Does Coronary Microvascular Spasm Exist? Objective Evidence from lntracoronary Doppler Flow Measurements During Acetylcholine Testing

Fabian Guenther,MD ,Andreas Seitz,MD ,Valeria Martínez Pereyra,MSc ,Raffi Bekeredjian,MD ,Udo Sechtem,MD ,Peter Ong,MD

1 Department of Cardiology,Robert-Bosch-Krankenhaus,Auerbachstr.110,70376 Stuttgart,Germany

Abstract

A 43-year-old woman with recurrent atypical angina underwent invasive coronary angiography including intracoronary Doppler blood flow assessment and coronary spasm provocation testing.While obstructive epicardial disease could be ruled-out angiographically,the patient experienced reproduction of her angina symptoms after intracoronary administration of acetylcholine (100 μg) during spasm provocation testing.Simultaneously,the ECG showed new-onset ST-segment depression in the absence of epicardial spasm.In addition,coronary flow velocity was signif cantly reduced after acetylcholine compared to the baseline condition.Following intracoronary administration ofinitroglycerine (200 μg),the patient’s symptoms as well as the ECG changes and coronary flow reduction were reversed.Considering the ongoing challenges in appropriate evaluation of the pathophysiological mechanisms of coronary microvascular dysfunction,si multaneous intracoronary Doppler flow measurement during spasm testing-as shown in this case-may provide objective evidence for microvascular spasm in addition to the standardized diagnostic criteria,especially if they are ambiguous.

Keywords:acetylcholine;coronary microcirculation;coronary flow reserve;coronary spasm

lntroduction

Coronary artery spasm is a well-known and frequent cause of angina pectoris in patients with unobstructed coronary arteries.Coronary spasm can occur at the level of the epicardial arteries as well as in the coronary microcirculation.Current standardized diagnostic criteria for microvascular spasm include reproduction of the patient ’ s angina symptoms and ischemic ECG changes in the absence of epicar -dial spasm during intracoronary spasm provocation testing using,for example,acetylcholine [1].Nevertheless,proof of coronary microvascular spasm remains challenging in some patients.

Case Report

A 43-year-old woman presented to our hospital with progressive angina pectoris after a prolonged viral respiratory infection 6 months before.The reported angina symptoms occurred predominantly at rest,but recently were also induced by exercise.They were accompanied by dyspnea (New York Heart Association class III),which led to a signif -cant physical limitation in the patient ’ s everyday life for the previous 5 weeks.The medical history included an interventional occlusion of a persisting foramen ovale 10 years earlier as well as atrioventricular nodal reentrant tachycardia with slow pathway ablation 8 years earlier.Regular medication comprised aspirin once per day.The cardiovascular risk profile included a family history of coronary artery disease.Her father had had a myocardial infarction at the age of 47 years.

At the time of presentation to our hospital,the patient’ s ECG as well as the vital parameters were normal (blood pressure 120/80 mmHg,heart rate 90 beats per minute).The blood tests showed normal levels of high-sensitivity troponin T and N-terminal prohormone oflbrain natriuretic peptide and no elevation of the levels of C-reactive protein and leukocytes.Electrolytes were balanced,and the kidney function was normal.

To further investigate the initial presumptive diagnosis of a myocarditis,cardiac MRI was per -formed,which showed neither signs of myocar -dial scarring nor signs of myocardial edema in the T1 and T2 mapping.Volumetric measurements showed normal ventricular dimensions and a left ventricular ejection fraction of 72%.

In the search for coronary artery disease and to assess the dif ferential diagnosis of vasospastic angina,we performed invasive coronary angiography,including acetylcholine spasm provocation testing with intracoronary Doppler flow measurements.Thereby,only mild coronary atherosclerotic plaques were found without relevant epicardial stenosis (Figure1).Subsequently,acetylcholine spasm provocation testing was performed via a diagnostic catheter placed in the left coronary artery.Neither angina symptoms nor epicardial spasm or ECG changes were observed at rest and after the lowest dose (2 μ g) of acetylcholine (Figure2).After administration of 20 μ g acetylcholine,an isolated T-wave inversion in aVL,but no symptoms or epicardial spasm,was reported.After administration of 100 μ g acetylcholine,the patient reported her usual angina symptoms,which were accompanied by new-onset ischemic ECG changes (ST depression) in the inferolateral leads (II,III,aVF,V5,and V6).Moreover,average coronary peak flow velocity determined with use of an intracoronary Doppler flow wire placed in the middle segment of the left anterior descending artery was signif cantly reduced after acetylcholine administration (1 1 cm/s) compared with the baseline value (25 cm/s).After intracoronary administration ofinitroglycerin (200 μ g),the ischemic ECG findings reversed,coronary flow increased,and the patient reported relief of symptoms.Further assessments of coronary flow reserve and fractional flow reserve in the middle segment of the left anterior descending artery with an intracoronary bolus injection of 200 μ g adenosine showed a reduced coronary flow reserve of 2.0 and a nor -mal fractional flow reserve of 0.95.Accordingly,a combined coronary microvascular disorder (i.e.,impaired microcirculatory function and microvascular spasm) was diagnosed,and respective treatment with a calcium channel blocker (lercanidipine,5 mg once daily) and ranolazine (375 mg twice daily) was initiated.At follow-up 3 months later,the patient reported only mild residual angina pectoris at night and dyspnea during intensive exercise.Hence the medication was adjusted by increasing the dosage of ranolazine to 500 mg twice daily and adding an additional 10 mg lercanidipine in the evening.

Discussion

Managing patients with angina pectoris despite unobstructed coronary arteries is challenging,and such patients have an increased risk of adverse car -diovascular events [2].About two-thirds of these patients have some form of microvascular dysfunction [3],and hence it is inevitable that cardiologists pay more attention to the microvasculature.Even though standardized diagnostic criteria for microvascular angina have been established [1],they are often not routinely used yet because there is still a controversial discussion about the existence and clinical relevance of coronary microvascular spasm,despite a growing body of scientif c evidence.This is due to the lack of visibility of the coronary microvasculature on the angiogram because the microvasculature escapes the resolution of currently used angiographic techniques [4] and inconclusive findings in some patients not fulfilling the standardized criteria (e.g.,symptoms or ECG findings only).Furthermore,it is sometimes challenging to identify the specif c endotype of microvascular dysfunction that triggers microvascular angina in the individual patient,as shown in the present case,but this is of clinical relevance to initiate optimal treatment [5].Therefore it is essential to distinguish between an impaired microcirculatory vasodilatory capacity,which can be diagnosed by measuring coronary flow reserve or microvascular resistance,and microvascular spasm determined by intracoronary acetylcholine administration.Acetylcholine is known to increase coronary blood flow in patients with normal endothelial microvascular function [3,6].In patients with endothelial dysfunction and/or vascular smooth muscle hyperreactivity,acetylcholine may trigger paradoxical vasoconstriction of the microvasculature,resulting in diminished coronary flow.As the microvasculature escapes the resolution of cur -rently used angiography techniques,novel methods are needed to provide further objective evidence for microvascular spasm,particularly in patients where despite a high clinical suspicion the standardized criteria are not fully met (e.g.,acetylcholineinduced symptom reproduction,but no signif cant ECG changes or preexisting bundle branch blocks).

In the case presented,the patient suffered from both aspects of microvascular dysfunction.In addition to the standardized diagnostic criteria of microvascular spasm [1],intracoronary Doppler flow measurement during acetylcholine testing was used to provide objective evidence for severe microvascular spasm.The drastic reduction of coronary flow after intracoronary acetylcholine injection and the ischemic ECG alterations and reproduction of the patient ’ s anginal symptoms were all reversed by intracoronary administration ofinitroglycerin and in the absence of epicardial spasm.Hence the only plausible explanation for these findings is microvascular spasm.

Conclusions

Real-time coronary blood flow velocity measurement during acetylcholine spasm provocation testing using a Doppler -sensor-equipped wire may facilitate the diagnosis of coronary microvascular spasm,especially if other criteria are ambiguous as emphasized in the recent European Society of Cardiology guidelines for chronic coronary syndromes [4].

Confl ict ofilnterest

The authors declare that they have no conf icts of interest.

Funding

This work was funded by the Robert Bosch Stiftung,Stuttgart,Germany,and the Berthold Leibinger Stiftung,Ditzingen,Germany.