coronary vasospasm: is it a myth?

Coronary Vasospasm: Is it a Myth?Udo Sechtem, Peter Ong, Anastasios Athanasiadis, Matthias Vohringer, Rimma Merher and Ali Yilmaz

Department of Cardiology, Robert-Bosch-Krankenhaus, Stuttgart, Germany

Abstract This review addresses some myths about coronary vasospasm as the cause of angina pectoris. Coronary

artery vasospasm is a common phenomenon, which is clinically encountered by busy cardiologists almost on

a daily basis. It is the cause of resting angina inmany patients without significant coronary artery disease, but

also in patients with atherosclerotic coronary artery disease but no subtotal lesion. Although coronary

artery vasospasm can be suspected clinically, proof cannot usually be obtained by non-invasive means but

is easily available during cardiac catheterization. Patients with vasospastic angina are repeatedly exposed

to this invasive procedure as most cardiologists suspect a coronary lesion requiring intervention as the cause

of the patient’s resting angina. Adding an intracoronary acetylcholine test to the catheterization procedure

may establish the correct diagnosis and enable treatment with calcium antagonists and nitrates. Epicardial

vasospasm may be observed during the test in patients with and without angiographically visible lesions in

the coronary arteries. Almost 50% of all pathological tests, however, do not show epicardial vasospasm but

reproduction of symptoms and electrocardiogram signs of ischemia indicating spasm of the microvessels.

1. Introduction

Interest in coronary vasospasm has almost fallen into ob-

livion in recent years as a result of the enthusiasm generated by

modern concepts such as plaque rupture as the cause of acute

coronary syndromes and the therapeutic possibilities available

with the advancements in stent technology. In contrast to the

dramatic appearance of coronary occlusions and high-grade

coronary stenoses of atherosclerotic coronary disease, coro-

nary vasospasm is rarely observed angiographically without

provocation tests. Although coronary angiography is liberally

used in western societies, however, and the indications for

stenting have broadened considerably, pharmacological testing

for coronary vasospasm is still regarded as difficult and fraught

with complications. In Japan, however, coronary vasospasm

continues to be regarded as a valid explanation of resting an-

gina in patients with and without significant coronary artery

disease, and invasive provocation tests for coronary artery

vasospasm are commonly employed in Japanese catheter-

ization laboratories.[1] This review should help to correct some

commonly held but erroneous views on coronary vasospasm,

and will present evidence demonstrating that coronary artery

vasospasm is still a common phenomenon, which is clinically

encountered by busy cardiologists almost on a daily basis.More-

over, it is hoped that some of the prejudices associated with

invasive spasm testing can be corrected.

2. The Myths

A recent review article by Stern and Bayes de Luna[2] ap-

pearing in Circulation commendably reminded the cardiology

community of the existence of coronary vasospasm. In addition

to reminding us of some important truths, however, some

statements may have strengthened numerous old myths about

this phenomenon.

One of these myths is that the frequency of coronary vaso-

spasm has declined in the western world. It is undoubtedly true

that coronary vasospasm is less and less frequently diagnosed in

western countries. Vasospasm is, however, present in many

patients seen in a cardiology office. An illustration of this fact is

that patients with chronic stable angina often experience vari-

able thresholds of their angina from day to day and even during

the same day. This symptom variability is the result of a

variable degree of vasoconstriction at the site of a critical

stenosis and/or distal coronary vessels including the micro-

vasculature.[3] In a sizeable proportion of these patients, chest

pain may occasionally occur even at rest. This is the conse-

quence of superimposed coronary vasospasm in patients with

stenosing coronary artery disease.[4]

Resting angina is also not uncommon in women, but coro-

nary angiography may not reveal coronary artery stenosis,

prompting clinicians to attribute symptoms to a non-cardiac or

psychosomatic origin. Alterations in vascular tone culminating

REVIEWARTICLEAm J Cardiovasc Drugs 2010; 10 Suppl. 1: 19-26

1175-3277/10/0001-0019/$49.95/0

ª 2010 Adis Data Information BV. All rights reserved.

in coronary vasospasm may, however, be a more logical ex-

planation for their chest pain.[5]

As coronary vasospasm is often not ruled out as the true

cause of the clinical presentation, patients with resting angina

and plaques that are not critically obstructing the vessel may

undergo coronary artery stenting in a misguided effort to treat

the patients’ problem.

3. Case Vignette 1

Such a clinical scenario is illustrated by the case of a 40-year-

old heavy smoker who woke up at 06.00 hours as a result of

severe chest pain. This chest pain lasted for 10min and subsided

in the emergency ambulance on the way to the hospital. Upon

arrival in the hospital the resting electrocardiogram (ECG) was

normal and there was no troponin rise. The patient reported

that his father had had a myocardial infarction aged 50 years

and his mother and his brother had died as a result of sudden

cardiac arrest. His high-density lipoprotein cholesterol was

25mg/dl (normal ‡40mg/dl) and his low-density lipoprotein

cholesterol level was normal. The patient reported that he had

experienced a similar episode of resting chest pain in the early

morning approximately 1 year earlier. This had been treated by

a stent to his mildly stenosed left anterior descending coronary

artery (LAD).

On the day following admission his exercise ECG was nor-

mal at 200 Watts without ST-segment depression or angina.

During and after exercise, however, he developed ventricular

premature beats. Because of his risk profile and the severe

resting angina, he underwent cardiac catheterization and cor-

onary angiography. His left ventricle was normal. The right

coronary artery showed irregularities but no stenosis (figure 1).

The left coronary artery showed less severe atheromatous

changes, but was also irregular with a protruding stent in the

middle of the vessel (figure 1).

What to do now? This patient represents a typical example of

the dilemma that the interventional cardiologist faces when

performing coronary angiography in a patient with typically

described severe resting angina. There is a tendency in inter-

ventionalists to overestimate obstructions caused by coronary

plaques in this situation and proceed to stenting, although it has

recently been shown that measuring coronary flow reserve may

help avoid unnecessary and risky interventions in patients with

stable or unstable coronary artery disease.[6,7] Demonstrating

that intervention is not necessary does not explain why symp-

toms occur and does not help in terms of preventing further

attacks. In such a situation acetylcholine provocation testing is

helpful to exclude coronary vasospasm. Unfortunately, Stern

and Bayes de Luna[2] state in their review article: ‘further phar-

macological testing, such as provocation with intravenous

ergonovine, should be used only under special conditions and

with extreme care’. Although they do not comment on intra-

coronary acetylcholine testing, such a statement may preserve

the myth that spasm testing should not be an integral part of

diagnosis in interventional catheterization laboratories. We do

agree, however, that intravenous ergonovine may indeed be

highly dangerous in the case we describe because severe mul-

tivessel coronary vasospasm may be provoked.[8] In contrast,

intracoronary acetylcholine testing can be performed quickly

and without danger to the patient in such a situation,[9] as most

patients presenting under these circumstances will undergo in-

vasive coronary angiography anyway, and the test itself adds

little extra time and risk to this procedure.

In brief, coronary spasm testing is currently performed in

our laboratory by injecting incremental doses of acetylcholine

2, 20, 100 and 200 mg [acetylcholine solutions are freshly pre-

pared fromMiochol (CIBAVision, Basel, Switzerland) powder

in the catheterization laboratory] into the left main coronary

artery via the diagnostic catheter after significant coronary

lesions (‡50%) have been excluded. Injections are made slowly

over 3min. Microvascular spasm is defined as reproduction of

the patients’ usual chest pain plus ST-segment depression or

rarely ST-segment elevation without angiographic narrowing

of the epicardial portion of the vessels, and epicardial spasm is

defined as reproduction of the patients’ usual symptoms plus

severe reduction of the diameter of an epicardial coronary ar-

tery with or without concomitant ECG changes. If a coronary

microvascular or epicardial spasm occurs, the injection is stop-

ped and we wait up to 2min for a spontaneous recovery. This

a

RCA LCA

b

Stent

Fig. 1. Coronary angiogram of patient case 1, a 40-year-old smoker with

severe resting angina, showing (a) the right coronary artery (RCA), which has

diffuse disease throughout the vessel but no stenosis, and (b) the left

coronary artery (LCA), which shows luminal irregularities but no stenosis.

The previously placed stent in the left anterior descending coronary artery

is marked with an arrow.

20 Sechtem et al.

ª 2010 Adis Data Information BV. All rights reserved. Am J Cardiovasc Drugs 2010; 10 Suppl. 1

occurs in almost all patients because of the short half-life of

acetylcholine, although complete recovery from microvascular

spasm may take a few minutes more. Our standard protocol is

to finish testing in the left coronary artery and then infuse

acetylcholine 80 mg over 3 min into the right coronary artery. If

the symptoms are unusually severe, however, and do not sub-

side quickly, nitroglycerin is injected into the coronary artery

producing the spasm and the test is stopped. If symptoms

subside quickly, the right coronary artery is also tested to ex-

clude multivessel spasm. We have stopped inserting a right

ventricular temporal pacemaker to perform the test in the right

coronary artery because the atrioventricular block disappears

spontaneously after a few seconds as a result of the short half-

life of acetylcholine. At the end of each injection a 12-lead ECG

is recorded and an angiogram is taken for documentation of

coronary artery narrowing. In addition, the patients’ symptoms

are recorded in detail. If a full test has been completed including

the left and the right coronary artery, nitroglycerin 0.2mg is

injected into the right coronary artery and after 1min the angio-

gram is repeated. The left coronary catheter is then reinserted

into the left coronary artery and nitroglycerin 0.2mg is injected

into the left coronary artery. A final angiogram is taken from

this coronary artery 1min later to document the status of the

vessel following nitroglycerin injection.

After the test, we measure coronary diameters using appro-

priate quantification software (QCA, Medis, Leiden, The

Netherlands) and use the following definition for epicardial

coronary vasospasm: vasospasm is present if the patients’

symptoms are reproduced and if the coronary artery diameter

has narrowed more than 75% compared with the diameter

following nitroglycerin injection. This test procedure is similar

to that used in the ENCORE Study.[10] It is important to stress

that incremental doses need to be used in the left coronary

artery in order to avoid complications. In patients who respond

with severe spasm to the smallest dose of 2 mg, injection of a

higher dose could result in pump failure. At our institution, 558

such tests were performed in 2008 without any complications.

Back to the patient in the vignette: he did not have any symp-

tomswith acetylcholine 2mg, but after a dose of 20mg he reportedsevere chest symptoms similar to those he experienced on the

morning of hospital admission. Angiographically (figure 2) the

LAD was partly occluded and only the stented segment re-

mained visible. The symptoms subsided only very slowly,

consequently the test was stopped and nitroglycerin was given

(figure 2). Clearly, the cause of the patient’s symptoms was

coronary vasospasm. Retrospectively, at the time of stent-

ing 1 year earlier when the patient reported identical symptoms,

there was no critical stenosis in the LAD (figure 3). In our

experience, patients have often already been treated with a stent

for subcritical lesions by the timewe see themwhen they present

with repeated resting angina as a result of severe coronary

vasospasm.

4. More Myths

This case also illustrates that another statement from the

paper by Stern and Bayes de Luna[2] is a myth, namely the

suggestion that the ambulatory ECG and the exercise ECG

may often be helpful to establish the diagnosis. Indeed, coro-

nary artery vasospasm may be an occasional occurrence (al-

though the patient in vignette 1 admitted upon re-questioning

that he had mild episodes of retrosternal pain once or twice per

week but that he did not pay much attention to this) and may

not occur or be too mild during a normal 24-h Holter ECG.

Prinzmetal et al.[11] already noted that establishing the diag-

nosis of vasospastic angina by recording an ECG during an

acute attack might not be an easy task. In fact, he wrote that

‘hospitalization often is required so that electrocardiograms

may be taken promptly whenever pain occurs’. Some of his

patients spent weeks in the hospital. Therefore, if it is not

possible to record an ECG during a typical attack of coronary

vasospasm, an acetylcholine provocation test may be advisable.

Of course, the exercise ECG is usually normal in a patient with

resting chest pain, and unless microvascular disease is also

NTGACH2 20μg

a b

Stent

Fig. 2. Provocation testing in patient case 1, showing left coronary artery

following intracoronary injection with (a) acetylcholine (ACH2) and (b) nitro-

glycerin (NTG). In (a), a selective coronary catheter (Multi-functional Probing

catheter by Boston Scientific Corp., Maple Grove, Minnesota, USA) was

placed in the coronary vessel over a guide wire, which is seen in the left

anterior descending coronary artery (open black arrows). The dark dot (black

arrow) marks the tip of the catheter. There is total occlusion (open white

arrows) behind the stent (marked by the white arrow) and subtotal occlusion

before the stent in the region of the guide wire tip. The circumflex coronary

artery is diffusely narrowedby approximately 50% and even the leftmain stem

shows substantial narrowing. In (b), the vessel has an appearance similar to

the one at baseline (figure 1b).

Coronary vasospasm 21


present, there is usually no flow-limiting lesion in the coronary

artery.

The vignette also illustrates that invasive testing is not

dangerous but helps to make an unequivocal and therapeuti-

cally and prognostically[12] important diagnosis. Consequently,

coronary angiography with invasive testing is also a class IIa

recommendation of the AmericanHeart Association guidelines

for the management of chronic stable angina.[13]

5. ST-Segment Shifts During Coronary Vasospasm

The issue of coronary vasospasm has been greatly confused

because most textbooks define coronary vasospasm strictly

according to Prinzmetal’s original description of variant angi-

na. This is also reiterated in the review by Stern and Bayes de

Luna.[2] We need to look carefully at the landmark paper of

1959 by Prinzmetal et al.[11] to understand the context in which

he made his observations. Prinzmetal described ‘another type

of angina pectoris which appears to be a separate entity, and

has not been set apart from the heterogeneous group of anginal

syndromes. It does not show the two major characteristics of

the classic form and, in addition, has other important clinical

and experimental differences. In this variant type of angina the

pain comes on with the subject at rest or during ordinary activ-

ity during the day or night. It is not brought on by effort.

During an attack, the ST-segments are transiently and often

remarkably elevated and there are reciprocal ST-depressions in

the standard leads.’ The report of Prinzmetal et al.[11] encom-

passes just 32 patients and ECG were not recorded in all of

them. Most importantly, none of those patients underwent

coronary angiography and in no patient was the angiographic

morphology of spasm demonstrated. As most patients had se-

vere coronary atherosclerosis (as shown post-mortem by pa-

thology), the mechanism of Prinzmetal’s angina may differ

from that occurring in the large group of patients without se-

vere or any coronary atherosclerosis in whom provocation tests

are currently performed.

The typical ST-segment elevation characteristic of acute

myocardial infarction only occurs in coronary vasospasm if the

spasm leads to complete occlusion of the vessel, which is often

the site of (usually substantial) atherosclerotic narrowing. In-

deed, coronary vasospasm is still often exclusively defined as an

occlusion or 99% occlusion of the proximal ormid vessel during

acetylcholine infusion.[1] A more diffuse and distally aug-

mented sort of coronary vasospasm is, however, frequently seen

in Japanese patients,[14] which is associated with ST-segment

depression during the attack. This type of spasm is also what we

see inmost patients with positive acetylcholine tests in the south

of Germany. This pattern of spasm is responsible for the pa-

tients’ clinical symptoms because exact reproduction of these

symptoms is achieved during the test. Interestingly, ST-segment

depression occurs frequently at rest or during normal non-

stressful daily activities in patients with coronary artery disease

on Holter monitoring.[15] Such a diffuse, more distally located

type of spasm, which does not usually lead to complete occlu-

sion of the vessel, may cause ischemia just by microvascular

constriction.

What is the mechanism behind these ST-segment shifts? The

‘classic’ responses to intracoronary acetylcholine or ergonovine

are both occlusive segmental spasm (probably corresponding

to Prinzmetal’s clinical observations) and subtotal segmental

occlusion, with faint delayed distal filling. Both may cause

transmural ischemia with ST-segment elevation in the ECG. In

our experience, both of these conditions occur very rarely. In

contrast (as already mentioned above) diffuse distal accen-

tuated narrowing of the entire vessel (sometimes to the point of

total or subtotal occlusion) or microvascular spasm only are

frequently encountered in our patients. The constriction pro-

duced predominantly in distal, secondary and tertiary epi-

cardial coronary artery branches rather than the proximal

segments[16] will lead to subendocardial ischemia resulting in

ST-segment depression. We do not know whether this type of

spasm can occur without any atherosclerosis in the coronary

vessels. Although we have often observed completely or almost

completely normal vessels by coronary angiography, we

know from intravascular ultrasound studies that subclinical

atherosclerosis is often present in such vessels. Indeed, diffuse

intimal thickening of coronary arteries is commonly seen

by intravascular ultrasound in patients with coronary spastic

angina.[17]

Beforestent

Right anterior oblique view Left anterior oblique view

Beforestent

a b

Fig. 3. Coronary angiogram of patient case 1 at the time of the first attack

of severe angina and stenting of the left anterior descending coronary artery

one year earlier in (a) right anterior oblique view and (b) left anterior oblique

view. The mid-portion of the vessel shows marked irregularities (white

arrows) but no severe stenosis.

22 Sechtem et al.


6. Why is Vasospastic Angina Rarely Diagnosed Now?

Prinzmetal et al.[11] noted in 1959 that ‘the variant form of

angina pectoris is not uncommon. Cases are not diagnosed now

for several reasons: (1) Medical students are generally taught

that angina pectoris occurs with exhaustion and recedes with

rest. True angina pectoris, therefore, is generally regarded as

only that pain which is provoked by exhaustion or excitement.

Many authorities in fact refer to the syndrome as ‘‘effort an-

gina’’; (2) ECGs taken at the beginning or end of a severe attack

of the variant form or during a mild attack may be unchanged

or show spurious improvement; (3) If only one ECG is taken

during pain, myocardial infarction is diagnosed almost in-

evitably; and (4) Physicians are not aware of the complete

syndrome, its diagnosis and treatment.’

All of these statements from 1959 are still true 50 years later.

Therefore, our clinical approach to patients with resting angina

needs to be changed. First, we need to think of resting angina as

being potentially caused by coronary vasospasm. Second, we

need to remember that the diagnosis can often not be made by

recording ECG during an attack. Moreover, we need to re-

member that severe attacks with pronounced ECG changes

occur randomly and cannot be provoked by clinical maneuvers.

Therefore, recording a diagnostic ECG during an attack may

be very cumbersome, if not impossible. Finally, we need to learn

a lot about coronary vasospasm, its prevalence, its patho-

physiology and its treatment.

7. Case Vignette 2

Another case vignette illustrates that vasospastic angina

often occurs in elderly women. We saw an 81-year-old woman

who had strictly exercise-related angina for many years. She

had hypertension, with great variations in systolic blood pres-

sure (100–240mmHg) and hypercholesterolemia. She present-

ed to the emergency room with thoracic pain from low-level

exercise associated with anxiety and nausea. The threshold of

angina had become lower over the past few months. In pre-

ceding weeks she began experiencing episodes of resting angina

and she had collapsed at home in front of her grandson who

brought her to the hospital. Management of her hypertension

had proved difficult because of several episodes of hypotension.

Her physical examination and her laboratory values were

normal. A stress test was performed but stopped at 75 Watts

due to dyspnea, angina and nausea. The stress test showed no

ST-segment depression and no arrhythmias. The resting ECG

was remarkable only for a slightly negative T-wave in aVL. As

an elderly woman with typical angina has a high probability of

the presence of a flow-limiting stenosis as the cause of her chest

pain,[18] we proceeded to coronary angiography. The coronary

angiogram showed completely normal coronary arteries with-

out calcification. Acetylcholine provocation in the left coro-

nary artery revealed no abnormalities at the 2 mg dose. At a dose

of 20 mg, however, the patient reported mild chest pain of the

type occurring at home, and this was associated with negative

T-waves in V1–V3 (figure 4) and mild horizontal ST-segment

depression in V4–V6. At 100 mg the angina was as severe as

during the worst attacks at home. There was no epicardial

constriction of the coronary arteries but negative T-waves in

I and more pronounced in aVL (than at rest) with ST-segment

depression in V1–V4 with less pronounced ST-segment de-

pression in V5 and V6. Following the injection of nitroglycerin,

the ST-segment changes disappeared and the patient quickly

became pain free.

This is a typical case of microvascular spasm in which

provocation testing reproduced the patient’s usual symptoms

and demonstrated the absence of epicardial vasoconstriction

but the presence of ECG signs of severe ischemia. How then can

we explain the presence of her pre-existing long-term exercise-

related angina? We also performed magnetic resonance-perfu-

sion imaging with the application of adenosine (figure 5). Ad-

enosine provoked her typical angina and there was a circular

low signal intensity rim near the endocardium indicating sub-

endocardial severe ischemia. Therefore, the exercise-induced

angina in this patient was most likely caused by microvascular

dysfunction[19] (reduced coronary flow reserve due to micro-

vascular disease) associated with her hypertension and hy-

percholesterolemia. With disease progression, microvascular

dysfunction progressed to spontaneous microvascular spasm

leading to her attacks of resting angina and collapse. We could

not reproduce the collapse as there were no arrhythmias with

acetylcholine testing or upon infusion of adenosine. The oc-

currence of malignant ventricular arrhythmias with epicardial

vasospasm has, however, already been described by Prinzmetal

et al.[11] in 1959.

8. Coronary Vasospasm as a Cause of Unstable

Angina

Up to 30% of patients with acute coronary syndrome have

no significant coronary artery disease,[20] but the reason for this

has not been clarified. We hypothesized that some of these

unstable coronary syndromes might be caused by coronary

vasospasm. In a prospective study, Ong et al.[21] examined

consecutive patients over a 6-month period who underwent



coronary angiography for suspected acute coronary syndrome

but who had no culprit lesion. The patients underwent intra-

coronary provocation with acetylcholine. Of 488 patients, 138

(28%) had no culprit lesion. Twenty-two were found to have

another diagnosis. Acetylcholine testing was performed in 86 of

the remaining 116 patients. This testing confirmed coronary

vasospasm in 42 of the patients (49% of 86). Therefore, every

fourth patient with an acute coronary syndrome has no culprit

lesion and 50% of those have epicardial coronary vasospasm as

documented during acetylcholine testing. Therefore, coronary

vasospasm is a frequent cause of acute coronary syndrome and

should regularly be considered as a differential diagnosis.

Using data obtained between 2005 and 2007, the National

Cardiovascular Data Registry of the American College of Car-

diology showed that of all patients who underwent coronary

angiography with a positive stress result, only 41% had ob-

structive coronary artery disease. In patients who had no stress

test, obstructive coronary artery disease was found in 35%,

whereas the proportion of those with coronary artery disease

found by coronary angiography was even lower among those

who had a negative stress test result or an equivocal stress test

result (28% and 27%, respectively).[22] Presumably, many of

these patients had effort-related angina. In such patients,

Holter monitoring may reveal silent or mildly symptomatic

ST-segment shifts at rest and during normal daily activities.

Therefore, we recently initiated a systematic evaluation of how

commonly coronary vasospasm occurs in patients with stable

exercise-related angina but no culprit lesion. Clarification of

this question is of obvious importance because of the magni-

tude of the problem as outlined by Patel et al.[22] Our initial

impression is that a vasospastic reaction to acetylcholine is very

prevalent in these patients and that the microvascular type of

Baselinea b c dACh 20μg ACh 100μg Nitroglycerin

Fig. 4. Coronary angiograms (top panels) of the left coronary artery and corresponding electrocardiograms (ECG) (bottom panels) before and during

provocation testing of patient case 2, an 81-year-old woman with severe resting angina.* (a) Baseline: there is pronounced tortuosity of the vessel but no

appreciable plaque and the resting ECG shows a negative T-wave in aVL but is otherwise normal. (b) After 20mg acetylcholine (ACh) the patient reported

identical symptoms to her usual angina both with exercise and at rest but there were no angiographic changes. The ECG showed newST-segment depressions

with negative T-waves in V2–V4. The T-wave in aVL is now negative and there is a flat T-wave in I. (c) After 100mg of acetylcholine the patient reported

symptoms that were more severe and similar to the most severe symptoms experienced in daily life, but there was no perceptible angiographic change. ECG

changes were slightly more pronounced as compared with the 20mg dose. (d) After nitroglycerin, the pain disappeared immediately, and the left coronary artery

appeared slightly larger than after 100mg of acetylcholine but theECGwasnormalized. *Note that there is a slightly differentmagnification factor frombaseline to

the other three panels due to a slightly different distance between the table and the image intensifier.

Adenosine stress-perfusiona b Rest-perfusion

Fig. 5. Stress perfusion cardiacmagnetic resonance imagingof patient case

2 showing (a) subendocardial ischemia around the left ventricle as indicated

by the dark zones neighboring the bright blood-filled cavity (the patient re-

ported identical symptoms as in daily life) and (b) at rest, the dark zone has

disappeared.

24 Sechtem et al.


spasm is the most commonly observed. We hypothesize that

microvascular disease is the cause of effort-related angina in

these patients.

9. Therapeutic Implications of a Diagnosis

of Coronary Vasospasm

We usually begin treatment with calcium antagonists and

add nitrates to the regimen if there is insufficient response after

2 weeks. In addition, all patients are treated with an angio-

tensin-converting enzyme inhibitor (if blood pressure permits)

and a statin. In our experience, however, only approximately

one-third of patients become symptom free. Symptoms are

improved in 40% of patients but remain almost unchanged in

27% (unpublished data from our institution). Therefore, acetyl-

choline provocation testing enables successful targeted therapy

in two-thirds of patients with angina but normal coronary

angiograms. The presence of a group of non-responders chal-

lenges the assumption of opponents to invasive coronary vaso-

spasm testing that a trial of calcium antagonists alone in

patients with suspected vasospastic angina can verify the dia-

gnosis. Our experience shows that approximately one-third of

patients with vasospastic angina are unresponsive to treatment

and would therefore not have been diagnosed correctly with a

pharmacological trial of calcium antagonists alone.

Another important therapeutic aspect is that coronary vaso-

spasm often occurs in patients with arterial hypertension, as

shown in case vignette 2. It is not uncommon to learn from

patients that the frequency of anginal attacks increased after

the addition of a beta-blocking agent to their antihypertensive

medication. Although there are no data pertaining to modern

beta-blocking agents such as bisoprolol,metoprolol, carvedilol,

or nebivolol, data from Kern et al.[23] indicate that beta-

blockers increase coronary vasotone, thus facilitating the

occurrence of flow-limiting vasospasm in patients prone to this

problem. Therefore, before initiating treatment with beta-

blockers, it might be prudent to establish whether a patient

has a mild form of resting angina and avoid prescribing these

drugs if this is the case. Moreover, if resting angina occurs

shortly after adding beta-blockers the medication should be

discontinued.

Finally, as mentioned above, another obvious implication of

diagnosing coronary vasospasm, for instance, in the setting of

unstable angina, is that any form of invasive therapeutic pro-

cedure such as stenting or even bypass grafting is contra-

indicated unless severe atherosclerotic coronary disease is also

present.[24]

10. Conclusions

Coronary vasospasm should be an important differential

diagnosis in patients with angina pectoris, particularly when

occurring exclusively at rest. Coronary vasospasm occurs in old

and young persons, in men and women. The key for the diag-

nosis is not the observation of ST-segment elevation. If coro-

nary vasospasm was to be diagnosed solely on the basis of an

ECG showing this feature, we estimate that more than 90%of European patients with vasospastic angina would not be

correctly diagnosed. An ambulatory ECG may be helpful to

make the diagnosis but only rarely so. The coronary angiogram

is very important in these patients as spasm may occur with

significant coronary artery disease but also without it. Our

experience in patients who have no culprit lesion but who have

stress-related dyspnea/angina or angina at rest is that intra-

coronary acetylcholine testing is easily and quickly performed

once it is decided that a coronary angiography will be necessary

anyway. The notion that invasive spasm testing is dangerous

and rarely necessary is wrong. Calcium antagonists and short

and long-acting nitrates are effective medications but there is

a group of patients who are refractory to both drugs.

Acknowledgments

The authors would like to thank Tracy Harrison of inScience Com-

munications, a Wolters Kluwer business, who assisted with native English

editing and journal styling before submission. This assistance was funded

by Pfizer. None of the authors have any conflicts of interest that are di-

rectly relevant to the content of this review.

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Correspondence: ProfessorUdo Sechtem, Department of Cardiology, Robert-

Bosch-Krankenhaus, Auerbachstrasse 110, D-70376 Stuttgart, Germany.

E-mail: [email protected]

26 Sechtem et al.


coronary vasospasm: is it a myth?

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