Coronary Vasospastic Angina: Current Understanding and · PDF fileCoronary Vasospastic Angina: Current Understanding and the Role of Inflammation ... maleate, methylergonovine maleate,

Coronary Vasospastic Angina: Current

Understanding and the Role of Inflammation

Ming-Jui Hung and Wen-Jin Cherng

Coronary vasospastic angina (CVsA) plays an important role in myocardial ischemia including stable angina, acute

coronary syndromes, and sudden cardiac death. Inflammation status from either endothelium or adventitia can

cause endothelial dysfunction. Thereafter, the endothelial dysfunction further induces vascular smooth

muscle hypercontraction through the enhanced rho-kinase with the resultant clinical event. With better

understanding of the interactions between inflammation, endothelium, and smooth muscle cells, we and other

investigators have provided new insights into the basic pathophysiology of CVsA. Apart from calcium channel

blockers, nitrates, and the rho-kinase inhibitor fasudil, anti-inflammatory treatment is helpful in some patients

with refractory CVsA. Additional studies are needed to clarify the mechanisms of recurrent CVsA.

Key Words: Angina � Coronary vasospasm � Inflammation

HISTORY OF CORONARY VASOSPASM (CVsp)

In 1959, Prinzmetal and his colleagues described a

syndrome characterized by angina at rest with transient

ST-segment elevation in patients with diseased coronary

arteries, which is different from that seen in classic an-

gina.1

In these circumstances where the heart burden is

not increased, the angina must be due to a reduction in

coronary blood flow. Prinzmetal proposed the term “vari-

ant angina” and suggested that it was caused by spasm of

a major coronary artery, because it was relieved promptly

by administration of nitroglycerin. With the advent of

coronary angiography, it became apparent that variant

angina was caused by CVsp and it may occur at the site of

a coronary stenosis2

or in normal coronary arteries, the

so-called “variant of the variant”3

or “coronary vasospastic

angina (CVsA)”.4

Recently, many investigators found that

much of the underlying cause of CVsA is associated with

ST-segment depression rather than ST-segment elevation.5,6

Therefore, the term “variant angina” is usually denoted

as angina with transient ST-segment elevation.

CLINICAL CHARACTERISTICS OF CVsA

CVsA is different from typical atherosclerotic angina in

the pathophysiologies. CVsp, however, might be induced

by exercise, particularly in the morning in some patients

with variant angina,7

and might cause exercise-induced

angina with ST-segment depression in some patients with

stable effort angina5

(Figure 1). The authors postulated that

the spastic arteries are not normal, in that the spastic ar-

teries cannot dilate fully in response to exercise as in nor-

mal coronary arteries. There are daily, weekly, monthly,

and circadian variations in the incidence of CVsA.8

Circadian variation in the incidence of attacks in

patients with CVsA

CVsA occurs usually at rest, particularly from mid-

night to early morning.9

Yasue et al.10

compared coro-

1 Acta Cardiol Sin 2013;29:1�10

Review Article Acta Cardiol Sin 2013;29:1�10

Received: June 28, 2012 Accepted: September 19, 2012

Department of Cardiology and Medical Research Center, Chang

Gung Memorial Hospital, Keelung, Chang Gung University College of

Medicine, Taiwan.

Address correspondence and reprint requests to: Dr. Ming-Jui Hung,

Department of Cardiology, Chang Gung Memorial Hospital, No. 222,

Maijin Road, Keelung 20401, Taiwan. Tel: 886-2-2431-3131 ext.

3168; Fax: 886-2-2433-5342; E-mail: [email protected]

nary arteriograms recorded in the early morning with

those recorded in the afternoon in patients with variant

angina. In the early morning, the tone of the major cor-

onary artery was increased and its diameter was small.

Under such conditions, mild exercise could induce CVsp

resulting in attacks; the administration of nitroglycerin

dilated the artery markedly. In contrast, in the after-

noon, the major coronary artery was usually already di-

lated, and its tone was low on the control coronary ar-

teriograms. Under such conditions, exercise could in-

duce little coronary vasoconstriction and no attacks

usually occurred except in patients with severe organic

stenosis, in whom only a mild spasm could occlude the

artery and result in angina attacks. To record quantita-

tively the difference in the tone in the major coronary

arteries observed in the early morning and in the after-

noon, Yasue et al.10

measured the diameter of the major

coronary artery on both the control coronary arterio-

grams and the coronary arteriograms taken after nitro-

glycerin administration. The percentage increase in di-

ameter of the major coronary artery after nitroglycerin

administration was significantly greater in the early

morning than in the afternoon. This may be one of the

reasons that there is a circadian variation in the exercise

capacity of most patients with variant angina. A pathol-

ogy study illustrated the complexity of the local neural

events that modulate the tone of the coronary arter-

ies.11

The occurrence of CVsA in the early morning has

been noted to be associated with rapid eye move-

ment.12

Therefore, a rapid elevation of sympathetic ac-

tivity during augmented parasympathetic activity has

been suggested to be related to the occurrence of CVsA

in the early morning.

Acute coronary syndrome

There is general consensus in the medical commu-

Acta Cardiol Sin 2013;29:1�10 2

Ming-Jui Hung et al.

Figure 1. Treadmill exercise electrocardiograms (upper panels) and the coronary angiograms (lower panels) of a patient who had stable angina

pectoris. Resting (A) and peak exercise (B) status of 12-lead electrocardiograms show positive for stress-induced ischemia in the V3-6, I, and aVL leads.

The coronary angiograms reveal intracoronary methylergonovine-induced diffuse diameter reduction > 70% in the mid-to-distal portion of left ante-

rior descending coronary artery (C, arrows), which is relieved after intracoronary nitroglycerin 100 �g administration (D, arrows).

A B

C D

nity that intracoronary thrombus plays a major role in

the pathogenesis of acute myocardial infarction. Yasue

et al.13

found that CVsp was presumed to be responsible

for the acute myocardial infarction because the culprit

artery was patent without delay of visualization in

17.9% of patients in the early phase of acute myocardial

infarction. Our report also found that the responsible

coronary arteries were patent in 12% of patients with

acute myocardial infarction (Figure 2).14

There was in-

farct-related CVsp involvement in 95% in these patients.

This may be explained by the spontaneous resolution of

either spasm or thrombus, or both. Oshima et al.15

re-

ported that CVsp causes intracoronary thrombus forma-

tion, supporting the concept that CVsp is one of the pri-

mary factors contributing to acute myocardial infarc-

tion. Therefore, CVsp appears to play a role in the pro-

duction of acute myocardial infarction in these patients.

Most of the patients with CVsA present as angina

with ST-segment depression and/or T-wave inversion on

electrocardiogram, which is an acute coronary syn-

drome. If there is no cardiac enzyme elevation, we de-

fine the cardiac event as an unstable angina because

most of the CVsA occurs at rest. Angiographically normal

or near-normal coronary arteries occurs in 25% of pa-

tients with acute coronary syndrome irrespective of the

provocative agents.16,17

The CVsp can be induced in

50-60% of these patients. After initial management (i.e.

oxygen, aspirin, nitroglycerin, and/or morphine) for

acute coronary syndrome, follow-up electrocardiograms

are important to indicate the role of CVsp for the acute

coronary syndrome. If there is a normalized ST-segment

after the initial management, the CVsp may play a role

in acute coronary syndrome.

Intracoronary administration of methylergonovine

Provocative testing for CVsp is required to clarify its

role in the pathogenesis of angina pectoris, especially in

patients without significant obstructive coronary artery

disease (CAD). To ensure a valid provocative test, vasodi-

lators (calcium antagonists and nitrates) must be with-

drawn for at least 24 hours, except sublingual nitroglyc-

erin if necessary. The nitroglycerin solution must be well

prepared before starting intracoronary methylergo-

novine testing, in part to abolish intracoronary me-

thylergonovine-induced CVsp immediately through the

intracoronary route (50-1000 �g). There have been

several agents or procedures, including ergonovine

maleate, methylergonovine maleate, acetylcholine or

hyperventilation reported that induce CVsp in patients

with CVsA. Intracoronary ergonovine administration has

been a popular method to induce CVsp during angio-

graphic study because of its high sensitivity and specific-

ity.18

This test was administrated using a step-wise dose

of ergonovine (1, 5, 10, and 30 �g) every 3 minutes;


Inflammation and Coronary Vasospasm

Figure 2. A serial 12-lead electrocardiograms and the coronary

angiograpms of a patient who had coronary vasospasm-induced acute

myocardial infarction. The patient had normal coronary angiograms 1

year before acute myocardial infarction. Initial resting 12-lead electro-

cardiograms at emergency department showed complete atrioven-

tricular block with ST-elevation in the II, III, aVF and V1-4 (A) and right

ventricular infarction (B). The emergency coronary angiogram revealed

total occlusion of right coronary artery since the orifice (C, arrow)

inititally. After intra-aortic nitroglycerin 200 �g administration, patent

proximal and mid-portion of right coronary artery with thrombi-oc-

cluded (D, arrow) in the distal portion of right coronary artery was

noted. A thrombuster-catheter (E, arrow) was used to aspirate thrombi.

After thrombi suction and further intracoronary 200 �g nitroglycerin ad-

ministration, the right coronary artery was patent (F). The 12-lead elec-

trocardiograms recorded at the day after coronary intervention (G) and

6 months later (H) showed evolutional electrocardiographic ST-segment

and T-wave changes of inferior myocardial infarction.

A B

C D

E F

G H

the drug was first introduced into the right coronary ar-

tery and subsequently into the left coronary artery.

CVsp was defined as a decrease of � 50%19

or 70%20

in

the diameter of an arterial lumen with concurrent chest

pain and/or ischemic ST-T changes during the provoca-

tion testing. Recently, the Japanese Circulation Society

published a guideline to define a positive indicator on a

provocative test as a decrease of � 90% in the diameter

of an arterial lumen, with concurrent chest pain and/or

ischemic ST-segment changes during the provocation

test.4

However, Yasue et al.8

suggested that there are no

limits on the degree of lumen diameter reduction re-

quired to diagnose CVsp since ischemia must accom-

pany the changes of vessel size in a period of time. Al-

though there are different criteria in vessel diameter,

the angina and/or ischemic electrocardiographic changes

during provocation testing are necessary in defining a

positive provocation test result. After a CVsp had been

diagnosed, the administration of intracoronary ergo-

novine was stopped and 50-1000 �g of intracoronary ni-

troglycerin was administered. The ergonovine maleate

and acetylcholine are not available in Taiwan. Therefore,

only methylergonovine maleate was used in the CVsp

provocative testing in our studies, with the same in-

tracoronary dose regimen as in ergonovine maleate. Al-

though it is useful in the diagnosis of CVsA, safety is still

a major concern. The contraindications for intraco-

ronary methylergonovine testing included pregnancy,

severe hypertension (systolic blood pressure > 180 mm

Hg), moderate to severe aortic stenosis and uncon-

trolled ventricular arrhythmia.19

Some studies have re-

ported complications of intravenous injection of er-

gonovine in patients who underwent cardiac cathe-

terization, including ventricular tachycardia, ventricular

fibrillation, and death.21,22

The importance of intra-

coronary nitroglycerin rather than intravenous or sub-

lingual route in relieving provocative CVsp is empha-

sized.22

Since Hackett et al.18

introduced the intra-

coronary route for provocation testing in 1987, the gen-

eral consensus has been that the intracoronary rather

than the intravenous route is safer because of negligible

drug recirculation and avoidance of effects on branches

with critical stenosis.19

Recently, a Japanese multicenter

study found that intracoronary ergonovine provocation

testing induces ventricular tachycardia/ventricular fibril-

lation in 0.8% of patients with CVsA,23

which is similar to

our prior study.24

They concluded that spasm provoca-

tion tests have an acceptable level of safety; the evalua-

tion of spasm type may provide useful information for

the risk stratification of CVsA patients. Consistent with

the Japanese study, there was no mortality reported in

our prior study.24

Because ventricular tachycardia or

ventricular fibrillation is a possible complication follow-

ing intracoronary methylergonovine administration, its

use outside the cardiac catheterization laboratory is not

recommended.

In theory, the diagnosis of CVsp must be made on

the coronary angiographic findings during the attack.

However, it is not practical to perform coronary angio-

graphy during an attack in every patient, and this step is

unnecessary. During coronary angiography, adequate

doses (50-1000 �g) of intracoronary nitroglycerin ad-

ministration help cardiologists differentiate spontane-

ous CVsp from fixed obstructive CAD. Angina pectoris

that is relieved promptly after nitroglycerin may be diag-

nosed as CVsA even without angiographic evidence, if

one of following characteristics is noticed:8

1) the attack

occurs at rest, particularly from midnight to early morn-

ing; 2) there is marked circadian variation of exercise ca-

pacity, the attack easily induced by exercise in the

morning but not by even vigorous exercise in the after-

noon; 3) the attack is associated with ST-segment eleva-

tion on the electrocardiogram; 4) the attack is induced

by hyperventilation; or 5) the attack is suppressed by

calcium antagonists, but not by beta-blockers.

Prevalence of CVsp

In the Japanese population, CVsp frequency appears

to be greater than that in Western populations,25

and

the diagnosis of variant angina (angina with transient

ST-segment elevation) is made in a high percentage

(10% to 70%) of patients with anginal symptoms re-

ferred to Japanese medical centers. Our prior investiga-

tion also found that 27% of angina patients who under-

went coronary angiography and had CVsA (angina with

and without transient ST-segment elevation).26

In pa-

tients who had angina and no significant obstructive

CAD, the prevalence of CVsp was around 50%.27

In pa-

tients who had acute coronary syndrome and no signifi-

cant obstructive CAD, the prevalence of CVsp was esti-

mated to be 57%,17

which is similar to data from Ger-

many.16

The diagnosis of CVsp depends on angiographic



protocols and provocation tests, which varies from labo-

ratory to laboratory. Premedication with spasmolytic

drugs such as nitroglycerin or calcium antagonists,

avoidance of coronary constrictors, and daily or monthly

variation of disease activity may lead to a failure to diag-

nose CVsp. Therefore, an estimate of the prevalence of

CVsp in different populations remains to be defined. Al-

though the racial difference in coronary constrictor re-

sponse has been strongly suggested,25

the underestima-

tion of CVsp worldwide is an important issue in the cur-

rent percutaneous coronary intervention era.

Risk factors for the development of CVsA

Cigarette smoking was found to be an unequivocal

risk factor for CVsA in the literature (adjusted odds ratio

of 2.41).28

Similarly, our investigation29

has found a

multivariate-adjusted odds ratio of 2.58, which is similar

to other studies. In our recent study, synergistic interac-

tion was verified between smoking and high-sensitivity

C-reactive protein (hs-CRP) in the development of

CVsp.29

This interaction was linear and monotonic among

smokers. In nonsmokers, however, hs-CRP had a th-

reshold effect on CVsp development. A decreased odds

ratio to 2.12 was observed when hs-CRP was added into

the multivariate analysis between smoking and CVsp,

suggesting that hs-CRP was an important covariate of

CVsp. Further analysis showed that the relationship be-

tween hs-CRP and CVsp differs between men and wo-

men.30

The non-threshold model in men and a threshold

model in women provide evidence that more smokers in

men (life-style) and age (induction time) contribute to

the natural history of CVsp development. In addition,

we also found that hypertension is a negative predictor

for CVsp, which suggests that the pathogenesis of CVsp

differs from that of coronary atherosclerosis.

Treatment and prognosis of CVsA

Table 1 depicts the treatment strategies for CVsA

patients. Calcium antagonists play a cornerstone role in

the management of CVsA.8

Of importance, the long-act-

ing calcium antagonist should be given before going to

bed at night as CVsA occurs usually from midnight to the

early morning.8

Usually, a high-dose long-acting calcium

antagonist (e.g. nifedipine 80 mg/day, amlodipine 20

mg/day, diltiazem 360 mg/day, or verapamil 480 mg/

day) is started.31

It may require 2 calcium antagonists

(dihydropyridine and non-dihydropyridine) to relieve

CVsA. While long-acting nitrates are also effective in

preventing CVsA attack, the occurrence of nitrate toler-

ance may limit their use as a first-line approach.8,32

In

contrast, �-blockers do not suppress, but rather may ag-

gravate CVsp in patient with variant angina.32

Although

platelets may play a role in precipitating or aggravating

CVsp, intravenous prostacyclin or cyclooxygenase inhibi-

tors have thus far not been shown to have beneficial ef-

fects.32

Recent clinical research shows that magnesium,

antioxidants, rho-kinase (ROCK) inhibitor fasudil, and

fluvastatin are also beneficial to treat CVsA.8

Addition-



Table 1. Treatment strategies for CVsA

Strategy Recommendation

Cigarette cessation Obligatory

Long-acting calcium antagonist 1. Use before going to bed at night

2. Combination of dihydropyridine and non-dihydropyridine if recurrent CVsA

Long-acting nitrates Decreased potency by tolerance

Statin Fluvastatin

Magnesium Intravenous infusion

RhoA/ROCK inhibitor Intravenous or oral Fasudil

Vitamin C Intravenous infusion

Vitamin E Oral

Valsartan A case report

Prednisolone Case reports

Coronary artery bypass surgery Controversial

Coronary stenting Controversial

Implantable cardioverter defibrillator For life-threatening ventricular arrhythmias

CVsA, coronary vasospastic angina; ROCK, Rho-associated coiled-coil containing protein kinase.

ally, the aggravating factors for CVsA such as cigarette

smoking, catecholamines, muscarinic agonists, ergot al-

kaloids, prostaglandins, alcohol, emotional stress, and

propranolol must be avoided. Coronary intervention

plays a limited role in patients with CVsA and organic

stenosis.33

In the current coronary stenting era, there

are some reports of coronary stenting in the manage-

ment of drug-refractory CVsA.34-36

Gaspardone et al.34

reported that coronary stent placement is effective in

preventing angina attacks and methylergonovine-in-

duced CVsp in 6 of 9 patients 6 months after stenting.

They performed coronary stent placement in CVsA pa-

tients because of persistent angina attacks despite med-

ical treatment (up to 960 mg diltiazem or 100 mg

nifedipine and nitrates). Other reports also showed suc-

cessful coronary stenting in the management of CVsA.

However, their reports did not use the combination and

maximal doses of 2 calcium antagonists in terms of ag-

gressive medical therapy for CVsA.35,36

In theory, the cor-

onary stenting is considered to be effective to abolish

the CVsA in the absence of concomitant calcium antago-

nist treatment after coronary stenting. Calcium antago-

nists were still used after coronary stenting in these re-

ports indicating that single-vessel or multi-vessel CVsp

may develop at sites different from the initial stenosis.

Therefore, Yuksel et al.37

suggested that before coronary

stenting can be advocated as an established treatment

resistant to maximal medical therapy, a randomized trial

should be carried out. Nevertheless, approximately 20%

of CVsA patients do not respond to treatment with 2 cal-

cium antagonists plus a long-acting nitrates.31

Under the

circumstances, coronary stenting in combination with

adequate coronary vasodilators doses may be helpful in

patients CVsA and severe organic stenosis.4,31,32,38

On

the other hand, coronary interventions are contraindi-

cated in patients with CVsA without severe organic ste-

nosis.4,31,38

As coronary arteries treated with coronary

interventions show time-dependent loss of endothe-

lial-dependent and -independent vasomotor function,

with imbalanced contraction/dilation capacity,39

the

suggestion has been that cardiologists must keep CVsA

in mind before performing coronary intervention.8,34,37

An implantable cardioverter defibrillator with aggressive

medical therapy for CVsA was reported to be effective in

patients who had syncope, ventricular tachycardia, or

survived cardiac arrest outside the hospital.4

The prognosis among Japanese patients with variant

angina is better than that among western patients.40,41

The difference is probably due to the fact that the per-

centage of patients with multivessel disease or impaired

left ventricular function or both was smaller, and the

percentage of patients who received a calcium antago-

nist (diltiazem or nifedipine) as the initial treatment was

higher in the Japanese series.40

By multivariate analysis,

the intake of calcium antagonists, extent and severity of

coronary artery disease, and multivessel CVsp were

shown to be significantly independent predictors of sur-

vival without myocardial infarction. In Taiwanese pa-

tients who had CVsA and no significant obstructive CAD,

the long-term prognosis was found to be good despite

11% of recurrent CVsA.42

The most common factors for

recurrent CVsA are continued smoking and self-discon-

tinuation of calcium antagonists. The occurrence of an-

gina attacks is difficult to assess in individuals with CVsA

because their frequency tends to fluctuate spontane-

ously and the attacks are not necessarily accompanied

by symptoms. Based on the observation of recurrent an-

gina pectoris, it appears reasonable to suggest that

treatment should not be discontinued in cases of CVsA,

even when the patients are asymptomatic.42,43

INFLAMMATION AND CVsA

Determinants of CVsp: endothelium and smooth

muscle

There is no single mechanism that can explain the

entire process of CVsA. In 1980s, the autonomic nervous

system was found to play an important role in the

pathophysiology of CVsA.8

In the 1990s, oxidative stress,

deficiency of nitric oxide activity, respiratory alkalosis,

magnesium deficiency and insulin deficiency were iden-

tified as other possible mechanisms for CVsA.8

In the

late 1990s and early 2000s, mutation of the promoter in

endothelial nitric oxide synthase gene8

and polymor-

phism of paraoxonase gene44

were found to be associ-

ated with CVsA. In another large Japanese cohort

study,45

The nicotinamide adenine dinucleotide hydro-

gen/nicotinamide adenine dinucleotide phosphate hy-

drogen oxidase p22 phox gene is a susceptibility locus

for CVsp in men, and the stromelysin-1 and interleukin-

6 genes are susceptibility loci in women. In this study,



the inflammation gene was firstly identified to be as-

sociated with CVsp. These findings indicate that dys-

functional endothelium secondary to down-regulation

of endothelial nitric oxide synthase and oxidative inacti-

vation of nitric oxide is one of the major mechanisms re-

sponsible for CVsA. In addition, inflammation is indi-

cated as a possible contributor in the development of

CVsA. However, a deficiency of endothelial nitric oxide

may not explain the complete mechanism of CVsA be-

cause all atherosclerotic coronary arteries are not nec-

essarily associated with CVsp in spite of the deficiency

of nitric oxide activity. In 2006, Kakket et al.46

found that

spontaneous CVsp occurs in KATP mutant mice, which

arise from a smooth muscle-extrinsic process. They pos-

tulated that endothelial dysfunction with loss of KATP

channels and decreased nitric oxide production and/or

bioavailability promotes smooth hypercontraction. Ano-

ther possibility includes the sympathetic neurons,

where opening of presynaptic KATP channels decreases

norepinephrine release, enhancing smooth muscle relax-

ation to dilate coronary arteries. A defect in these chan-

nels decreasing the threshold for norepinephrine re-

lease might be associated with CVsp. In 2011, Qipshidz

et al.47

found that folic acid treatment attenuates acetyl-

choline-induced coronary vasoconstriction in hyper-

homocysteinemic cystathionine beta synthase hyter-

zygote mice. They suggested that CVsp is related to the

regulation of endothelial nitric oxide synthase expres-

sion, nitric oxide availability, and tissue homocysteine.

In addition to deficient endothelial nitric oxide ac-

tivity, hyperreactivity of the coronary smooth muscle

seems to play an important role in the pathogenesis of

CVsA.48

Shimokawa and colleagues developed swine

models of CVsp and showed that ROCK activity is en-

hanced in coronary artery smooth muscle after wrap-

ping the coronary artery with interleukin-1 beads.48

They also demonstrated that ROCKs expression and ac-

tivity are enhanced at the inflammatory/arteriosclerotic

coronary lesions.49

Recently, we50

found that ROCK ac-

tivity in circulating neutrophils is a useful biomarker for

the diagnosis and disease activity assessment in patients

with CVsA. Some investigators found that decreased en-

dothelial nitric oxide synthase activity increase ROCK ac-

tivity in coronary arteries.51

These findings connect the

activity of ROCK to endothelial nitric oxide and are in

agreement with the clinical observations that spastic

arteries are inflammatory and are supersensitive to

both vasoconstrictor agonists and nitrates.

Role of inflammation

In 1978, Lewis et al.52

first reported a patient who

died of cardiogenic shock due to variant angina and lo-

calized pericarditis. They postulated that there was a

link between inflammation and CVsA. In the mid and

later 2000s, we showed that chronic inflammation was

associated with CVsA, as evidenced by elevated peri-

pheral leukocyte and monocyte counts, hs-CRP, inter-

leukin-6, and adhesion molecules.27

It was demon-

strated that the serum level of cortisol, one of the im-

portant stress hormones, causes coronary hyperre-

activity through activation of ROCK in pigs in vivo.53

Cigarette smoking, a major risk factor for CVsA, is as-

sociated with low-grade inflammation.54

These findings

suggest that there is increased inflammatory status in

patients with CVsA and the inflammation may con-

tribute to the occurrence of CVsp. An interaction be-

tween smoking and hs-CRP was recently reported by

our group and the relationship between hs-CRP and

CVsA differed between men and women.30

We also

have recently demonstrated that ROCK activity in pe-

ripheral leukocyte independently predicts the presence

and severity of CVsA and the level of ROCK activity cor-

relates with plasma interleukin-6.50

These findings sug-

gest that there is increased inflammatory status in pa-

tients with CVsA and the inflammation may cause endo-

thelial dysfunction, ROCK activity accentuation and fi-

nally contribute to the vascular smooth muscle hyper-

contraction, the occurrence of CVsp.

Some investigators found that inflammatory clinical

condition is associated with CVsA.8

Several reports have

suggested a possible link between allergic disease and

CVsA.55,56

The pathogenesis of bronchial asthma has

been recently attributed to hyperreactivity of the air-

way caused by inflammation, and corticosteroids are

considered to work by alleviating that inflammation.57

There is an analogy with the pathophysiology of CVsA

and bronchial asthma; that is CVsp may be induced by

arterial hyperreactivity caused by local inflammation in

the coronary arterial wall and corticosteroids suppress

the hyperreactivity by alleviating the inflammation in

the vessel wall. In fact, Forman et al.58

reported a pa-

tient with CVsA complicated by sudden death in whom



mast cell infiltration was found at the site of angio-

graphic documentation of CVsp, which indicates that

CVsp can also occur as the result of adventitial inflam-

mation in addition to endothelial inflammation. Some

other studies also reported that focal infiltration of in-

flammatory cells was seen in the adventitia or plaque of

the coronary artery in patients with CVsA.59

Even where

there is no evident narrowing during angiography, dif-

fuse intimal thickening or intimal bump by precursor

medial contraction is demonstrated from optical coher-

ence tomography.60,61

Nitric oxide availability is reduced

under the circumstances of low-grade inflammation of

atherosclerosis or diffuse intimal thickening.62

Endothe-

lial nitric oxide synthase has been reported to be quan-

titatively associated with caveolin-1 in endothelial cells.

The vascular relaxation in response to acetylcholine was

also much larger in aortic rings collected from caveolin-

1–/–

mice than in their wild-type littermates.63

Of note,

isolated aortic rings from caveolin-1–/–

mice were unable

to maintain a constant contractile tone, oscillating at 1

Hz frequency. These studies support the proposition

that, in the basal condition, endothelial nitric oxide

synthase becomes hyperactivated in the absence of

caveolin-1. Based on the above analyses, it appears rea-

sonable to speculate that CVsp is an early inflammatory

coronary artery condition because of the presence of

low-grade inflammation-related endothelial dysfunction

with resulting diffuse intimal thickening and impaired ni-

tric oxide production.64

Because the lack of normal nitric

oxide activity does impact the normal vessel, the vessel

tends to constrict in the presence of low-grade inflam-

mation such as cigarette smoking, stress, airway dis-

ease, and allergy.

CONCLUSION

Identification of CVsp is important in our daily

clinical practice because of a wide disparity between

treatment strategies for fixed obstruction versus vaso-

spasm of coronary arteries. Adequate doses of intra-

coronary nitroglycerin administration help cardiologists

differentiate spontaneous CVsp from fixed obstructive

CAD. However, cessation of cigarette smoking and

adequate dose and timing of calcium antagonists are

the cornerstone for CVsA therapy. Accumulating evi-

dence suggests that inflammation substantially con-

tributes to the development of CVsA. Clinical studies

with antiinflammtory therapies further support the role

of inflammation in CVsA. Release of inflammatory medi-

ators, such as interleukin-6, histamine, or serotonin

leads to nitric oxide availability reduction, endothelial

dysfunction, and precursor medial contraction. The final

common pathway in CVsp is vascular smooth muscle

contraction by increased ROCK activity. With the under-

standing of interactions between inflammation, endo-

thelium, and smooth muscle cells, we and other investi-

gators have provided some insights into the basic patho-

physiology of CVsp. More studies are needed to clarify

the mechanisms of recurrent CVsA.

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