Journal of the American College of Cardiology Vol. 59, No. 7, 2012© 2012 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00

Coronary Artery Disease

High Prevalence of a Pathological Responseto Acetylcholine Testing in Patients With StableAngina Pectoris and Unobstructed Coronary ArteriesThe ACOVA Study (Abnormal COronary VAsomotion inpatients with stable angina and unobstructed coronary arteries)

Peter Ong, MD,* Anastasios Athanasiadis, MD,* Gabor Borgulya, MD, MSC,†Heiko Mahrholdt, MD,* Juan Carlos Kaski, MD, DSC,‡ Udo Sechtem, MD*

Stuttgart, Germany; and London, United Kingdom

Objectives This study aimed at determining the prevalence of epicardial and microvascular coronary spasm in patients withanginal symptoms, despite angiographically normal coronary arteries.

Background Despite a typical clinical presentation with exercise-related anginal symptoms (chest pain or dyspnea) with orwithout occasional attacks of resting chest pain suggestive of coronary artery disease, 40% of patients undergo-ing diagnostic angiography have normal or “near” normal coronary arteriograms. Many of these patients aregiven a diagnosis of noncardiac chest pain, and some are considered to have microvascular angina. However,we speculate that abnormal coronary vasomotion (reduced vasodilatation with exercise � reduced coronary flowreserve and/or vasospasm at rest) might also represent a plausible explanation for the symptoms of the patient.

Methods This was a prospective study in 304 consecutive patients (50% men, mean age 66 � 10 years) with exertionalanginal symptoms undergoing diagnostic angiography. A total of 139 patients (46%) had �50% coronary arterydisease in at least 1 coronary artery, 21 patients (7%) had luminal narrowings ranging from �20% to 49%, and144 patients (47%) had normal coronary arteries or only minimal irregularities (�20% diameter reduction).

Results One hundred twenty-four patients of the latter (86%) underwent intracoronary acetylcholine (ACH) testing, whichelicited coronary spasm in 77 patients (62%), 35 patients (45%) with epicardial spasm (�75% diameter reduc-tion with reproduction of the symptoms of the patient) and 42 patients (55%) with microvascular spasm (repro-duction of symptoms, ischemic electrocardiographic changes, and no epicardial spasm).

Conclusions Nearly 50% of patients undergoing diagnostic angiography for assessment of stable angina had angiographicallynormal or near normal coronary arteriograms. The ACH test triggered epicardial or microvascular coronaryspasm in nearly two-thirds of these patients. Our results suggest that abnormal coronary vasomotion plays apathogenic role in this setting and that the ACH test might be useful to identify patients with cardiac symptoms,despite normal coronaries. (Abnormal Coronary Vasomotion in Patients With Suspected CAD But Normal Coro-nary Arteries; NCT00921856) (J Am Coll Cardiol 2012;59:655–62) © 2012 by the American College ofCardiology Foundation

Published by Elsevier Inc. doi:10.1016/j.jacc.2011.11.015

Recent studies have shown that approximately 40% ofpatients undergoing diagnostic coronary angiography fortypical exertional chest pain (i.e., stable angina) have com-pletely normal arteries or nonobstructive coronary artery

From the *Robert-Bosch-Krankenhaus, Department of Cardiology, Stuttgart, Ger-many; †St. George’s University of London, Clinical Trials Unit, London, UnitedKingdom; and the ‡Cardiovascular Sciences Research Centre, St. George’s Universityof London, London, United Kingdom. All authors have reported that they have norelationships relevant to the contents of this paper to disclose. Drs. Kaski and Sechtemcontributed equally to this study.

Manuscript received August 16, 2011; revised manuscript received October 20,2011, accepted November 1, 2011.

disease (CAD) (1–3). The presence of normal or near-normal coronary arteriograms often leads the managingphysician to make a diagnosis of noncardiac chest pain.

See page 663

However, cardiac mechanisms such as increased coronaryartery vasomotion (i.e., epicardial or microvascular coronaryspasm) (4,5) and/or abnormal coronary microvascularvasodilatory function, as seen in patients with microvascularangina (6), can be responsible for the occurrence of anginal

symptoms in these patients. Indeed, several studies have

s

656 Ong et al. JACC Vol. 59, No. 7, 2012Pathological ACH Response in Stable Angina February 14, 2012:655–62

shown that both abnormal epi-cardial and abnormal microvas-cular vasomotor responses canlead to myocardial ischemia in pa-tients without atherosclerotic cor-onary artery obstructions (7–10).It is not known, however, howoften this mechanism can explainthe presence of anginal symp-toms in individuals referred todiagnostic angiography for theassessment of stable angina who

are found to have nonobstructive CAD or completelynormal coronary arteriograms. Therefore, the present studysought to assess the prevalence of epicardial and microvas-cular coronary spasm among patients presenting with stableanginal symptoms but who had angiographically normalcoronary arteries or only minimal irregularities (�20%narrowings).

Methods

Patients. The present study, ACOVA (Abnormal COronaryVAsomotion in patients with stable angina and unob-structed coronary arteries), is a prospective trial involving376 consecutive patients undergoing diagnostic coronaryangiography between December 2007 and December 2008,

Abbreviationsand Acronyms

ACH � acetylcholine

CAD � coronary arterydisease

ECG � electrocardiogram/electrocardiographic

LCA � left coronary artery

RCA � right coronaryartery

Figure 1 Study Flow Chart

The flow chart visualizes the number of patients in the respective groups accordinin patients with normal or “near” normal coronary arteries. CAD � coronary artery

for the assessment of stable angina pectoris. For inclusion inthe study, patients had to have exercise-related anginalsymptoms suggestive of CAD (chest pain or dyspnea, withor without occasional attacks of resting chest pain) and a leftventricular ejection fraction �50%, as assessed by leftventriculography. Patients with acute coronary syndrome,valvular heart disease, cardiomyopathy, myocarditis, chronicobstructive pulmonary disease, chronic renal failure, or ahistory of dysphagia or gastroesophageal reflux were notincluded in the study. Furthermore, we excluded patientswith a history compatible with Prinzmetal’s variant angina(i.e., purely rest angina, despite a preserved exercise capacity,and documented transient ST-segment elevation duringchest pain, relieved spontaneously or by nitrates and/orangiographic evidence of focal coronary spasm). Traditionalcardiovascular risk factors, including hypertension, diabetes,hypercholesterolemia, current cigarette smoking, and a pos-itive family history for cardiovascular disease (i.e., myocar-dial infarction or stroke in a first-degree relative �65 yearsof age), were recorded in every patient.

Three hundred four patients (80%) were found to beeligible for inclusion in the study. They were divided into 3groups according to the degree of epicardial narrowing onangiography: Group 1: 0% to 20% narrowings (n � 144),Group 2: �50% stenosis (n � 139), Group 3: �20% to 49%tenosis (n � 21) (Fig. 1). Our study focused on groups 1

e degree of epicardial stenosis and the result of the acetylcholine (ACH) teste.

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657JACC Vol. 59, No. 7, 2012 Ong et al.February 14, 2012:655–62 Pathological ACH Response in Stable Angina

and 2 only. Thus, we report results on 283 patients (137men; mean age 66 � 10 years), of whom 240 (85%)nderwent exercise stress testing before angiography, whichhowed ischemic electrocardiographic (ECG) changes in51 (53%) patients. The remainder underwent diagnosticoronary angiography on the basis of a high pre-test likelihoodor obstructive CAD. The study complied with the Declara-ion of Helsinki, and the study protocol was approved by theocal ethics committee. All patients gave written informedonsent before study entry. Trial registry information is givenfter abstract.tudy protocol. The study flowchart is shown in Figure 1.atients with normal coronary arteries or only minimal

rregularities on baseline diagnostic angiography (Group 1)nderwent standardized intracoronary acetylcholine (ACH)rovocation for the assessment of coronary vasomotor func-ion (ACH test). We have previously reported our standard-zed procedure for the assessment of coronary vasomotorbnormalities in our institution (4,11). As per our institu-ional protocol, cardiovascular medications able to affectoronary vasomotor responses (calcium channel blockers,eta blockers, long acting nitrates) were discontinued ateast 24 h before coronary angiography. Sublingual glycerylrinitrate administration, however, was permitted for theelief of chest pain at all times. None of the patients requiredhis treatment �4 h before angiography.

Incremental doses of ACH 2, 20, 100, and 200 �g11,12) were administered over a period of 3 min each intohe left coronary artery (LCA) via the angiographic catheter.n the patients who did not develop symptoms or ischemicCG changes, we subsequently injected ACH into the

ight coronary artery (RCA) (80 �g ACH over 3 min).fter the administration of ACH or when chest pain and/or

oronary spasm developed, 0.2 mg glyceryl trinitrate (Per-inganit, Schwarz Pharma, Monheim, Germany) were in-ected into both the LCA and RCA. Heart rate, bloodressure, and the 12-lead-ECG were continuously moni-ored during ACH testing.

easurements. The angiographic images were quantita-ively analyzed with QCA-CMS (version 7.0, Medis-oftware, Leiden, the Netherlands). The following binaryariables were obtained for analysis: reproduction of thesual chest pain of the patient, presence of coronary vaso-onstriction �75%, and ischemic ECG changes (i.e., ST-egment depression or ST-segment elevation of �0.1 mVr T-wave peaking in at least 2 contiguous leads).Both the location and type of epicardial spasm (i.e., focal

s. diffuse) were also assessed (13). “Focal” spasm wasefined as a circumscribed transient vessel narrowing withinhe borders of 1 isolated coronary segment as defined by themerican Heart Association (13). “Diffuse” spasm wasiagnosed when the vessel narrowing was observed in �2djacent coronary segments. Proximal spasm was defined asasoconstriction occurring in segments 1, 5, 6, or 11.

id-vessel spasm was recorded when occurring in segments

, 3, or 7, whereas distal spasm was defined as that occurring p

n segments 4, 8, 9, 10, 12, 13, 14, or 15. No incidents ofatheter-induced spasms were observed.

efinition of coronary spasm on ACH testing. TheCH test was considered “positive” and indicative of

picardial coronary spasm, in the presence of �75% focal oriffuse coronary artery diameter reduction, compared withhe relaxed state achieved with the intracoronary adminis-ration of glyceryl trinitrate, associated with a reproductionf the symptoms of the patient (Figs. 2A and 2B) (4). Forhe definition of microvascular spasm, we used the criteriastablished by Mohri et al. (5). Hence, in our study, weiagnosed microvascular spasm when the injection ofCH reproduced the symptoms usually experienced by

he patient and triggered ischemic ECG changes (i.e.,T-segment depression or ST-segment elevation of �0.1V or T-wave peaking in at least 2 contiguous leads), in

he absence of epicardial spasm (�75% diameter reduc-ion) (Figs. 2C and 2D) (5).tatistical analysis. Data analysis was carried out withPSS (version 16.0, SPSS, Inc., Chicago, Illinois). Resultsre expressed as mean � SD. The t test was used to compareontinuous variables. For values without normal distribu-ion, median and interquartile ranges are stated, and the

ann-Whitney U test was used for analysis. The Fisher’sxact test was used for categorical variables. After univariatenalysis, multivariate logistic regression analysis was per-ormed in a forward likelihood fashion to identify indepen-ent predictors for obstructive CAD as well as abnormaloronary vasomotion. A 2-tailed p value of �0.05 wasonsidered statistically significant.

esults

linical characteristics. The clinical characteristics of allatients included in the study (i.e., type of anginal symp-oms, cardiovascular risk factors, and their response tooninvasive exercise stress testing) are shown in Table 1.nivariate and multivariate analysis comparing patientsith and without CAD are shown in Tables 1 and 2,

espectively. Compared with patients in Group 1, thoseith obstructive CAD (Group 2) were more likely to beale and older. They also had a higher prevalence of

ypercholesterolemia. In addition, they more often com-lained of purely effort-induced chest pain than effort chestain or dyspnea with occasional attacks of chest pain at rest.oreover, they showed ischemic ECG changes during non-

nvasive stress testing more often than patients in Group 1p � 0.01, respectively).

CH testing. The ACH test was performed in 124 of the44 patients in Group 1 (86%). In 20 patients, the test couldot be performed due to logistic reasons. There were noerious complications during ACH testing (e.g., myocardialnfarction, refractory spasm, sustained ventricular arrhyth-

ias, or need for resuscitation). Transient atrioventricularlock was frequently observed and occurred mostly during

rovocation of the RCA; it always resolved within seconds

658 Ong et al. JACC Vol. 59, No. 7, 2012Pathological ACH Response in Stable Angina February 14, 2012:655–62

after reducing the speed of the ACH injection, due to theshort half-life of ACH. Coronary spasm was seen in 77patients (62%). Thirty-five (45%) patients had epicardialcoronary spasm, and 42 had microvascular spasm (55%)(Fig. 1).

Among patients with epicardial spasm, 30 (86%) had diffuseand 5 (14%) had focally pronounced spasm. Epicardial spasmwas usually confined to the distal segments of the coronaryarteries (diffuse spasm in 25, and focal in 1 patient; 74%).Proximal segment spasm was only seen in 1 patient (focal),mid-coronary segment spasm was seen in 3 (all focal), andspasm in all segments was seen in 5 cases (all diffuse).

Fifty-two percent of the patients with microvascular spasmhad �25% epicardial constriction during ACH-provocation.Intermediate constriction (25% to 50% epicardial narrowing)was seen in 36%, and the remaining 12% showed epicardialconstriction between 50% and 74%.

The ACH test was negative according to our definitionsin 47 patients (38%). Twenty-nine of these patients, how-

Figure 2 2 Representative Patients

The upper panels show left coronary artery angiograms and electrocardiograms (Erowing of the left anterior descending coronary artery (wraps around the apex) duriand resolution of both findings after intracoronary nitroglycerin (B). The lower pansion the patient had reproduction of chest pain and ischemic ECG changes but nochanges resolved (D). Please see the accompanying Online Video.

ever, reported some chest pain (n � 14), had ischemic ECG

changes (n � 7), or had diffuse asymptomatic epicardialnarrowing �75% (n � 8) during the test.

Univariate analysis revealed that, compared with patientswith a “negative” ACH test (n � 47), those with evidenceof abnormal coronary vasomotion (n � 77) were more likelyto be female. Furthermore, they more often had effort-induced chest pain, and they also had a higher prevalence ofa positive family history for cardiovascular disease, com-pared with patients with a “negative” ACH test (Table 3).On multivariate analysis, the same variables (female gender,effort-induced chest pain, and a positive family history) wereidentified as significant independent predictors for abnor-mal coronary vasomotion (Table 2). Because diabetes andhypertension have long been recognized to be associatedwith structural changes in the microvasculature, both vari-ables were included into the multivariate analysis, althoughthey did not reach statistical significance on univariateanalysis. Moreover, the presence of both hypertension anddiabetes was tested. Either alone or in combination, these

a patient with epicardial spasm. Note the diffuse but distally accentuated nar-tylcholine infusion together with ischemic ECG shifts in the inferior leads (A)w an example of a patient with microvascular spasm. During acetylcholine infu-

rdial vasoconstriction (C). After intracoronary nitroglycerin, chest pain and ECG

CGs) inng aceels shoepica

variables did not reach statistical significance in the multi-

659JACC Vol. 59, No. 7, 2012 Ong et al.February 14, 2012:655–62 Pathological ACH Response in Stable Angina

variate analysis, which was independent of the selectionprocedure.

No significant differences were found with regard to clinicalpresentation and cardiovascular risk factors, when patients withepicardial and microvascular spasm were compared.

Discussion

We found a high prevalence of patients with normal or“near” normal coronary arteriograms among patients withstable angina referred for diagnostic coronary angiography,as previously reported by other investigators (1–3,14). Thenovel finding in our study, however, is the high prevalenceof epicardial and coronary microvascular spasm in this groupof patients.

Patients with typical anginal symptoms and unobstructedcoronary arteries are usually considered by the treatingphysician to have noncardiac chest pain or are sometimesdiagnosed as having microvascular angina, a conditionthought to be caused by a reduced vasodilatory ability of the

Clinical Characteristics in Study PatientsTable 1 Clinical Characteristics in Study Patients

All Patients(N � 283)

Male 137 (48%)

Age, yrs 66 � 10

Exertional chest pain pectoris 141 (50%)

Exertional dyspnea with occasional chest pain pectoris at rest 32 (11%)

Exertional chest pain with occasional symptoms at rest 110 (39%)

Noninvasive test for ischemia performed 240 (85%)

Ischemic ECG changes during noninvasive test for ischemia 151 (53%)

Risk factors

Hypertension 214 (76%)

Diabetes mellitus 66 (23%)

Hypertension and diabetes mellitus 55 (19%)

Hypercholesterolemia 191 (67%)

Smokers 38 (13%)

Positive family history for CVD 107 (38%)

Values are n (%) or mean � SD.CAD � coronary artery disease; CVD � cardiovascular diseases; ECG � electrocardiographic.

Multivariate Logistic Regression AnalysisTable 2 Multivariate Logistic Regression Analysis

HR (95% CI) p Value

CAD vs. no CAD

Age 1.07 (1.03–1.11) �0.01

Male 5.82 (2.83–12.00) �0.01

Purely effort-induced chest pain 4.22 (2.21–8.05) �0.01

Ischemic ST-segment changes duringnoninvasive exercise test

3.27 (1.65–6.50) �0.01

Hypercholesterolemia 3.80 (1.83–7.86) �0.01

Abnormal vs. normal coronaryvasomotor response

Female 3.20 (1.26–8.12) 0.014

Purely effort-induced chest pain 0.26 (0.09–0.78) 0.016

Positive family history for CVD 0.11 (0.04–0.30) �0.01

Hazard ratios (HRs), 95% confidence intervals (CIs), and p values are presented.CAD � coronary artery disease; CVD � cardiovascular diseases.

coronary microcirculation (6). Microvascular spasm hasmainly been seen in Japanese patients where functionaltesting is an integrated part of invasive coronary angiogra-phy. It has been reported that microvascular spasm was lesscommon in Caucasian cohorts (5) but functional coronarytesting is not broadly applied in Europe or the UnitedStates. However, in the present prospective study in acontemporary European patient cohort referred for diagnos-tic coronary angiography and found to have normal or nearnormal coronary arteries, we observed microvascular spasmin a large proportion of our patients. The results of our studyare of clinical importance, because we have shown for thefirst time that both epicardial (mainly distal) and microvas-cular spasm can be responsible for or associated with anginalsymptoms and ST-segment changes in a large proportion ofpatients with stable angina and unobstructed coronaryarteries.

The observation in our study that patients with unob-structed coronary arteries were more often women than menis in line with previous work from Bell et al. (14), whoshowed that, among 22,795 patients undergoing coronaryangiography, 24% of men and 48% of women had unob-structed coronary arteries. Similar observations were madein the large American College of Cardiology NationalCardiovascular Data Registry database of 565,504 patients(3), where the median rate of obstructive CAD (anyepicardial stenosis �50%) was only 45%. Although onecannot necessarily apply our results to such a large popula-tion in the United States, one can still speculate about theimplications for the health care system if approximately 30%to 50% of patients with anginal symptoms and unobstructedcoronary arteries would have a coronary vasomotor abnor-mality as an explanation for their symptoms.

In both of the large studies quoted in the previousparagraph, women were more likely than men to have

(>50% Coronary Stenosis)(n � 139 [49%])

Unobstructed Coronary Arteries(n � 144 [51%]) p Value

93 (67%) 44 (31%) �0.01

69 � 10 64 � 10 �0.01

97 (70%) 44 (31%) �0.01

5 (4%) 27 (19%) �0.01

37 (27%) 73 (51%) �0.01

122 (88%) 118 (82%) 0.19

95 (68%) 56 (39%) �0.01

112 (81%) 102 (71%) 0.07

35 (25%) 31 (22%) 0.49

31 (22%) 24 (17%) 0.29

108 (78%) 83 (58%) �0.01

16 (12%) 22 (15%) 0.39

47 (34%) 60 (42%) 0.18

CAD

unobstructed coronary arteries, despite the presence of

660 Ong et al. JACC Vol. 59, No. 7, 2012Pathological ACH Response in Stable Angina February 14, 2012:655–62

angina symptoms. This corresponds to our finding that,among patients with unobstructed coronary arteries in ourstudy, women were also more often found to have abnormalcoronary vasomotion than men. To assess the potentialreasons for this was beyond the remit of our study, but thisis an issue that requires further investigation.

Our finding that a positive family history for cardiovas-cular disease was more often present in patients withabnormal coronary vasomotion compared with those with-out is in line with previous studies (15), underpinning thepotential impact of the genetic background in the setting ofcoronary vasomotor disorders. Various genetic mutationshave been described as potential explanations (16,17).

Previous studies have suggested a higher prevalence ofepicardial spasm among Asian compared with Caucasianpatients (18). However, recent studies on Caucasian pa-tients have cast doubt on this discrepancy (19). The findingof our study that 28% of patients with unobstructed coro-nary arteries were found to have epicardial spasm is in linewith data from Asian patients (20) supporting the notionthat epicardial coronary spasm might be equally frequent inAsian and Caucasian patients.

A puzzling finding in our study is that, even in thesubgroup of patients with purely effort-induced chest pain,epicardial coronary spasm was elicited by ACH-injectionand was shown to reproduce the chest pain of the patient.Exercise-induced epicardial coronary spasm has been previ-ously reported by different authors (21–23). An increasedactivity of the sympathetic autonomic nervous system cou-pled with parasympathetic withdrawal during exercise andleading to adrenergic alpha-receptor–induced epicardialcoronary spasm has been proposed as a potential explanation

Clinical Characteristics of Patients With Stable Angina, UnobstrucTable 3 Clinical Characteristics of Patients With Stable Angina

All Patients WithUnobstructed Coronary Arteries

(<20% Narrowings) and ACH Test(n � 124)

Age, yrs 63 � 10

Male 37 (30%)

Exertional chest pain 32 (26%)

Exertional dyspnea withoccasional chest pain at rest

25 (20%)

Exertional chest pain withoccasional symptoms at rest

67 (54%)

Noninvasive test for ischemia performed 102 (82%)

Ischemic ECG changes duringnoninvasive test for ischemia

45 (36%)

Risk factors

Hypertension 86 (69%)

Diabetes mellitus 25 (20%)

Hypertension and diabetes mellitus 20 (16%)

Hypercholesterolemia 69 (56%)

Smokers 18 (15%)

Positive family history for CVD 55 (44%)

Values are n (%) or mean � SD. *p value refers to the comparison of all 3 patient groups.ACH � acetylcholine; other abbreviations as in Table 1.

(24). However, an alternative explanation for this finding

could be that ACH-provoked epicardial spasm is merely amarker for the presence of an abnormal coronary vasculartone preventing appropriate vasodilatation with exercise.

The finding that epicardial spasm was most often diffuseand located in the distal segments of the coronary arteries andthat it was often preceded by ischemic ECG shifts and/orreproduction of the symptoms of the patient (data not shown)suggests that epicardial spasm in our patients often began withmicrovascular spasm. This indicates that there is a spectrumof coronary vasomotion in response to ACH ranging fromsubtle changes via findings compatible with microvascularspasm to severe distal and diffuse epicardial spasm (8).

Microvascular spasm has been described as a pathogenicmechanism for resting chest pain in patients with normalcoronary angiograms, albeit mainly Japanese (5,25). Thehigh prevalence of microvascular spasm in the present studysuggests an important role of coronary microvascular dys-function also as a possible cause of exercise-induced anginain patients with chest pain and unobstructed coronaryarteries (26). Although microvascular dysfunction cannot bevisualized directly, it has been shown that abnormal coro-nary vasomotion in response to ACH is associated withperfusion defects on cardiac stress magnetic resonanceimaging with adenosine (27). Moreover, impaired micro-vascular reactivity to adenosine has been shown to bepredictive of major adverse outcomes among women eval-uated for suspected ischemia (28), underpinning the prog-nostic implications of microvascular dysfunction.

That microvascular spasm was demonstrated in patientswith effort-induced anginal symptoms indicates that abnor-mal microvascular vasomotion might be triggered by phys-ical exercise. It is conceivable that the full spectrum of

oronary Arteries (<20% Narrowings) and ACH Testbstructed Coronary Arteries (<20% Narrowings) and ACH Test

ardial Spasm� 35 [28%])

Microvascular Spasm(n � 42 [34%])

ACH Test Uneventful(n � 47 [38%]) p Value*

65 � 11 64 � 11 62 � 9 0.32

8 (23%) 7 (17%) 22 (47%) �0.01

14 (40%) 11 (26%) 7 (15%) 0.04

3 (9%) 10 (24%) 12 (26%) 0.13

18 (51%) 21 (50%) 28 (60%) 0.64

28 (80%) 35 (83%) 39 (83%) 0.91

9 (26%) 21 (50%) 15 (32%) 0.06

21 (60%) 32 (76%) 33 (70%) 0.30

5 (14%) 8 (19%) 12 (26%) 0.48

4 (11%) 7 (17%) 9 (19%) 0.65

17 (49%) 24 (57%) 28 (60%) 0.60

4 (11%) 3 (7%) 11 (23%) 0.09

20 (57%) 28 (67%) 7 (15%) �0.01

ted C, Uno

Epic(n

abnormal coronary vasomotion operates in these patients

661JACC Vol. 59, No. 7, 2012 Ong et al.February 14, 2012:655–62 Pathological ACH Response in Stable Angina

(i.e., a background of endothelial and/or medial smoothmuscle dysfunction involving the whole coronary tree,which can lead to severe coronary constriction in response toa diversity of stimuli, including exercise, anxiety, and yetunidentified triggers).

Intracoronary ACH provocation testing has been re-ported to be a sensitive and safe test for the assessment ofcoronary vasomotor function in the catheterization labora-tory (29). A stepwise infusion approach with incrementaldoses, as in the present study, ensures a very low rate ofserious complications (�1%) (30), which is in the orderreported for diagnostic coronary angiography (31). Withsuch a protocol, the infusion of ACH did not result in anyserious complications in more than 2,500 such tests per-formed at our institution since 2006.Clinical implications of our findings. The high preva-lence of epicardial and microvascular coronary spasm in ourstudy suggests that functional abnormalities of the coronaryarteries should regularly be considered as a differentialdiagnosis in patients with stable angina but angiographicallyunobstructed coronary arteries. Moreover, they should besuspected especially in female patients with effort-inducedchest pain, a positive family history for cardiovasculardisease, and coronary arteriograms with only minimal irreg-ularities. Intracoronary provocation tests (e.g., with ACH)might represent a useful clinical tool to establish thediagnosis of a functional abnormality underlying the symp-toms of the patient. Such a diagnostic algorithm might alsorepresent a cost-effective approach, minimizing the need forrepeated invasive and noninvasive tests for myocardial isch-emia and CAD commonly performed in this type of patientin the attempt to establish a diagnosis, which often proveselusive (32,33).Study limitations. We focused, for inclusion in the study,on patients with exercise-related anginal symptoms, but anabnormal exercise stress test was not required. This mighthave led to different results with regard to the prevalence ofunobstructed coronary arteries and abnormal coronary va-somotion on ACH testing. However, the aim of our studywas to assess a representative real-world clinical cohort ofpatients, and it is common practice that patients withexertional chest pain and cardiovascular risk factors undergocoronary angiography without noninvasive testing for tran-sient myocardial ischemia (34).

For the administration of ACH, we used the sameprotocol as in the ENCORE II (Evaluation of Nifedipineand Cerivastatin on the Recovery of Endothelial Function)study (11), with the exception that, whereas investigators inthe ENCORE II study selectively injected incrementalACH doses of 2, 20, and 100 �g into the left anteriordescending and left circumflex arteries, respectively, weadministered graded doses of ACH through the diagnosticcatheter into the left main stem, with a maximum dose of200 �g. This slight modification of the protocol was carried

out for logistic reasons (to avoid instrumentation of the

coronary vessels) and is unlikely to have resulted in majordifferences in the coronary responses.

Because direct visualization of the coronary microcircu-lation in the clinical setting is not possible at present,microvascular spasm remains a diagnosis of exclusion. How-ever, we used an accepted definition of microvascular spasmas proposed by Mohri et al. (5). Due to the paucity of datawith regard to coronary microvascular spasm, the definitionby Mohri et al. (5) has not been validated in larger trials.However, according to our experience, this definition ispractically useful when performing ACH provocation test-ing, because the response described by Mohri et al. (5) isfrequently encountered. Furthermore, the fact that a path-ological ACH test result is associated with perfusion defectson cardiac stress magnetic resonance imaging (27) under-lines the ischemic origin of such disorders.

Conclusions

Nearly 50% of patients undergoing diagnostic angiographyfor the assessment of stable angina had angiographicallyunobstructed coronary arteries. Intracoronary ACH provo-cation triggered epicardial as well as microvascular coronaryspasm leading to reproduction of the symptoms of thepatient combined with ischemic ST-segment changes innearly two-thirds of these patients. Our results suggest thatintracoronary ACH provocation might be a useful clinicaltool for the assessment of patients with suspected CAD whoare found to have unobstructed coronary arteries.

Reprint requests and correspondence: Dr. Peter Ong, Robert-Bosch-Krankenhaus, Department of Cardiology, Auerbach Street110, 70376 Stuttgart, Germany. E-mail: Peter.Ong@rbk.de.

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Key Words: acetylcholine y coronary spasm y normal coronary arteriesy stable angina.

APPENDIX

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