hyperoxaemia), and pharmacological (atrial natriuretic peptide, cyclosporin-A, and exenatide) therapeutic strategies, for preventing myocardial RI, many of which have shown promise in initial proof-of-principle clinical studies. In this article, we review the pathophysiology underlying myocardial RI, and highlight the potential therapeutic interventions which may be used in the future to prevent RI and improve clinical outcomes in patients with CHD.
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              Limitation of excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure: insights from the randomized aldactone evaluation study (RALES). Rales Investigators.

              In congestive heart failure (CHF), extracellular matrix turnover is a major determinant of cardiac remodeling. It has been suggested that spironolactone may decrease cardiac fibrosis. We investigated the interactions between serum markers of cardiac fibrosis and the effect of spironolactone on outcome in patients with CHF. A sample of 261 patients from the Randomized Aldactone Evaluation Study (RALES) were randomized to placebo or spironolactone (12.5 to 50 mg daily). Serum procollagen type I carboxy-terminal peptide, procollagen type I amino-terminal peptide, and procollagen type III amino-terminal peptide (PIIINP) were assessed at baseline and at 6 months. Baseline PIIINP >3.85 microgram/L was associated with an increased risk of death (relative risk [RR] 2.36, 95% CI 1.34 to 4.18) and of death+hospitalization (RR 1.83, 95% CI 1.18 to 2.83). At 6 months, markers decreased in the spironolactone group but remained unchanged in the placebo group. The spironolactone effect on outcome was significant only in patients with above-median baseline levels of markers. RR (95% CI) values for death among patients receiving spironolactone were 0.44 (0.26 to 0.75) and 1.11 (0.66 to 1.88) in subgroups of PIIINP levels above and below the median, respectively. Similarly, RR (95% CI) values for death+hospitalization among patients receiving spironolactone were 0.45 (0.29 to 0.71) and 0.85 (0.55 to 1.33), respectively. In patients with CHF, high baseline serum levels of markers of cardiac fibrosis synthesis are significantly associated with poor outcome and decrease during spironolactone therapy. The benefit from spironolactone was associated with higher levels of collagen synthesis markers. These results suggest that limitation of the excessive extracellular matrix turnover may be one of the various extrarenal mechanisms contributing to the beneficial effect of spironolactone in patients with CHF.
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                Author and article information

                Contributors
                Journal
                Am Heart J
                Am. Heart J
                American Heart Journal
                Mosby
                0002-8703
                1097-6744
                1 May 2019
                May 2019
                : 211
                : 60-67
                Affiliations
                [a ]Hatter Cardiovascular Institute, London, United Kingdom
                [b ]Barts Heart Centre, St Bartholomew's Hospital, London, United Kingdom
                [c ]Charité - Universitätsmedizin Berlin, Germany
                [d ]London School of Hygiene and Tropical Medicine, London, United Kingdom
                [e ]Essex Cardiothoracic Centre, Basildon, United Kingdom
                [f ]Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom
                [g ]The National Institute of Health Research University College London Hospitals Biomedical Research Centre, London, United Kingdom
                [h ]National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore
                [i ]Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore, Singapore
                [j ]Yong Loo Lin School of Medicine, National University Singapore, Singapore
                [k ]Tecnologico de Monterrey, Centro de Biotecnologia-FEMSA, Nuevo Leon, Mexico
                Author notes
                [* ]Reprint requests: Professor Derek J Hausenloy, MD, PhD, Cardiovascular & Metabolic Diseases Program, Duke-NUS Graduate Medical School Singapore, 8 College Road, Singapore 169857. derek.hausenloy@ 123456duke-nus.edu.sg
                [1]

                These authors contributed equally.

                Article
                S0002-8703(19)30026-2
                10.1016/j.ahj.2019.02.005
                6483973
                30893577
                f4644946-65b0-40f2-ba0b-6dcd53d0ecd5
                © 2019 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 20 May 2018
                : 11 February 2019
                Categories
                Article

                Cardiovascular Medicine
                Cardiovascular Medicine

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