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

• Type of Material: Article
• Authors: C. Noel Bairey Merz, Cedars-Sinai Heart Institute; Eileen M. Handberg, University of Florida; Chrisandra Shufelt, Cedars-Sinai Heart Institute; Puja Mehta, Emory University; Margo B. Minissian, Cedars-Sinai Heart Institute; Janet Wei, Cedars-Sinai Heart Institute; Louise E.J. Thomson, Cedars-Sinai Heart Institute; Daniel S. Berman, Cedars-Sinai Heart Institute; Leslee Shaw, Emory University; John W. Petersen, University of Florida; Garrett H. Brown, University of Florida; R. David Anderson, University of Florida; Jonathan J. Shuster, University of Florida; Galen Cook-Wiens, Cedars-Sinai Heart Institute; André Rogatko, Cedars-Sinai Heart Institute; Carl J. Pepine, University of Florida
• Language: English
• Date: 2016-05-14
• Publisher: Oxford University Press (OUP)
• Publication Version: Final Published Version
• Copyright Statement: © The Author 2015. Published by Oxford University Press on behalf of the European Society of Cardiology.
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1093/eurheartj/ehv647
• Title of Journal or Parent Work: European Heart Journal
• ISSN: 0195-668X
• Volume: 37
• Issue: 19
• Start Page: 1504
• End Page: 1513
• Grant/Funding Information: Funding to pay the Open Access publication charges for this article was provided by the Barbra Streisand Women's Heart Center, Los Angeles CA, USA.; This work was supported by an unrestricted research grant from Gilead and by contracts from the National Heart, Lung and Blood Institutes, nos N01-HV-68161, N01-HV-68162, N01-HV-68163, N01-HV-68164, a GCRC grant MO1-RR00425 from the National Center for Research Resources, the National Center for Research Resources, grant UL1RR033176, the NIH/National Center for Advancing Translational Sciences (NCATS), UCLA CTSI grant UL1TR000124 and UF CTSI grant UL1TR001427, grant R01 HL089765, and grants from the Gustavus and Louis Pfeiffer Research Foundation, Denville, New Jersey, the Women's Guild of Cedars-Sinai Medical Center, Los Angeles, California, the Edythe L. Broad Women's Heart Research Fellowship, Cedars-Sinai Medical Center, Los Angeles, California, the Constance Austin Women's Heart Research Fellowship, the Barbra Streisand Women's Cardiovascular Research and Education Program, Cedars-Sinai Medical Center, Los Angeles, and the Erika Glazer Women's Heart Health Project, Cedars-Sinai Medical Center, Los Angeles.
• Keywords: Life Sciences & Biomedicine; Cardiovascular System & Cardiology; Coronary microvascular dysfunction; FLOW RESERVE; ISCHEMIA SYNDROME EVALUATION; CARDIOVASCULAR MAGNETIC-RESONANCE; Angina; Cardiac & Cardiovascular Systems; SYNDROME EVALUATION WISE; EXERCISE TOLERANCE
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Pharmacology

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.