(VII- I-2A.2) Postpartum aortic dissection: Ehlers Danlos Syndrome Agnieszka Rosławiecka MD, Anna Kabłak-Ziembicka MD, PhD, Mariusz Trystuła, MD, PhD, Tadeusz Przewłocki MD, PhD, Prof. Piotr Podolec MD, PhD

Background
The Ehlers-Danlos Syndrome (EDS) is clinically and genetically heterogenic group of connective tissue diseases caused by collagen biosynthesis impropriety (1:25 000).
The Vascular type of EDS is caused by mutation in gene for type 3 procollagen (COL3A1).
The vascular type of EDS is rare (<4%) but the most dangerous type of EDS.
Vascular walls defect caused by collagen biosynthesis impropriety stand for propensity to spontaneous ruptures and dissections of thin-walled arteries. Vessel rupture is typical for not primarily widened vessels. Tendency for spontaneous arteries dissections, false aneurysm and arterio-venosus is considerable. False aneurysm are common. However the true aneurysms are rare finding. Vascular symptoms occur in 40% of pts <40y.o.
Affected patients are although at risk for organs (i.e. bowel, uterine, heart) rupture, but the timing of these events, their frequency, and the course of the disease are not well documented. Pregnancy in women with type IV EDS has a 12% risk for death from peripartum arterial rupture or uterine rupture.
The tolerance of connective tissue injuries and the course of the disorder is inpredictable and various in time. The mean age of diagnosis is 28.5 ± 11 y.o. What is more – the vascular type of Ehlers Danlos syndrome results in premature death. The prognosis is poor (mean lifetime ~54 y.o.). The most frequent causes of death: aortic rupture, carotid artery dissection.
The clinical diagnosis of Ehlers–Danlos syndrome type IV, the vascular type, is based
on clinical Villefranche criteria.

Vascular EDS – diagnostic Villefranche criteria:

The definite diagnosis is confirmed by 2 kind of available molecular tests:
– the demonstration that cultured fibroblasts synthesize abnormal type III procollagen molecules
– or by the identification of a mutation in the gene for type III pro-collagen (COL3A1)
There are no specific therapies that would protect from complications in patients with vascular type of Ehlers Danlos Syndrome. However the precise molecular diagnosis may influence the management of surgery, pregnancy and reproductive counseling as well as the major complications and adverse events.

Case presentation
Patient M.H. 28 y.o., otherwise in good health, without any seriuos medical problems, without risk factors of atheromatosis in 2008 got pregnant for the first time in her life. The preganacy itself and the caesarean birth in december 2008 were uncomplicated.
The newborn was healthy and vivid girl (Apgar 10). One week later the young mother suffered from unexpected spontaneous aortic dissection (Stanford B) with dramatic and eventful clinical course (cardiogenic shock and acute ischemic renal failure). She was successfully treated by complex endovascular interventions. She underwent staged complex lifesaving procedure with implantation of 2 aortic stentgrafts (Valiant & Reliant) in descending aorta, angioplasty of the right renal artery, angioplasty of the superior mesenteric artery and palliative fenestration of intimal flap in descending aorta.
Routine follow-up angioCT scan 28 months after procedure (april 2011) showed optimal long-term result of stentgrafts implantation, with no evident leaks. Left subclavian artery remained stenosed (jailed) by stentgraft prosthesis and the reversal flow in left vertebral artery was present in routine doppler duplex (clinically asymptomatic steal syndrome).
Patient remained in follow-up and 3 years after primary lifesaving procedure routine doppler ultrasound of carotid and subclavian arteries showed the new and unexpected finding – tthe aneurysm of the right subclavian artery.
Precise anatomy of the aneurysm and its dimensions were definied by angioCT scan of aortic arch branches in may 2012. The scan revealed that aneurysm was located in the very proximal aspect of the right subclavian artery, and its exact dimensions were 2 cm x 3.7 cm
The right vertebral artery was shown to be rising directly from aneurysmal ampulla.
The left vertebral artery was known to be functionally inactive (aortic stentgraft covers ostium of left subclavian artery). Another new finding in CT scan was asymetrical bilateral elongation of common and internal carotid arteries. The scans showed arterial loops of RICA and LICA in intracranial section (clinically silent).

Closer investigation of patient past history revealed some interesting data:
– Since childhood myopia (at the moment -5D/-5.75D).
– Bilateral retinal degeneration in recent tests.
– Lasercoagulation due to retinal detachment of the right eye in I.2012
– Since childhood remittent subluxations of the right ankle joint
– Overflexibility and hypermobility in the majority of joints and muscle fatigue
– Easy bruising and propensity to ecchymoses (inadequately to injury)
– In lab tests no evidence for haemorrhagic diathesis
– Abnormal wound healing, tendency to atrophic scars formation,
– Known mitral valve prolaps (no significant mitral regurgitation)

Physical examination revealed:
BP (R arm) 90/60, 148/88 mmHg
BP (L arm) unmeasurable (due to stentgraft in aorta, which covers ostium LSA)
JOINTS overflaxible and loose with evident hypermobility:
– joints of palms (5/9 according to scale of Beighton)
– both, elbow and knee, bending backwards > 10 degrees
– able to place flat hands on the floor with straight legs
Deformities of the spine and advanced s-letter-like scoliosis.
SKIN
– translucent (veins can easily be seen)
– with wide atrophic scar (whence tracheostomy)
Varicose veins of lower extermities
Characteristic facial appearance (small chin, sunken cheeks, thin nose and lips)

Genetical counseling was strongly advised at this point.
Based on clinical criteria the clinical diagnosis of vascular type of Ehlers-Danlos Syndrome (EDS) was established. The patient fulfilled all major Villefranche criteria (the ≥ 2 major criteria are diagnostic for type IV of EDS). Genetical diagnosis would exclude other overlapping syndromes and confirm the clinical diagnosis however it is not yet available in Poland. The presence of mutation in the gene for type 3 collagen (COL3A1) would be diagnostic in this case.

The proceeding dilemma and clinical question were how to treat this young patient with progressive specific vasulopathy? The patient was presented on Heart Team multidisciplinary consultation. The possible options were:
1. Conservative approach accompanied by close follow–up and monitoring of symptoms and aneurysm dimensions
2. Surgical procedure (sternotomy)
surgical anastomosis RVA-RCCA + implantation of prosthesis into RSA
3. Hybrid procedure (less traumatic)
surgical anastomosis RVA-RCCA + implantation of covered stent into RSA

Summary

Diagnosis:
Ehlers Danlos Syndrome type IV (clinical Villefranche criteria; genetic diagnosis: incompleted)
Descending aorta dissection in 2008.
Right subclavian artery aneurysm.
Left vertebral artery steal syndrome.

The Heart Team recommendation:
Hybrid treatment of RSA aneurysm.
The argumentation was to protect the patients from potentially fatal consequences of aneurysm rupture due to unpredictable course of main disease (EDS type IV).

Rp:
Acard 75mg 1-0-0
Enarenal 20mg 1-0-1
Betaloc ZOK 100mg 1-0-0

Current guidelines
There are no suitable guidelines for management of subclavian artery aneurysms even for average, otherwise healthy patients. The most important, highlighted in literature issues are spontaneous ruptures of aneurysms and thrombosis withe consequent embolic events. Experts recommend reconstructions only in symptomatic cases (symptoms due to compression caused by aneurysm).
The data from retrospective analyses and literature reviews of case histories of patients with EDS (typ IV) treated with vascular surgery procedures (implantation of prostheses) show high rate of vascular complications. The poor long-term outcome and mortality in this group of patients is known to be related to peri- i postprocedural bleeding (37%) and remote complications connected to vascular prostheses (40%) such as: anastomosis rupture, aneurysm formation in site of primary of anastomosis, thrombosis of the vascular graft.

References
1. GS Oderich et al. The spectrum, management and clinical outcome of Ehlers-Danlos syndrome type IV: A 30-year experience; J Vasc Surg 2005; 42:98-106
2. Freeman RK, Swegle J, Sise MJ. The surgical complications of Ehlers-Danlos syndrome. Am Surg 1996;62:869-73.
3. Beighton P, De Paepe A, Steinmann B, Tsipouras P, Wenstrup RJ. Ehlers-Danlos syndromes: revised nosology, Villefranche, 1997. Am J Med Genet 1998;77:31-7.
4. North KN, Whiteman DA, Pepin MG, Byers PH. Cerebrovascular complications in Ehlers-Danlos syndrome type IV. Ann Neurol 1995;38:960-4.
5. Bergqvist D. Ehlers-Danlos type IV syndrome: a review from a vascular surgical point of view. Eur J Surg 1996;162:163-70.
6. Pepin M, Schwarze U, Superti-Furga A; Clinical and genetic features of Ehlers–Danlos Syndrome Type IV, The Vascular Type, N Engl J Med 2000;342:673-80

Expert’s comments:(Written authorization required from each expert)

1. Bogusław Kapelak, MD, PhD
We should remember that long term prognosis of patients treated with surgical intervention is influenced by complications of prostheses. Periprocedural period is although dangerous due to possible bleeding and vascular complications in patients with vasulopathy. I would advice on observation and reconsultation in case of aneurysm progression or development of symptoms.

2. Prof. Piotr Odrowąż – Pieniążek MD, PhD
Less traumatic alternative to surgical treatment is percutaneous intervention. However treatment RSA aneurysm by covered stent implantation in this case is controversial because of right vertebral artery flow would be stopped (by covered sent) and imminent symptoms of stroke / TIA might develop. The localization of aneurysm in very proximal aspect of RSA is another problem – it produces the risk of stent malposition an leaks. The reasonable alternative would be implantation of 2 self-expandable stents – one in another.

3. Prof. Roland Hetzer MD, PhD
Highlighted high risk of spontaneous aneurysm rupture and strongly adviced on intervention even if the only alternative would be sternotomy and implantation of grafts.

4.Jakub Podolec, MD
Ehlers Danlos syndrome is a rare disease with adverse outcomes and wide range of complications including vascular ruptures with or without mural dissection [1]. It may be the cause of multiple aneurysms/dissections in this patient in future [2]. Positive results from emergency treatment with transcatheter coil embolization of subclavian artery rupture have been presented by Iida Y. et al. [3]. This patient has already survived serious adverse event in the past and probably will need to undergo not only one surgery in the future. According to that, less traumatic procedures should be of great benefit to such patients. Successful hybrid procedure with covered stent implantation in subclavian artery and thoracoscopic ligation of the internal mammary artery has been reported in patient with Ehlers Danlos syndrome [4]. Therefore endovascular repair and hybrid procedures seem to be preferred and present with fewer cardiopulmonary complications [5]. Last CT scan was done five months ago, therefore control CT scan should be obtained before decision making especially due to the short proximal landing zone for the covered stent visualized in the previous CT. If endovascular covered stent implantation procedure is technically possible, then less invasive strategy should be recommended. If not, decision should be made according to the level of increase of the aneurysm diameter. In case of rapid diameter increase conservative surgical approach is also reasonable.

References
1. Shields LB. et al. Sudden and unexpected death in three cases of Ehlers-Danlos syndrome type IV. J Forensic Sci. 2010 Nov;55(6):1641-5.
2. de Paiva Magalhães E, et al. Ehlers-Danlos syndrome type IV and multiple aortic aneurysms–a case report. Angiology. 2001 Mar;52(3):223-8.
3. Iida Y, et al. Successful coil embolization for rupture of the subclavian artery associated with Ehlers-Danlos syndrome type IV. J Vasc Surg. 2009 Nov; 50(5):1191-5.
4. Raval M, et al. Covered stent use after subclavian artery and vein injuries in the setting of vascular Ehlers-Danlos. J Vasc Surg. 2012 Feb;55(2):542-4.
5. Vierhout BP et al. Changing profiles of diagnostic and treatment options in subclavian artery aneurysms. Eur J Vasc Endovasc Surg. 2010 Jul;40(1):27-34.

5.Krzysztof Bederski, MD, PhD
Ehlers Danlos Syndrome – Postpartum aortic dissection.
Acute aortic dissection is a life-threatening event. Although rare, an association between pregnancy and aortic dissection has been reported. The first reviews were published in 1944 by Schnitker and Bayer[1] and in 1957 by Pedowitz and Perell[2]. They hypothesized that the “physiologic changes of pregnancy” accelerated the development of pathologic changes in the arterial wall. Because of increasing cardiovascular stress during pregnancy the risk of aortic dissection or rupture of an aneurysm increases with gestational age[2]. In this situation dissection and rupture of the aorta carry a high risk of maternal mortality and, if prepartum, fetal demise.The threat of such a catastrophe for the mother and her unborn child has prompted some to recommend against pregnancy in patients with Marfan syndrome[3], who are at the highest risk, if the aortic root is enlarged. Presently all recommendations focus on the occurrence of acute Type A dissection in Marfan patients. No recommendations are available concerning Type B dissection. Furthermore, Marfan syndrome is responsible for up to 50% of the reports[4],[5] published in the literature.Pregnancy in women with type IV EDS has a 12% risk for death from peripartum arterial rupture or uterine rupture.[6]
The exact nature of vascular lesions in type IV of Ehlers – Danlos Syndrome has also been a matter of debate and confusion in the literature[7]. It is thought that most vascular complications are either arterial dissections, often associated with aneurysmal degeneration, or arterial tears resulting in contained hematomas, false aneurysms, or intracavitary bleeding. It is possible that some dissections actually represent subintimal hematomas associated with intimal tears. Most “aneurysms” described in the literature probably represent false aneurysms[7]; however, a small group of patients (up to 14%) do have true fusiform aneurysms[8]. Arterial ruptures or dissections are responsible for the majority of deaths as they are unpredictable and because the fragility of arterial walls often makes the surgical repair difficult[9].

Pregnancy can increase the likelihood of a uterine or vascular rupture in women suffering from EDS type IV (particularly during the last three months). Maternal mortality stands at around 12%. The highest is the risk during labour, delivery and immediate post-partum period. Uterine haemorrhages occur frequently during the post-partum period and are sometimes only treatable by hysterectomy. The value of a caesarean carried out before the onset of labour (in order to minimise the risks related to contractions and take better control of haemostasis) has not yet been the subject of a controlled study. The prophylactic use of desmopressin to control primary haemostasis has been proposed[9].

References
1. Schnitker MA, Bayer CA. Dissecting aneurysm of the aorta in young individuals, particularly in association with pregnancy. Ann Intern Med 1944;29:486–511.
2. Pedowitz P, Perell A. Aneurysms complicated by pregnancy: Part I. Aneurysms of the aorta and its major branches. Am J Obstet Gynecol 1957;73:720–35.
3. Shabetai R. Cardiac diseases. In: Creasy RK, Resnick R, eds. Maternal-fetal medicine: principles and practice. Third edition. Philadelphia: WB Saunders 1994:768–91.
4. Rutherford RB, Nolte JE. Aortic and other arterial dissections associated with pregnancy. Semin Vasc Surg 1995;8:299–305.
5. Zeebregts CJ, Schepens MA, Hameeteman TM, Morshuis WJ, de la Riviere AB. Acute aortic dissection complicating pregnancy. Ann Thorac Surg 1997;64:1345–8.
6. Immer F, Bansi A, Immer-Bansi A et al: Aortic Dissection in Pregnancy: Analysis of Risk Factors and Outcome. Ann Thorac Surg. 2003;76:309–14.
7. Barabas A: Ehlers-Danlos syndrome type IV. N Eng J Med, 343 (2000): 366.
8. Oderich GS, Panneton JM, Bower TC et al: The spectrum, management and clinical outcome of Ehlers-Danlos syndrome type IV: a 30-year experience.J Vasc Surg. 2005 Jul;42(1):98-106.
9. Germain DP: Ehlers-Danlos syndrome type IV. Orphanet J Rare Dis. 2007;2: 32.

Expert’s conclusions:
The risk of multiple vascular complications in patient with IV type of Ehlers Danlos Syndrome is significant. Close follow – up of these patients with dopler duplex is reasonable because of its effectiveness and safety in detecting asymptomatic and otherwise unexpected progression of vasculopathy.
Interventional treatment of asymptomatic aneurysms of subclavian arteries is arguable.
In patient with strong suspicion of IV type of Ehlers Danlos the risk of vascular rupture is higher but unpredictable and can various in time. Provisional follow-up and ad hoc interventional treatment seem to be the two alterative options in the subset of asymptomatic patients. Both options, conservative and interventional, have its pros and cones. Long term prognosis of patients with vascular type EDS is poor regardless the way of treatment.

Authors:
Agnieszka Rosławiecka MD¹, Anna Kabłak-Ziembicka MD, PhD¹, Mariusz Trystuła, MD, PhD¹, Tadeusz Przewłocki MD, PhD¹, Prof. Piotr Podolec MD, PhD¹

Experts:
Bogusław Kapelak MD, PhD², Prof. Piotr Odrowąż- Pieniążek MD, PhD¹, Prof. Roland. Hetzer MD, PhD³, Jakub Podolec, MD⁴, Krzysztof Bederski, MD, PhD⁵

¹Department of Cardiac and Vascular Diseases, Jagiellonian University College of Medicine, John Paul II Hospital, Krakow, Poland
²Department of Cardiac, Vessels Surgery and Transplantology, Jagiellonian University College of Medicine, John Paul II Hospital, Krakow, Poland
³Medical Director and Chair of the Executive Management Board, DeutschesHerzzentrum, Berlin, Germany
⁴Department of Hemodynamics and Angiocardiography, Cardiology Institute, Collegium Medicum, Jagiellonian University, Krakow, Poland; Center for Interventional Cardiac and Vascular Diseases, John Paul II Hospital, Kraków, Poland
⁵Department of Thoracic Surgery in John Paul II Hospital, Krakow