J Cardiol 2004 Oct; 44（4）: 161 – 164

Inhibition of Rho-Kinase by Fasudil
Prevents Anginal Attacks Associated With Spastic Angina: A Case
ReportJunko

HIROKI, MD

Yoshihiro FUKUMOTO, MD
Hiroaki SHIMOKAWA, MD,FJCC
Yoshitaka

HIROOKA, MD

Akira TAKESHITA, MD, FJCC
Abstract ─────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────
An 86-year-old woman was admitted with unstable angina pectoris. Plain old balloon angioplasty（POBA）
was performed for 90% stenosis at segment 7 of the left coronary artery with concomitant treatment with nitrate, calcium antagonists, and nicorandil. Five days after POBA, she again suffered chest pain
at rest with ST depression by electrocardiography, despite increased doses of calcium-antagonist and nicorandil. Coronary arteriography showed no evidence of restenosis（50%）at the POBA site. The involvementof coronary artery spasm was considered and intravenous treatment with a Rho-kinase inhibitor, fasudil,
was started, which resulted in disappearance of the anginal attacks. She refused to continue the fasudil
treatment on day 5, which resulted in reappearance of anginal attacks. Third coronary angiography showed
a 90% restenosis at POBA site and percutaneous coronary intervention was again performed. This casesuggests that a Rho-kinase inhibitor is potentially effective to prevent anginal attacks in spastic angina.
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Key Words
Unstable angina spastic

Vasodilator agents Rho-kinase inhibitor

INTRODUCTION
The rupture of vulnerable plaques in the coronary arteries mainly triggers acute coronary syndromes, such as unstable angina and acute myocardial infarction 1）. Coronary artery spasm is also
important in the occurrence of cardiovascular
events including acute coronary syndromes2）. We
recently demonstrated that Rho-kinase is a novel
therapeutic target for the treatment of cardiovascular diseases such as coronary vasospasm 3）. The
Rho-kinase inhibitor, fasudil, suppresses coronary
artery spasm in patients with vasospastic angina4）,
but the potential for the treatment of acute coronary
syndromes remains to be examined. Here we reporta patient with unstable angina pectoris in whomfasudil was effective for controlling anginal attacks.
CASE REPORTAn 86-year-old woman with unstable angina
pectoris was admitted to our hospital, complainingof worsening chest pain on mild exertion anddiminishing after 10 minutes rest. She had hypertension and had taken diltiazem hydrochloride（90 mg/day）for 20 years. Her height was 150 cm
and weight was 50 kg. Her blood pressure was150/90 mmHg. Physical examination found ejection
systolic murmur（Levine Ⅲ/Ⅵ）at the fourth rightsternal border and loud bruit in the abdomen. Chest
radiography showed mild cardiomegaly（cardiothoracic ratio 56%）. Electrocardiography indicatednormal sinus rhythm and left axis deviation without──────────────────────────────────────────────
九州大学大学院医学研究院 循環器内科 : 〒 812−8582 福岡市東区馬出 3−1−1
Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka
Address for correspondence : FUKUMOTO Y, MD, Department of Cardiovascular Medicine, Kyushu University Graduate School ofMedical Sciences, Maidashi 3−1−1, Higashi-ku, Fukuoka 812−8582
Manuscript received March 1, 2004 ; revised April 26, 2004 ; accepted May 17, 2004

161

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Hiroki, Fukumoto, Shimokawa et al

Chest pain ++ + ++Diltiazem 120 mg
Metoprolol
Isosorbide
Benidipine++
180 mg

60 mg

++

30 mg

20 mg
8 mg
16 mg

Nicorandil

20 mg

10 mg30 mg
90%
50%
CAG（segment 7）
POBA 50%0 1
6 7 820 21Fasudil

90%
Stent 0%26 29（days）

Fig. 1 In-hospital course of a patient with unstableangina, showing chest symptoms, antianginal
medical treatment, and coronary intervention
CAG ＝ coronary angiography ; POBA ＝ plain old balloon angioplasty.

Day 1Aabnormal ST-T changes. Mild exercise test induced
an ischemic ST-segment depression with a negative
U wave in leads Ⅴ3 −Ⅴ5 . Echocardiography
revealed no left ventricular wall motion abnormality, mild aortic regurgitation, and minimal mitral
regurgitation. During the first week after admission,
she repeatedly suffered from chest pain either onexertion or at rest, which worsened day by day.
Antianginal treatment was started with isosorbide dinitrate（20 mg/day）, diltiazem hydrochloride（120 mg/day）, and metoprolol（60 mg/day ; Fig. 1）.
Coronary angiography showed a 90% stenosis atsegment 7 of the left coronary artery（Fig. 2−A）.
Plain old balloon angioplasty（POBA）of the stenotic segment was performed which reduced the stenosis to 25%（Fig. 2−B）. Five days after the proce-Day 8CDay 29DCAG

BEAfterPCIFig. 2 Coronary angiograms of a patient with unstable angina
A : Left CAG on admission showing the culprit lesion in segment （7 arrow）.
B : CAG after plain old balloon angioplasty showing a 25% stenosis in segment （7 arrow）.
C : Second left CAG showing a 50% restenosis in segment （7 arrow）.
D : Third left CAG showing a 90% restenosis in segment （7 arrow）.
E : CAG after stenting to segment 7 showing resolution of the stenosis（arrow）after stenting.
PCI ＝ percutaneous coronary intervention. Other abbreviation as in Fig. 1.

J Cardiol 2004 Oct; 44（4）: 161 – 164

Rho-Kinase Inhibitor and Spastic Angina

dure, she complained of chest pain at rest with thesame ST-segment depression as before. Benidipinehydrochloride was added（8 mg/day）and the dose
was increased（16 mg/day）the next day（Fig. 1）.
Chest symptoms occurred, but repeat coronary
angiography showed no significant stenosis at thePOBA site（50% restenosis ; Fig. 2−C）. We did
not choose re-POBA at this time, because we considered that coronary artery spasm was the majorreason for the anginal attacks at rest. Even after
increasing the dose of diltiazem hydrochloride to
180 mg, decreasing the dose of metoprolol to
30 mg, and adding 20 mg of nicorandil, she continued to complain of chest pain at rest.
Intravenous treatment with the Rho-kinase
inhibitor fasudil（30 mg, three times every 8 hr）was
then started. During the treatment with fasudil, no
anginal attacks were noted（Fig. 1）. However, thefasudil treatment was discontinued on day 5,
because she did not like continuous intravenous
administration. Three days later, she again had
chest pain. Third coronary angiography showed a90% restenotic lesion at the POBA site
（Fig. 2−D）.
Coronary stenting was performed at the lesion（Fig.
2−E）. After this procedure, no anginal attacks
were noted.
DISCUSSION
The administration of the Rho-kinase inhibitor
要

fasudil was effective in controlling anginal attacks
in the present patient with spastic angina, although
we have no evidence that fasudil directly relieved
coronary vasospasm in this patient. Rho-kinase issubstantially involved in the molecular mechanismsof coronary artery spasm and fasudil suppresses thespasm in both humans and animals3−6）. Rho-kinase
inhibits myosin phosphatase activity by phosphorylating the myosin-binding subunit of the enzyme
and thus augments vascular smooth muscle contraction at a given calcium concentration 7）.
Increased calcium sensitization of vascular smoothmuscle cells mediated by the activated Rho-kinase
pathway is very important in coronary artery
spasm 2,8）. Fasudil hydrochloride is the only
inhibitor of Rho-kinase that can be applied tohumans9−12）. It has a reasonable inhibitory effect onRho-kinase, 10 times and 100 times more potent
than on protein kinase C and myosin light chain
kinase, respectively10）. Importantly, fasudil attenuates only abnormally hyperconstrictive responses ofspastic coronary arteries and does not affect thoseof normal coronary arteries4−6,8）. Rho-kinase inhibition suppresses cell migration and may have potential adverse effects on atherosclerotic progression3）,
although the present patient showed restenosis at
the POBA site. The present case suggests that Rhokinase is a new class of vasodilator for the treatment of spastic angina.
約

ファスジルによる Rho キナーゼ阻害が狭心症発作に有効であった
安静時狭心症の 1 例
廣木潤子

福本義弘

下川宏明

廣岡良隆

竹 下彰

症例は不安定狭心症で入院した 86 歳の女性．冠動脈造影上，左冠動脈前下行枝（分節 7）に 90% 狭窄を認め，同部位に冠動脈拡張術（POBA）を施行した．5 日後に心電図上 ST 低下を伴う安静時胸痛が出現し，Ca 拮抗薬およびニコランジル投与下でも安静時胸痛が消失しなかったため，再度冠動脈造影を施行した．POBA 施行部に 50% 再狭窄を認めたが，安静時のみの症状であったため，冠動脈攣縮の関与を考慮し，この時点では冠動脈再拡張術を施行しなかった．Rho キナーゼ阻害薬であるファスジルを点滴投与することにより胸痛は消失したが，5 日間の投与後，患者の要望によりファスジルを中止した．その後，再び胸痛が出現するようになったため，冠動脈造影を施行し，POBA 部に 90% 再狭窄を認めたため，ステント留置術を行い，狭心痛の消失を得た．この症例により Rho キナーゼ阻害が攣縮性狭心症に対し有用であることが示唆された．

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