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      A randomized, placebo-controlled trial of late Na current inhibition (ranolazine) in coronary microvascular dysfunction (CMD): impact on angina and myocardial perfusion reserve

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          Abstract

          Aims

          The mechanistic basis of the symptoms and signs of myocardial ischaemia in patients without obstructive coronary artery disease (CAD) and evidence of coronary microvascular dysfunction (CMD) is unclear. The aim of this study was to mechanistically test short-term late sodium current inhibition (ranolazine) in such subjects on angina, myocardial perfusion reserve index, and diastolic filling.

          Materials and results

          Randomized, double-blind, placebo-controlled, crossover, mechanistic trial in subjects with evidence of CMD [invasive coronary reactivity testing or non-invasive cardiac magnetic resonance imaging myocardial perfusion reserve index (MPRI)]. Short-term oral ranolazine 500–1000 mg twice daily for 2 weeks vs. placebo. Angina measured by Seattle Angina Questionnaire (SAQ) and SAQ-7 (co-primaries), diary angina (secondary), stress MPRI, diastolic filling, quality of life (QoL). Of 128 (96% women) subjects, no treatment differences in the outcomes were observed. Peak heart rate was lower during pharmacological stress during ranolazine (−3.55 b.p.m., P < 0.001). The change in SAQ-7 directly correlated with the change in MPRI (correlation 0.25, P = 0.005). The change in MPRI predicted the change in SAQ QoL, adjusted for body mass index (BMI), prior myocardial infarction, and site ( P = 0.0032). Low coronary flow reserve (CFR <2.5) subjects improved MPRI ( P < 0.0137), SAQ angina frequency ( P = 0.027), and SAQ-7 ( P = 0.041).

          Conclusions

          In this mechanistic trial among symptomatic subjects, no obstructive CAD, short-term late sodium current inhibition was not generally effective for SAQ angina. Angina and myocardial perfusion reserve changes were related, supporting the notion that strategies to improve ischaemia should be tested in these subjects.

          Trial registration

          clinicaltrials.gov Identifier: NCT01342029.

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          Most cited references32

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          Coronary microvascular reactivity to adenosine predicts adverse outcome in women evaluated for suspected ischemia results from the National Heart, Lung and Blood Institute WISE (Women's Ischemia Syndrome Evaluation) study.

          We investigated whether coronary microvascular dysfunction predicts major adverse outcomes during follow-up among women with signs and symptoms of ischemia. Altered coronary reactivity occurs frequently in women evaluated for suspected ischemia, and the endothelium-dependent component is linked with adverse outcomes. Possible links between endothelium-independent microvascular coronary reactivity and adverse outcomes remain uncertain. As part of the National Heart, Lung and Blood Institute-sponsored WISE (Women's Ischemia Syndrome Evaluation), we investigated relationships between major adverse outcomes and baseline coronary flow reserve (CFR) after intracoronary adenosine in 189 women referred to evaluate suspected ischemia. At a mean of 5.4 years, we observed significant associations between CFR and major adverse outcomes (death, nonfatal myocardial infarction, nonfatal stroke, or hospital stay for heart failure). An exploratory receiver-operator characteristic analysis identified CFR or=2.32 event rate 12.2%; p = 0.01). Lower CFR was associated with increased risk for major adverse outcomes (hazard ratio: 1.16, 95% confidence interval: 1.04 to 1.30; p = 0.009). This held true among the 152 women without obstructive coronary artery disease (CAD) (hazard ratio: 1.20, 95% confidence interval: 1.05 to 1.38; p = 0.008). The CFR significantly improved prediction of adverse outcomes over angiographic CAD severity and other risk conditions. Among women with suspected ischemia and atherosclerosis risk factors, coronary microvascular reactivity to adenosine significantly improves prediction of major adverse outcomes over angiographic CAD severity and CAD risk factors. These findings suggest that coronary microvessels represent novel targets for diagnostic and therapeutic strategies to predict and limit adverse outcomes in women. (Women's Ischemia Syndrome Evaluation [WISE]; NCT00000554). Copyright (c) 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
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            Effects of sex on coronary microvascular dysfunction and cardiac outcomes.

            Coronary microvascular dysfunction (CMD) is a prevalent and prognostically important finding in patients with symptoms suggestive of coronary artery disease. The relative extent to which CMD affects both sexes is largely unknown.
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              Patient non-compliance with paper diaries.

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                Author and article information

                Journal
                Eur Heart J
                Eur. Heart J
                eurheartj
                ehj
                European Heart Journal
                Oxford University Press
                0195-668X
                1522-9645
                14 May 2016
                27 November 2015
                27 November 2015
                : 37
                : 19
                : 1504-1513
                Affiliations
                [1 ]Barbra Streisand Women's Heart Center, Cedars-Sinai Heart Institute , Los Angeles, CA, USA
                [2 ]Division of Cardiology, University of Florida , Gainesville, FL, USA
                [3 ]S. Mark Taper Foundation Imaging Center, Cedars-Sinai Medical Center , Los Angeles, CA, USA
                [4 ]Program in Cardiovascular Outcomes Research and Epidemiology, Emory University , Atlanta, GA, USA
                [5 ]Health Outcomes and Policy, University of Florida Clinical and Translational Science Institute, University of Florida , Gainesville, FL, USA
                [6 ]Biostatistics and Bioinformatics Research Center, Cedars-Sinai Medical Center , Los Angeles, CA, USA
                Author notes
                [* ]Corresponding author. Tel: +1 310 423 9680; Fax: +1 310 423 9681; Email: noel.baireymerz@ 123456cshs.org
                Article
                ehv647
                10.1093/eurheartj/ehv647
                4872284
                26614823
                90fbe473-2bc6-422e-b59b-4dfb536c6444
                © The Author 2015. Published by Oxford University Press on behalf of the European Society of Cardiology.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                : 16 October 2015
                : 4 November 2015
                : 9 November 2015
                Funding
                Funded by: National Heart, Lung and Blood Institutes
                Award ID: N01-HV-68161
                Award ID: N01-HV-68162
                Award ID: N01-HV-68163
                Award ID: N01-HV-68164
                Award ID: MO1-RR00425
                Funded by: National Center for Research Resources http://dx.doi.org/10.13039/100000097
                Funded by: National Center for Research Resources http://dx.doi.org/10.13039/100000097
                Award ID: UL1RR033176
                Funded by: NIH/National Center for Advancing Translational Sciences (NCATS), UCLA CTSI
                Award ID: UL1TR000124
                Award ID: UL1TR001427
                Award ID: R01 HL089765
                Funded by: Gustavus and Louis Pfeiffer Research Foundation, Denville, New Jersey
                Funded by: Women's Guild of Cedars-Sinai Medical Center, Los Angeles, California
                Funded by: Edythe L. Broad Women's Heart Research Fellowship, Cedars-Sinai Medical Center, Los Angeles, California
                Funded by: Constance Austin Women's Heart Research Fellowship
                Funded by: Barbra Streisand Women's Cardiovascular Research and Education Program, Cedars-Sinai Medical Center, Los Angeles
                Funded by: Erika Glazer Women's Heart Health Project, Cedars-Sinai Medical Center, Los Angeles
                Categories
                Aha FASTTrack
                Coronary Artery Disease
                Fast Track

                Cardiovascular Medicine
                coronary microvascular dysfunction,angina
                Cardiovascular Medicine
                coronary microvascular dysfunction, angina

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