Journal of Cardiology (2009) 53, 458—462

CASE REPORT

Vascular Ehlers-Danlos syndrome—–All threecoronary artery spontaneous dissections

Michinari Nakamura (MD)a,∗, Junji Yajima (MD)a, Yuji Oikawa (MD)a,Ken Ogasawara (MD)a, Tokuhisa Uejima (MD)a, Keiko Abe (MD)b,Tadanori Aizawa (MD, FJCC)a

a Department of Cardiology, The Cardiovascular Institute, 7-3-10 Roppongi, Minato-ku,Tokyo 106-0032, Japanb Department of Pathology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi,Aoba-ku, Sendai-shi 980-8575, Japan

Received 10 August 2008; accepted 11 September 2008Available online 8 November 2008

KEYWORDSVascular Ehlers-Danlossyndrome;Connective-tissuedisorder;Acute coronarysyndrome;Spontaneous coronaryartery dissection

Summary Vascular Ehlers-Danlos syndrome is an inherited connective-tissue dis-order causing arterial and gastrointestinal fragility and spontaneous rupture of thelarge arteries, uterus, or bowel. Among arterial dissections and ruptures, spon-taneous coronary artery dissection is extremely rare in this disorder. The specifictherapeutic strategy for this disorder and its complications has not yet been estab-lished. In this report, we describe a 33-year-old woman with all three coronary arteryspontaneous dissections, resulting in cardiogenic shock and therapy-resistant ven-tricular fibrillation. We could successfully complete revascularization of all threecoronary arteries and terminate the life-threatening arrhythmia. Biochemical find-ings finally revealed a point mutation in the COL3A1 gene, consistent with a diagnosisof vascular Ehlers-Danlos syndrome. To the best of our knowledge, this is the firstcase of vascular Ehlers-Danlos syndrome causing all three coronary artery sponta-neous dissections. Our case also suggests that, from vascular fragility even if it isspontaneous coronary dissection, physicians always consider connective-tissue dis-orders as a differential diagnosis at an early stage even though that would be a firstcomplication, and percutaneous coronary intervention with stenting using intravas-

cular ultrasound could be a strategic option for even repeated and fatal spontaneouscoronary artery dissections in vascular Ehlers-Danlos syndrome.© 2008 Japanese College ofreserved.

∗ Corresponding author. Tel.: +81 3 3408 2151;fax: +81 3 3401 0469.

E-mail address: nmichi-kyu@umin.ac.jp (M. Nakamura).

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0914-5087/$ — see front matter © 2008 Japanese College of Cardiolodoi:10.1016/j.jjcc.2008.09.007

Cardiology. Published by Elsevier Ireland Ltd. All rights

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pontaneous coronary artery dissection is uncom-on, but has been increasingly recognized as

gy. Published by Elsevier Ireland Ltd. All rights reserved.

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ascular Ehlers-Danlos syndrome—–All three coronar

n important cause of acute coronary syndromer sudden death. Though spontaneous coronaryissection typically affects young women dur-ng the peripartum period without cardiovascularisk factors, the pathophysiology remains unclear.eanwhile, connective-tissue disorders underlie

pontaneous coronary dissection in some cases.regnancy-related deaths in patients with vascularhlers-Danlos syndrome (Ehlers-Danlos syndromeype IV) reach 14.8% [1]. Most patients with vascularhlers-Danlos syndrome survive the first and sec-nd major complications; however, after repeatedardiovascular events, the clinical outcome of vas-ular surgery remains unsatisfactory. Spontaneousoronary artery dissection in patients with vascu-ar Ehlers-Danlos syndrome is very rare, and alsoreatment for this disorder and the therapeutictrategy for its complications have not yet beenstablished. We herein report a patient with vas-ular Ehlers-Danlos syndrome, undergoing the fifthystemic manifestation including spontaneous dis-ections of all three coronary arteries.

ase report

33-year-old woman, who was born to a Japaneseother and an American father, without traditional

oronary risk factors presented with bilateral loweraw pain 4 months after cesarean section at her firstregnancy due to the rupture of a splenic arteryneurysm. A similar symptom had been experiencedyears ago. She was referred to our hospital forore investigations 2 weeks after the onset of the

ymptom.There was no history of ischemic heart disease

r sudden death in her family. Her physical exami-ation results were within normal limits, includinglinically significant craniofacial findings. T waveas inverted in leads II, III, aVF, and V5-6 in the elec-

rocardiogram. Troponin I (0.2 ng/mL) remainedlightly elevated. Delayed enhanced magnetic reso-ance imaging (MRI) revealed two separate regionalnhancements in the anterior and inferolateralalls, indicating two previous myocardial infarc-

ions. Coronary angiography revealed the dissectionf the posterolateral branch of the left circumflexoronary artery (LCx); therefore, intervention wasot performed. She was treated with medicationsncluding aspirin, nicorandil, and an angiotensin II-eceptor blocker.

Two weeks later, however, she suffered suddenrecordial chest pain, when the electrocardio-ram showed ST segment elevation in leads V1-5.rgent coronary angiography revealed both dis-ection and total occlusion of the left anterior

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escending artery (LAD) and dissection of the rightoronary artery (RCA) (Fig. 1). Intravascular ultra-ound (IVUS), which had been previously reportedo be helpful in diagnosing spontaneous coronaryrtery dissection [2], revealed a prominent dissec-ion flap with a false lumen (Fig. 2). Because ofreserved blood flow in the RCA, coronary angio-lasty with stenting of only the LAD was performed,hich required intra-aortic balloon pumping (IABP)nd percutaneous cardiopulmonary support (PCPS).ven after successful angioplasty, therapy-resistantentricular fibrillation repeatedly occurred. There-ore, a second coronary angiography was performedfter 6 h, which revealed the dissection of the LCx.pontaneous dissections at the RCA and the LCxere successfully treated with stenting using IVUS,nd the termination of the life-threatening arrhyth-ia after complete revascularization in all three

oronary arteries made her vital signs remain sta-le.

Several hours later, however, bleeding in bothhe retroperitoneal and abdominal cavities sud-enly occurred. Computed tomography showedupture of the right common iliac artery, but no sur-ical intervention for this rupture could have been atrategic option in this case because of systemic andevere fragile vessels. Disseminated intravascularoagulation promoted massive hemorrhage, result-ng in multiple organ failure, and unfortunately theatient died during hospitalization.

Autopsy revealed severe thinning and fragilityf the aortic wall. Pathological findings disclosededial degeneration in the systemic arteries, sug-

esting the cause of dissection may have beenonnective-tissue disorders (Fig. 3). The diagnosisf vascular Ehlers-Danlos syndrome, was con-rmed by the identification of a point mutationc.1988G > A), in one allele of the COL3A1 gene.

single nucleotide change resulted in the substi-ution of aspartic acid for glycine (G496D) withinhe triple helical region of the type III collagenolecule.

iscussion

ascular Ehlers-Danlos syndrome is an autosomalominant connective-tissue disorder, resulting fromutations affecting the COL3A1 gene encoding

or type III procollagen synthesis. The estimatedrevalence of the Ehlers-Danlos syndromes varies

etween 1/10,000 and 1/25,000 with no ethnicredisposition, and among all Ehlers-Danlos syn-romes, vascular Ehlers-Danlos syndrome accountsor approximately 5—10% of cases. The clinical diag-osis of vascular Ehlers-Danlos syndrome is made

460 M. Nakamura et al.

Figure 1 Coronary angiography showing (A) the dissecting right coronary artery (RCA), (B) the left coronary arteryand dissection starting from the proximal site of the left anterior descending coronary artery (LAD) associated withcontrast agent pooling and the distal total occlusion, (C) the LAD after stenting, (D) the dissecting left circumflexcoronary artery (LCx), (E) the left coronary artery after stenting, and (F) the RCA after stenting.

Figure 2 Intravascular ultrasound showing a dissecting intramural hematoma in a false lumen [F] and collapse of thetrue lumen [T]. (A) The distal LAD, (B) the proximal LAD, (C) the distal LCx, (D) the proximal LCx, (E) the distal RCA,and (F) the proximal RCA.

Vascular Ehlers-Danlos syndrome—–All three coronary artery spontaneous dissections 461

Figure 3 Sections from the coronary arteries showing a dissecting intramural hematoma [H] in false lumen [F] betweenadventitia [A] and media [M], collapse of the true lumen [T], and medial degeneration with marked elastin fragmen-t , (B( , (H)

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ation, stained with EVG stain (x12.5). (A) The distal LADE) the mid LCx, (F) the proximal LCx, (G) the distal RCA

ased on the finding of at least two of four clin-cal criteria: easy bruising, thin skin with visibleeins, characteristic facial features, and rupturef arteries, uterus, or intestines, but moleculartudies are required for confirmation [3]. Accordingo the previously published articles including caseeports, surgical interventions such as coronaryrtery bypass grafting and heart transplantation,ercutaneous coronary intervention with stenting,nd only observation without invasive interventionould be strategic options for spontaneous coronaryrtery dissection; however, until now, managementnd treatment for the disorder and therapeutictrategy for its complications have not yet beenstablished, especially in repeated and fatal dis-ections [3,4].

Spontaneous coronary artery dissection was firstescribed in a 42-year-old woman at autopsy in

931 [5]. No single etiology completely explains theathogenesis. There are a number of associatedonditions such as pregnancy, abnormal trans-orming growth factor-beta signaling (e.g., Marfan

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) the mid LAD, (C) the proximal LAD, (D) the distal LCx,the mid RCA, and (I) the proximal RCA.

yndrome, vascular Ehlers-Danlos syndrome, andoeys-Dietz syndrome [6]), oral contraceptivese, sexual intercourse, cocaine abuse, vasculitise.g., Churg-Strauss syndrome), and intense phys-cal exercise. The pathology is also not specific,ut eosinophilic periadventitial inflammation wasbserved in some cases, and cystic medial necrosisr medial degeneration was observed in others.

Our patient had no craniofacial features ofascular Ehlers-Danlos syndrome, which are notndispensable for diagnosis of the disease, but helpiagnosis at an early age. The first manifestationight be an anterior myocardial infarction due

o spontaneous dissection of the LAD, which washought to be completely healed, at the age of9, presumed by echocardiography and delayednhanced MRI. The age was similar to the averagege of the first manifestation reported previously

23.5 years) [1]. The second was a splenic aneurysmupture at the age of 33 years in the last trimesterf pregnancy, then 4 months later, an inferolateralyocardial infarction, all three coronary artery dis-

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sections, and the rupture of the right common iliacartery. The age at death (33 years) was youngerthan the median survival of vascular Ehlers-Danlossyndrome (48 years) [1] mostly because the sur-vival depends on the dissection site and severityof ischemia, and in this case, her complicationsoccurred in coronary arteries. However, the dissec-tion or rupture site cannot be predicted and thereseems to be no relation between location of themutation in the COL3A1 gene and the type of man-ifestations [1].

The first angiographic finding of the distal LCxdissection made us decide on medical therapybecause spontaneous dissection had been pre-viously reported to be completely healed withmedical therapy, or observation in some cases[7,8], but after multiple coronary artery dissec-tions, we had to choose invasive interventionwith support of IABP and PCPS due to ongoingischemia and therapy-resistant ventricular fibril-lation. Although among arterial dissections invascular Ehlers-Danlos syndrome coronary arterydissection is extremely rare because vascular com-plication has a tendency toward arteries of largeand medium diameter [1,9], three of the patient’svascular complications were spontaneous coronarydissections.

Autopsy revealed that the site of rupture in theright common iliac artery was separated from thepuncture site, but it is unclear whether invasiveintervention including IABP and PCPS somewhatinfluenced the dissection; therefore, for fragile ves-sels, simpler and more careful procedures should bedemanded.

Vascular Ehlers-Danlos syndrome is unfamiliar,but once started, cardiovascular manifestationsare catastrophic. Angiotensin II-receptor block-ers, beta-blockers, exercise restrictions, frequentcardiovascular imaging, or vascular surgery is insuf-ficient for ‘dissection storm’, that is, repeateddissections in rapid succession. The trigger ofdissection and/or rupture in rapid succession isunknown, but pregnancy and some hormonal unbal-ance are thought to be the causes. Although

spontaneous coronary artery dissection is a rareevent in vascular Ehlers-Danlos syndrome, if thefirst complication is coronary artery dissection, car-diologists and emergency care physicians should

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Available online at www.

M. Nakamura et al.

ay attention to tissue or vascular fragility and sus-ect connective-tissue disorders. A skin biopsy andolecular testing should be performed as soon asossible because a vascular manifestation is alwaysife-threatening.

In conclusion, we reported the first case ofascular Ehlers-Danlos syndrome undergoing spon-aneous all three coronary artery dissections thatas resolved by full-coverage bare-metal stentingf the dissection sites using IVUS. Our case indi-ates that even in vascular Ehlers-Danlos syndrome,ercutaneous coronary intervention can be thera-eutic strategy for repeated and severe coronaryrtery dissections with ongoing fatal ischemia.

cknowledgment

e would like to thank Dr Peter Byers of the Uni-ersity of Washington for the molecular testing.

eferences

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3] Beighton P, De Paepe A, Steinmann B, Tsipouras P, WenstrupRJ. Ehlers-Danlos syndromes: revised nosology, Villefranche,1997. Ehlers-Danlos National Foundation (USA) and Ehlers-Danlos Support Group (UK). Am J Med Genet 1998;77:31—7.

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5] Pretty HC. Dissecting aneurysm of a coronary artery in awoman aged 42. BMJ 1931, i:667.

6] Loeys BL, Schwarze U, Holm T, Callewaert BL, Thomas GH,Pannu H, et al. Aneurysm syndromes caused by mutations inthe TGF-beta receptor. N Engl J Med 2006;355:788—98.

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