title: A randomized, placebo-controlled trial of late Na current inhibition (ranolazine) in coronary microvascular dysfunction (CMD): impact on angina and myocardial perfusion reserve.
abstract: 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.
  
  
  
  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).
  
  
  
  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.
  
  
  
  clinicaltrials.gov Identifier: NCT01342029.
authors.affiliation: Barbra Streisand Women's Heart Center, Cedars-Sinai Heart Institute, Los Angeles, CA, USA noel.baireymerz@cshs.org.
authors.forename: C Noel
authors.initials: CN
authors.lastname: Bairey Merz
authors.affiliation: Division of Cardiology, University of Florida, Gainesville, FL, USA.
authors.forename: Eileen M
authors.initials: EM
authors.lastname: Handberg
authors.affiliation: Barbra Streisand Women's Heart Center, Cedars-Sinai Heart Institute, Los Angeles, CA, USA.
authors.forename: Chrisandra L
authors.initials: CL
authors.lastname: Shufelt
authors.affiliation: Barbra Streisand Women's Heart Center, Cedars-Sinai Heart Institute, Los Angeles, CA, USA.
authors.forename: Puja K
authors.initials: PK
authors.lastname: Mehta
authors.affiliation: Barbra Streisand Women's Heart Center, Cedars-Sinai Heart Institute, Los Angeles, CA, USA.
authors.forename: Margo B
authors.initials: MB
authors.lastname: Minissian
authors.affiliation: Barbra Streisand Women's Heart Center, Cedars-Sinai Heart Institute, Los Angeles, CA, USA.
authors.forename: Janet
authors.initials: J
authors.lastname: Wei
authors.affiliation: S. Mark Taper Foundation Imaging Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Louise E J
authors.initials: LE
authors.lastname: Thomson
authors.affiliation: S. Mark Taper Foundation Imaging Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Berman
authors.affiliation: Program in Cardiovascular Outcomes Research and Epidemiology, Emory University, Atlanta, GA, USA.
authors.forename: Leslee J
authors.initials: LJ
authors.lastname: Shaw
authors.affiliation: Division of Cardiology, University of Florida, Gainesville, FL, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Petersen
authors.affiliation: Division of Cardiology, University of Florida, Gainesville, FL, USA.
authors.forename: Garrett H
authors.initials: GH
authors.lastname: Brown
authors.affiliation: Division of Cardiology, University of Florida, Gainesville, FL, USA.
authors.forename: R David
authors.initials: RD
authors.lastname: Anderson
authors.affiliation: Health Outcomes and Policy, University of Florida Clinical and Translational Science Institute, University of Florida, Gainesville, FL, USA.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Shuster
authors.affiliation: Biostatistics and Bioinformatics Research Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Galen
authors.initials: G
authors.lastname: Cook-Wiens
authors.affiliation: Biostatistics and Bioinformatics Research Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: André
authors.initials: A
authors.lastname: Rogatko
authors.affiliation: Division of Cardiology, University of Florida, Gainesville, FL, USA.
authors.forename: Carl J
authors.initials: CJ
authors.lastname: Pepine
mesh_terms: D000284:Administration, Oral; D000787:Angina Pectoris / Q000188:drug therapy / Q000503:physiopathology; D003327:Coronary Disease / Q000188:drug therapy / Q000503:physiopathology; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006439:Hemodynamics / Q000502:physiology; D006801:Humans; D018810:Magnetic Resonance Angiography; D008297:Male; D055118:Medication Adherence; D055806:Microvessels; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000188:drug therapy*; D011788:Quality of Life; D000069458:Ranolazine / Q000008:administration & dosage* / Q000009:adverse effects; D026941:Sodium Channel Blockers / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome
chemical_list: D026941:Sodium Channel Blockers; D000069458:Ranolazine
keywords: Angina; Coronary microvascular dysfunction