ABSTRACT: Objective: The aim of this study is to determine whether, in a group of patients with an established familial pattern of aortic disease, there is a risk of development of new aneurysm in the follow-up period, and whether this risk differs from that of patients without family history. Methods: All patients in investigational device exemption trials at a single institution who were available for an interview to determine family history were included. Standardized diameter measurements were recorded at 9 aortic segments for patients for whom a family history was obtained. Patients were grouped and analyzed based on the absence or presence of aneurysmal disease in their family history, either aortic or intracranial. Results: Data from 487 patients were available for analysis: 187 with family history and 300 patients without. The mean interval between preoperative and most recent imaging was 2.8 years (range 0 to 12 years). The medical comorbidities were similar between both groups. The patients with a family history of aneurysm were younger at initial presentation. All patients demonstrated gradual growth in unrepaired segments of aorta over time. There was no statistically significant difference in growth rate of proximal aorta between the family history group and those with no family history. However, in multivariable analysis, family history was associated with a higher frequency of reintervention over time (P=.031). Growth in the proximal aorta was more likely in patients who were younger, and who were followed up for longer periods of time. Conclusions: Patients with family history of aortic aneurysm are more likely to require reintervention during follow-up after aneurysm surgery. All patients with a history of aneurysm repair do demonstrate growth throughout the rest of their aorta during the course of follow-up.  

VASCULAR DISEASE MANAGEMENT 2016;13(2):E42-E52

Key words: abdominal aortic aneurysm, endovascular surgery, genetics, aneurysm repair, aortic aneurysm stent graft, endovascular therapy

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A genetic cause of aneurysm disease can be found in 15% to 30% of patients with aortic aneurysm and/or dissection.^1-3 Compared with patients who have non-familial disease, a family history of aneurysms has been associated with a more aggressive growth rate and greater incidence of late failure (LF) after initial repair.^4-7 Similarly, late failure and family history are independently associated with more extensive disease at the time of initial repair.^6,8

Patients with connective tissue disorders causing aortic dilation, such as Marfan syndrome, Ehler’s Danlos type IV, and disorders in the transforming growth factor-beta (TGF-beta) signaling pathway have a different and more aggressive natural history of aortic pathology than patients with thoracic aortic aneurysms and dissections attributed to degenerative or atherosclerotic disease^.2,9 They also present earlier and with a greater incidence of proximal disease.^2,9 Although familial aneurysms may have no identifiable genetic etiology, the more aggressive nature of their natural history compared with patients without a family history of aneurysms supports the hypothesis that familial aneurysm disease may represent an aggressive form of an unrecognized genetic disorder. Given the renewed interest in the incidence of contiguous aneurysms and the role they may play in the failure of endovascular repair,^10,11 identifying patients with predilection to develop further aortic aneurysms is important. Certainly the ability to detect areas of the aorta that could be vulnerable to degeneration would prove useful for device planning and surveillance imaging protocols.  

In this manuscript, we analyze imaging and follow-up for a group of patients in whom familial pattern of aortic disease has been established to determine if there is any likelihood of developing aneurysms in normal-caliber segments of the aorta over the follow-up period.  We hypothesize that patients with a family history will be more likely than those with no family history to develop aneurysms in proximal segments of the aorta even after their presenting pathology is repaired.

Methods

This manuscript builds on the work published by our group in Brown et al.⁸ The study is a review of 1,543 patients enrolled in 1 of 3 physician-sponsored endovascular device trials (NIH numbers NCT00583050, NCT005834141, NCT00583817) to treat abdominal, thoracic, or thoracoabdominal aortic aneurysms from November 1999 to March 2013. An institutional review board granted approval for the study, and all patients signed an informed consent, as previously published.⁸

Demographic, historic, and imaging details, as well as outcomes and need for reintervention for each patient were obtained from a prospectively collected database (Oracle Clinical) as previously published.^8,11,12 Imaging was reviewed according to standard operating procedures within the study protocol and reported in accordance with the Society for Vascular Surgery reporting standards.^3,13 Computed tomography (CT) scans were obtained at fixed intervals and standardized measurements were obtained for each aortic segment with 3-dimensional imaging software and centerline of flow analysis (Tera Recon). The aneurysmal segments and size threshold were previously described.⁸ The same criteria were applied to both males and females. Disease progression was defined within a segment by the transition from nonaneurysmal to aneurysmal between imaging time points. Aortic reinterventions were performed for aneurysmal degeneration. Segments for which there were no initial or follow-up data to analyze – for example, if the imaging performed did not extend to that anatomical region or were obscured by artifact – were excluded, except for the purposes of the sensitivity analysis, to statistically validate the exclusion of the unimaged or unknown segments diameters.

Patients were interviewed to obtain a full family history analysis to determine the presence of family members with arterial aneurysms (aortic and/or intracranial). Family histories were obtained by in-person or phone interviews by a clinical geneticist, genetic counselor, research nurse, or study investigator as defined previously.⁸ Family history of aneurysms is defined as the past medical history of relatives with aneurysmal disease, connective tissue disorders, or other genetic abnormalities validated by imaging studies, surgical reports, death certificates, or autopsy data. Relatives who died of sudden death with an unknown etiology were included in the family history cohort. This was done to capture patients with a potential family history of aneurysmal disease that may not be aware of their familial predisposition to aneurysmal degeneration. A prior study by our group showed that there was no statistical significance in results when patients with a family history of sudden death were excluded from the analysis.⁸ Late graft failure is defined as open or endovascular repair that requires a reintervention, which may be due to material fatigue, incomplete initial treatment, or progression of aortic pathology not previously identified. The term “late graft failure” may also refer to limb thrombosis, graft degeneration, and infection, but aneurysmal degeneration is the focus of this study.

A detailed family history was obtained on 487 patients, which is 61 patients in addition to the cohort from the previous publication.⁸ The remainder of the patients could not be reached, declined, were unable to provide information, or did not know their family history. 

Statistical Methods

Patients were grouped based on the absence or presence of aneurysmal disease in their family history. Patients with a family history of aortic aneurysms were compared with the no-family-history group to determine differences in demographics, age at aneurysm presentation, number and location of aneurysmal segments, and progression of aneurysmal degeneration at each segment post intervention.

Categorical factors were described using frequencies and percentages, while continuous measures were described using medians and ranges. Initial comparisons between those with a family history of aneurysms or sudden death and those without were performed using chi-square tests. For continuous measures, two-sample t tests were used to compare the diameters between family history groups. Analyses were performed using SAS software (version 9.2). A significance level of 0.05 was considered statistically significant.

Results

Of the 487 patients analyzed, 38% had a family history of aneurysm (187/487 patients) (Table 1). Patients with any family history of aneurysm were younger at the time of their index surgery than patients without a family history of aneurysms (73.6 years vs 71.5 years, P=.007). Patients with and without a family history of aneurysmal disease do not differ in their history of major medical comorbidities (Table 1). No statistically significant difference was found in the number of prior aortic surgeries between the two groups. The interval time from first imaging to most recent imaging was 2.8 years in the entire cohort.

Impact of family history of aortic disease/cerebral aneurysms/sudden death on aneurysms. In patients with a family history of aneurysms, most had one first-degree relative with aneurysmal disease (122/187 patients, 65.2%) (Table 2). Patients with larger families may have more than 1 sibling affected, with 31 patients having 2 siblings and 10 patients with 3 siblings affected. The more distant the degree of family relatedness, the fewer the number of patients who report a positive history of aneurysmal disease, with a total of 46/487 patients (9.4%) reporting second-degree relatives with any aneurysm and only 8/487 patients reporting a third-degree relative with any aneurysm (Table 2). Most patients with aneurysmal disease and a family history of a cerebral aneurysm have 1 family member affected (29/36 patients, 74.4%). Patients with aortic aneurysms have a history of sudden death in the family, with 7 patients with aneurysmal disease reporting a family history of sudden death but no family history of aneurysmal disease (Table 2).

Characteristics of aorta based on family history of aortic disease. Patients with a family history of aortic disease are more likely to have an aortic arch repair (P=.043) and a descending thoracic aorta repair (P=.028) than patients without a family history of aortic disease (Table 3). No statistical significance was found in the incidence of repair in other segments of the aorta, including the thoracoabdominal aorta, infrarenal aorta, common iliac artery, hypogastric artery, or repair of a type A or B dissection (Table 3). Patients with a family history of aortic disease are more likely to have a larger descending thoracic aorta at the time of repair than patients without a family history of aortic disease (P=.033) (Table 4). Regardless of the presence of family history of aortic disease, there is a significant growth of the ascending aorta, the aortic arch, and the descending thoracic aorta over a mean follow-up of 2.8 years (Tables 4 and 5).

In a univariable analysis of predictors of the increase in size of the ascending aorta or aortic arch adjusted for follow-up time, the factors found to be significant were age (P=.008), myocardial infarction (MI) (P=.039), reinterventions (P=.006) and follow-up time (P<.001) (Table 6). The presence of family history of aortic disease was not a statistically significant predictor of absolute growth in the ascending aorta or aortic arch (P=.51), however it did predict need for intervention (P=.031). In a multivariable analysis, age, myocardial infarction, and follow-up time remained statistically significant (Table 7). 

Discussion

Our group previously showed that patients with a family history of aneurysms present with a more extensive aneurysm involving a greater length of the aorta, more frequently affecting the proximal aorta, and at a younger age than those with sporadic aneurysms.⁸ We analyzed the follow-up imaging in this cohort, with some additional patients collected since the last publication: in total, 487 people were reviewed, 300 with no family history and 187 with a family history of aortic aneurysmal disease, intracranial aneurysm disease, or sudden death. In all patients, proximal territories of the aorta have a positive growth rate over time. We found that the average growth rate was 2.4 mm over 2.5 years in arch/ascending aorta, and 2.7 mm over 2.7 years in the descending thoracic aorta, suggesting that there is ongoing aortic growth in patients with aneurysm even after treatment of an adjacent aortic territory with very short follow-up regardless of history of family history. 

Within the follow-up period, there was no difference in growth rate in patients with family history compared with those without. Because of limitations of data, we were unable to conclude if a simpler aortic repair (infrarenal vs thoracoabdominal) was associated with arch/ascending growth compared with patients with more aggressive initial presentation requiring complex repair. Family history was associated with a statistically significant higher rate of reintervention over time (P=.031). These data suggest that surveillance of the entire aorta in patients with history of previous repair is likely necessary regardless of family history, and that the proximal aorta should be included in the surveillance.

As understanding of the field evolves and surveillance imaging becomes more routine after surgery, it is becoming apparent that aneurysm disease is a progressive process. In the published literature, many patients undergoing aneurysm repair have had prior surgeries to treat aortic aneurysms. 

In a meta-analysis of 19 articles looking at open thoracic or thoracoabdominal aortic aneurysm repair after a previous abdominal aortic aneurysm surgery, 12.4% of patients with thoracic aortic aneurysms and 18.7% of patients with thoracoabdominal aortic aneurysms have had prior aortic interventions.¹⁴ Over 8 years, patients with an abdominal aortic aneurysm have a 2.2% chance of developing a more proximal thoracic aortic aneurysm and 2.5% chance of developing a thoracoabdominal aneurysm.¹⁴ 

In a study of patients after thoracoabdominal aortic aneurysm repair, 10% had “late aortic events,” which the authors defined as aortic disease causing death, requiring a subsequent intervention, or a graft-related complication, including infection, pseudoaneurysm, or branch occlusion after discharge from the index surgery. At the time of the index thoracoabdominal repair, 19.7% of patients had aneurysmal disease in other segments of the arterial tree that were left untreated.¹⁵ These nontreated aneurysmal segments during the initial repair were independently predictive of late aortic events with an odds ratio of 4.2. After a mean of 30 months from the index surgery, 23% of these patients had evidence of >5 mm expansion of the remaining native aorta, with an odds ratio of 2.5 as an independent predictor of late aortic events.15 It must also be taken into consideration that much of these data are retrospective in nature and generated in an era when routine surveillance imaging after aneurysm repair was not the norm.

Predicting which patients will develop further aneurysms after index repair, and thus staging the repairs appropriately, is the challenge of today’s aortic surgeon. There is evidence that a normal-appearing aorta adjacent to aneurysm on imaging may carry histologic and biochemical markers of severe disease at the time of operative repair, which questions the sensitivity of current imaging studies to identify diseased aorta.⁹ Thus, alternative risk factors beyond morphologic appearance on cross-sectional imaging need to be explored to explain the proclivity for failure after repair. 

Patients with a family history of abdominal or thoracic aneurysm are at higher risk of developing an aortic aneurysm compared with those who have no family history.^4,5,7,16-19 First-degree relatives with an aneurysm have been reported in 20% of patients with abdominal or thoracic aortic aneurysm.^4,5,20 Younger patients are more likely to have aneurysms that are more aggressive and involving the proximal aorta, such as the juxtarenal, suprarenal, or thoracoabdominal aorta.²¹ Given this evidence, our goal was to further refine the phenotype of patients with family history of aneurysm disease who may have no identifiable genetic mutations but present with a more aggressive form of disease.

Patients with connective tissue disorders, such as Marfan syndrome, Ehler’s Danlos type IV, and disorders in the TGF-beta signaling pathway have a different natural history of aortic pathology than patients with thoracic aortic aneurysms and dissections and patients with a family history of aneurysms with unidentified genetic disorders.^4,5 The genes with the strongest association with aortic aneurysms affect the proteolytic enzymes matrix metalloproteinase-2 and -9, tissue inhibitors of metalloproteinases, genes encoding proteins affecting the structure of the vessel wall, TGF-beta signaling, and inflammatory proteins.^18,22-26 Unlike patients with named connective tissue disorders, the phenotype of patients with a family history of aortic disease is highly variable. The data gained from the cohort described above indicate that family history of aneurysms is a proxy for genetic risk and is an important indicator of a more aggressive phenotype, which should be considered in the repair strategy and should be considered when planning a surveillance regimen. More research is needed into the role that family history will play on recommendations for repair modality, extensiveness of repair, or threshold for intervention.  

The limitations of this study are numerous. Although this is the largest cohort of patients described for this purpose in the literature, it is a relatively small cohort of patients with short follow-up. During analysis, it became clear that longer follow-up might influence the outcome. The reintervention rate is likely proportional to follow-up time, and a subsequent long-term analysis of the data may correlate length of follow-up time to the reintervention rate. 

Given these limitations, the findings of growth in both groups are notable. Large epidemiologic studies are needed linking family history to aneurysmal degeneration over the lifetime of patients and their families. Furthermore, collection of imaging data was limited in its retrospective nature, and many patients who had infrarenal repairs in this cohort did not have proximal aortic imaging included in their surveillance strategy, thus the ability to predict their proclivity to develop proximal aneurysms was limited. 

Conclusion

Family history of aortic disease is associated with larger proximal aortic segments at presentation, more involvement of multiple aortic territories, and an increased frequency of reintervention after successful surgery. Further work is needed to refine the phenotype and genotype of patients with family history of aortic disease to inform medical and surgical intervention.

Editor’s note: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Eagleton reports consultancy to Bolton Medical and Cook Medical and reimbursements from Cook Medical. Dr. Mastracci reports consultancy to and proctoring for Cook Medical. The remaining authors report no related disclosures.

Manuscript received April 24, 2015; provisional acceptance given August 3, 2015; manuscript accepted October 13, 2015.

Address for correspondence: Roy Miler, MD, Cleveland Clinic Department of Vascular Surgery, 9500 Euclid Ave F30, Cleveland, OH 44195, United States. Email: milerr@ccf.org 

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