Journal of Cardiology (2011) 57, 2—7
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/jjcc
Review
The role of vascular failure in coronary artery spasm
Hiroaki Kawano (MD, PhD) ∗, Koichi Node (MD, PhD, FJCC)
Department of Cardiovascular & Renal Disease Medicine, Saga University, Saga, 5-1-1, Nabeshima, Saga City 849-8501, Japan
Received 8 August 2010; accepted 11 August 2010
Available online 9 November 2010
KEYWORDS
Coronary spasm;
Endothelium;
Vascular smooth
muscle;
Vascular failure
Summary Coronary artery spasm plays an important role in the pathogenesis of angina pectoris as well as acute coronary syndrome and sudden death. The prevalence of coronary spasm
is greater in East Asian populations than in other parts of the world. Although the mechanism
of coronary spasm is still unclear, both endothelial and smooth muscle dysfunction have been
reported to play a role. We recently proposed a new concept termed ‘vascular failure’ that represents an integration of endothelial and smooth muscle abnormalities. Thus, vascular failure
is the primary cause of coronary artery spasm.
© 2011 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Contents
Introduction ................................................................................................................
Vascular failure.............................................................................................................
Endothelial function in coronary spasm .....................................................................................
Coronary smooth muscle in coronary spasm.................................................................................
Conclusions.................................................................................................................
References .................................................................................................................
Introduction
Angina pectoris is a clinical syndrome caused by transient
myocardial ischemia due to an imbalance between the
myocardial oxygen supply and demand. Classical or exertional angina is characterized by the following features: (I)
the attack is induced by exertion and relieved by rest or
∗ Corresponding author. Tel.: +81 952 34 2364;
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E-mail addresses: [email protected],
[email protected] (H. Kawano).
2
4
4
6
6
6
nitroglycerin administration; and (II) the attack is associated
with ST-segment depression on the electrocardiogram.
Coronary spasm plays an important role in angina pectoris as well as acute coronary syndrome [1]. Coronary
spasm is defined as abnormal contraction of an epicardial
coronary artery resulting in myocardial ischemia (Fig. 1).
The manifestations commonly associated with myocardial
ischemia are chest discomfort and ST elevation or depression
on the electrocardiogram. ST elevation denotes transmural
myocardial ischemia, whereas ST depression indicates nontransmural or subendocardial ischemia. The most sensitive
marker of myocardial ischemia is the appearance of a wall
motion abnormality, which can be detected by echocardio-
0914-5087/$ — see front matter © 2011 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.jjcc.2010.08.007
The role of vascular failure in coronary artery spasm
Figure 1
Representative case of coronary spasm [36].
graphy [2]. The production of lactate is a metabolic marker
of myocardial ischemia [3].
To evaluate the incidence of coronary spasm in Japanese
patients with angina pectoris, we investigated 2195 patients
with angina who were consecutively admitted to one of the
Figure 2
3
major institutes in Japan from 1998 to 1999 (mean age,
65.2 years). Of the 2195 patients with angina, 921(42%)
had coronary spasm. The number of patients with angina
pectoris increases with an increase in age. The mean
age of the patients with coronary spasm was 62.5 ± 10.3,
Prevalence of coronary spasm in Japan.
4
H. Kawano, K. Node
injury that ultimately leads to the formation of atheromatous or fibrous plaques. We recently proposed a new
concept termed ‘vascular failure’ that represents an integration of the endothelial and smooth muscle abnormalities
[4] (Fig. 4).
It is now well recognized that endothelial dysfunction is the initial stage of atherosclerosis. Endothelial
dysfunction is characterized by an impairment of the
balance between endothelium-derived relaxing factors
and endothelium-derived constricting factors [5,6]. Thus,
endothelial dysfunction is not only the initial stage of
atherosclerosis but also plays a key role in angina pectoris
induced by coronary spasm.
Endothelial function in coronary spasm
Figure 3 Age distribution of coronary spastic angina and stable effort angina in Japanese patients with angina pectoris.
whereas that of the patients with stable effort angina
was 67.0 ± 9.2 (p < 0.01). The age distribution was relatively younger in the patients with coronary spasm than
in those with stable effort angina (Figs. 2 and 3). The
prevalence of hypertension, diabetes mellitus, and low
high-density lipoprotein (HDL)-cholesterol was lower in the
patients with coronary spasm than in those with stable
effort angina (hypertension, 39.8% vs. 49.0%; diabetes,
12.4% vs. 23.2%; low HDL cholesterol, 16.6% vs. 30.6%;
p < 0.01). In contrast, the proportion of smokers was higher
in the patients with coronary spasm than in the patients
with stable effort angina (42.6% vs. 32.6%, p < 0.01). Most
of the patients with coronary spasm did not have significant fixed coronary stenosis, whereas all patients with
stable effort angina had significant fixed coronary stenosis
(Table 1).
Vascular failure
Atherosclerosis is a progressive disease characterized by
the response of the vessel wall to chronic, multifactorial
Table 1
The endothelium is a flat monolayer of cells that covers
the vascular lumen throughout the human body. Endothelial cells are not merely constituents of the vessel wall,
but play important roles in several biological processes [7].
Thus, the vascular endothelium has been characterized as
a multifunctional organ that it is essential to normal vascular physiology and plays a critical role in the pathogenesis
of vascular disease. In fact, there are several studies that
show that endothelial dysfunction is an independent predictor of cardiovascular events [8—10]. The presence of
endothelial dysfunction is an essential component of vascular failure.
Acetylcholine causes vasodilation by releasing nitric
oxide or closely-related substances [5,6]. Coronary spasm
can be induced by methacholine or acetylcholine in
patients with coronary spasm via muscarinic receptors
[11,12] (Table 2). In humans, acetylcholine, serotonin, histamine, and ergonovine are all endothelium-dependent
vasodilators, since they release nitric oxide and induce
coronary dilation in young healthy subjects; however,
they cause vasoconstriction in patients with atherosclerosis [6,13—15]. Thus, patients with coronary spasm have a
disturbance in endothelial function of the coronary arteries
[16].
Characteristics of patients with coronary spasm or stable effort angina.
Age (years)
Sex (men)
Hypertension
Diabetes
Hypercholesterolemia
Low HDL-cholesterolemia
Hypertriglyceridemia
Smoker
Obesity
Family history
Coronary stenosis
No stenosis
Single vessel
Multivessel
HDL, high-density lipoprotein.
Coronary spasm (n = 921)
Stable effort angina (n = 1274)
62.5 ± 10.3
607(65.9%)
367(39.8%)
114(12.4%)
216(23.5%)
153(16.6%)
264(28.7%)
392(42.6%)
242(26.3%)
142(15.4%)
67.0 ± 9.2
896(70.3%)
624(49.0%)
296(23.2%)
311(24.4%)
390(30.6%)
401(31.5%)
465(36.5%)
350(27.5%)
208(16.3%)
<0.0001
<0.05
<0.0001
<0.0001
NS
<0.0001
NS
0.004
NS
NS
83.1%
12.6%
4.3%
0%
36.7%
63.3%
<0.0001
<0.0001
<0.0001
The role of vascular failure in coronary artery spasm
Figure 4
Schema of mechanism for coronary spasm.
Smoking is closely associated with coronary spasm [17],
but the mechanism(s) is still unclear. In animal models,
cigarette smoke extract suppressed acetylcholine-induced,
endothelium-dependent dilation, and this suppression was
prevented by antioxidants or superoxide dismutase [18—20].
Thus, smoking reduces nitric oxide activity via oxygenderived free radicals contained in cigarette smoke [21,22].
Both basal and acetylcholine-induced coronary endothelial
dysfunction are improved by the intracoronary injection of
vitamin C, an antioxidant, in patients with coronary spasm
[23]. Vitamin E concentration is relatively low in patients
with coronary spasm as compared with healthy subjects
Table 2
5
Precipitating factors for coronary spasm.
1. Physiological factors
(1) Rest
(2) Physical and emotional stress
(3) Coronary spasm
(4) Straining
(5) Exposure to cold
(6) Hyperventilation
(7) Aging
(8) Others
2. Pharmacological agents
(1) Catecholamines (epinephrine/norepinephrine,
dopamine/dobutamine, etc.)
(2) Parasympathomimetic agents (acetylcholine,
methacholine, etc.)
(3) Anticholinesterase agents (physostigmine, neostigmine,
etc.)
(4) Ergot alkaloids (ergonovine, ergotamine, etc.)
(5) Others (serotonin, prostaglandins, histamine, smoking,
CaCl2 , Tris-buffer, etc.)
3. Genetic factors
[24], and vitamin E administration is an effective treatment
for coronary spasm [25]. Thus, administration of antioxidants in addition to conventional treatment is beneficial for
coronary spasm.
Insulin resistance has been reported to play an important role in the pathogenesis of coronary heart disease
[26,27]. Insulin causes endothelium-dependent vasodilation
by releasing nitric oxide [28], and endothelium-dependent
vasodilation is impaired in patients with insulin resistance [29]. Insulin sensitivity and endothelial function are
decreased by cigarette smoking, and antioxidants such as
vitamin C improve insulin sensitivity and endothelial function in smokers [30]. The decreased endothelium-dependent
vasodilation observed in these subjects may result from the
inactivation of endothelium-derived nitric oxide by reactive
oxygen species [31]. The fasting glucose levels were not
different between patients with coronary spasm and controls, whereas fasting insulin levels were higher in patients
with coronary spasm than in controls [32]. Insulin sensitivity, as assessed by the steady state plasma glucose
method, was impaired in patients with coronary spasm
compared with controls. Antioxidants, such as vitamin C,
can improve insulin sensitivity and endothelial function in
patients with coronary spasm. Thus, reactive oxygen species
and/or decreased nitric oxide bioactivity may play important roles in the genesis of both endothelial dysfunction and
insulin resistance in patients with coronary spasm.
The endothelium plays an important role in the regulation of blood flow to insulin-sensitive tissues, and insulin
induces endothelium-dependent vasodilation [28,32]. Reactive oxygen species cause endothelial dysfunction that may
contribute to insulin resistance through impaired delivery
of insulin to insulin-sensitive tissues such as skeletal muscle
[33]. In addition, it is possible that reactive oxygen species
may cause flow-independent insulin resistance by inhibiting
insulin receptor signaling [34].
6
Coronary smooth muscle in coronary spasm
Contraction of vascular smooth muscle depends on an
increase of intracellular calcium ions [35]. Coronary smooth
muscle of patients with coronary spastic angina shows a
hypercontractile response to various stimuli such as acetylcholine or histamine [11,12,16,20,36]. This phenomenon
may be caused by increased smooth muscle cell mass and/or
increased receptor activation. Increased intimal thickening
and hyperplasia of coronary arteries is involved in coronary
spastic angina [37,38]. The phosphorylation of myosin light
chain is the initial step for vascular smooth muscle contraction [35]. The contraction of coronary arteries occurs
via Ca2+ /calmodulin-activated myosin light chain kinase
with subsequent phosphorylation of myosin light chain [35].
Myosin light chain phosphorylation is augmented in animal models with vascular spasm [39]. Rho-kinase augments
myosin phosphorylation by inhibiting myosin phosphatase,
leading to contraction of vascular smooth muscle [40].
Shimokawa and colleagues reported that protein kinase
C and Rho-kinase activity were augmented in coronary
smooth muscle of animal models with coronary spasm
[41]. Thus, coronary spasm can also be regarded as a
hypercontraction of coronary smooth muscle induced by
an increase of intracellular calcium ions [42,43]. Calcium
antagonists, which can block the entry of calcium ions into
the cell, are very effective in suppressing coronary spasm
[44].
Conclusions
Coronary spasm plays an important role in the pathogenesis of ischemic heart disease in general, including
acute coronary syndromes. Acetylcholine, which is an
endothelium-dependent vasodilator, can provoke coronary
spasm possibly due to the presence of injured endothelium.
Thus, patients with coronary spasm have a disturbance in
endothelial function of the coronary arteries as well as a
hypercontractile response of vascular smooth muscle. These
findings suggest that vascular failure plays a crucial role in
the pathogenesis of coronary spasm.
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