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J O U R N A L O F T H E AM E R I C A N C O L L E G E O F C A R D I O L O G Y VO L . 7 1 , N O . 9 , 2 0 1 8

ª 2 0 1 8 T H E A U T H O R S . P U B L I S H E D B Y E L S E V I E R O N B E H A L F O F T H E A M E R I C A N

C O L L E G E O F C A R D I O L O G Y F OU N D A T I O N . T H I S I S A N O P E N A C C E S S A R T I C L E U N D E R

T H E C C B Y L I C E N S E ( h t t p : / / c r e a t i v e c o mm o n s . o r g / l i c e n s e s / b y / 4 . 0 / ) .

Diagnosis of Microvascular Angina UsingCardiac Magnetic Resonance

Alexander Liu, MBBS,a Rohan S. Wijesurendra, MB, BCHIR,a Joanna M. Liu, MBBS,a John C. Forfar, MD, PHD,b

Keith M. Channon, MD,c Michael Jerosch-Herold, PHD,d Stefan K. Piechnik, DSC, PHD, MSCEE,a Stefan Neubauer, MD,a

Rajesh K. Kharbanda, MBCHB, PHD,c Vanessa M. Ferreira, MD, DPHILa

ABSTRACT

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BACKGROUND In patients with angina and nonobstructive coronary artery disease (NOCAD), confirming symptoms due

to coronary microvascular dysfunction (CMD) remains challenging. Cardiac magnetic resonance (CMR) assesses myocardial

perfusion with high spatial resolution and is widely used for diagnosing obstructive coronary artery disease (CAD).

OBJECTIVES The goal of this study was to validate CMR for diagnosing microvascular angina in patients with NOCAD,

compared with patients with obstructive CAD and correlated to the index of microcirculatory resistance (IMR) during

invasive coronary angiography.

METHODS Fifty patients with angina (65 � 9 years of age) and 20 age-matched healthy control subjects underwent

adenosine stress CMR (1.5- and 3-T) to assess left ventricular function, inducible ischemia (myocardial perfusion reserve index

[MPRI]; myocardial blood flow [MBF]), and infarction (late gadolinium enhancement). During subsequent angiography within

7 days, 28 patients had obstructive CAD (fractional flow reserve [FFR]#0.8) and 22 patients had NOCAD (FFR>0.8) who

underwent 3-vessel IMR measurements.

RESULTS In patients with NOCAD, myocardium with IMR <25 U had normal MPRI (1.9 � 0.4 vs. controls 2.0 � 0.3;

p ¼ 0.49); myocardium with IMR $25 U had significantly impaired MPRI, similar to ischemic myocardium downstream of

obstructive CAD (1.2 � 0.3 vs. 1.2 � 0.4; p ¼ 0.61). An MPRI of 1.4 accurately detected impaired perfusion related to CMD

(IMR $25 U; FFR >0.8) (area under the curve: 0.90; specificity: 95%; sensitivity: 89%; p < 0.001). Impaired MPRI in pa-

tients with NOCAD was driven by impaired augmentation of MBF during stress, with normal resting MBF. Myocardiumwith

FFR >0.8 and normal IMR (<25 U) still had blunted stress MBF, suggesting mild CMD, which was distinguishable from

control subjects by using a stress MBF threshold of 2.3 ml/min/g with 100% positive predictive value.

CONCLUSIONS In angina patients with NOCAD, CMR can objectively and noninvasively assess microvascular angina.

A CMR-based combined diagnostic pathway for both epicardial and microvascular CAD deserves further clinical validation.

(JAmColl Cardiol 2018;71:969–79)©2018TheAuthors. PublishedbyElsevier onbehalf of theAmericanCollege of Cardiology

Foundation. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

I n patients with angina, up to 90% have nonob-structive coronary artery disease (NOCAD), asshown in the recent PROMISE (Prospective

Multicenter Imaging Study for Evaluation of ChestPain) trial (1,2). Although these patients with

N 0735-1097

m the aOxford Centre for Clinical Magnetic Resonance Research, Division

dicine, University of Oxford, Oxford, United Kingdom; bOxford Heart Cent

ivision of Cardiovascular Medicine, Radcliffe Department of Medicine, U

righam and Women’s Hospital, Radiology, Cardiovascular Imaging, Bos

ded by a British Heart Foundation Clinical Research Training Fellowship

chnik, and Neubauer are supported by the National Institute fo

s. Wijesurendra, Neubauer, Piechnik, and Ferreira acknowledge supp

search Excellence (RE/08/004). All other authors have reported that the

s paper to disclose. Drs. Kharbanda and Ferreira contributed equally to

nuscript received September 18, 2017; revised manuscript received Decem

“microvascular angina” are often reassured ashaving a low risk for ischemic heart disease orempirically treated with antianginal medications,they experience reduced quality of life and adverseclinical outcomes and contribute to increased

https://doi.org/10.1016/j.jacc.2017.12.046

of Cardiovascular Medicine, Radcliffe Department of

re, John Radcliffe Hospital, Oxford, United Kingdom;

niversity of Oxford, Oxford, United Kingdom; and

ton, Massachusetts. This study and Dr. Liu were

grant (FS/15/11/31233). Drs. Ferreira, Wijesurendra,

r Health Research Biomedical Research Centre.

ort from the British Heart Foundation Centre of

y have no relationships relevant to the contents of

this work and are joint senior authors.

ber 1, 2017, accepted December 26, 2017.

ABBR EV I A T I ON S

AND ACRONYMS

AUC = area under the curve

CAD = coronary artery disease

CI = confidence interval

CMD = coronary microvascular

dysfunction

CMR = cardiac magnetic

resonance

FFR = fractional flow reserve

IMR = index of microcirculatory

resistance

LGE = late gadolinium

enhancement

MBF = myocardial blood flow

MPR = myocardial perfusion

reserve

MPRI = myocardial perfusion

reserve index

NOCAD = nonobstructive

coronary artery disease

QCA = quantitative coronary

angiography

ROC = receiver-operating

characteristic

Liu et al. J A C C V O L . 7 1 , N O . 9 , 2 0 1 8

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970

health care bills (1,3,4). Ischemia due to coro-nary microvascular dysfunction (CMD) re-mains a diagnostic challenge in generalcardiology practice.

Currently, fractional flow reserve (FFR) isthe invasive gold standard for assessing flowlimitation across an epicardial coronary ste-nosis, but it does not assess the microcircu-lation (5). The index of microcirculatoryresistance (IMR) is an invasivethermodilution-based marker of microvas-cular function (6) associated with microvas-cular obstruction and adverse prognosis afteracute coronary occlusion (7,8). In patientswith stable angina and NOCAD, CMD can beidentified by using an IMR threshold of $25 U(9,10), and an elevated IMR is linked to lowerDuke treadmill scores (10), with prognosticvalue in predicting long-term major adversecardiac events (11). However, IMR can only bedetermined during invasive coronary angi-ography by experienced operators. Thus,being able to noninvasively and convenientlyassess CMD is highly desirable for clinical riskstratification and guiding patient therapy.

Cardiac magnetic resonance (CMR) is an idealnoninvasive modality for assessing patients withangina (4,12). Adenosine stress CMR evaluatesmyocardial perfusion with high spatial resolution andaccurately detects ischemia due to obstructiveepicardial CAD (13,14). Although previous studieshave evaluated myocardial perfusion in patients withNOCAD using CMR (15–17), these studies haveincluded heterogeneous patient cohorts, withoutobjective validation against an invasive marker ofCMD; the result is conflicting findings with limiteddirect clinical applicability (15–18). There is currentlyno accepted objective diagnostic threshold forassessing CMD using CMR.

SEE PAGE 980

The goal of the present study was to validate stressperfusion CMR to objectively and noninvasively di-agnose microvascular angina, with correlation toinvasive coronary measures (FFR and IMR). We alsoexamined the underlying mechanism for impairedmyocardial perfusion reserve (MPR) in CMD, usingabsolute quantification of myocardial blood flow(MBF) at rest and during adenosine stress, as vali-dated against IMR.

METHODS

STUDY POPULATION. Fifty patients with angina andsuspected or known CAD referred for outpatient

diagnostic coronary angiography were recruitedfor study. Patients underwent CMR scans at 2commonly used clinical field-strengths: 1.5-T (n ¼ 25;Magnetom Avanto; Siemens Healthcare GmbH,Erlangen, Germany) or 3-T (n ¼ 25; Magnetom Trio, ATim System; Siemens Healthcare GmbH). We alsorecruited 20 age-matched healthy control subjects (nocardiovascular disease, no regular medications, andnormal electrocardiogram) to undergo CMR at 1.5-T(n ¼ 10) and 3-T (n ¼ 10) using the same CMR scan-ners and protocol as the study patients. Perfusionmeasures (myocardial perfusion reserve index [MPRI]and MBF) were comparable between the 1.5-T and 3-Tscans in control subjects and patients (all p > 0.50).

All study procedures were approved by a localethics committee (Reference: 13/SC/0376), and allsubjects provided written informed consent.

CMR PROTOCOL. All subjects abstained fromcaffeine for 24 h before the CMR. The CMR was per-formed by using established techniques, includingcine, adenosine stress and rest perfusion, and late-gadolinium enhancement (LGE) imaging, as previ-ously described (19) (Online Appendix). All subjectshad good hemodynamic stress response (>10 beats/min increase in heart rate and $1 adenosine-relatedsymptom [e.g., chest tightness]) (20). In addition,60% (30 of 50) of patients and all control subjects hada significant (>10 mm Hg) drop in systolic bloodpressure during stress.

INVASIVE CORONARY ANGIOGRAPHY AND PHYSIOLOGY

ASSESSMENTS. Within 7 days post-CMR, all 50 pa-tients underwent invasive coronary angiography.Quantitative coronary angiography (QCA) was alsoperformed offline by using Medcon QCA software(Medcon Ltd., Tel Aviv, Israel), as previouslydescribed (21).

FFR and IMR were measured, as described else-where (22) (Online Appendix), by operators blinded tothe research CMR. IMR (distal coronary pressure �hyperemic mean transit time) was corrected by usingthe Yong formula to account for any effects ofcollateral circulation (23).

In total, 28 patients had significant epicardialCAD ($50% visual angiographic stenosis; 23 with1-vessel CAD, 3 with 2-vessel CAD, and 2 with 3-vesselCAD). In these patients, 86% of epicardial lesions (30of 35 vessels) were functionally obstructive(FFR #0.8). The remaining 22 patients all had angio-graphic NOCAD (<50% visual stenosis), where 100%(66 of 66) of coronary arteries were FFR-negative(>0.8), and IMR was assessed in all 66 vessels.

CMR IMAGE ANALYSIS. All CMR images wereanalyzed by using the commercially available cmr42

TABLE 1 Subject Characteristics

Normal ControlSubjects(n ¼ 20)

Patients WithObstructive CAD

(n ¼ 28)

Patients WithAll NOCAD(n ¼ 22) p Value

Age, yrs 61 � 7 64 � 9 65 � 8 0.31

Body mass index, kg/m2 25 � 5 28 � 4 31 � 5 0.07

Male 13 (65) 20 (71) 14 (64) 0.82

Angina characteristics

CCS angina score – 1.9 � 0.6 1.9 � 0.5 0.84

Diamond andForrester score, %

– 57 (13–93) 56 (7–94) 0.89

Comorbidities

Ex-smoker 0 (0) 16 (57) 13 (59) 0.98

Diabetes mellitus 0 (0) 6 (21) 8 (36) 0.34

Hypertension 0 (0) 13 (46) 13 (59) 0.41

Hyperlipidemia 0 (0) 15 (54) 10 (45) 0.78

Known CAD – 15 (54) 0 (0) <0.001

Previous PCI – 7 (25) 0 (0) <0.001

Previous CABG – 0 (0) 0 (0) –

Medications

Aspirin 0 (0) 28 (100) 20 (91) 0.19

Beta-blocker 0 (0) 25 (89) 16 (72) 0.16

ACE inhibitors/ARBs 0 (0) 16 (57) 11 (50) 0.78

Statin 0 (0) 16 (57) 11 (50) 0.78

Nitrates 0 (0) 15 (54) 13 (59) 0.78

Nicorandil 0 (0) 3 (11) 4 (18) 0.68

Ranolazine 0 (0) 1 (4) 2 (9) 0.58

CMR hemodynamic data

Resting heart rate,beats/min

63 � 10 63 � 14 65 � 11 0.70

Stress heart rate,beats/min

90 � 11 93 � 10 89 � 15 0.53

Rest SBP, mm Hg 135 � 16 139 � 31 141 � 20 0.41

Stress SBP, mm Hg 130 � 11 132 � 17 130 � 17 0.65

Resting RPP,beats/min ∙ mm Hg

9,200 � 2,000 9,100 � 2,600 9,200 � 2,400 0.79

Stress RPP,beats/min∙ mm Hg

11,700 � 2600 12,100 � 3,200 11,800 � 2,900 0.24

Values are mean � SD, n (%), or mean (range). p values were determined by using an analysis of variance with aBonferroni post hoc method for continuous variables and Fisher exact test for categorical variables.

ACE ¼ angiotensin-converting enzyme; ARB ¼ angiotensin receptor blocker; CABG ¼ coronary artery bypassgrafting; CAD ¼ obstructive epicardial coronary artery disease; CCS ¼ Canadian Cardiovascular Society;CMR ¼ cardiac magnetic resonance; NOCAD ¼ nonobstructive coronary artery disease; PCI ¼ percutaneouscoronary intervention; RPP ¼ rate pressure product; SBP ¼ systolic blood pressure.

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software (Circle Cardiovascular Imaging Inc., Calgary,Alberta, Canada) (19,24). Myocardial perfusion im-ages were analyzed as previously described (19),blinded to clinical information, other CMR, andinvasive coronary data (Online Appendix). MPRI wasderived semi-quantitatively (J.M.L.) as the stress/restratio of myocardial signal intensity upslopes,normalized to the arterial input function (19). Abso-lute quantification of MBF (in milliliters per minuteper gram) was performed (A.L.) by using model-independent Fermi deconvolution of myocardialand arterial input signal intensity curves, as previ-ously described (25).

To enable correlation between perfusion measures(MPRI and MBF) and invasive coronary measure-ments (FFR and IMR) on a per-vessel basis, myocar-dial perfusion images were segmented and allocatedto each coronary artery territory according to theAmerican Heart Association’s 16-segment model, ac-counting for coronary artery dominance (as describedelsewhere [26]). Segmental MPRI and MBF valueswere then averaged for each coronary artery territoryand matched to FFR and IMR data for further anal-ysis. Left ventricular function and LGE imaging wereanalyzed as previously described (19).

STATISTICAL ANALYSIS. An optimal MPRI thresholdfor symptomatic inducible ischemia on stress perfu-sion CMR was first derived using the 28 patients withangina and obstructive epicardial CAD and the 20normal control subjects. A receiver-operating char-acteristic (ROC) curve was used with myocardiumdownstream of FFR #0.8 vessels as true-positives forischemia and normal controls as true-negatives. ThisMPRI threshold was then applied in 22 patients with3-vessel NOCAD to determine its diagnostic perfor-mance for detecting significantly impaired perfusiondue to CMD with high IMR.

All continuous variables were normally distributed,as checked by using the Kolmogorov-Smirnov test,and are expressed as mean � SD. Each patient with3-vessel NOCAD contributed 3 IMR values (total 66),and the intraclass correlation coefficient was calcu-lated to determine the need to adjust the data forclustering (27). The intraclass correlation coefficientwas very low for IMR (0.02; 95% CI: –0.09 to 0.12),indicating that the values were not strongly relatedwithin the same patient; the relations between IMRand CMR data were analyzed on a per-vessel basis.Due to the highly statistically significant comparisonsobserved throughout the study, we used a conserva-tive approach to compensate for potential multiplecomparisons and any remaining within-individualcorrelations of IMR data by reducing the threshold

p value from the conventional 0.05 to 0.01. Thisapproach likely overcompensates for the worst-casescenario of 3 fully dependent variables within thesame individual. For all analyses, p values <0.01were considered statistically significant.

Comparisons between 2 separate data groups wereperformed by using unpaired Student’s t-test. Com-parisons between $3 separate data groups were per-formed by using analysis of variance with aBonferroni post hoc method. Categorical data werecompared by using the Fisher exact test. Correlationswere assessed by using the Spearman’s rank correla-tion coefficients (rho). For ROC analysis, area under

FIGURE 1 Study Flowchart

Patients with Angina(n = 50)

Normal Controls(n = 20)

CMRCMR

Normal Controls(n = 20)

CAD patients(n = 28)

30 FFR ≤0.8 vessels 66 FFR >0.8 vesselsIMR assessed

NOCAD patients(n = 22)

Invasive coronaryangiography

Numbers represent either the number of patients or the number of coronary arteries, as

indicated. CAD ¼ coronary artery disease; CMR ¼ cardiac magnetic resonance;

FFR ¼ fractional flow reserve; IMR ¼ index of microcirculatory resistance;

NOCAD ¼ nonobstructive coronary artery disease.

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the curve (AUC) with 95% confidence intervals (CIs)are reported, as well as sensitivity, specificity, accu-racy, positive predictive values, and negative pre-dictive values where appropriate. All analyses wereperformed by using MedCalc version 12.7.8 (MedCalcSoftware, Ostend, Belgium).

RESULTS

SUBJECT CHARACTERISTICS. Subject characteristicsare summarized in Table 1. The 28 patients withobstructive epicardial CAD contributed a total of 30FFR-positive (mean FFR: 0.60; range: 0.28 to 0.79)coronary arteries to the analysis (Figure 1), whichwere also angiographically significant (75 � 3% ste-nosis) on QCA. The 22 patients with NOCAD contrib-uted a total of 66 FFR-negative vessels (mean FFR:0.92; range: 0.80 to 1.00), with minimal angiographicdisease (10 � 5%) on QCA.

Table 2 presents a summary of coronary physiologymeasures. In patients with NOCAD, IMR was notsignificantly affected by the Yong formula corrections(23) (IMR before correction: 27 � 14 U vs. IMR aftercorrection 27 � 14 U; paired p ¼ 0.30), suggestingminimal influence from collateral circulations. IMRwas not significantly correlated to FFR (rho ¼ 0.07;p ¼ 0.59).

Myocardial infarct scars were detected in 4 of 28patients with obstructive CAD on CMR LGE imaging(all <50% transmurality). Patients with NOCAD andcontrol subjects had no scars on LGE. To present atrue representation of myocardial perfusion in non-infarcted myocardium, segments with scars wereexcluded. This method did not lead to exclusion ofany patients.

PATTERNS OF MPRI IN CONTROL SUBJECTS AND

PATIENTS WITH OBSTRUCTIVE CAD AND NOCAD.

As a reference, myocardium downstream of obstruc-tive CAD (FFR #0.8) had significantly lower MPRIthan control subjects (1.2 � 0.4 vs. 2.0 � 0.3;p < 0.001). Downstream of NOCAD (FFR >0.8)vessels, MPRI correlated significantly with IMR(rho ¼ –0.67; p < 0.001) (Figure 2) and coronary flowreserve (rho ¼ 0.41; p < 0.001) (Online Figure 1)but not with FFR (rho ¼ 0.04; p ¼ 0.48).

CMD was defined as myocardium with IMR $25 Udownstream of NOCAD (FFR >0.8) vessels, as previ-ously described (28). Myocardium with IMR <25 Uhad similar MPRI compared with normal controlsubjects (1.9 � 0.4 vs. 2.0 � 0.3; p ¼ 0.49) (Figure 3A).In contrast, myocardium with IMR $25 U hadimpaired MPRI (1.2 � 0.3), similar to myocardiumdownstream of obstructive (FFR #0.8) CAD in pa-tients with angina (1.2 � 0.3 vs. 1.2 � 0.4; p ¼ 0.61).

MPRI THRESHOLDS FOR ASSESSING MICROVASCULAR

INDUCIBLE ISCHEMIA. An MPRI threshold of 1.4 wasoptimal for detecting inducible myocardial ischemiafrom obstructive (FFR #0.8) CAD (AUC: 0.95; 95% CI:0.85 to 0.99; p < 0.001). Myocardium downstream ofobstructive (FFR #0.8) CAD served as true-positives;normal myocardium of control subjects served astrue-negatives.

This threshold for inducible ischemia was thenapplied to patients with 3-vessel NOCAD. The MPRIthreshold of 1.4 also accurately detected inducibleischemia due to CMD (IMR $25 U) (AUC: 0.90; 95% CI:0.80 to 0.96; p < 0.0001), with a specificity of 95%(95% CI: 82% to 99%), a sensitivity of 89% (95% CI:78% to 98%), and accuracy of 92% (95% CI: 80% to99%) (Figure 3B). An MPRI threshold of 1.6 yielded ahigh negative predictive value (95%; 95% CI: 79% to99%) and sensitivity (94%; 95% CI: 77% to 99%) forruling out significant inducible ischemia due to CMD.

Downstream of nonobstructive FFR $0.8 coronaryarteries in patients with obstructive CAD (30 vessels),the same MPRI threshold of 1.4 also accuratelydetected CMD (IMR $25 U) (AUC: 0.89; 95% CI: 0.81 to0.96; p < 0.001).

TABLE 2 Coronary Physiology and CMR Parameters

Normal ControlSubjects(n ¼ 20)

Patients WithObstructive CAD

(n ¼ 28)

Patients WithAll NOCAD(n ¼ 22)

pValue

CMR parameters

LV EDVi, ml/m2 75 � 11 78 � 11 77 � 13 0.40

LV ESVi, ml/m2 28 � 8 32 � 12 30 � 12 0.26

LV SVi, ml/m2 47 � 6 46 � 10 47 � 12 0.91

LV ejection fraction, % 62 � 5 59 � 9 61 � 10 0.35

LV mass index, g/m2 58 � 10 59 � 11 56 � 13 0.25

Mean LV wallthickness, mm 7.9 � 0.6 7.5 � 1.5 7.4 � 0.7 0.23

MPRI 2.0 � 0.3 1.2 � 0.4* 1.6 � 0.5*† <0.001

Rest MBF 1.1 � 0.2 1.1 � 0.3 1.1 � 0.2 0.80

Stress MBF 3.0 � 0.5 1.4 � 0.4* 2.1 � 0.8*† <0.001

LGE, % 0 � 0 10 � 5* 0 � 0† <0.001

Coronary physiology

FFR – 0.60 (0.28–0.79) 0.92 (0.80–1.00) <0.001

IMR, U – 27 � 15 27 � 14 0.91

IMRcorr, U – 21 � 11 27 � 14 0.05

Distribution of FFR and IMR

Total vesselsassessed

– 60 (71) 66 (100) 0.17

FFR <0.8 andIMR $25 U

– 10 (17) 0 (0) <0.001

FFR <0.8 andIMR <25 U

– 20 (33) 0 (0) <0.001

FFR $0.8 andIMR $25 U

– 11 (18) 28 (42) <0.001

FFR $0.8 andIMR <25 U

– 19 (32) 38 (58) <0.001

Values are mean� SD, mean (range), or n (%). All p values for CMR parameters were determined by using an analysisof variance with Bonferroni post hoc method. All p values for coronary physiology were determined by using anunpaired Student’s t-test. *p < 0.01 compared with control subjects. †p < 0.01 compared with patients with CAD.

EDVi ¼ end-diastolic volume index; ESVi ¼ end-systolic volume index; FFR ¼ fractional flow reserve;IMR ¼ index of microvascular resistance; IMRcorr ¼ Yong formula–corrected IMR; LGE ¼ late gadoliniumenhancement; LV ¼ left ventricular; MBF ¼ myocardial blood flow; MPRI ¼ myocardial perfusion reserve index;SVi ¼ stroke volume index; other abbreviations as in Table 1.

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PATTERNS OF MBF IN CONTROL SUBJECTS AND

PATIENTS WITH OBSTRUCTIVE CAD AND NOCAD.

To further understand the impaired MPRI observed inNOCAD, absolute quantification of MBF was per-formed at rest and during stress. Resting MBF wassimilar between normal control subjects, myocardiumdownstream of epicardial CAD, myocardium down-stream of NOCAD with IMR <25 U and myocardiumdownstream of NOCAD with IMR $25 U, p ¼ 0.76(Figure 4A).

During adenosine stress, myocardium downstreamof obstructive epicardial CAD (FFR #0.8) had signifi-cantly lower stress MBF than normal control subjects(1.4 � 0.4 ml/min/g vs. 3.0 � 0.5 ml/min/g; p <

0.0001) (Figure 4B). Downstream of NOCAD (FFR>0.8), myocardium with IMR $25 U had a similardegree of impairment in stress MBF as myocardiumdownstream of obstructive epicardial CAD (1.5 �0.4 ml/min/g vs. 1.4 � 0.4 ml/min/g; p ¼ 0.14).Interestingly, although myocardium with IMR <25 Uhad higher stress MBF (2.6 � 0.7 ml/min/g) than bothmyocardium with IMR $25 U (1.5 � 0.4 ml/min/g) andmyocardium downstream of obstructive CAD (1.4 �0.4 ml/min/g; all p < 0.001), it was still significantlyblunted compared with that of healthy age-matchedcontrol subjects (2.6 � 0.7 ml/min/g vs. 3.0 �0.5 ml/min/g; p < 0.01).

The quantitatively derived MPR (stress MBF /resting MBF) showed a similar pattern as for semi-quantitatively derived MPRI (Figure 4C). On ROCanalysis, semi-quantitative MPRI, quantitative MPR(stress MBF / resting MBF), and stress MBF alone allhad similar diagnostic performance for detectingimpaired perfusion due to CMD (IMR $25 U) (AUC0.90 vs. AUC 0.87 vs. AUC 0.91, respectively; allcomparisons p > 0.70). Figure 5 presents the assess-ment of a patient with microvascular angina usingCMR MPRI.

IDENTIFICATION OF SUBTLE DEFICITS IN STRESS

MBF IN PATIENTS WITH NOCAD. In patients withNOCAD (FFR >0.8) and normal IMR (<25 U) butblunted stress MBF compared with control subjects(Figure 4B), stress MBF was not significantly corre-lated to IMR (range: 10 to 25 U; rho ¼ 0.09;p ¼ 0.58). This impaired augmentation of stressMBF suggests possible mild or early CMD, insensi-tive to detection with the use of ratio-based mea-sures (MPRI and quantitative MPR). A stress MBFthreshold of 2.3 ml/min/g distinguished this mildCMD from normal control subjects with 100%specificity (95% CI: 83% to 100%) and 100% positivepredictive value (95% CI: 81% to 100%), (AUC 0.76;95% CI: 0.63 to 0.86; p < 0.0001).

DISCUSSION

The present study used adenosine stress CMR toobjectively assess inducible ischemia due to CMD inpatients with angina and NOCAD, as validated againstthe IMR. Impairments in MPR due to CMD (IMR $25 U)were driven by blunted augmentation of hyperemicMBF and were comparable to ischemic myocardiumdownstream of FFR-positive obstructive CAD (5).An MPRI threshold of 1.4 accurately detectedsignificant CMD-related hypoperfusion. Furthermore,a quantitatively derived stress MBF threshold of2.3 ml/min/g can detect mild CMD. Integration ofMPRI and MBF assessment into the clinical CMRworkflow can provide a noninvasive approachfor evaluating both epicardial and microvascularCAD in patients with angina (Central Illustration),which deserves further validation in an all-comerspopulation.

FIGURE 2 Relations Between MPRI and IMR in Patients With Angina and NOCAD

4

3

2

MPR

I

1

00 20

rho = –0.67p < 0.001

40IMR

60 80

Each dot represents data from a single vessel (66 vessels from 22 patients with NOCAD).

Rho is the Spearman’s correlation coefficient. MPRI ¼ myocardial perfusion reserve

index; other abbreviations as in Figure 1.

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MICROVASCULAR INDUCIBLE ISCHEMIA IS CHALLENGING

TO DETECT VISUALLY. In stress perfusion CMR,obstructive epicardial CAD leads to regional perfusiondefects that can be visually distinguished from areas

FIGURE 3 Patterns of MPRI in Normal Control Subjects and Patient

3

NS2

MPR

I

1

0Normal

ControlsIMR <25 IMR ≥25 FFR ≤0.8

FFR >0.8

NS *

*A

(A) Myocardium downstream FFR >0.8 vessels with IMR <25 U (38 ves

myocardium downstream FFR >0.8 vessels with IMR $25 U (28 vessel t

obstructive (FFR #0.8) epicardial CAD (30 vessel territories in 28 patien

NOCAD (66 vessel territories in 22 patients) for detecting ischemia related

All bars represent mean � 1 SD. Area under the curve, p < 0.0001. Bra

p > 0.10. Abbreviations as in Figures 1 and 2.

without perfusion defects. In the absence of obstruc-tive epicardial CAD, CMD may also induce myocardialhypoperfusion, but this process rarely results inregional or global perfusion defects that can beassessed visually. Furthermore, qualitative assess-ment of hypoperfusion as a binary “yes/no” outputcannot inform about the severity or the distributionof microvascular disease.

Advances in CMR image post-processing methodsenabled detailed examination of MPR and MBF,which are well validated for detecting obstructiveCAD (13,29,30). However, because visual assessmentof perfusion images is already accurate for detectingobstructive CAD in routine clinical workflow, thesemore sophisticated post-processing methods havelargely remained in the realm of research. Fordetecting microvascular inducible ischemia, howev-er, these more advanced methods are invaluablebecause visual assessment is not possible.

In previous studies, microvascular ischemia haslargely been a diagnosis of exclusion, rather thanbeing objectively demonstrated (15–17), due to eitherthe complete lack of validation against invasivereference standards for CMD (15,16,18) or validationagainst invasive markers that are not specific for themicrocirculation, such as coronary flow reserve orcoronary reactivity testing (17). Moreover, non-obstructive coronary arteries in previous studies were

s With Obstructive CAD and Patients With All NOCAD

100

80

60

MPRI 1.4 accurately detectsmicrovascular ischemiain patients with NOCAD

Specificity 95%89%92%

SensitivityAccuracy

Sens

itivi

ty

40

20

00 20 40

100-Specificity

AUC 0.90 [0.80-0.96]

60 80 100

B

sel territories in 17 patients) had MPRI similar to control subjects;

erritories in 15 patients) had impaired MPRI, similar to downstream

ts). (B) The diagnostic performance of MPRI in patients with all

to coronary microvascular dysfunction (FFR >0.8 and IMR$25 U).

ckets include 95% confidence intervals. *p < 0.01; NS denotes

FIGURE 4 MBF Patterns in Patients and Control Subjects

NormalControls

IMR <25 IMR ≥25 FFR ≤0.8FFR >0.8

NS

4

Rest

MBF

(ml/m

in/g

)

3

2

1

0NormalControls

IMR <25 IMR ≥25 FFR ≤0.8FFR >0.8

NS

4 *

*

Stre

ss M

BF (m

l/min

/g)

3

2

1

0Normal

ControlsIMR <25 IMR ≥25 FFR ≤0.8

FFR >0.8

NS

NS4*

*

MPR

3

2

1

0

A B C

Patterns of myocardial blood flow (MBF) (A) at rest, (B) during adenosine stress, and (C) myocardial perfusion reserve (MPR: stress MBF / rest MBF) in normal control subjects

and patients. The number of patients and vessel territories are as per Figure 3. All bars represent mean� SD. *p< 0.01; NS denotes p> 0.10. Other abbreviations as in Figure 1.

FIGURE 5 Assessment of Microvascular Inducible Ischemia Using CMR

This 68-year-old male patient with angina had a normal resting electrocardiogram, and an

exercise electrocardiogram was aborted early due to severe angina. A single photon-emission

computed tomography scan was negative for inducible ischemia, and dobutamine stress

echocardiography showed possible inferior wall hypokinesia during stress. He was referred for

invasive coronary angiography. On 3-T CMR pre-angiography (normal ejection fraction: 60%;

no regional wall motion abnormalities), the patient had no obvious regional reversible

perfusion defects, and nomyocardial infarction on late gadolinium enhancement (LGE) imaging,

suggesting no obstructive epicardial CAD. However, the MPRI was globally impaired (<1.4),

corresponding to 3 nonobstructive coronary arteries with elevated IMR (>25 U) on invasive

angiography. This case shows that CMR may provide an objective one-stop assessment of

microvascular ischemia, potentially avoiding multiple tests and invasive procedures. LAD ¼ left

anterior descending artery; LCx ¼ left circumflex artery; RCA ¼ right coronary artery; other

abbreviations as in Figures 1 and 2.

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defined according to angiographic appearances alone(12,15–18), which informs little about their physio-logical significance. This limitation of previousstudies introduces disease heterogeneities, leading toconflicting results (15–18), which render the deriva-tion of objective diagnostic thresholds highly chal-lenging thus far.

MICROVASCULAR ISCHEMIA DETECTION. As arepresentative threshold for inducible ischemia, anMPRI cutoff based on myocardium downstream ofobstructive epicardial CAD was established, definedusing the clinically accepted FFR (#0.8) method (5).This threshold (MPRI 1.4) then accurately detectedsignificantly impaired myocardial perfusion due toCMD in a separate group of patients with angiograph-ically and physiologically (FFR >0.8) nonobstructivecoronary arteries, as referenced to invasive IMR. Inthis way, we adjudicated that myocardial perfusiondeficits were related to an invasive marker of CMD,enabling the derivation of an objective threshold onCMR for diagnosing microvascular ischemia.

The impaired MPR downstream of NOCAD withhigh IMR ($25 U) being similar to downstreamFFR #0.8 CAD supports the presence of microvas-cular inducible ischemia that could account forangina symptoms. This perfusion reserve impairmentwas driven by blunted hyperemic MBF, with normalresting MBF, indicating a functional vasodilatorydeficit, despite achieving good hemodynamicresponse to adenosine stress in all these patients.Overall, it would seem that when myocardial perfu-sion becomes significantly impaired (MPRI <1.4),symptoms of angina would ensue, whether thisoutcome is due to obstructive epicardial CAD or cor-onary microvascular dysfunction.

CENTRAL ILLUSTRATION ClinicalDiagnostic PathwayUsingCMRforEpicardial andMicrovascular CAD

Visual assessment:Reversible perfusion defect?

Consider ObstructiveEpicardial CAD

YES

Semi-quantitativeMPRI assessment

NO

Stress perfusion CMR

Patients with angina

ConsiderMicrovascular CAD

MPRI <1.4 MPRI 1.4-1.6 MPRI >1.6

Absolute Quantificationof Stress MBF

Consider MildMicrovascular CAD

Stress MBF ≤2.3 Stress MBF >2.3

Significant Epicardial andMicrovascular CAD Unlikely

Liu, A. et al. J Am Coll Cardiol. 2018;71(9):969–79.

A potential integrated clinical pathway for diagnosing both epicardial and microvascular coronary artery disease (CAD) using noninvasive

cardiac magnetic resonance (CMR). Using this pathway, patients with obstructive epicardial CAD can be diagnosed on stress perfusion CMR

according to conventional visual assessment. Patients without significant visual perfusion defect on CMR can undergo semi-quantitative

myocardial perfusion reserve index (MPRI) assessment for microvascular CAD. Patients with an MPRI <1.4 have a high likelihood of having

significant microvascular CAD; an MPRI >1.6 makes this diagnosis unlikely. For patients with an MPRI between 1.4 and 1.6, more detailed

assessment of stress myocardial blood flow (MBF) can enable the detection of milder forms of microvascular CAD.

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Intriguingly, myocardium without significantepicardial CAD (FFR >0.8) or CMD (IMR <25 U) stillhad blunted stress MBF compared with that of normalcontrol subjects. Here, CMR detects changes in MBFand may be sensitive to early or mild changes in CMD.Furthermore, this possible mild CMD in patients withstable angina was insensitive to detection with theuse of ratio-based measures such as MPRI or quanti-tative MPR, which remained indistinguishable fromnormal (possibly due to the subtle nature of the

findings). The underlying mechanisms for thisobservation, including structural (e.g., microvascularrarefaction) and/or functional (e.g., vasodilatoryhyporeactivity) abnormalities, deserve furtherinvestigation. Absolute quantification of MBF repre-sents a strength of CMR in the comprehensive,noninvasive assessment of these patients.

CMD is classically described as a global phenome-non across the myocardium (3). Although thisdescription is consistent with our results in patients

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with NOCAD and 3-vessel high IMR ($25 U) who hadglobally impaired MPRI with little regional variations,approximately one-half of our patients with NOCADhad a combination of vessels with high IMR and vesselswith normal IMR. This interesting finding revealed acoronary-specific distribution of microvasculardysfunction in some patients; in fact, as the number ofvessels with high IMR increased in each patient, therewas progressive worsening of the global MPRI. Thisoutcome may explain the heterogeneities in myocar-dial perfusion seen in previous studies, in which pa-tients with angiographic NOCAD but varyingdistribution of CMD may have been studied (15–17).Clinically, the knowledge of single-vessel versusmultivessel CMD may offer better risk stratificationand disease monitoring tailored to the individual pa-tient. This concept deserves further investigation.CLINICAL POTENTIAL OF CMR-BASED ASSESSMENT

OF EPICARDIAL AND MICROVASCULAR CAD.

Because stress perfusion CMR is excellent for rulingout obstructive epicardial CAD (31), integration ofMPRI assessment may enable a dual evaluation ofepicardial CAD (visual analysis) and microvasculardysfunction (MPRI/MBF) in a single CMR scan(Central Illustration). MPRI can be assessed by usingcommercially available software for direct clinicalapplication, and stress MBF may enable the detectionof subtle microvascular dysfunction, when the post-processing methods become available beyond expe-rienced centers (12,25). The prognostic implications ofthese approaches and their roles in guiding clinicalmanagement of patients with angina are the subjectof active research.

There are 3 major clinical dilemmas surroundingpatients with angina and NOCAD. First, objectivelydiagnosing microvascular angina is challenging due tothe lack of noninvasive reference standard tests inclinical practice (4). Second, even when the clinicalsuspicion of microvascular angina is high, the clinicianis hampered by a limited armamentarium of disease-modifying therapies for CMD. Patients are thereforeeither started empirically on antianginal medicationsor not treated at all. Third, there is currently a lack ofobjective methods for disease monitoring; hence, thetrue natural history of CMD progression in the clinicalarena remains unclear. Objective diagnostic thresh-olds using CMR (or IMR) can offer patients withmicrovascular angina an objective explanation fortheir symptoms, which can improve psychologicalwell-being. For clinicians, these markers may allowthem to provide a more confident diagnosis for thepatient, a firmer indication for commencing medicaltherapy, and potentiate the development and testing

of novel therapies for microvascular ischemia. Inaddition to monitoring the changes in symptoms overtime, which can be subjective, MPRI may provide anobjective disease-monitoring tool in patients withangina and NOCAD. The prognostic values of MPRI andMPRI-guided therapy are important topics of activeongoing research.STUDY LIMITATIONS AND FUTURE DIRECTIONS.

This study was conducted in a single tertiary-carecenter with a relatively small number of patients withNOCAD, although the 3-vessel assessment of coronaryphysiology (IMR and FFR) with matching multi-parametric CMR data is unique. Admittedly, there iscurrently no true “gold standard” marker for myocar-dial ischemia, and this fact remains a limitation ofmostsimilar studies. In this study, CMR was chosen due toits high spatial resolution for assessing myocardialperfusion, and IMR was used as a reproducible inva-sive marker for CMD (28). The combination of highIMR $25 U and impaired MPRI, similar to downstreamof significant FFR-positive epicardial CAD, stronglysupported the presence of microvascular inducibleischemia in patients with NOCAD. Although CMRperfusion imaging achieved high diagnostic perfor-mance for diagnosing microvascular ischemia in thisstudy, a CMR-based comprehensive diagnosticpathway that enables pre-angiography clinicaldecision-making in patients with angina and NOCADdeserves further validation in a larger prospectivestudy. Future studies using position emission tomog-raphy and advanced metabolic imaging (e.g., hyper-polarized CMR imaging [32]), as well as other invasivemethods (e.g., Doppler wire–based techniques), maybe further informative for defining cellular myocardialischemia in the context of CMD.

CONCLUSIONS

In angina patients with NOCAD, CMR can objectivelyand noninvasively assess microvascular angina. ACMR-based combined diagnostic pathway for bothepicardial and microvascular CAD deserves furtherclinical validation.

ACKNOWLEDGMENT The authors thank Ms. NatalieBrechin for her support with patient recruitment.

ADDRESS FOR CORRESPONDENCE: Dr. Vanessa M.Ferreira, Oxford Centre for Clinical Magnetic Reso-nance Research, Division of Cardiovascular Medicine,Radcliffe Department of Medicine, University ofOxford, John Radcliffe Hospital, Oxford OX3 9DU,United Kingdom. E-mail: vanessa.ferreira@cardiov.ox.ac.uk.

PERSPECTIVES

COMPETENCY IN PATIENT CARE AND PROCEDURAL

SKILLS: In patients with angina and nonobstructive

coronary atherosclerosis (FFR >0.8), stress CMR can di-

agnose microvascular angina in viable myocardium using

an MPRI threshold of 1.4, as validated against an

elevated invasive IMR ($25 U). The degree of impaired

perfusion is similar to that in patients with angina due to

obstructive CAD.

TRANSLATIONAL OUTLOOK: Further research is

required to determine the prognostic implications of MPRI

thresholds to guide therapy and monitor patients for

coronary microvascular dysfunction.

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KEY WORDS cardiac magnetic resonance,index of microcirculatory resistance,inducible ischemia, microvasculardysfunction, myocardial perfusion reserveindex

APPENDIX For an expanded Methods sectionand supplemental figure, please see the onlineversion of this paper.