JACC: CARDIOVASCULAR INTERVENTIONS VOL. 12, NO.

10, 2019

ª 2019 PUBLISHED BY ELSEVIER ON BEHALF OF THE

AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

STATE-OF-THE-ART REVIEW

The Potential Use of the Index of

Microcirculatory Resistance to Guide
Stratification of Patients for Adjunctive
Therapy in Acute Myocardial Infarction
Annette M. Maznyczka, MBCHB (HONS), BSC (HONS), MSC,a,b Keith G. Oldroyd, MD (HONS),a,b
Peter McCartney, MBCHB, BMEDSCI,a,b Margaret McEntegart, MBCHB, PHD,a,b Colin Berry, BSC, MBCHB, PHDa,b

ABSTRACT

The goal of reperfusion therapies in ST-segment elevation myocardial infarction has evolved to include effective
reperfusion of the microcirculation subtended by the culprit epicardial coronary artery. The index of microcirculatory
resistance is measured using a pressure- and temperature-sensing coronary guidewire and quantifies microvascular
dysfunction. The index of microcirculatory resistance is an independent predictor of microvascular obstruction, infarct
size, and adverse clinical outcomes. It has the advantage of being immediately measurable in the catheterization
laboratory, before the results of blood biomarkers or noninvasive imaging become available. This provides an opportunity
for additional intervention that may alter outcomes. In this review, the authors provide a critical appraisal of the
published research on the emerging role of the index of microcirculatory resistance as a tool to guide the stratification
of patients for adjunctive therapeutic strategies in acute ST-segment elevation myocardial infarction. (J Am Coll Cardiol
Intv 2019;12:951–66) © 2019 Published by Elsevier on behalf of the American College of Cardiology Foundation.

P rimary percutaneous coronary intervention

(PCI) for acute ST-segment elevation myocar-
dial infarction (STEMI) routinely achieves
successful coronary reperfusion. However, failed
myocardial reperfusion affects about one-half of all
treated patients, calling into question the definition
of procedure success (1,2). Persistent microvascular
dysfunction predicts worse outcomes in the longer
term (3,4). Microvascular obstruction (MVO) can be
accurately assessed noninvasively using cardiovas-
cular magnetic resonance (CMR), but this is not
feasible early after reperfusion.
reperfusion of the microcirculation should be identi-
fied at the time of primary PCI, allowing risk strati-
fication and the selected use of targeted therapy
(Central Illustration).
The index of microcirculatory resistance (IMR) is
an invasive measure of the minimal achievable
myocardial microvascular resistance. IMR has the
advantage of being immediately measurable in the
catheterization laboratory, before results of blood
biomarkers or noninvasive imaging are available,
and allows clinicians to intervene with stratified
Ideally, failed therapy. This review provides a critical appraisal of

From the aBritish Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences,
University of Glasgow, Glasgow, United Kingdom; and the bWest of Scotland Heart and Lung Centre, Golden Jubilee National
Hospital, Clydebank, United Kingdom. Dr. Maznyczka is supported by a British Heart Foundation Clinical Research Training
Fellowship (FS/16/74/32573). Prof. Berry is supported by a British Heart Foundation Centre for Research Excellence awards (RE/13/
5/30177; RE/18/6/34217). The University of Glasgow and Prof. Berry have institutional research and/or consultancy agreements
with Abbott Vascular, HeartFlow, Opsens, Philips, and Siemens Healthcare. Dr. Oldroyd has research and/or consultancy agree-
ments with Abbott Vascular, Boston Scientific, and Biosensors. All other authors have reported that they have no relationships
relevant to the contents of this paper to disclose.

Manuscript received September 10, 2018; revised manuscript received December 20, 2018, accepted January 3, 2019.

ISSN 1936-8798/$36.00 https://doi.org/10.1016/j.jcin.2019.01.246

952 Maznyczka et al. JACC: CARDIOVASCULAR INTERVENTIONS VOL. 12, NO. 10, 2019

IMR to Guide Therapy in Acute Myocardial Infarction MAY 27, 2019:951–66

ABBREVIATIONS the emerging role of IMR as a tool to guide

AND ACRONYMS HIGHLIGHTS
the stratification of patients for adjunctive
therapeutic strategies in acute STEMI.  Impaired microcirculatory reperfusion
CFR = coronary flow reserve
negatively affects one-half of all patients
CI = confidence interval
METHODS following PCI for acute STEMI, and
CMR = cardiovascular magnetic
resonance
prognosis is affected.
For this review, the Preferred Reporting
IMR = index of microcirculatory  IMR is a prognostic biomarker, easily
resistance
Items for Systematic Reviews and Meta-
Analyses recommendations (5) were consid-
measured during primary PCI and useful
MVO = microvascular
ered. However, because of the small number
for risk-stratification for targeted
obstruction
of publications fulfilling the inclusion criteria
therapy.
Pa = aortic pressure

PCI = percutaneous coronary

and the relatively large number of ongoing,
intervention or unpublished, relevant studies, a full
Pd = distal coronary pressure nonsystematic review was also performed.
PICSO = pressure-controlled There were few published (6,7) or ongoing
intermittent coronary sinus (8–11) randomized studies involving IMR in
occlusion
non-STEMI, and for this reason the review is
Pw = coronary wedge pressure focused on IMR in STEMI. The inclusion
STEMI = ST-segment elevation criteria were randomized or nonrandomized
myocardial infarction
studies investigating pharmacological or de-
Tmn = mean transit time
vice interventions in addition to standard PCI
in patients with STEMI and incorporating IMR. A
systematic search for registered trials was performed
using ClinicalTrials.gov and the Australian New Zea-
land Clinical Trials Registry. Published studies were
searched for using MEDLINE and PubMed (2003 to
August 2018) on August 11 and 12, 2018. The search
terms were “index of microcirculatory/microvascular
resistance” or “IMR,” combined with “myocardial
infarction” or “acute coronary syndrome”
“STEMI.” The search was restricted to the English
language. Case reports and reviews were excluded.
Conference abstracts from recent major cardiology
meetings were also searched. One author (A.M.M.)
extracted data from included studies and assessed
study quality. The methodological validity
included studies was reported and assessed using
criteria for minimization of bias, including definition
and measurement of outcomes, randomization
method, blinding, presence of a control group, and
sample size. A second author (P.M.) validated the
search (Figure 1).
INVASIVE ASSESSMENT OF
MICROVASCULAR FUNCTION
IMR is measured using a pressure- and temperature-
sensing guidewire (Abbott Vascular, Santa Clara,
California). The calibrated wire is equalized to guide
catheter pressure, then advanced to the distal third of
the infarct-related artery. Using standard thermodi-
lution methodology, the mean transit time (Tmn) of a
hand-injected 3-ml bolus of room-temperature
 Stratified therapy informed by IMR holds
promise. More research is needed to
identify novel therapies to prevent and
treat microvascular obstruction.
saline is measured in triplicate at rest and during
steady-state maximal hyperemia induced by adeno-
sine. IMR is quantified by distal coronary pressure
(Pd)
Tmn during hyperemia (12).
When a functionally significant coronary stenosis
is present (fractional flow reserve #0.8), IMR may
overestimate microvascular resistance and requires
correction using either coronary wedge pressure
(Pw) if it is available (corrected IMR ¼ aortic pres-
sure [Pa]
Tmn
[(Pd  Pw)/(Pa  Pw)]) (13) or
Yong’s formula incorporating fractional flow reserve
(corrected IMR ¼ Pa
Tmn
[(1.35
Pd/Pa) 
0.32]) (14), with Pa, Tmn, and Pd measured during
or hyperemia. However, in the setting of primary PCI,
when IMR is measured after stenting, there is usu-
ally no residual epicardial stenosis and corrections
are not required. In patients with stable ischemic
heart disease (i.e., not in the setting of acute
STEMI), IMR may be influenced by the amount of
of myocardium subtended by the epicardial artery un-
der study (15).
Hyperemic microvascular resistance and zero-
flow pressure can also be used to assess microvas-
cular resistance and are measured with a combined
Doppler-pressure wire (Philips Volcano Corporation,
San Diego, California). Hyperemic microvascular
resistance is the ratio of mean Pd to mean Doppler
flow peak velocity and correlates with MVO (optimal
cutoff >2.5 mm Hg/cm/s) (16,17), infarct size (18),
adverse left ventricular remodeling (19), regional
wall motion abnormalities (20), and
clinical outcomes (17,21). In the setting of a flow-
limiting stenosis, hyperemic microvascular resis-
tance requires correction for the contribution of
collateral flow to myocardial flow. However, when
hyperemic microvascular resistance is measured af-
ter primary PCI in STEMI with no or minimal
JACC: CARDIOVASCULAR INTERVENTIONS VOL. 12, NO. 10, 2019 Maznyczka et al. 953
MAY 27, 2019:951–66 IMR to Guide Therapy in Acute Myocardial Infarction

C ENTR AL I LL U STRA T I O N Index of Microcirculatory Resistance for Prognostication and Future

Directions to Guide Stratification of Patients for Adjunctive Therapy in Acute STEMI

Maznyczka, A.M. et al. J Am Coll Cardiol Intv. 2019;12(10):951–66.

The potential value of the index of microcirculatory resistance (IMR) as a prognostic biomarker, mechanisms for microvascular obstruction
(MVO), and scenarios for examining IMR in randomized trials are summarized. *Distal embolization of atherothrombotic debris and soluble
thrombogenic, vasoconstrictor, and inflammatory factors (e.g. thromboxane A2, endothelin-1, and tumor necrosis factor–alpha). Impaired
vasodilatation is due partly to imbalance between reactive oxygen species (ROS) and nitric oxide. Neutrophils plugging capillaries can
degranulate proteolytic enzymes and generate ROS, leading to inflammation and edema. IC ¼ intracoronary; LV ¼ left ventricular; PCI ¼
percutaneous coronary intervention; PICSO ¼ pressure-controlled intermittent coronary sinus occlusion; STEMI ¼ ST-segment elevation
myocardial infarction.
954 Maznyczka et al.
IMR to Guide Therapy in Acute Myocardial Infarction
F I G U R E 1 Flow Diagram of the Search of Published Research
The number of records identified is shown. ANZCTR ¼ Australian New Zealand Clinical Trials Registry; IMR ¼ index of microcirculatory resistance; PCI ¼ percutaneous
coronary intervention; STEMI ¼ ST-segment elevation myocardial infarction.
epicardial stenosis, corrections for the impact of
collateral vessels are not required (22). Hyperemic
microvascular resistance is limited by 1) lack of a
validated normal range or longer term outcome
data; and 2) technical challenges related to Doppler
flow velocity tracings.
Zero-flow pressure is the Pd at which, theoretically,
coronary flow would cease (Figure 2) and is associated
mainly with external microcirculatory compression
(23). Zero-flow pressure predicts early infarct size
(18), microvascular perfusion defects (16), adverse
left ventricular remodeling (24), myocardial salvage
index, and left ventricular function (25). Zero-flow
pressure appears less transferable to clinical prac-
tice, because of: 1) difficulties acquiring high-quality,
artifact-free Doppler tracings; 2) offline
processing; and 3) lack of a validated normal range
or longer term outcome data.
Coronary flow reserve (CFR) is the ratio of hyper-
emic to resting coronary blood flow (26,27). CFR is
unable to distinguish between resistance to flow in
the epicardial and microvascular compartments, and
previous studies suggest that it does not add to the
predictive utility of IMR (1,28). IMR has superior
reproducibility to CFR, with a mean coefficient of
JACC: CARDIOVASCULAR INTERVENTIONS VOL. 12, NO. 10, 2019
MAY 27, 2019:951–66
variation of 6.9  6.5% for IMR compared with
18.6  9.6% for CFR (29). Moreover, IMR is largely
independent of changes in systemic hemodynamic
status, whereas CFR decreases during pacing-induced
tachycardia or dobutamine infusion (29). Another
reported parameter of coronary microvascular func-
tion is the resistive reserve ratio (basal resistance
during resting conditions divided by IMR), which as-
sociates closely with CFR (30).
ASSOCIATIONS BETWEEN IMR,
NONINVASIVE IMAGING PARAMETERS,
AND CLINICAL OUTCOMES AFTER STEMI
The initial validation of IMR was in animals (12), with
post- subsequent human validation against echocardiog-
raphy (31,32), positron emission tomography (33),
single-photon emission computed tomography (34),
and CMR (1,2,28,32,35,36).
In STEMI, IMR parallels the adequacy of micro-
vascular reperfusion, evidenced by correlation with
MVO (2,35,37) and myocardial hemorrhage (micro-
vascular destruction) (2,38,39). Elevated IMR equates
to poor microvascular reperfusion, with a high like-
lihood of limited salvage and worse recovery of
JACC: CARDIOVASCULAR INTERVENTIONS VOL. 12, NO. 10, 2019 Maznyczka et al. 955
MAY 27, 2019:951–66 IMR to Guide Therapy in Acute Myocardial Infarction

F I G U R E 2 Summary of the Main Invasive Measures of Microvascular Function in Acute ST-Segment Elevation Myocardial Infarction

Invasive parameters are divided into flow or resistance based and thermodilution or Doppler derived. CFR ¼ coronary flow reserve; HMR ¼ hyperemic microvascular
resistance; IMR ¼ index of microcirculatory resistance; LV ¼ left ventricular; MVO ¼ microvascular obstruction; PCI ¼ percutaneous coronary intervention; Pd ¼ distal
coronary pressure; Pzf ¼ zero-flow pressure; STEMI ¼ ST-segment elevation myocardial infarction; Tmn ¼ mean transit time.

infarct size (1,2,31,33,35,39). Elevated
correlates with other downstream consequences of
microvascular injury, including adverse left ventric-
ular remodeling and worse left ventricular function
(1,31,32,35,36).
Fearon et al. (31) reported that an IMR #32
(median) immediately after primary PCI predicted
recovery of left ventricular function,
using echocardiography. IMR #32 correlated with
improvement in wall motion score index (from 25.4
 6.6 at baseline to 19.5  3.6 at 3 months; p ¼
0.0002). Patients with IMR >32 had no change in
wall motion score index. Faustino et al. (32) showed
that lower IMR (<26) correlated
myocardial global longitudinal strain, acutely post-
STEMI, and at 3 months correlated with better re-
covery of left ventricular function and wall motion
score index on echocardiography. Another study
using positron emission tomography (33) showed
IMR also that high IMR correlated with less myocardial
viability post-STEMI, and IMR #33 optimally pre-
dicted recovery in wall motion score index on
echocardiography at 6 months. Immediately after
primary PCI, an IMR >27 has been most closely
associated with MVO and myocardial hemorrhage on
CMR (2,28,38).
assessed Perhaps most clinically important, an IMR >40
post-PCI is predictive of all-cause death, heart fail-
ure readmission, and major adverse cardiac events
(1,37,40). Fearon et al. (37) reported that IMR >40
(mean) immediately after primary PCI was inde-
pendently associated with all-cause death (hazard
with better ratio: 4.3, 95% confidence interval [CI]: 1.3 to 15.0;
p ¼ 0.02) or all-cause death or rehospitalization for
heart failure at 1 year (hazard ratio: 2.2; 95% CI: 1.1
to 4.5; p ¼ 0.03) (n ¼ 253) (37). An IMR >31 (me-
dian) was independently associated with all-cause
death or rehospitalization for heart failure at 1
956 Maznyczka et al. JACC: CARDIOVASCULAR INTERVENTIONS VOL. 12, NO. 10, 2019

IMR to Guide Therapy in Acute Myocardial Infarction MAY 27, 2019:951–66

T A B L E 1 Published Randomized Clinical Studies Using Index of Microcirculatory Resistance to Select Patients With ST-Segment Elevation Myocardial Infarction for
Interventions and/or Measure the Efficacy of Interventions

Study/First Author (Ref. #) (Year) NCT# Sample Size Intervention Blinding Primary Outcome

Thrombolytic drugs
Sezer et al. (59) (2007) 41 (21 streptokinase group, Intracoronary streptokinase Participant, care provider, IMR and CFR at
NCT00302419 20 control group) post-PCI vs. standard PCI outcomes assessor 2 days and
blinded infarct size at
6 months

Sezer et al. (61) (2009) 95 in main study (51 streptokinase, Intracoronary streptokinase Participant, care provider, Infarct size at
NCT00627809 44 control group); 85 had IMR post-PCI vs. standard PCI outcomes assessor 6 months
(48 streptokinase group, blinded
37 control group)

Direct thrombin inhibition

BIVAL study/van Geuns 64 (main trial per protocol Bivalirudin vs. unfractionated No blinding Infarct size by
et al. (54) (2017) population); 52 (IMR substudy) heparin CMR, 5 days
Study was discontinued early for post-PCI
expected futility

Vasodilatory/antiplatelet drugs
Kirma et al. (55) (2012) 49 (25 intracoronary bolus tirofiban Intracoronary only vs. intravenous No blinding IMR and CFR 4–5
only, 24 intravenous bolus and GP IIb/IIIa inhibitor tirofiban, days post-PCI
maintenance infusion) then maintenance infusion

Salahaddin et al. (56) (2017) 100 Intravenous cangrelor (bolus then No blinding Platelet inhibition
NCT02733341 (abstract) infusion), then oral ticagrelor vs.
oral ticagrelor only
CV-TIME trial/Park et al. (57) 76 (38 clopidogrel, 38 ticagrelor Oral clopidogrel vs. oral ticagrelor No blinding IMR
(2016) NCT02026219 groups)

Ito et al. (60) (2013) 60 (crossover trial 30 received Intracoronary nicorandil vs. Investigators analyzing IMR
nicorandil first then nitroglycerin, intracoronary nitroglycerin data blinded
and 30 received nitroglycerin first) post-PCI

Aspiration thrombectomy
Woo et al. (62) (2014) 63 Thrombus aspiration vs. Not clearly specified in IMR
standard PCI paper

IMPACT trial/Hoole 41 (21 aspiration thrombectomy, Aspiration thrombectomy vs. Investigator analyzing IMR
et al. (63) (2015) 20 balloon angioplasty) balloon angioplasty data blinded

ICAT trial/Ahn et al. (58) (2014) 40 (10 GP IIb/IIIa inhibitor only, Intracoronary bolus GP IIb/IIIa No blinding IMR
NCT01404507 10 aspiration thrombectomy only, inhibitor (abciximab) vs.
20 both) aspiration thrombectomy vs. both

BIVAL ¼ Bivalirudin Infusion for Ventricular Infarction Limitation; CFR ¼ coronary flow reserve; CMR ¼ cardiovascular magnetic resonance; CV-TIME ¼ Clopidogrel Versus Ticagrelor on Coronary Microvascular
Injury in ST-Segment Elevation Myocardial Infarction; GP ¼ glycoprotein; ICAT ¼ Efficacy of Combination of IntraCoronary Bolus Abciximab and Aspiration Thrombectomy in STEMI; IMPACT ¼ Serial
Assessment of the Index of Microcirculatory Resistance During Primary Percutaneous Coronary Intervention Comparing Manual Aspiration Catheter Thrombectomy With Balloon Angioplasty; IMR ¼ index of
microcirculatory resistance; MVO ¼ microvascular obstruction; PCI ¼ percutaneous coronary intervention; SPECT ¼ single-photon emission computed tomography; STEMI ¼ ST-segment elevation myocardial
infarction; WMSI ¼ wall motion score index.
JACC: CARDIOVASCULAR INTERVENTIONS VOL. 12, NO. 10, 2019 Maznyczka et al. 957
MAY 27, 2019:951–66 IMR to Guide Therapy in Acute Myocardial Infarction

T A B L E 1 Continued

IMR Used to Select IMR Used to Measure

Patients for Therapy Response to Therapy and Difference in
and IMR Threshold IMR Timing Difference in IMR Infarct Characteristics

No Yes Yes No
IMR and CFR 2 days post- Mean IMR was lower in the streptokinase group (16.29 No difference in infarct size by SPECT at 6 months in
PCI vs. 32.49; p < 0.001) streptokinase vs. control group (27.84% vs.
Mean CFR was higher in the streptokinase group (2.01 37.28%; p ¼ 0.17)
vs. 1.39; p ¼ 0.002)
No Yes Yes Yes
IMR and CFR 2 days post- Mean IMR was lower in the streptokinase vs. control Infarct size by SPECT 6 months after primary PCI was
PCI group (20.2 vs. 34.2; p < 0.001) smaller in the streptokinase vs. control group
Mean CFR was higher in the streptokinase vs. control (22.7% vs. 32.9%; p ¼ 0.003)
group (2.5 vs. 1.7; p < 0.001)

No Yes Yes No
IMR immediately post-PCI Mean IMR was lower in the bivalirudin vs. unfractionated No difference in mean infarct size on CMR in
heparin group (43.5 vs. 68.7; p ¼ 0.014) bivalirudin vs. heparin group (25.0% vs. 27.1%;
p ¼ 0.75)
No difference in MVO extent in bivalirudin vs. heparin
group (5.3 g vs. 7.7 g; p ¼ 0.17)

No Yes No No
IMR and invasive CFR 4–5 Mean IMR did not differ in intracoronary vs. intravenous No difference in infarct size on SPECT at 6 months in
days post-PCI tirofiban group (27 vs. 35; p ¼ 0.08) intracoronary vs. intravenous tirofiban groups
Mean CFR did not differ in intracoronary vs. intravenous (18% vs. 12%; p ¼ 0.26)
tirofiban group (2.2 vs. 1.9; p ¼ 0.25)
No Yes No No
IMR immediately post-PCI No difference in IMR between cangrelor and ticagrelor No difference in infarct size on CMR 12 weeks post-PCI
groups between cangrelor and ticagrelor groups
No Yes Yes No
IMR immediately post-PCI Mean IMR was lower in the ticagrelor vs. clopidogrel No difference in estimated infarct size by WMSI on
group (22.20 vs. 34.40; p ¼ 0.005) echocardiography in ticagrelor vs. clopidogrel
group at 24 h (1.55 vs. 1.61; p ¼ 0.41) or after
3 months (1.42 vs. 1.47; p ¼ 0.57)
No Yes Yes Not measured/not reported
IMR immediately post-PCI As a first administration nicorandil reduced median IMR
before and after study more than nitroglycerin (10.8 vs. 2.1; p ¼ 0.0002)
drug As a second administration, nicorandil further reduced
IMR, while nitroglycerin did not (p < 0.0001)

No Yes Yes Yes

IMR immediately post-PCI Mean IMR was lower in the thrombus aspiration group
vs. control group (23.5 vs. 34.2; p ¼ 0.018)
No Yes No
IMR immediately post-PCI No difference in mean IMR between the aspiration
thrombectomy vs. balloon angioplasty group (43.3
vs. 44.6; p ¼ 0.90); in patients with IMR <32,
balloon angioplasty or aspiration thrombectomy
prior to stenting resulted in a significant increase in
IMR (baseline 21.7  8.0 vs. post-device 36.9 
25.9; p ¼ 0.006)
No Yes Yes
IMR immediately post-PCI Mean IMR was lower in the combination group vs.
abciximab-only group (23.50 vs. 66.90; p ¼ 0.001)
No difference in mean IMR between the combination vs.
aspiration thrombectomy–only group (23.50 vs.
37.20; p ¼ 0.07)
Reduction in WMSI on echocardiography during first
admission for STEMI and 6 months later was
greater in the thrombus aspiration group vs.
control group (0.12 vs. 0.004; p ¼ 0.001)
No
No difference in MVO occurrence or infarct size on
CMR 24 h post-PCI in aspiration thrombectomy vs.
balloon angioplasty groups
Yes
MVO occurrence on CMR 5 days post-STEMI was lower
in the combination group vs. abciximab-only
group (18.8% vs. 88.9%; p ¼ 0.002); no
difference in MVO occurrence in the combination
vs. aspiration thrombectomy–only group (18.8%
vs. 66.7%; p ¼ 0.054)
958 Maznyczka et al. JACC: CARDIOVASCULAR INTERVENTIONS VOL. 12, NO. 10, 2019

IMR to Guide Therapy in Acute Myocardial Infarction MAY 27, 2019:951–66

T A B L E 2 Published Nonrandomized Clinical Studies Using Index of Microcirculatory Resistance to Select Patients With ST-Segment Elevation Myocardial Infarction
for Interventions and/or Measure Efficacy of Interventions

Study/First Author (Ref.#) Primary IMR Used to Select Patients for

(Year) NCT# Sample Size Intervention Blinding Outcome Therapy and IMR Threshold

Vasodilatory drugs
Ito et al. (50) (2010) 40 Intracoronary nicorandil post-PCI Investigators analyzing IMR No
vs. placebo data blinded
Kostic et al. (51) (2015) 32 Intracoronary nicorandil post-PCI No blinding IMR No
(no control group)
Morimoto et al. (52) (2012) 18 Intracoronary sodium nitroprusside No blinding IMR Yes
(no control group) IMR $30 immediately post-PCI
PICSO
OxAMI-PICSO 105 (25 PICSO, 50 historical PICSO vs. standard PCI No blinding IMR Yes
De Maria et al. (46) (2018) controls with IMR >40, Pre-stenting IMR >40
NCT03473015 30 with IMR #40)
Post-dilatation with high
pressure balloons
Karamasis et al. (53) (2018) 32 Post-dilatation with noncompliant No blinding IMR No
NCT02788396 (abstract) balloons at high pressures
(no control group)

Study/First Author (Ref.#) IMR Used to Measure Response to Difference in Infarct

(Year) NCT# Therapy and IMR Timing Difference in IMR Characteristics

Vasodilatory drugs
Ito et al. (50) (2010)
Kostic et al. (51) (2015)
Morimoto et al. (52) (2012)
PICSO
OxAMI-PICSO
De Maria et al. (46) (2018)
NCT03473015
Post-dilatation with high
pressure balloons
Karamasis et al. (53) (2018)
NCT02788396 (abstract)
Yes Yes Not measured/not reported
IMR immediately post-PCI before Median IMR was lower post-nicorandil vs.
and after study drug pre-nicorandil (18.7 vs. 27.7; p < 0.0001); no
difference in median IMR post- vs. pre-placebo
(23.8 vs. 24.3; p ¼ 0.8193)
In subgroup analysis nicorandil reduced IMR in
subjects with baseline IMR $21 but did not change
IMR in those with baseline IMR <21
Yes Yes Yes
IMR immediately post-PCI and 10 min Mean IMR lower post-nicorandil vs. pre-nicorandil Improvement in WMSI at 3 months
post-nicorandil (9.90 vs. 14.10; p < 0.001) post-PCI vs. 24 h post-PCI (1.07 vs.
1.14; p ¼ 0.004)
Yes Yes Not measured/not reported
IMR immediately post-PCI before and Mean IMR improved before vs. after study drug
after study drug (76 vs. 45; p ¼ 0.0006).
Yes Yes Yes
IMR immediately post-PCI in all patients Median IMR was lower 24–48 h post-PCI in the Final infarct size on CMR 6 months post-
IMR 24–48 h post-PCI in 20 PICSO PICSO vs. control group (24.8 vs. 45.0; p < 0.001) PCI was lower in the PICSO vs. control
patients and in 31 controls No significant difference in IMR measured immediately group (26.0% vs. 33.0%; p ¼ 0.006)
with IMR >40 post-PCI (p ¼ 0.40) No difference in acute infarct size within 48
h post-PCI in the PICSO vs. control
group (39.0 vs. 41.0; p ¼ 0.42)
No difference in MVO occurrence in the
PICSO vs. control group (64.7% vs.
86.2%; p ¼ 0.08)
Yes No Not measured/not reported
IMR immediately post-stent pre- No significant difference in mean IMR pre-dilatation
dilatation, and post-dilatation vs. post-dilatation (44.9 vs. 48.8; p ¼ 0.287)

OxAMI-PICSO ¼ Oxford Acute Myocardial Infarction–Pressure-Controlled Intermittent Coronary Sinus Occlusion; PICSO ¼ pressure-controlled intermittent coronary sinus occlusion; other abbreviations as
in Table 1.

year (hazard ratio: 3.1; 95% CI: 1.4 to 6.6; p ¼
0.004) but not with all-cause death alone (37).
Subsequently, Carrick et al. (1) reported that IMR
>40 independently correlated with all-cause death
or heart failure readmissions at 2 years in 283
patients with STEMI (odds ratio: 4.36; 95% CI: 2.10
to 9.06; p < 0.001). Fahrni et al. (40) showed that
IMR >40 predicted major cardiac complications
30 days post-STEMI (16.7% vs. 0%; p < 0.001)
(n ¼ 261).
JACC: CARDIOVASCULAR INTERVENTIONS VOL. 12, NO. 10, 2019
MAY 27, 2019:951–66
STRATIFIED MEDICINE
Stratified medicine is the identification of patient
subgroups (or endotypes) within a heterogeneous
population, these being distinguishable by disease
severity and potential for response to therapy (41). A
theragnostic biomarker is a metric that predicts
therapeutic response. We will next discuss the
potential role of IMR as a theragnostic biomarker to
guide stratified medicine in STEMI.
IMR THRESHOLD FOR USE AS A
THERAGNOSTIC BIOMARKER
Patients in a stable condition without microvascular
disease generally have IMR values <25 (42–44).
In patients with nonobstructive coronary artery dis-
ease, IMR <25 correlated with a normal myocardial
perfusion reserve index on CMR, whereas IMR
$25 correlated with impaired myocardial perfusion
reserve index, similar to ischemic myocardium in
patients with obstructive coronary artery disease (44).
There is discordance between an IMR >40 and
MVO on CMR in one-third of STEMI cases (39), which
raises the question of what IMR threshold or range
should be used to select patients for adjunctive
treatments in acute STEMI. IMR reflects a continuum
of microvascular resistance, but binary cutoff values
are useful to inform decision-making. IMR is a func-
tional measure of the viability of the microvascula-
ture within the distribution of the culprit vessel (39),
which differs from and in some patients correlates
poorly with the anatomic damage reflected by MVO
on CMR (45). The majority (two-thirds) of discordant
cases with MVO despite IMR #40 had IMR between 25
and 40 (i.e., still above normal) (39). However,
compared with patients with MVO and IMR #40,
those with MVO and IMR >40 had more extensive
myocardial hemorrhage (3% vs. 1%; p ¼ 0.004) and
larger infarcts at 6 months (p ¼ 0.001) (39).
Identifying patients with IMR >40 after primary PCI
could select patients who are at highest risk for more
extensive microvascular dysfunction, larger infarcts,
and adverse outcomes but could exclude some pa-
tients with less severe microvascular dysfunction who
might still benefit from adjunctive therapy. It may be
that patients with the highest IMRs have sustained
irreversible myocardial damage, which might be less
modifiable by adjunctive therapies. Indeed, De Maria
et al. (39) showed that patients with MVO and IMR >40
immediately post-PCI had no regression in infarct size,
whereas infarct size regressed in those with MVO and
IMR #40 (34.4% vs. 22.3%; p ¼ 0.001). In patients
Maznyczka et al. 959
IMR to Guide Therapy in Acute Myocardial Infarction
without MVO, those with IMR #40 had regression in
infarct size, whereas those with IMR >40 did not.
These findings indicate that IMR and MVO are not
synonymous and may have distinct clinical signifi-
cance. Importantly, these measurements are typically
obtained at different time points after myocardial
infarction (immediately vs. several days post-PCI),
using different methods (thermodilution vs. contrast
CMR, invasive vs. noninvasive).
STUDIES USING IMR AS A
THERAGNOSTIC BIOMARKER
There are no published randomized studies using IMR
to select patients with STEMI for adjunctive therapies
(Table 1). The OxAMI-PICSO (Oxford Acute Myocardial
Infarction–Pressure-Controlled Intermittent Coronary
Sinus Occlusion) study (Table 2) used IMR >40 to
stratify patients for pressure-controlled intermittent
coronary sinus occlusion (PICSO) before stenting (46).
The premise is that cyclic balloon inflations in the
coronary sinus could redistribute blood from the
remote nonischemic myocardium to the ischemic
zone, potentially reducing final infarct size. IMR was
repeated immediately post-stenting and again 24 to
48 h later in 20 PICSO-treated patients and compared
with 31 historical control subjects with IMR >40.
There was no between-group difference in IMR
immediately post-PCI. However, at 24 to 48 h post-
PCI, IMR was lower in the PICSO group (24.8 vs.
45.0; p < 0.001). There was no difference in acute
infarct size or MVO occurrence, but final infarct size
on CMR 6 months post-PCI was lower in the PICSO
group (26.0% vs. 33.0%; p ¼ 0.006). OxAMI-PICSO
demonstrates the feasibility of using intraprocedural
IMR to guide adjuvant therapy in acute STEMI. The
results of this observational study support the ratio-
nale for a randomized trial.
Stratified medicine using IMR in STEMI is being
examined in 3 ongoing studies (Table 3). A large ran-
domized trial (target n ¼ 880) is evaluating deferred
stenting in patients with STEMI on the basis of IMR
pre-stenting (NCT03581513) (47). The comparator
groups are IMR #40 randomized to: 1) immediate
stenting or 2) deferred stenting; and IMR >40 ran-
domized to 3) immediate stenting or 4) deferred
stenting. IMR is remeasured after primary PCI. The
primary outcome is the prevalence of heart failure,
repeat myocardial infarction, or target vessel revas-
cularization at 1 year.
RESTORE-AMI (Restoring Microcirculatory Perfu-
sion in ST-Elevation Myocardial Infarction [STEMI];
ACTRN12618000778280) (48) is a phase 3 trial that
960 Maznyczka et al. JACC: CARDIOVASCULAR INTERVENTIONS VOL. 12, NO. 10, 2019

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T A B L E 3 Registered, Unpublished, Randomized, Clinical Studies Using Index of Microcirculatory Resistance to Select Patients With ST-Segment Elevation
Myocardial Infarction for Interventions and/or Measure Efficacy of Interventions

Estimated Sample Size, IMR Used to Select IMR Used to Measure

Study (Ref. #)/ Start Date, and Primary Patients for Therapy Response to Therapy
Registration Number Recruitment Status Intervention Blinding Outcome and IMR Threshold and IMR Timing

Thrombolytic drugs
T-TIME IMR substudy n ¼ 108 (sample size Intracoronary alteplase Participant, care IMR No Yes
(64) NCT02257294 for IMR substudy, (10 and 20 mg) provider, IMR immediately
sample size for pre-stenting vs. investigator post-PCI
main trial is 440) placebo blinded
Start: 2016
Status: active, not
recruiting
RESTORE-AMI (48) n ¼ 800 Intracoronary Participant, Clinical outcomes Yes Yes
ACTRN12618000778280 Start: 2018 tenecteplase post- caregiver, at 24 mo Subjects with IMR IMR after study drug
Status: not yet stenting vs. placebo outcome assessor >32 post-PCI
recruiting blinded randomized;
subjects with
IMR <32 post-PCI
in registry
OPTIMAL (49) n ¼ 80 Intracoronary alteplase Participant and Ratio of infarct size Yes Yes
NCT02894138 Start: 2016 (20 mg) post- outcome assessor to area at risk Post-stenting IMR Change in IMR and CFR,
Status: unknown stenting vs. placebo blinded on CMR at 2–6 >30 before and
days and 3 mo immediately after
study drug
Vasodilatory/anti-
inflammatory/anti-
platelet drugs
REDUCE-MVI (66,67) n ¼ 110 Oral ticagrelor vs. No blinding IMR No Yes
NCT02422888 Start: 2015 prasugrel IMR measured
Status: active, not immediately
recruiting post-PCI and after
1 month
ACTRN12615000019505 n ¼ 64 Oral atorvastatin (80 Participants, IMR No Yes
(68) Start: 2014 mg) before primary caregiver, IMR immediately after
Status: completed PCI vs. placebo investigators, primary PCI
outcome
assessors blinded
NCT01245894 (71) n ¼ 87 High-dose vs. low-dose Single blinding IMR No Yes
Start: 2007 rosuvastatin for 1 yr (investigator) IMR immediately
Status: completed after STEMI post-PCI and after 1 yr
Other drugs
NCT02976701 (70) n ¼ 40 Oral DLBS1033 vs. Participant, IMR No Yes
Start: 2016 placebo, caregiver, Change in IMR
Status: recruiting administered the investigator, immediately
day after primary outcome assessor post-PCI and after 4
PCI, continued blinded weeks
thrice daily for 4
weeks
Deferred stenting
NCT03581513 (47) n ¼ 880 Immediate vs. deferred Single blinding Clinical outcomes Yes Yes
Start: 2017 stenting (1 week (participant) at 1 yr IMR <40 pre-PCI, IMR post-PCI
Status: recruiting later) randomized to
immediate or
deferred stenting;
IMR $40 pre-PCI,
randomized to
immediate or
deferred stenting
Thrombectomy
PATA-STEMI (69,82) n ¼ 128 Aspiration Participant and IMR No Yes
NCT01824641 Start: 2012 thrombectomy vs. outcome assessor IMR immediately
Status: unknown standard PCI blinded post-PCI
Remote ischemic conditioning
ERIC-PPCI IMR substudy n ¼ 180 (estimated Remote ischemic Participant, care IMR No Yes
(65) NCT02342522 sample size for conditioning vs. provider, IMR pre-stent and
IMR substudy) control investigator, post-PCI
outcome assessor
blinded

ERIC-PPCI ¼ Effect of Remote Ischaemic Conditioning on Clinical Outcomes in STEMI Patients Undergoing PPCI; OPTIMAL ¼ Optimal Coronary Flow After PCI for Myocardial Infarction—A Pilot Study; PATA-STEMI ¼
Physiologic Assessment of Thrombus Aspiration in Acute ST-segment Elevation Myocardial Infarction Patients; REDUCE-MVI ¼ Reducing Micro Vascular Dysfunction in Acute Myocardial Infarction by Ticagrelor;
RESTORE-AMI ¼ Restoring Microcirculatory Perfusion in ST-Elevation Myocardial Infarction (STEMI); T-TIME ¼ Trial of Low-Dose Adjunctive Alteplase During Primary PCI; other abbreviations as in Table 1.
JACC: CARDIOVASCULAR INTERVENTIONS VOL. 12, NO. 10, 2019
MAY 27, 2019:951–66
T A B L E 4 Registered, Unpublished, Nonrandomized, Clinical Studies Using Index of Microcirculatory Resistance to Select Patients With
ST-Segment Elevation Myocardial Infarction for Interventions and/or Measure Efficacy of Interventions
Estimated Sample Size,
Registration Number Start Date, and
(Ref. #) Recruitment Status
NCT03238508 (83) n ¼ 60
Start: 2013
Status: recruiting
IMR ¼ index of microcirculatory resistance.
will use IMR as an inclusion criterion to stratify
enrollment. In this study, 1,660 patients will be
enrolled, and IMR will be measured after primary PCI.
Patients with IMR >32 will be eligible for progression
into the trial (n ¼ 800), and those with IMR #32 will
continue in a follow-up registry. The intervention is
adjunctive intracoronary tenecteplase (one-third of
the weight-based systemic dose) or placebo. IMR will
be measured again after administration of the study
drug. The primary outcome is cardiovascular mortal-
ity or rehospitalization for heart failure at 2 years.
Patients with ischemic times of up to 12 h will be
enrolled. The study will assess potential benefits and
risks. For example, some patients with prolonged
ischemic times may be at risk for hemorrhagic trans-
formation within the infarct zone (1,38), which could
be worsened by lytic therapy. Moreover, CMR is not
included, therefore information on
myocardial hemorrhage will be unknown.
OPTIMAL (Optimal Coronary Flow
for Myocardial Infarction—A Pilot Study) (NCT028
94138) (49) will randomize 80 patients with STEMI
presenting within 12 h of symptom onset with a post-
stenting IMR >30 to intracoronary alteplase (20 mg)
or placebo, in an open-label design. Change in IMR
immediately after compared with before administra-
tion of the study drug will be measured. The primary
outcome is the ratio of infarct size to area at risk on
CMR at 2 to 6 days and 3 months.
STUDIES USING IMR TO MEASURE
TREATMENT EFFICACY
Several studies have adopted IMR to assess the effi-
cacy of adjunctive treatments in patients with STEMI
(Tables 1 to 4). Study quality varies, with some non-
randomized (46,50–53), without blinding (46,51–58),
no control group (51–53), small sample
(50–53,55,58,59), or with no noninvasive imaging
(50,52,53,60). The main studies not already presented
in this review are discussed below.
Sezer et al. (61) randomized 95 patients (of whom
85 had invasive coronary physiology) to receive
Maznyczka et al. 961
IMR to Guide Therapy in Acute Myocardial Infarction
IMR Used to Select Patients IMR Used to Measure
Primary for Therapy and Response to Therapy
Intervention Blinding Outcome IMR Threshold and IMR Timing
Immediate vs. deferred No blinding IMR No Yes IMR 3–5 days after
stenting primary reperfusion
intracoronary streptokinase at the time of primary
PCI for STEMI (Table 1). Ischemic time was longer in
the streptokinase group (4.15  2.84 h vs. 2.96  1.38
h; p ¼ 0.01), despite which IMR was lower (20.2 vs.
34.2; p < 0.001) and CFR was higher (2.5 vs. 1.7; p <
0.001) (61). Infarct size at 6 months, evaluated by
single-photon emission computed tomography, was
smaller with streptokinase (22.7% vs. 32.9%; p ¼
0.003) (61).
The CV-TIME (Clopidogrel Versus Ticagrelor on
Coronary Microvascular Injury in ST-Segment Eleva-
tion Myocardial Infarction) trial (57) randomized 76
patients to ticagrelor or clopidogrel to test the hy-
pothesis that ticagrelor’s ability to inhibit cellular
adenosine reuptake may translate to less microvas-
cular dysfunction. Ischemic time was similar in tica-
grelor and clopidogrel groups (5.83  4.88 h vs. 6.47 
MVO and 7.02 h; p ¼ 0.65). IMR immediately after primary PCI
was lower with ticagrelor compared with clopidogrel
After PCI (22.2 vs. 34.4; p ¼ 0.005). However, there was no
difference in infarct size on echocardiography at 24 h
post-PCI. The study was not blinded.
Salahaddin et al. (56) randomized 100 patients to
intravenous cangrelor (followed by oral ticagrelor) or
oral ticagrelor only. There was no difference in IMR
immediately after primary PCI and no difference in
infarct size on CMR at 3 months. Because IMR was a
secondary outcome, it is possible that the study was
not powered to detect a between-group difference.
Furthermore, the study was not blinded.
In a crossover trial, Ito et al. (60) randomized pa-
tients with STEMI immediately post-PCI to receive
either 2 mg of nicorandil (n ¼ 30) or 250 m g of nitro-
glycerin (n ¼ 30) in a sequential, crossover design.
The hypothesis was that nicorandil, a hybrid adeno-
sine triphosphate–sensitive potassium channel
opener and nitric oxide donor, might improve
sizes microvascular dysfunction. IMR was measured
immediately post-PCI (baseline) and then again after
administration of the study drugs in sequential order.
The change in IMR was the primary outcome. Nicor-
andil reduced IMR more than nitroglycerin (10.8 vs.
2.1; p ¼ 0.0002). As a second administration,
962 Maznyczka et al. JACC: CARDIOVASCULAR INTERVENTIONS VOL. 12, NO. 10, 2019

IMR to Guide Therapy in Acute Myocardial Infarction MAY 27, 2019:951–66

T A B L E 5 Summary of Studies That Investigated Serial Index of Microcirculatory Resistance and Coronary Flow Reserve Measurements at Different Time Points
Post-Stenting or Index of Microcirculatory Resistance and Coronary Flow Reserve Measurements Pre- and Post-Stenting in Reperfused Patients With
ST-Segment Elevation Myocardial Infarction

First Author (Ref. #) Sample Timing of IMR or

(Year) Size CFR Measurements Findings

Cuculi et al. (78) (2014)
Neumann et al. (79) (1997)
Sezer et al. (34) (2010)
Cuculi et al. (80) (2014)
Hoole et al. (63) (2015)
De Maria et al. (81) (2015)
44 IMR and CFR immediately
post-stent and 1 day later
19 CFR immediately post-stent, 1 h
later, and 14 days later
35 IMR and CFR 2 days post-STEMI
and 5 months later
82 IMR and CFR immediately post-
stent, 1 day later, and at
6 months
41 IMR pre- and post-stent
85 IMR pre- and post-stent
 Immediately post-PCI, neither IMR nor CFR correlated with LVEF.
 At day 1, IMR was lower than immediately post-stent (more so in patients with
higher LVEFs).
 Serial CFR measurements in the infarct-related artery increased when measured
at 3 time points: 1) immediately post-stent (CFR ¼ 1.6); 2) 1 h later (CFR ¼ 2.0);
and 3) 14 days later (CFR ¼ 2.6).
 IMR decreased from 28.7  10.3 at 2 days to 19.1  6.7 at 5 months post-STEMI
(p < 0.001), and CFR increased over the same time period (p ¼ 0.001).
 Temporal improvements in IMR and CFR tracked with parallel improvements in
infarct size. Specifically, patients with reductions in IMR less than the mean
reduction for the cohort (<33%) had less improvement in infarct size (evaluated
by SPECT) over 5 months than those with IMR reductions greater than the mean
reduction for the cohort (17.2  22% vs. 40.1  30.1%; p ¼ 0.04).
 Patients with improvements in CFR less than the mean improvement for the
cohort (<41%) had less improvement in infarct size over 5 months than those
with CFR improvements greater than the mean improvement for the cohort
(19  26.2% vs. 47.2  28.2%; p ¼ 0.009).
 Temporal improvements in IMR also translated into improvement in LV volumes
and function over 5 months.
 IMR decreased over time (37.0  22.3 immediately post-PCI [n ¼82], 30.6  21.4
at day 1 [n ¼ 61], and 24.0  22.0 at 6 months [n ¼ 46]; p ¼ 0.002).
 CFR significantly increased over time (1.8  0.9 immediately post-PCI, 2.3  0.7
at day 1, and 3.1  1.1 at 6 months; p < 0.001).
 In patients with MVO present 1 day post-STEMI and in those with no MVO, IMR
was lower on day 1 compared with immediately post-PCI.
 In those with MVO present compared with those with no MVO, there was a trend
toward higher IMR at PCI (42.9  24.4 vs. 31.3  19) and at day 1 (32.5  21.2 vs.
22.8  8.2), but this did not reach statistical significance (p ¼ 0.07 for both).
 CFR was significantly higher in patients without MVO at primary PCI (2.3  1.1 vs.
1.6  0.7; p ¼ 0.02) and at 1 day (2.7  0.9 vs. 2.1  0.6; p ¼ 0.04), but not at 6
months.
 No difference in IMR measured pre- vs. post-stenting during primary PCI (35.6 
31.8 vs. 40.8  30.9; p ¼ 0.26).
 In a subgroup with IMR <32 (n ¼ 30), IMR was higher post- vs. pre-stenting (33.0
 23.7 vs. 21.2  7.9; p ¼ 0.01), which suggests that patients with less
microcirculatory dysfunction (IMR <32) may be more susceptible to iatrogenic
microcirculatory injury following stenting.
 IMR improved overall post- compared with pre-stenting (29.2 vs. 49.7;
p < 0.001).
 In subgroup analysis, patients with pre-stenting IMR >40 (n ¼ 28) had
improvement in IMR values post-stenting (IMR 67.7 vs. 36.7; p < 0.001) and
were more likely to have longer ischemic times, larger infarcts, and more TIMI
flow grade 0 at presentation.
 Conversely, patients with pre-stenting IMR #40 (n ¼ 57) had no significant
change in IMR or CFR post-stenting.
 Patients with increases in IMR post- compared with pre-stent and post-stent IMR
>40 were more likely to have higher volume stent implantation and higher
thrombotic burdens.
 Patients with pre-stenting IMR >40, which despite falling remained >40
post-stenting, were more likely to have longer ischemic times (>6 h).

All studies were in patients who underwent primary PCI.

LV ¼ left ventricular; LVEF ¼ left ventricular ejection fraction; TIMI ¼ Thrombolysis In Myocardial Infarction; other abbreviations as in Table 1.

nicorandil further reduced IMR, whereas nitroglyc-
erin did not (p < 0.0001). In an analysis according to
IMR at the end of PCI (baseline, before study drug
administration), superior efficacy of nicorandil versus
nitroglycerin was observed in patients with interme-
diate IMR (21.3 to <36) and high IMR ($36), but not in
patients with low IMR (<21.3).
In another study, IMR was lower in patients ran-
domized to thrombus aspiration compared with
standard PCI (23.5 vs. 34.2; p ¼ 0.018) (62). Reduction
in wall motion score index on echocardiography at
6 months compared with baseline was greater in
the thrombus aspiration group (0.12 vs. 0.004;
p ¼ 0.001). Conversely, the IMPACT (Serial Assess-
ment of the Index of Microcirculatory Resistance
During Primary Percutaneous Coronary Intervention
Comparing Manual Aspiration Catheter Thrombec-
tomy With Balloon Angioplasty) trial (63) reported no
JACC: CARDIOVASCULAR INTERVENTIONS VOL. 12, NO. 10, 2019
MAY 27, 2019:951–66
difference in IMR immediately post-PCI between
aspiration thrombectomy (n ¼ 21) and balloon angio-
plasty (n ¼ 20) groups (43.3 vs. 44.6; p ¼ 0.90). In
addition, there was no difference in MVO or infarct
size on CMR 24 h post-PCI (63) (Table 1). Ischemic
time was similar between the groups (3.4 vs. 3.0 h;
p ¼ 0.21).
Several registered ongoing trials are using IMR to
assess the impact of therapies on microvascular
function after STEMI. Notably, the British Heart
Foundation–funded IMR substudy of T-TIME (Trial of
Low-Dose Adjunctive Alteplase During Primary PCI)
(NCT02257294) has recently completed recruitment
(64). In this study, patients with ischemic times #6 h
were randomized to manual intracoronary infusion
of either placebo or alteplase (10 or 20 mg, repre-
senting one-tenth or one-fifth of the standard sys-
temic dose in STEMI). The study drug was
administered post-reperfusion but pre-stenting.
IMR was measured immediately post-PCI. Unlike
previously published studies that used streptoki-
nase (59,61), alteplase is fibrin specific. The main
trial enrolled 440 patients, with the primary
outcome being MVO on CMR 2 days post-STEMI.
The strengths of this study include: 1) a prospec-
tive, randomized, double-blind, placebo-controlled,
parallel group, multicenter design with a compara-
tively large sample size; and 2) patients and clini-
cians were blinded to the IMR. The rationale for
blinding to IMR was to avoid the possibility that
knowledge of a high IMR at the end of PCI might
bias physician behavior (e.g., to stimulate more
intensive therapy, such as giving a glycoprotein
IIb/IIIa inhibitor).
Other registered, unpublished trials include the
IMR substudy of ERIC-PPCI (Effect of Remote Ischae-
mic Conditioning on Clinical Outcomes in STEMI
Patients Undergoing PPCI) (NCT02342522) (65),
investigating remote ischemic conditioning with a
blood pressure cuff compared with control, in patients
with ischemic times <12 h, with IMR measured pre-
and post-stenting. The REDUCE-MVI (Reducing Micro
Vascular Dysfunction in Acute Myocardial Infarction
by Ticagrelor) study (NCT02422888) (66,67) is
comparing IMR measured immediately post-PCI and
at 1 month in patients with ischemic times <12 h
randomized to oral ticagrelor or prasugrel.
TIMING OF IMR MEASUREMENT TO ASSESS
TREATMENT EFFICACY
Timing for IMR measurement in studies to assess
therapeutic response varies. Most studies measured
Maznyczka et al. 963
IMR to Guide Therapy in Acute Myocardial Infarction
IMR post-PCI during the same procedure (47–54,
56–58,62–65,68,69), while some studies made an
additional IMR measurement 2 days (46), 1 month
(67,70), or 1 year (71) later, and some reported
measuring IMR only 2 days (59,61) or 3 to 5 days (55)
post-PCI.
The temporal change of MVO is very dynamic.
Within minutes of reperfusion, the zone of impaired
perfusion encompasses the subendocardium (72), but
by 3.5 h this extends to the midmyocardium in
approximately 25% of the area at risk (72). From 2 to 8
h post-reperfusion, there is little increase in the zone
of impaired perfusion, but from 8 to 24 h, hemor-
rhagic tissue expands (73). From 24 h post-
reperfusion, MVO stabilizes (74), and 1 week later
MVO persists in a variable proportion of patients
(linked to myocardial hemorrhage). By 2 weeks post-
reperfusion, the infarcted area evolves to ventricu-
lar thinning (scar) (75). By 1 month post-reperfusion
MVO has reversed in approximately 50% of patients
and persists (related to myocardial hemorrhage) in
the other 50% (76). By 7 to 8 months post-reperfusion,
MVO has usually resolved (77). In parallel with these
changes, microvascular dysfunction is also very dy-
namic and influenced by ischemic time. IMR and CFR
undergo partial recovery within 24 to 48 h post-
STEMI, with further recovery to 6 months (34,78–80)
(Table 5). Accordingly, it may be that in patients
with a short duration of ischemia, a decrease in IMR
over time post-PCI reflects a recovery response, with
positive microvascular remodeling. Whether addi-
tional adjuvant therapies might further improve
microvascular perfusion (and prognosis) remains to
be prospectively determined.
It is unknown whether the discriminatory ability of
IMR to detect differences between treatment groups
may be better at a fixed time point, such as approxi-
mately 48 h post-reperfusion, compared with imme-
diately post-PCI, or whether the change in IMR
between these 2 time points is more informative.
Repeated invasive procedures present logistical, cost,
and safety concerns.
IMPACT OF STENTING ON IMR
The impact of stenting on the microcirculation and
IMR should be considered. Both studies (63,81) that
investigated IMR pre- and post-stenting used wedge-
corrected IMR (Table 5). Hoole et al. (63) showed no
difference in average IMR measured pre- versus
post-stenting during primary PCI. However, a larger
study found that overall IMR improved post-
compared with pre-stenting (29.2 vs. 49.7; p < 0.001)
964 Maznyczka et al.
IMR to Guide Therapy in Acute Myocardial Infarction
(81). Stenting may itself lead to downstream embo-
lization and worsen MVO (no reflow), and these
mean group data conceal large between-patient
variations. Nevertheless, these studies (63,81) sug-
gest that the patients most likely to have significant
reductions in IMR post-stenting are those with
higher pre-stenting IMR, lower thrombotic burden,
and shorter ischemic time.
FUTURE PERSPECTIVES
The potential clinical utility of IMR to guide the
stratification of patients for adjunctive therapy dur-
ing acute STEMI is being intensively investigated
(Central Illustration). Ongoing and future studies
should clarify the optimal IMR threshold or range for
selecting patients for adjunctive therapy. More
research is needed to better define the optimal time
point after primary PCI for measuring IMR. Prospec-
tive randomized trials are ongoing to assess the
impact of fibrinolytic therapy, ischemic conditioning,
deferred stenting, antiplatelet therapy, and high-dose
statins on IMR (Table 3). Taken together, these
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MAY 27, 2019:951–66
studies will present exciting data on the potential for
stratified medicine guided by invasive coronary
physiology during acute STEMI.
CONCLUSIONS
IMR is useful for the early identification of micro-
vascular dysfunction in patients with acute STEMI.
Current evidence supports the feasibility of studies
using IMR as a theragnostic biomarker of micro-
vascular dysfunction and as a measure of treat-
ment effect. Compared with other invasive
indexes, IMR has more validation data, suggesting
a stronger potential for implementation into clin-
ical practice.
ADDRESS FOR CORRESPONDENCE: Prof. Colin
Berry, British Heart Foundation, Glasgow Cardiovas-
cular Research Centre Institute of Cardiovascular and
Medical Sciences, 126 University Place, University of
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KEY WORDS adjunctive therapy, index of
microcirculatory resistance, infarction,
microvascular obstruction, stratified
medicine, ST-segment elevation myocardial