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CASE REPORT

CLINICAL CASE

Coronary Microvascular Spasmas the Underlying Cause of theAngiographic Slow Flow Phenomenon

Valeria Martínez Pereyra, MSC, Andreas Seitz, MD, Astrid Hubert, PHD, Heiko Mahrholdt, MD, Raffi Bekeredjian, MD,Udo Sechtem, MD, Peter Ong, MD

ABSTRACT

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Slow coronary flow is frequently seen during angiography in patients with angina and unobstructed coronary arteries.

However, the pathophysiology of this finding remains largely unclear. We report a case of a 52-year-old woman with slow

coronary flow caused by acetylcholine-induced microvascular spasm, as confirmed by intracoronary flow measurements.

(Level of Difficulty: Beginner.) (J Am Coll Cardiol Case Rep 2020;2:35–9) © 2020 The Authors. Published by Elsevier on

behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license

(http://creativecommons.org/licenses/by-nc-nd/4.0/).

HISTORY OF PRESENTATION

A 52-year-old white female presented to the clinicwith exertional dyspnea (New York Heart Association[NYHA] functional classes II to III) and angina whichhad been occurring predominantly at rest for theprevious 4 months.

EARNING OBJECTIVES

The objectives of this case were to under-stand that microvascular spasm may lead tosevere impairment of coronary blood flowresulting in angina and ischemic electrocar-diography changes.An additional objective included consideringmicrovascular spasm as the underlyingpathophysiological mechanism in patientswith slow flow on coronary angiography.

N 2666-0849

m the Department of Cardiology, Robert-Bosch-Krankenhaus, Stuttgart,

sch Foundation and the Berthold Leibinger Foundation, Ditzingen, Germ

pport from the Robert-Bosch Foundation and the Berthold-Leibinger Fou

althcare, Pfizer/Bristol-Myers Squibb, Boehringer Ingelheim, and Sanofi.

ationships relevant to the contents of this paper to disclose.

ormed consent was obtained for this case.

nuscript received November 25, 2019; accepted November 27, 2019.

MEDICAL HISTORY

The patient’s cardiovascular risk factors consisted ofa family history of coronary artery disease, smoking(12 pack-years, which stopped about 30 years ago),and well-controlled hypertension.

DIFFERENTIAL DIAGNOSIS

Coronary artery disease (CAD) and coronary vaso-motor disorders were considered as differentialdiagnoses.

INVESTIGATIONS

The physical examination, laboratory results, androutine diagnostic test results, including restingelectrocardiography (ECG) and echocardiographyresults were unremarkable. During an exercise ECG,the patient experienced dyspnea without ischemic

https://doi.org/10.1016/j.jaccas.2019.11.059

Germany. This work was supported by the Robert

any. Ms. Martínez Pereyra and Dr. Hubert receive

ndation. Dr. Ong has received honoraria from Bayer

All other authors have reported that they have no

ABBR EV I A T I ON S

AND ACRONYMS

ACh = acetylcholine

CAD = coronary artery disease

CFR = coronary flow reserve

FFR = fractional flow reserve

LAD = left anterior descending

artery

NYHA = New York Heart

Association

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ECG changes. Considering the patient’s pre-test probability and clinical likelihood forobstructive CAD based on the current guide-lines of the European Society of Cardiology(1), noninvasive risk stratification was per-formed using coronary computed tomogra-phy angiography. Although only mild softplaques (Agatson score of 0) were reported inthe right coronary artery and the leftcircumflex artery, a moderate stenosis ofunclear hemodynamic significance was sus-

pected in the proximal left anterior descending (LAD)artery (Figure 1). For further evaluation of the sus-pected stenosis as well as assessment of the differ-ential diagnosis of coronary vasomotor disorder,invasive coronary angiography (Figure 2) includingcombined measurement of fractional flow reserve(FFR), coronary flow reserve (CFR) and hyperemicmicrovascular resistance (HMR) (Figure 3), as well asacetylcholine (ACh) spasm provocation testing(Figure 4), were carried out with a Doppler flow/pressure wire (Volcano ComboWire 9515, RanchoCordova, California) placed in the mid LAD/co-dominant diagonal branch.

Hemodynamic significance of the LAD stenosiscould be ruled out by intracoronary administrationof 125 mg of adenosine (FFR: 0.94). Microvascularvasodilator capacity in response to adenosine waspreserved (CFR: 2.5; HMR: 2.4 mm Hg$cm-1$s)(Figure 3).

Stepwise intracoronary ACh provocation testingwas performed according to a standardized protocol(2). After injecting 100 mg of ACh, the patient reportedreproduction of her usual chest pain, and newischemic ECG changes (ST-segment depression andnegative T waves in leads II, III, aVF, and V4 to V6)accompanied by severe diffuse coronary slow flow(Thrombolysis in Myocardial Infarction flow grade 1)could be observed. Coronary slow flow was confirmedby Doppler flow assessment showing a significantreduction of average peak flow velocity in theabsence of epicardial spasm. A subsequent intra-coronary application of 200 mg of nitroglycerin led toa full restoration of coronary flow on the angiogramand normalization of coronary flow velocity as well asresolution of the patient’s symptoms and ischemicECG changes (Figure 4, Videos 1, 2, and 3).

MANAGEMENT

The diagnosis of coronary microvascular spasm wasestablished, and treatment with a calcium channelblocker and nitrates was initiated.

DISCUSSION

This case provides evidence for the hypothesis thatcoronary microvascular spasm can be the underlyingpathophysiological mechanism of the slow coronaryflow phenomenon. It is well known that coronary flowis highly dependent on coronary microvascularresistance, which is increased during microvascularspasm. Intracoronary Doppler flow measurementsallow coronary blood flow velocity to be assesseddirectly under resting conditions or in response tovasoactive stimuli such as adenosine or ACh. Previousstudies demonstrated that slow coronary flow in theabsence of epicardial stenoses can be observed in upto 30% of patients undergoing coronary angiography(3). This phenomenon is thought to be caused bymicrovascular dysfunction (4), a condition thatwomen are more likely to develop (5).

In the present case, the diagnosis of coronarymicrovascular spasm could be established accordingto standardized criteria (6) in a female patient withepisodes of resting angina and was found to beassociated with severe coronary slow flow on angi-ography. Women have been reported to have a higherprevalence of microvascular dysfunction (microvas-cular spasm and/or impaired microvascular vasodi-lator function) than men. Moreover, women are athigher risk of future adverse events and experiencegreater impairment of quality of life (5). This may notonly be due to pathophysiological differences but canalso be explained by differences in clinical presenta-tion as well as less intensive and delayed diagnosticworkup. The present case emphasizes that micro-vascular spasm should be considered as the under-lying mechanism in patients with chest pain andcoronary slow flow despite unobstructed coronaries(3,7). Establishing the diagnosis is of paramountimportance to guide individualized pharmacologicaltreatment approaches and to adequately counsel thepatient. The current European Society of Cardiologyguideline recommends the use of calcium channelblockers and nitrates for the treatment of vasospasticand microvascular angina (1), but despite the broadspectrum of antivasospastic and antianginal drugscurrently available, morbidity remains high, particu-larly in female patients (5).

FOLLOW-UP

As often happens in patients with microvascularangina, symptom control proved to be challenging inthis patient. The CorMicA (Coronary MicrovascularAngina) trial recently showed that beta-blocker

FIGURE 1 Coronary Computed Tomography Angiography

A moderate stenosis of the proximal left anterior descending artery (LAD) (arrow) was suspected on coronary computed tomography angiography, which was per-

formed in search of coronary artery disease. LCX ¼ left circumflex artery.

FIGURE 2 Coronary Angiography

Invasive coronary angiography revealed plaques of (A) the right coronary artery (RCA) and (B) the left coronary artery without angio-

graphically significant stenosis. LAD ¼ left anterior descending artery; LCX ¼ left circumflex artery.

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FIGURE 3 Combined Intracoronary Measurement of FFR and CFR

Combined intracoronary measurement of fractional flow reserve (FFR) and coronary flow reserve (CFF) in the left anterior descending

artery (LAD). Hemodynamic significance of the LAD stenosis could be ruled out (FFR, 0.94 [upper white arrow]). The average peak flow

velocity (APV) at baseline (white arrow left) was 14 cm/s and increased to 35 cm/s during adenosine-induced vasodilation resulting in a

preserved CFR of 2.5 and an hyperemic microvascular resistance (HMR) of 2.4 (white arrow right).

FIGURE 4 ACh Provocation Testing in the Left Coronary Artery with Simultaneous Intracoronary Pressure/Flow Assessment

Coronary flow was assessed in the proximal co-dominant diagonal branch. Average peak flow velocity (APV) at rest was 22 cm/s (A). Intracoronary injection of 100 mg of

acetylcholine (ACh) led to symptom reproduction, severe coronary slow flow on angiography, ischemic electrocardiography (ECG) changes, and a significant reduction

of the APV (5 cm/s [white arrow]) (B). Intracoronary nitroglycerin (200 mg) resulted in normalization of coronary blood flow (APV, 57 cm/s) and the ECG shifts (C).

i.c. ¼ intracoronary.

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treatment is the first choice in patients with micro-vascular angina (8). However, in this patient, neithertreatment with a beta-blocker nor treatment with anon-dihydropyridine (DHP) calcium channel blockercould improve the patient’s symptoms. In addition toan angiotensin-converting enzyme inhibitor and astatin, treatment with a DHP calcium channel blocker,nitrates, and ranolazine led to a partial improvementof the patient’s symptoms.

CONCLUSIONS

This case report provides new insights into thepathophysiology of coronary slow flow. Coronary

microvascular spasm should be considered theunderlying mechanism in patients presenting withthis angiographic phenomenon. This is of specialimportance in female patients, because they havea higher prevalence and increased morbidityassociated with microvascular dysfunction thanmen.

ADDRESS FOR CORRESPONDENCE: Dr. Peter Ong,Robert-Bosch-Krankenhaus, Department of Cardiol-ogy, Auerbachstrasse 110, 70376 Stuttgart, Germany.E-mail: Peter.Ong@rbk.de.

RE F E RENCE S

1. Knuuti J, Wijns W, Saraste A, et al. 2019 ESCguidelines for the diagnosis and management ofchronic coronary syndromes. Eur Heart J 2019;100:106.

2. Ong P, Athanasiadis A, Borgulya G,Mahrholdt H, Kaski JC, Sechtem U. High preva-lence of a pathological response to acetylcholinetesting in patients with stable angina pectoris andunobstructed coronary arteries. The ACOVA study(Abnormal COronary VAsomotion in patients withstable angina and unobstructed coronary arteries).J Am Coll Cardiol 2012;59:655–62.

3. Arbel Y, Rind E, Banai S, et al. Prevalence andpredictors of slow flow in angiographically normal

coronary arteries. Clin Hemorheol Microcirc 2012;52:5–14.

4. Mehta HH, Morris M, Fischman DL, et al. Thespontaneous coronary slow-flow phenomenon:reversal by intracoronary nicardipine. J InvasiveCardiol 2019;31:42–5.

5. Gulati M, Shaw LJ, Bairey Merz CN. Myocardialischemia in women: lessons from the NHLBI WISEstudy. Clin Cardiol 2012;35:141–8.

6. Ong P, Camici PG, Beltrame JF, et al. Interna-tional standardization of diagnostic criteria formicrovascular angina. Int J Cardiol 2018;250:16–20.

7. Sanati H, Kiani R, Shakerian F, et al. Coro-nary slow flow phenomenon clinical findings

and predictors. Res Cardiovasc Med 2016;5:e30296.

8. Ford TJ, Stanley B, Good R, et al. Stratifiedmedical therapy using invasive coronary functiontesting in angina: the CorMicA trial. J Am CollCardiol 2018;72:2841–55.

KEY WORDS coronary flow, coronarymicrovascular spasm, coronary vasomotordisorders, microvascular dysfunction, slowcoronary flow

APPENDIX For supplemental videos,please see the online version of this paper.