Endovascular treatment of genetically linked aortic diseases

Background The most important structural proteins of the vascular wall are collagen and elastin. Genetically linked connective tissue diseases lead to degeneration, aneurysm formation and spontaneous dissection or rupture of arteries. The most well-known are Marfan syndrome, vascular Ehlers-Danlos syndrome (type IV), Loeys-Dietz syndrome and familial aortic aneurysms and dissections. Objective This review article addresses the current status of endovascular treatment options for important connective tissue diseases. Material and methods Evaluation of currently available randomized studies and registry data. Results The treatment of choice for patients that are mostly affected at a young age is primarily conservative or open repair. There is only limited evidence for endovascular aortic repair (EVAR) of abdominal aneurysms or thoracic endovascular aortic repair (TEVAR). Conclusion The progression of the disease with dilatation leads to secondary endoleaks and high reintervention rates with uncertain long-term results. For this reason, there is currently consensus that EVAR and TEVAR should be limited to justified exceptional cases and emergency situations in patients with genetically linked aortic diseases.


Introduction
Over the past 10 years endovascular treatment has become the method of first choice for both infrarenal aortic aneurysms (AAA) and thoracic aortic disease, e.g. aneurysms, Stanford B dissection, intramural hematoma (IMH), penetrating aortic ulcer (PAU) and traumatic rupture. This is supported by numerous randomized studies (e.g. EVAR1, DREAM OVER, INSTEAD and ADSORB) [1][2][3][4][5][6][7], as well as large international registry studies (ENGAGE and GREAT) [8,9]. Endovascular repair has also become established as the firstline approach in the emergency setting of ruptured AAA in many centers with the relevant practical experience [10]. Here again, results from randomized studies (IMPROVE, AJAX, ECAR) are now available and provide valuable data on establishing the indications and choosing the method [11][12][13][14]. Establishing the indications for endovascular aortic repair (EVAR) in AAA is guided by conventional aneurysm surgery and allows treatment from an aneurysm diameter of 5 cm. As is well known, aneurysm morphology, comorbidities, patient treatment wishes and operator or center-specific perioperative mortality and morbidity rates influence the choice of treatment. In contrast, establishing the indications for thoracic endovascular aortic repair (TEVAR) in the heterogeneous group of thoracic aortic diseases depends on the diameter in the case of asymptomatic thoracic aortic aneurysm The German version of this article can be found under doi: 10.1007/s00772-016-0192-0.
(TAA) and PAU and, in the case of complex type B dissections or IMH, on symptoms, the presence of organ complications or imaging predictors of rapid progression [15].
Technical and clinical success is based in the long and the short term on adequate and "healthy" landing zones, both proximal and distal to the aortic pathology, for the planned endograft. Higher reintervention rates and increased mortality are known and have been described following EVAR in which the instructions for use (IFU) were not fully observed [16].

» Technical and clinical success depends on adequate landing zones
Age and gender also impact treatment outcomes. For example, females with aortic dissection exhibit a higher complication rate in the spontaneous course  [17]. Although females had somewhatsmallerAAA (5.2 vs. 5.4 cm), both groups were comparable in terms of age and comorbidities. No gender-specific differences were observed in terms of 30-day mortality or in the mean follow-up in terms of migration, reintervention or conversion rate. Other overview articles, however, reported higher long-term mortality rates among females with AAA 5 years following EVAR [18]. Against this backdrop, genetic aortic diseases, such as Marfan or Ehlers-Danlos syndromes, play a particularly prominent role. These patient groups are young, experience syndromespecific multimorbidity and the aortic disease shows greater progressive dilatation. The aim of this overview article  ns not specified is to briefly discuss the most important aortic diseases through the prism of endovascular treatment options and the importance.

Genetic aortic diseases
The following provides a short overview of the four best-known diseases or disease complexesinvolvingimpaired vascularor aortic wall integrity due to genetic connective tissue defects. As such, they are referred to as connective tissue diseases (CTD). The description of diseases in this article makes no claim to be exhaustive and the reader is referred to further literature [19][20][21].

Marfan's syndrome (MS)
With a prevalence of 1 in 10,000 individuals Marfan's syndrome, an autosomal dominant disorder first clinically described in 1896 by Antonin-Bernard Marfan and genetically confirmed in the early 1990s, is caused by a mutation of the fibrillin-1 gene (FBN1), which maps to chromosome 5q21.1. The Ghent criteria, as well as complementary genetic tests that have become limited in their practicability due to the now >600 different mutations, are used for the typing and confirmation of Marfan's syndrome [21]. In addition to the eyes and musculoskeletal system, large lumen arteries are particularly affected. Involvement of the cardiac valve and aortic root as well as the risk of aortic dissection and rupture associated with dilatation, crucially affect the prognosis. Dilatation of the sinus of Valsalva already begins in intrauterine life during the embryonic period. There are no absolute diameters on which to base the indications for surgery in children and adolescents. Growth of >1 cm/year or severe valve insufficiency and a Z score (statistical value with respect to mean value and standard deviation in aortic root diameter) >2-3 provide orientation. Surgery is recommended in adults with an aortic root diameter of 50 mm and above [21]. Isolated infrarenal aortic involvement is not known. Thanks to early identification and treatment, the mean life expectancy of patients with Marfan's syndrome can now be increased to as much as 60 years [22].

Vascular type (type IV) Ehlers-Danlos syndrome (EDS)
Ehlers-Danlos syndrome (EDS) is a heterogeneous, genetically linked and generally autosomal dominant disorder of collagen synthesis for which 10 subtypes have been identified (. Table 1

Loeys-Dietz syndrome (LDS)
Loeys-Dietz syndrome (LDS) is an aortic syndrome characterized by aortic aneurysm formation associated with marked vascular tortuosity, craniofacial abnormalities and bifid uvula. It is caused by heterozygous mutations in the genes encoding transforming growth factor beta (TGFbeta) receptors I and II [27]. The LDS is clinically distinct from Marfan's syndrome in that the aortic root may rupture and dissect in early childhood and at a small diameter. Establishing a family history and screening are crucial. As with EDS,

Abstract · Zusammenfassung
Gefässchirurgie 2017 · 22 (Suppl 1):S1-S7 DOI 10.1007/s00772-016-0221-z © The Author(s) 2016. This article is available at SpringerLink with Open Access.  [28]. Aneurysmal widening of the aorta affects only approximately 9% of LDS patients. A rapid growth rate of 1.8 mm/year in the case of a thoracic localization is worthy of note. Although the infrarenal aorta is less susceptible to aneurysmal lesions, it is generally elongated by a factor of two [29].

Endovascular treatment of genetically linked aortic diseases
In addition to the administration of beta-blockers and possibly also losartan, current recommendations include conventional surgical treatment. The indications for prophylactic surgery need to be Fig. 1 8 Highly comorbid female patient with suspected type IV Ehlers-Danlos syndrome and 60-mm asymptomatic juxtarenal abdominal aortic aneurysm that was declined for a fenestrated endograft and, due to morphology, untreatable using a chimney technique.Preoperative computed tomography angiography (CTA) shows the origin of the more proximal left renal artery at the level of the superior mesenteric artery (a), the juxtarenal start of the aneurysm (b) and the maximum transverse diameter (c). Intraoperative digital subtraction angiography (DSA) before and after implantation of a Nellixgraft showinganeurysm occlusionandnoindicationofanendoleak (d, e). Postoperative CTA at 6 weeks shows a regularly perfused endograft and no indication of migration or type Ia endoleak; however, there is evidence of a type II endoleak in the region of the right distal Nellix limb. Emergency CTA approximately 6 months following implantation shows a secondary-type Ia endoleak (g) as well as the dorsally contained rupture with contrast medium extravasation and retroperitoneal hematoma (h). Images kindly provided by the Department of Diagnostic and Interventional Radiology, Heidelberg University Hospital made on an individual basis, taking risks and benefits into consideration. On average, vascular repair is necessary at the average age of 16.9 years [22]. In adults, the indication to treat the thoracoabdominal and infrarenal aorta is established at 4.0 cm [21]. Multiple interventions and reinterventions are common in EDS.
As FTAAD occurs at a young age, it is considered a more aggressive clinical entity [29]. Aneurysms are most frequently localized in the thoracic aorta (66%), followed by AAA (25%) and cerebral aneurysms (8%). Aneurysms and dissections are equally distributed at 50%. The indications to treat aneurysms are based on thresholds in sporadic or non-syndromic aneurysms: thoracic 6.0 cm and infrarenal 5 cm. As with LDS, a rapid growth rate is seen in the familial form (0.21 cm/year) compared with 0.16 cm/ year in sporadic aneurysms. Further information on familial abdominal aortic aneurysms (fAAA) can be found in the recommended overview articles by van de Luijtgaarden et al. [30,31].

EVAR and TEVAR in genetic aortic disease (GAD)
In principle, endovascular techniques are not intended for the treatment of the thoracic and abdominal aorta in patients with genetic connective tissue disease. In relevant approval trials, the commercially available endografts were either not investigated in the fragile milieu of the marfanoid aorta or indeed excluded for this indication. The long-term radial force of the endograft, the prerequisite of an anchor zone with sealing properties, cannot be predicted in this patient group. Thus, the application of endovascular techniques in genetic aortic disease (GAD) patients falls a priori outside the IFU (. Fig. 1). Milewicz et al. [19] recommend EVAR/TEVAR only for late, chronic pseudoaneurysms of residual native aortic segments in a graft-to-graft approach. . Fig. 2 presents a case study with this indication from our own patient population. A 2008 consensus publication, as well as the European Society of Vascular Surgery (ESVS) guidelines due to be published shortly, clearly oppose primary endovascular treatment [20,32]. In individual cases, patients with a significantly increased risk for an open surgical procedure can be considered for an endovascular approach at a recognized center for the treatment of complex aortic diseases [20,32]. It is generally accepted in such cases that the indication is given for patients in an emergency setting in whom endovascular treatment represents a lifesaving bridging procedure until definitive open repair can be performed. This means that patients can be taken out of the life-threatening situation posed by rupture or the threat of rupture in the case of aortic pain or organ malperfusion while an elective conversion is planned in the interim.
Our own working group reported in 2008 on early clinical experiences in 167 GAD patients, 8 of which underwent TEVAR. Striking features at a mean follow-up of 34 months included a high primary endoleak rate of 38%, a reintervention rate of 25% and, in particular, a rate of disease progression with de novo aneurysms of again 38%. There were no aorta-related deaths [33]. In conclusion, TEVAR was deemed viable as a bridging method due to the low periprocedural mortality rate. A 2015 review conducted by Parisi et al. [34] summarized the largest published series in table form (. Table 2

and 3).
Endovascular treatment in patients with EDS (type IV) primarily comprises coil embolization of supra-aortic branches of the aortic arch or other medium-sized arteries in the context of bleeding [25]. These endovascular occlusion techniques are particularly suited to cases of spontaneous tearing in the visceral artery walls, particularly the hepatic and splenic arteries. A frequent and classical complication of type IV EDS is a carotid cavernous fistula, which presents as insidious, progressive proptosis (exophthalmos) or in association with headaches. Coil embolization can be performed in selected patients if the risk of sacrificing the intracranial internal carotid artery and subsequent stroke can be ruled out at the planning stage using high-resolution imaging techniques.
If there is a relevant predisposition to false aneurysm formation and access vessel rupture (generally the common femoral artery), percutaneous access needs to be considered as opposed to open surgical cut-down, particularly in the case of relevant sheath diameters (>8 French) [35]. Open repair is recommended in the case of access complications of this kind [21]. As there are no large series on EVAR and TEVAR in type IV EDS, it is not possible to make study-based recommendations at this point; however, similar considerations to those in Marfan's syndrome apply. Due to the fragility of the aortic wall, the questionable durability of endovascular treatment and the resulting higher reintervention rate, extreme caution is advised. Although, in the authors' opinion, there is a justification for exceptions, such as emergency bridging, these need to be justified on an individual basis, require that patients be provided with detailed information on alternatives if time permits and require careful documentation in the surgical report. It is generally accepted that EVAR and TEVAR should be avoided for type IV EDS [20]. Due to the extremely high risk of injury and rupture, even supposedly simple angiography should be avoided. A study by Cikrit et al. reported a 67% complication rate and a 12% mortality rate for digital subtraction angiography (DSA) [35]. It is possible that future low-profile catheters and endografts may be able to reduce these relevant rates. The use of non-invasive crosssectional imaging with the possibility of three-dimensional reconstruction is increasingly reducing these risks. Should endovascular treatment nevertheless be necessary, direct suture of the access vessel is recommended.
Endovascular treatment is not recommended in LDS and, apart from individual exceptions is not performed due to the young age of these patients, the rarity of the syndrome and the associated aortic disease. A recent bibliography search (as of 25 July 2016 in MEDLINE/ PubMed, https://www.ncbi.nlm.nih.gov/ pubmed. nih.gov/pubmed) with "Loeys-Dietz syndrome" and "endovascular therapy" produced only two hits. In 2015, Kalra et al. [36] reported on two patients with LDS and contained ruptures of the descending aorta that were successfully managed by endovascular repair. No follow-up is available. Colby [37] reported on the technically successful treatment of a 23-year-old female patient with a large, dysplastic cavernous intracerebral arterial aneurysm using the Pipeline TM embolization device (Covidien, Medtronic, Santa Rosa, CA). Complete aneurysm oc-clusion was seen at 10 months following endovascular treatment.
As in Marfan's syndrome, conservative drug therapy with beta-blockers is initially recommended. Due to the pathophysiological correlations with increased TGFbeta activity in the vessel wall, there appears to be a clear rationale for treatment with losartan. Randomized studies on losartan treatment yielded conflicting results. A recently published metaanalysis by Gao et al. [38] summarized the results from 6 randomized studies of 1398 patients and demonstrated that although losartan treatment significantly reduced aortic root dilatation, no survival benefit was seen compared with the control group. Initial results from small case series on open surgery, particularly on the aortic root, revealed low perioperative mortality rates; however, secondary rupture at other sites was seen during follow-up. Numerous specialist medical societies also recommend specialized interdisciplinary treatment in LDS due the complexity of the disease [39]. » There are no large series on EVAR and TEVAR in genetically linked aortic disease The treatment strategy in FTAAD is complex and non-uniform due to the variable penetrance and expression of the disease and the lack of genotype and phenotype correlation. No endovascular approach has been propagated or published as yet. To date, the available consensus documents have advised against such an approach. This may be attributable to publications from single center studies, among others, showing that patients with fAAA exhibit a high aneurysm-related complication rate. Despite similar aneurysm morphology in 51 out of 255 fAAA patients, van de Luijtgaarden et al. reported a two-fold higher complication rate of 35.3% vs. 19.1% (hazard ratio 2.1, 95% confidence interval 1.2-3.7), a significantly increased reintervention rate (39.2% vs. 20.1%, p = 0.004) and greater AAA growth following EVAR (20.8 vs.9.5%, p = 0.03). The fact that too little attention is paid in the diagnostic work-up to the possible pres-ence of FTAAD undoubtedly represents a problem in clinical routine.

Summary
The level of evidence or grade of recommendation on establishing the indications for endovascular treatment of GAD is limited (evidence grade II, level C). The data on technical and clinical treatment outcomes following EVAR and TEVAR in genetically linked aortic disease are also scant. Knowledge and implementation of the recommendations made by specialist societies should form strict requirements. The diagnosis, treatment and follow-up of patients with GAD (e.g. MS, EDS, LDS and TAAD) are complex, challenging and need to be performed in an interdisciplinary approach [26,[40][41][42]. Thus, the management of GAD should be reserved for specialized centers with appropriate clinical and surgical experience. quently related tortuosity are causative in the high endoleak and reintervention rates and hence in the less favorable treatment outcomes with EVAR and TEVAR compared with non-syndromic aortic disease. 4 Commercially available stent grafts have not been investigated for this indication and, as such, are not approved for the treatment of GAD (use out of IFU). 4 As technological advances in stent grafts may have a favorable impact on therapy concepts and treatment outcomes in the future, the significance of endovascular methods for the treatment of GAD requires continuous re-evaluation.