Refractory Vasospasms of the Coronary Arteries due to

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963

□ CASE REPORT □

Refractory Vasospasms of the Coronary Arteries due toMultiple Factors: An Autopsy Case

Kentaro Arakawa 1, Hideo Himeno 1, Toshikazu Gondo 2, Jin Kirigaya 1, Fumie Otomo 1,

Kensuke Matsushita 1, Hidefumi Nakahashi 1, Satoru Shimizu 1, Manabu Nitta 1, Hideto Yano 1,

Mitsuaki Endo 1, Kazuo Kimura 3 and Satoshi Umemura 4

Abstract

A 41-year-old man was admitted with decompensated heart failure. Mechanical ventilation was maintained

with a large dose of propofol. On day 4, significant ST elevation with complete atrioventricular block was

noted, which subsequently induced cardiopulmonary arrest. Treatment with percutaneous cardiopulmonary

support and therapeutic hypothermia was initiated. Emergent cardiac angiography showed simultaneous mul-

tivessel coronary spasms. Although nitroglycerin and nicorandil were ineffective, the intracoronary admin-

istration of fasudil, a Rho-kinase inhibitor, successfully resolved the vasospasms. However, during rewarming,

the coronary vasospasms recurred, and the patient died of cardiogenic shock. In addition to hypertrophy, the

autopsied heart demonstrated the accumulation of inflammatory cells in the pericardium and adventitia of the

coronary arteries.

Key words: coronary artery spasm, inflammation, hypertrophic cardiomyopathy

(Intern Med 53: 963-967, 2014)(DOI: 10.2169/internalmedicine.53.1900)

Introduction

Variant angina, first described by Prinzmetal and col-

leagues in 1959, is caused by severe coronary vasospasms

associated with transmural myocardial ischemia (1). Most

patients respond to nitrates or calcium channel blockers.

However, in some cases, medical treatment-resistant vaso-

spasms have been reported. We herein present an autopsy

case of vasospastic angina refractory to conventional ther-

apy. Multiple factors are associated with the occurrence of

coronary vasospasms that cannot be relieved with medical

management.

Case Report

A 41-year-old man was admitted to our hospital with

dyspnea and chest pain. Cardiomegaly and pulmonary ve-

nous congestion were evident on a chest roentgenogram.

Electrocardiography and the laboratory data showed no evi-

dence of myocardial ischemia (Fig. 1). An echocardiogram

demonstrated concentric hypertrophy and a reduced systolic

function of the left ventricle (Fig. 2A, B). Mechanical venti-

lation was induced and maintained with a large dose of in-

travenous propofol. To treat the acute decompensated heart

failure, a continuous infusion of carperitide and nitroglycerin

was administered in addition to diuretics. On day 4, signifi-

cant ST elevation was noted on the telemetry monitor. Sub-

sequent electrocardiography revealed ST elevation in leads

II, III and aVF with complete atrioventricular block, which

subsequently induced cardiopulmonary arrest (Fig. 3). The

patient received prolonged cardiopulmonary resuscitation

and percutaneous cardiopulmonary support with therapeutic

hypothermia. Emergent cardiac angiography showed diffuse

severe narrowing of the right coronary artery (RCA) and to-

tal occlusion of the mid left anterior descending artery

１Division of Cardiology, Fujisawa City Hospital, Japan, ２Division of Pathology, Fujisawa City Hospital, Japan, ３Division of Cardiology, Yoko-

hama City University Medical Center, Japan and ４Department of Medical Science and Cardiorenal Medicine, Yokohama City University, School

of Medicine, Japan

Received for publication October 9, 2013; Accepted for publication November 24, 2013

Correspondence to Dr. Kentaro Arakawa, [email protected]

Intern Med 53: 963-967, 2014 DOI: 10.2169/internalmedicine.53.1900

964

Figure　1.　A chest X-ray and electrocardiogram obtained on admission. A: A decubitus anteropos-terior chest X-ray showing cardiomegaly and pleural effusion. B: A 12-lead electrocardiogram show-ing sinus tachycardia, biatrial enlargement and left ventricular hypertrophy.

Figure　2.　A transthoracic echocardiogram obtained on admission showing concentric hypertrophy with a reduced systolic function of the left ventricle (A: long-axis view; B: M-mode).

Figure　3.　An electrocardiogram obtained immediately prior to cardiopulmonary arrest in the intensive care unit. Marked ST-elevation in the inferior leads and complete atrioventricu-lar block were evident.

(LAD). Intravascular ultrasound demonstrated a myocardial

bridge in the LAD and non-calcified mildly atherosclerotic

lesions with negative arterial remodeling in both the LAD

and RCA, which suggested that the angiographic appearance

was due to multivessel coronary vasospasms (Fig. 4A-D).

However, the repeated intracoronary administration of nitro-

glycerin and nicorandil was ineffective in resolving the

spasms. Therefore, we administered fasudil, a Rho-kinase

inhibitor, into the spastic arteries, which successfully re-

solved the spasms with resolution of the inferior ST eleva-

tion and an improvement in the myocardial ischemia

(Fig. 4E, F). We discontinued the propofol and initiated the

continuous intravenous administration of fasudil. However,

on day 6, during rewarming following treatment with thera-

peutic hypothermia, the ST elevation in the inferior leads

and complete atrioventricular block recurred. The intrave-

nous infusion of hydrocortisone and diltiazem was ineffec-

tive in resolving the myocardial ischemia. The patient’s va-

sopressor requirements increased, and he died of cardiogenic

shock six hours later. An autopsy was carried out 24 hours

after his death. At autopsy, the heart weighted 980 g. Con-

centric hypertrophy of the left ventricle was observed with

extensive myocardial necrosis in the inferior wall. A small

abscess was noted in the pericardial sac. Multiple transverse


965

Figure　4.　Coronary angiogram and intravascular ultrasound findings. A, B: Initial angiograms showing diffuse severe narrowing of the right coronary artery (RCA) and total occlusion of the mid left anterior descending artery (LAD). C, D: Intravascular ultrasound images obtained following the intracoronary administration of nitroglycerin demonstrating non-calcified mildly atherosclerotic le-sions with negative arterial remodeling in the RCA (black arrows) and a large myocardial bridge with a myocardial band overlying a segment of the LAD (white arrows). E, F: Final angiograms showing fasudil-induced dilatation with residual fixed narrowing.

sections of the coronary arteries exhibited luminal narrowing

due to the presence of atherosclerotic plaques in 25% to

75% of the cross-sections, including the area involved in the

spasms; however, no occlusion was observed. A histological

examination demonstrated marked hypertrophied and bizarre

myocytes with disarray in addition to the accumulation of

inflammatory cells in the pericardium and adventitia of the

coronary arteries at the site of the vasospasms, even inside

the perivascular nerve tissue (Fig. 5A-F). The infiltrating

cells in the epineurium and endoneurium were primarily

lymphocytes.

Discussion

Simultaneous multivessel coronary spasms, one of the

most severe forms of coronary spastic angina due to the

presence of severe and extensive myocardial ischemia, are

often associated with refractory angina and multiple medica-

tions are often used to relieve the vasospasms (2).

In the present case, even fasudil was only transiently ef-

fective. Several factors are associated with the occurrence of

coronary vasospasms refractory to conventional medications.

First, in patients with hypertrophic cardiomyopathy, an

impaired sympathetic nerve function and the genetic variants

of the delta-sarcoglycan and the endothelial nitric oxide syn-

thase are associated with increased vasomotor activity (3-5).

Additionally, mechanical stimulation at the myocardial

bridge site of the mid LAD induces endothelial dysfunction

and enhanced local susceptibility to vasoconstrictor stim-

uli (6).

Second, the continuous infusion of large doses of propo-

fol can result in autonomic imbalances and lipid metabolic

disorders, including the presence of remnant-like particles

associated with an upregulated Rho-kinase expression in

coronary vascular smooth muscle cells and a markedly en-

hanced coronary vasospastic activity (7).


966

Figure　5.　Photomicrographs of the autopsied heart. A: Subserial ventricular myocardial sections of the autopsied heart showing marked diffuse thickening of the left ventricular walls. There is suben-docardial hyperemia (arrowheads) within a nearly transmural inferior myocardial infarct. B: Histo-logical appearance of the left ventricle (non-infarct area). Marked hypertrophied and bizarre myo-cytes with disarray were observed. C: Histological appearance of the pericardium showing the accumulation of inflammatory cells, primarily lymphocytes and macrophages. D: A transverse sec-tion of the right coronary artery at the site of the spasms. Although no coronary thrombi were found, luminal narrowing due to atherosclerotic plaque was evident and the coronary arterial adventitia was thickened with collagen. E, F: Higher magnification views of the areas #1 and #2 in D. Many inflam-matory cells, primarily lymphocytes, were clustered in the adventitia around and even inside the perivascular nerve tissue.

Third, rewarming following treatment with therapeutic hy-

pothermia can trigger the recurrence of vasospasms. Experi-

mental studies of isolated human middle cerebral arteries

have shown that human arteries dilate only slightly with

cooling and undergo a more profound constrictor response

upon rewarming (8). Both an increase in metabolic demands

and ventilator requirements and the massive reproduction of

cytokines and oxygen free radicals can occur during re-

warming (9).

Fourth, inflammation associated with intense pericarditis

may spread to the adventitia of atherosclerotic coronary ar-

teries. Recently, enhanced inflammation in perivascular fat

has been reported to influence vascular homeostasis and the

development of atherosclerosis in coronary arteries (10, 11).

The coronary adventitia is richly innervated with automatic

fibers that form a network around the entire length of each

coronary vessel. The degeneration of these autonomic ner-

vous fibers due to irritation by inflammatory cells induces

irregularities in the sympathetic activity, including the vaso-

motor activity (12). Moreover, chronic inflammation of the

adventitia is reported to induce alterations in smooth muscle

phenotypes toward dedifferentiation (13). In this way, the

smooth muscle cells of the coronary arterial media are

stimulated directly by chemical mediators secreted by in-

flammatory cells or indirectly by irritated autonomic ner-

vous fibers involved in the inflammatory process.

In conclusion, we herein described an autopsy case of re-

fractory vasospasms of the coronary arteries due to multiple


967

factors. Early intervention to address causative factors, such

as providing treatment with calcium channel-blockers and

anti-inflammatory drugs, may help to improve outcomes in

patients with refractory vasospastic angina.

The authors state that they have no Conflict of Interest (COI).

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Refractory Vasospasms of the Coronary Arteries due to