Endovascular treatment of genetically linked aortic diseases

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) [1‐7], as well as large international registry studies (ENGAGE and GREAT) [8, 9]. Endovascular repair has also become established as the first-line 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 [11‐14]. 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 (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].

Age and gender also impact treatment outcomes. For example, females with aortic dissection exhibit a higher complication rate in the spontaneous course as well as postoperatively. The Cleveland working group led by Ourielund and Greenberg was able to show the effect of gender on the outcome of EVAR in their own patient population (n = 704, 606 males, 86.1%) [17]. Although females had somewhat smaller AAA (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 syndrome-specific multimorbidity and the aortic disease shows greater progressive dilatation. The aim of this overview article is to briefly discuss the most important aortic diseases through the prism of endovascular treatment options and the importance.

The following provides a short overview of the four best-known diseases or disease complexes involving impaired vascular or 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 [19‐21].

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 life-saving 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 cross-sectional 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 occlusion 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 meta-analysis 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].

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 presence of FTAAD undoubtedly represents a problem in clinical routine.

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, 40‐42]. Thus, the management of GAD should be reserved for specialized centers with appropriate clinical and surgical experience.