Impact of Ranalozine on Coronary Microcirculatory Resistance- A Prospective Single Center Study to Evaluate the Effect of Ranalozine in Microcirculatory Resistance (MICRO Study)
Phase: NA
Conditions: Coronary Microcirculation, Coronary Artery Disease, Myocardial Disease, Ischemia
Sponsor: University of New Mexico

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Impact of Ranolazine on Coronary Microcirculatory Resistance (MICRO Study) 
Bina Ahmed MD, Yasmin Hamirani MD, Allon Rafael MD, Wyatt Voyles MD, Mark Sheldon MD, Mark 
Ricciardi MD, Noel Bairey Merz MD 
I.  Background: 
The coronary microcirculation (CMC) plays an essential and complex role in regulating coronary blood 
flow and myocardial perfusion.  Recent clinical classification of CMC dysfunction by Camici et al includes 
a heterogeneous group of patients including those with CMC dysfunction without evidence of 
obstructive epicardial coronary artery disease (CAD) or myocardial disease (Type I); CMC dysfunction in 
the presence of myocardial diseases such as primary and secondary cardiomyopathies (Type II); CMC 
dysfunction in the presence of obstructive CAD (Type III) and iatrogenic CMC dysfunction (Type IV) 1.  
Unlike epicardial CAD, where the link between ischemia and angiographic coronary anatomy lends a 
target for therapy, the study and treatment of the disorders of the CMC are still in evolution.  However, 
over the last two decades our understanding of CMC has broadened and our ability to study CMC 
function has evolved.  
Importance of the Coronary Microcirculation:   CMC function is adversely effected by various forms of 
myocardial diseases 2-4 and both endothelial dependant and independent CMC dysfunction can increase 
long-term risk of adverse cardiovascular events among patients with all types of CMC dysfunction5, 6. 
Assessment of Coronary Microcirculation:  In the absence of direct visualization, there are several 
approaches to indirectly measuring CMC function.   Non-invasive tools have included perfusion cardiac 
MRI, positron emission topography and myocardial contrast echocardiography based measurement of 
microcirculatory blood flow 7-10.  However, requirements for dedicated software programs, lack of 
uniform definition of findings and inferior reproducibility strongly limit non-invasive assessment of the 
CMC.  Currently, the gold standard for measuring CMC function involves invasive measurement using 
Doppler or thermodilution methods to quantify coronary blood flow and vasoreactivity in response to 
vasoactive stimuli 11, 12.  Historically, the more accurate invasive method of measurement has been 
limited by complicated protocols which mandate pre-procedural mixing of restricted medications such 
as acetylcholine; the need to withhold chronic medications and the lack of reproducibility of the 
measurements obtained.  
A simpler and more reproducible method of measuring global coronary microcirculatory resistance has 
recently been validated13-16.  The index of microcirculatory resistance (IMR) is based on the premise that 
at peak hyperemia, variability of resting vascular tone and hemodynamics is reduced to give an accurate 
assessment of minimum microvascular resistance.  It is defined as distal coronary pressure divided by 
the inverse of the hyperemic mean transit time (a correlate to absolute flow), measured simultaneously 
using a temperature sensor/ pressure tipped guidewire.  Compared  to traditional Doppler based 
coronary flow measurements,  IMR is easier to use, allows quantification of blood flow and pressure 
measurements while reducing the impact of basal flow conditions to provide superior reproducibility 
and less hemodynamic variability compared to doppler based measurements 15.   An IMR measurement 
of <20u is associated with normal CMC function. 
 
Treatment of Coronary Microcirculatory Dysfunction:  Treatment of patients with CMC dysfunction has 
focused on reducing atherosclerotic burden and symptom relief.  There is a paucity of data evaluating 
the impact of drug therapy on CMC function.  Ranolazine is a late sodium current inhibitor thought to 

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decrease left ventricular compressive forces resulting in increased myocardial blood flow and 
improvement in signs and symptoms of angina 17-23.  In a porcine model, Ranolazine was also shown to 
cause transient increase in epicardial coronary blood flow and decrease in coronary vascular resistance 
via alpha-1 blockade24.  Direct impact of Ranolazine on the microcirculation remains unknown. 
Clinically, among patients with Type I CMC dysfunction (CMC dysfunction in the absence of obstructive 
CAD or myocardial disease), Ranolazine has been shown to improve symptoms of angina and cardiac 
MRI based perfusion compared to treatment with placebo 25.  Whether this symptomatic improvement 
is due to actual improvement in CMC function remains unknown.    
 
II:  Specific Aims 
1:  Does Ranolazine treatment improve CMC function among patients with Type I CMC dysfunction?   
2:  Is symptomatic improvement in chest pain with Ranolazine related to improved CMC function? 
 
III:  Design and Methods 
This single center, prospective study is designed as a pilot proposal evaluating the effect of Ranolazine 
among patients with Type I CMC dysfunction.   
Inclusion Criteria: 
-  Patients with subjective symptoms of ischemia without flow limiting angiographic CAD (<50% 
epicardial coronary stenosis) and abnormal IMR (>20 U).  
- Definition of ischemia (any one): 
• 
chest pain with dynamic ischemic ECG changes (t wave inversions or > 1 mm ST 
depressions  
• 
Exercise treadmill testing induced chest pain with ≥1 mm of downsloping or flat 
ST segment depression during exercise or recovery; ≥2 mm of ischemic ST 
depression at a low workload (stage 2 or less or ≤130 beats/min); early onset 
(stage 1) or prolonged duration (>5 min) of ST depression; multiple leads (>5) 
with ST depression 
• 
Nuclear stress perfusion defect > 10% 
• 
Stress echocardiogram with stress induced wall motion abnormality 
 Exclusion Criteria: 
- Age < 18 yrs 
- Flow Limiting epicardial CAD >50% 
- Life expectancy < 6 months 
- Recent (<1 week) myocardial infarction or positive biomarkers 
- Severe aortic stenosis  
- Contraindications to IMR testing including inability to utilize antithrombotic therapy and/or 
intravenous adenosine 
- Contraindications to Ranolazine therapy: 
-Patients with known hepatic insufficiency, prolonged QT or renal failure (GFR < 60) 
-use of drugs that inhibit CYP3A such as diltiazem, verapamil, ketoconazole, macrolides and HIV 
protease inhibitors 
- Pregnancy, breastfeeding  
- Patients taking drugs which prolong QT interval 
 
Study Flow: 
Patients meeting entry criteria will undergo detailed history regarding demographics, cardiovascular risk 
profile, clinical presentation, laboratory analysis and current medical therapy.  After enrollment in the 
study, participants will initiate Ranolazine for 4 weeks.  The participant’s usual anti-anginal medication 

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regimen will be continued unchanged throughout study duration.  Patients will receive Ranolazine 500 
mg orally twice daily for 1 week, and the dose will be increased to 1,000 mg twice daily for an additional 
3 weeks if tolerated.   
-All participants will complete baseline Seattle Angina Questionnaire (SAQ) and Duke Activity Status 
Index (DASI). 
-1 week:  Patients will undergo phone f/u and if tolerated, drug dose will be increased to 1000 mg twice 
daily.    
- 4 weeks:  Patients will be scheduled to return for a follow-up cardiac catheterization and IMR at no 
charge.  Patients will be asked to complete SAQ and DASI questionnaires.  
 
Procedures: 
 
Coronary Angiogram and left heart catheterization:  Patients will undergo an initial clinically indicated 
coronary angiogram and left heart catheterization with IMR testing and then undergo post Ranolazine 
follow-up coronary angiogram and left heart catheterization using standard technique by one of three 
experienced interventional cardiologists (B.A, M.S or M.R). The study sponsor will pay for the follow –up 
cardiac catheterization and IMR. 
Assessment of Coronary Microvascular Function:  Coronary physiologic indexes will be measured in a 
stenosis free area of the left anterior descending coronary artery when possible, or in the left circumflex 
artery as a secondary choice.  Appropriate coronary guide catheter will be used to engage left main 
coronary artery.  After adequate heparinization, a temperature sensor/ pressure tipped guidewire (Radi 
pressure wire, St Jude Medical Systems) will be advanced through the guide catheter and placed and 
secured at least 3 cm distal to guide catheter in the coronary artery and secured.   After injecting 3 cc of 
room temperature normal saline, proximal and distal temperature sensors on guidewire will calculate 
mean transit time using thermodilution.  This is repeated three times to obtain an average baseline 
transit time.  Next, intravenous adenosine (140 μg per kilogram of body weight per minute through a 
central vein) is used to induce hyperemia.  We then inject 3 cc of room temp normal saline and calculate 
hyperemic transit time.  This is performed at 120, 150 and 180 seconds after initiation of intravenous 
adenosine and averaged to obtain a mean hyperemic transit time.  In addition, simultaneous hyperemic 
pressure gradient is measured in the proximal and distal vessel.   Once data is obtained, the following 
calculations are made: 
1:  Index of Microvascular Resistance (IMR):  IMR is defined as hyperemic distal coronary pressure 
divided by the inverse of hyperemic mean transit time.  IMR is based on the assumption that at peak 
hyperemia the variability of resting vascular tone and hemodynamics will be eliminated, and the 
minimum microvascular resistance will be achieved.  Studies have correlated IMR value <20 to normal 
microvascular resistance 13, 16, 26.   
 
IV:  Data and Analysis  
Sample Size:  The sample size of 20 patients is not powered for a specific end point as this is a pilot 
exploratory analysis meant to determine the effect of Ranolazine on IMR.  It is our intention to use this 
data to determine feasibility and power of an appropriately sized multicenter randomized clinical trial. 
Feasibility:   The historic incidence of CMC dysfunction can vary depending on the patient population 
being studied.  The estimated historical incidence of Type I CMC dysfunction is approximated to be 20-
30% 27.  At the University of New Mexico, we anticipate performing approximately 400 cardiac 
catheterizations for the indication of objective ischemia (as outlined in entry criteria).  Of these, we 
estimate that 50% have non-obstructive CAD.  Current data from the IMR patient registry at UNM shows 

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that approximately 50% of patients with ischemia and non-obstructive CAD have IMR >20 U (mean 26.7 
± 13.1). We conservatively approximate 40 patients per year who meet entry criteria for the study at 
University of New Mexico.  
Data Safety: Data will be monitored by Dr. Abinash Achrekar. 
Primary Endpoint:   
1:  Relative change in IMR before and after Ranolazine therapy.  Mean change between the groups will 
be analyzed using a paired t test. 
Secondary endpoints: 
1:  Absolute change in SAQ and DASI scores before and after Ranolazine therapy.  Mean change between 
the groups will be analyzed using a paired t test. 
2:  Compare relative change in IMR among patients with and without symptomatic improvement in 
angina burden based on SAQ and DASI scores. 
V:  Scientific Focus 
CMC dysfunction continues to be a disease entity with limited therapeutic targets.  More recently, 
therapeutic trials, including those using Ranolazine, have shown improvement in angina burden and 
myocardial perfusion among patients with CMC dysfunction 25, 28 but no study has evaluated mechanism 
for this therapeutic effect.   
The primary purpose of our study is to obtain pilot data showing mechanistic effect of Ranolazine on 
microcirculatory resistance.  Our project meets the scientific focus put forth and explores a novel 
diagnostic and therapeutic strategy among patients with coronary microvascular ischemic heart disease.  
We hope to help elucidate the mechanism of effect of Ranolazine among patients with CMC dysfunction 
and to correlate invasively measured microvascular resistance with subjective burden of angina.  If 
shown to improve CMC function, Ranolazine would represent a therapeutic strategy among patients 
with CMC dysfunction and support a larger scale multi-center trial.     
VI:  Potential Challenges 
1:  Study Feasibility:  There may be two potential limitations to recruitment.  One may be due to 
insufficient patients meeting entry criteria.  The true prevalence of Type I CMC dysfunction is 
speculative.  Review of the literature shows a varied rate between 10-30% of patient with chest pain and 
no epicardial CAD.  Buchthal et al. studied 35 women with ischemic chest pain and no flow limiting CAD 
and found that 20% had abnormal metabolic response to exercise most likely due to CMC dysfunction 27.  
We used a similar estimate to calculate annual number of patients who would meet entry criteria for 
our study.  It is conceivable that the true prevalence of Type I CMC dysfunction is lower making 
feasibility more difficult.  I 
2:  Evidence of true hyperemia:  Use of intravenous Adenosine is well validated for the induction of 
coronary hyperemia.  Literature review suggests that mean time to maximal hyperemia using 
intravenous adenosine is 84±46 seconds (range, 23-125 seconds) and time from discontinuation of 
infusion to return of coronary flow to basal levels is 145±67 seconds 29.  To ensure standardized IMR 
measurement under maximal hyperemia, all cases will undergo three measurements at 120 seconds, 
Formatted: Font: Italic, Underline

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150 seconds and 180 seconds after initiation of intravenous adenosine (140 μg per kilogram of body 
weight per minute through a central vein). 
 
VII:  Relevant Contributions 
 
At the University of New Mexico, we have implemented IMR into clinical practice among patients 
meeting criteria for evaluation of CMC function.  Our protocol adheres to meticulous technique and a 
standardized protocol.  In addition to the proposed study, we are currently evaluating the role of CMC 
dysfunction among patients with ACS and no angiographic culprit.  As a clinical fellow, I worked with Dr. 
Noel Bairey Merz and the WISE study group to develop a protocol for doppler based coronary 
microvascular testing among women with chest pain and normal coronary arteries at Cedars Sinai 
Medical Center.  In addition, at the University of Vermont, I was an investigator in a pilot project 
comparing quantitative measures of myocardial blood flow on first-pass CT imaging with microsphere-
derived absolute values in an animal model of regional coronary ischemia and hyperemia.     
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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