Late sodium channel blockade improves angina and myocardial perfusion in patients with severe coronary microvascular dysfunction: Women's Ischemia Syndrome Evaluation–Coronary Vascular Dysfunction ancillary study

• Type of Material: Article
• Authors: Cecil A. Rambarat, University of Florida; Islam Y. Elgendy, University of Florida; Eileen M. Handberg, University of Florida; C. Noel Bairey Merz, Cedars-Sinai Medical Center; Janet Wei, Cedars-Sinai Medical Center; Margo B. Minissian, Cedars-Sinai Medical Center; Michael D. Nelson, Cedars-Sinai Medical Center; Louise E. J. Thomson, Cedars-Sinai Medical Center; Daniel S. Berman, Cedars-Sinai Medical Center; Leslee Shaw, Emory University; Galen Cook-Wiens, Cedars-Sinai Medical Center; Carl J. Pepine, University of Florida
• Language: English
• Date: 2019-02-01
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018 Elsevier B.V.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.ijcard.2018.09.081
• Title of Journal or Parent Work: International Journal of Cardiology
• Volume: 276
• Start Page: 8
• End Page: 13
• Grant/Funding Information: This work was supported by an unrestricted research grant from Gilead; and by contracts from the National Heart, Lung and Blood Institutes [N01-HV-68161, N01-HV-68162, N01-HV68163, N01-HV- 68164, R01 HL090957, R01 HL089765]; GCRC grant from the National Center for Research Resources [MO1-RR00425]; National Center for Research Resources [UL1RR033176]; NIH/National Center for Advancing Translational Sciences (NCATS) UCLA CTSI grant [UL1TR000124] and UF CTSI grant [UL1TR001427]; American Heart Association [16SDG27260115]; 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; the Gatorade Trust through funds distributed by the University of Florida Department of Medicine, and PCORnet-OneFlorida Clinical Research Consortium CDRN-1501–26692, University of Florida, Gainesville, FL.
• Keywords: Adult; Female; Myocardial Perfusion Imaging; Cross-Over Studies; Humans; Coronary Circulation; Microcirculation; Middle Aged; Aged; Angina; Severity of Illness Index; Sodium Channel Blockers; Angina Pectoris; Coronary Artery Disease; Double-Blind Method; Ranolazine; Myocardial Ischemia; Late sodium channel inhibition; Coronary microvascular dysfunction; Coronary Angiography
• Research Categories: Health Sciences, Medicine and Surgery

Abstract

Background: In a prior trial of late sodium channel inhibition (ranolazine) among symptomatic subjects without obstructive coronary artery disease (CAD) and limited myocardial perfusion reserve index (MPRI), we observed no improvement in angina or MPRI, overall. Here we describe the clinical characteristics and myocardial perfusion responses of a pre-defined subgroup who had coronary flow reserve (CFR) assessed invasively. Methods: Symptomatic patients without obstructive CAD and limited MPRI in a randomized, double-blind, crossover trial of ranolazine vs. placebo were subjects of this prespecified substudy. Because we had previously observed that adverse outcomes and beneficial treatment responses occurred in those with lower CFR, patients were subgrouped by CFR <2.5 vs ≥2.5. Symptoms were assessed using the Seattle Angina Questionnaire and the SAQ-7, and left-ventricular volume and MPRI were assessed by magnetic resonance imaging (MRI). Coronary angiograms, CFR, and MRI data were analyzed by core labs masked to treatment and patient characteristics. Results: During qualifying coronary angiography, 81 patients (mean age 55 years, 98% women) had invasively determined CFR 2.69 ± 0.65 (mean ± SD; range 1.4–5.5); 43% (n = 35) had CFR <2.5. Demographic and symptomatic findings did not differ comparing CFR subgroups. Those with low CFR had improved angina (p = 0.04) and midventricular MPRI (p = 0.03) with ranolazine vs placebo. Among patients with low CFR, reduced left-ventricular end-diastolic volume predicted a beneficial angina response. Conclusions: Symptomatic patients with CFR <2.5 and no obstructive CAD had improved angina and myocardial perfusion with ranolazine, supporting the hypothesis that the late sodium channel is important in management of coronary microvascular dysfunction. Trial registration: clinicaltrials.gov Identifier NCT01342029