Co-prevalence of arterial aneurysm location – a correlation analysis based on a retrospective cross-sectional observational study.

Summary:Background: The aim of this retrospective single-centre cross-sectional observational study was to investigate co-prevalence of arterial aneurysm location systematically. Patients and methods: Patients with the diagnosis of any arterial aneurysm from January 2006 to January 2016 were investigated in a single centre. Patients with hereditary disorders of connective tissue, systemic inflammatory disease, or arterial pathologies other than true aneurysms were excluded. Aneurysm locations were assessed for every patient included. For patients with at least two co-existing aneurysms, co-prevalence of aneurysm location was investigated by calculating correlation coefficients and applying Fisher's exact test. This study report is prepared according to the STROBE statement. Results: Of 3107 identified patients with arterial aneurysms, 918 were excluded. Of the remaining 2189 patients, 951 patients with at least two aneurysms were included in the study. Bilateral aneurysm combinations of paired iliac, femoral and popliteal arteries showed the highest correlation (ϕ=0.35 to 0.67), followed by bilateral combinations of subclavian (ϕ=0.36) and internal carotid (ϕ=0.38) arteries. Abdominal aortic aneurysms in combination with visceral artery aneurysms (ϕ=−0.24 to −0.12), popliteal arteries (ϕ=−0.22) and the ascending aorta (ϕ=−0.19) showed the lowest correlation, followed by the descending aorta in combination with the common iliac arteries (ϕ=−0.12 to −0.13). Conclusions: In our study sample, aneurysm co-prevalence was highly non-random. This should be considered in the context of aneurysm screening programs.

Keywords: Peripheral arterial aneurysm; aortic aneurysm; co-prevalence; screening

As a chronic disease, arterial aneurysms usually progress asymptomatically over years [[1]]. In case of rupture or distal embolization with subsequent vessel occlusion, life-threatening conditions need urgent treatment. The most common occurrence of a true arterial aneurysm is in the abdominal aorta. The prevalence of an abdominal aortic aneurysm (AAA) in 65 year old men is 1.7% in the Swedish screening program (with an additional 0.5% of already known AAA patients), 1,3% in the United Kingdom national screening program and 3.3% in a Danish screening program for men between age 65 and 74 [[2], [4]]. The AAA prevalence in the United States is 1.4% in patients between age 50 and 84 [[5]]. AAA rupture is associated with a 30 to 50 percent in-hospital mortality rate, whereas only approximately 50 percent of the patients reach the hospital for treatment [[6]]. However, aneurysm development is not limited to the abdominal aorta and contributing pathophysiological processes can be transferred to the entire arterial system [[8]]. Systemic etiological influences – such as atherosclerosis, arterial hypertension, hypercholesterolemia and tobacco use – lead to focal inflammatory processes with structural degradation of the arterial wall's integrity. Nevertheless, some arterial segments are more likely to aneurysm formation and growth [[9]]. Among peripheral arteries, popliteal artery aneurysms (PAA) are most common with a prevalence of one percent in a screening study of male patients between 65 and 80 years [[10]]. Approximately 10–14% of male AAA patients present a co-existing PAA [[11]]. One out of six patients with an arterial aneurysm have a second co-existing aneurysm at another arterial location, increasing to one out of four in patients with a PAA involved [[9]].

Aneurysm co-prevalence raises the question of different etiological influences depending on the location. Furthermore, detailed knowledge could revise screening recommendations. Higher or lower aneurysm prevalence – depending on its location – bias the analysis of respective aneurysm location co-prevalence. This could possibly mask both similarities and differences in influences on aneurysm formation depending on their location. The resulting question is: Is the known aneurysm location co-prevalence particularly high due to the increased independent natural prevalence of these aneurysms? To investigate this assumption, this study aims to analyse aneurysm location co-prevalence without the natural distribution bias, based on a retrospective cross-sectional observational study.

Screened for inclusion were primarily all patients diagnosed with an arterial aneurysm between January 1st, 2006, and January 1st, 2016. The patients were identified by the ICD-10 (ICD-10-GM) classification system (code I71 and I72). Patients with a diagnosed hereditary disorder of connective tissue (e.g., Marfan syndrome, Ehlers-Danlos syndrome, Loeys-Dietz syndrome) or a diagnosed vasculitis (e.g., Behcet's disease, Buerger disease, Kawasaki disease, Takayasu arteritis, etc.) were excluded. Patients with other arterial pathologies than true aneurysms (dissection, intramural hematoma, penetrating aortic ulcer or false aneurysm) were also excluded. Aneurysm location of every included patient was assessed by the most recent medical report (up to January 2016). Aneurysms were diagnosed according to the recent respective guideline and radiological modality [[1], [13], [15]]. In case of imprecise data in the medical records such as the extend of an aneurysm over several arterial segments, review of available imaging was performed by a single observer. Imaging of all abdominal aortic aneurysms was assessed to exclude aorto-iliac extension of aneurysmatic disease.

Age at initial diagnosis and number of aneurysms were assessed and compared between subgroups (single aneurysm versus at least two aneurysms) by calculating group-wise mean±SD and an unpaired two-tailed t-test. Cardiovascular risk factors were assessed and compared between subgroups by calculating group-wise incidence, relative risk, and Fisher's exact test. The 95% confidence intervals for relative risk were calculated by the Koopman asymptotic score.

To evaluate arterial aneurysm co-prevalence regardless their natural frequency of occurrence, statistical analysis was performed including all patients with at least two aneurysms. For every location A, the binary variable YA indicates whether a patient has an aneurysm at location A. For every pair of locations A and B, the ϕ coefficient ϕ(YA, YB) of YA and YB was calculated. In this setting, the ϕ coefficient is equal to the Pearson correlation coefficient. It can take values between −1 and 1, where ϕ(YA, YB)>0 indicates higher than expected co-prevalence, ϕ(YA, YB)=0 indicates independent prevalences, and ϕ(YA, YB)<0 indicates lower than expected co-prevalence of locations A and B. The p-value of Fisher's exact test quantifies how likely the observed deviations are by chance. All p-values are purely descriptive. The cut-off 0.05 for the p-values was used to identify aneurysm location combinations with considerably high or low correlation.

The study protocol was approved by the institutional ethics committee (file reference: S-452/2016). This study report is prepared according to the STROBE statement.

Three thousand one hundred seven patients with an arterial aneurysm were identified, whereas 918 were excluded due to the exclusion criteria. Thus, 2189 patients with true arterial aneurysms without known confounding systemic disease were identified (Table I and Figure 1). Of those, 951 patients presented at least two independent arterial aneurysms and were considered for statistical analysis. Correlation analysis of respective aneurysm locations is presented in the electronic supplementary material (ESM) 1. There was no considerable difference between the subgroups of patients with a single aneurysm and patients with at least two aneurysms regarding sex, age at initial diagnosis, hypertension, diabetes mellitus, hypercholesterolemia, and smoking (Table I). History of coronary artery disease (p=0.015) and peripheral artery disease (p=0.007) was considerably higher in patients with at least two aneurysms compared to patients with a single aneurysm.

Graph: Figure 1 Number of aneurysms in each respective arterial segment for a) all patients with the diagnosis of a true arterial aneurysm (all AA; n=2189; 3775 aneurysms in total; mean age at initial diagnosis: 67.37 years) and for b) patients with at least two arterial aneurysms (≥2 AA; n=951; 2543 aneurysms in total; mean age at initial diagnosis: 64.47 years). Abbreviations. Ao. asc.: Ascending aorta; ACI: Internal carotid artery; A. subcl.: Subclavian artery; Ao. desc.: Descending aorta; Tr. coel.: Celiac trunk; A. lien.: Lienal artery; AMS: Superior mesenteric artery; A. ren.: Renal artery; Ao. abd.: Abdominal aorta; AIC: Common iliac artery; AII: Internal iliac artery; AIE: External iliac artery; AFC: Common femoral artery; AFS: Superficial femoral artery; APF: Deep femoral artery; A. pop. Popliteal artery; R: Right; L: Left. Parts of this figure were created with BioRender.com (accessed on 7 February 2022).

Graph

Table I Characteristics of the study sample and subgroups

The highest correlation occurred for bilateral aneurysms below the aortic bifurcation, namely of deep femoral (ϕ=0.67), popliteal (ϕ=0.6), common femoral (ϕ=0.51), common iliac (ϕ=0.5) and internal iliac arteries (ϕ=0.46) (Figure 2). Overall, the ten highest correlations all occurred for side-matched arteries, complemented by the internal carotid (ϕ=0.38), superficial femoral (ϕ=0.37), subclavian (ϕ=0.36) and external iliac arteries (ϕ=0.35). High correlation for visceral arteries occurred for aneurysm combination of the celiac trunk and the superior mesenteric artery (ϕ=0.19), as well as bilateral for the renal arteries (ϕ=0.11). Arteries below the aortic bifurcation showed frequent high correlation in almost every possible combination (ϕ=0.1 to 0.24).

Graph: Figure 2 Aneurysm locations with high correlation (p<0.05 and ϕ>0.1). Phi-coefficient from 0.7 to 0.5 in purple, from 0.5 to 0.3 in blue, from 0.3 to 0.15 in green and from 0.15 to 0.1 in yellow. Abbreviations. ACI: Internal carotid Aartery; A. subcl.: Subclavian artery; Tr. coel.: Celiac trunk; A. ren.: Renal artery; AMS: Superior mesenteric artery; AIC: Common Iliac artery; AIE: External iliac artery; AII: Internal iliac artery; AFC: Common femoral artery; AFS: Superficial femoral artery; A. pop.: Popliteal artery; R: Right; L: Left. Parts of this figure were created with BioRender.com (accessed on 7 February 2022).

Regarding aneurysm combinations with low association, the abdominal aorta showed the lowest correlation (ϕ=−0.24 to −0.12) (Figure 3). This occurred for combinations with visceral arteries (lienal artery: ϕ=−0.24; renal arteries: ϕ=−0.15 to −0.12; superior mesenteric artery: ϕ=−0.14; celiac trunk: ϕ −0.13), as well as for popliteal arteries (ϕ=−0.22), the ascending aorta (ϕ=−0.19) and the left internal carotid artery (ϕ=0.1). Aneurysms of the descending aorta showed low correlation with common iliac artery aneurysms (ϕ=−0.12 to −0.13).

Graph: Figure 3 Aneurysm locations with low correlation (p<0.05 and ϕ<−0.1). Phi-coefficient from −0.3 to −0.15 in red and from −0.15 to −0.1 in orange. Abbreviations. ACI: Internal carotid artery; A. subcl.: Subclavian artery; Ao. asc.: Ascending thoracic aorta; Ao. desc.: Descending thoracic aorta; Tr. coel.: Celiac trunk; A. lien.: Lienal artery; A. ren.: Renal artery; AMS: Superior mesenteric artery; AIC: Common iliac artery; A. pop.: Popliteal artery; R: Right; L: Left. Parts of this figure were created with BioRender.com (accessed on 7 February 2022).

In this study, co-prevalence of arterial aneurysm location was analysed systematically in a patient cohort of 951 patients. Side-matched arteries showed the highest correlation. Simultaneous occurrence of aneurysms among arteries below the aortic bifurcation (iliac, femoral, popliteal) was high. In contrast, aneurysm correlation of the abdominal aorta with visceral and popliteal arteries, as well as with the ascending aorta, was lower as compared to other combinations. Likewise, aneurysms of the descending aorta were rarely associated with popliteal artery aneurysms.

In a study by Chapman et al., 11.1% of patients with a thoracic aortic aneurysm (TAA) had an additional PAA [[16]]. In a recent systematic review, AAA patients had additional aneurysms in various arterial segments (TAA: 18.3–31.9%; common iliac artery aneurysm: 10–31.7%; common femoral artery aneurysm: 3.9–85%; PAA: 11.5–68.9%) [[9]]. Body site differentiation was not considered in respective studies. Aneurysm location co-prevalence frequencies in the literature show high variability, most likely due to inhomogeneous screening methods or study cohorts. Previous studies mostly focus on two to three arterial locations and imaging modalities vary, which affects non ultrasound accessible arterial locations in particular. To the best of our knowledge, this is the first systematic survey to investigate arterial aneurysm location co-prevalence, and the first survey regarding body site differentiation.

In this study, the characteristics of patients with a single aneurysm and patients with at least two aneurysms differed only regarding the presence of coronary and peripheral artery disease (PAD). The reason for the higher frequency of PAD in patients with more than one aneurysm could be due to thrombotic or post-interventional complications of aortic, iliac or femoropopliteal aneurysms.

It has to be pointed out that the results of this study apply to the described population, e.g. patients with at least two arterial aneurysms without known confounding systemic disease, diagnosed in a vascular surgery department. Furthermore, we only described associations of aneurysm locations which do not necessarily translate to increased absolute risks of co-prevalence. For example, if locations A and B have a positive ϕ coefficient and A and C have a zero-ϕ coefficient, this means that combinations of A and B are more frequent than randomly expected. However, patients with an aneurysm at A can still be more likely to have an aneurysm at C, e.g. if the aneurysm prevalence at C is generally large.

The highest correlation in this study was observed for bilateral iliac, femoral, popliteal, and supra-aortic aneurysms. These findings support the assumption that aneurysm formation in different arterial segments underlies different pathological mechanisms. The non-randomized aneurysm distribution raises the question of differences in aneurysm formation in different arterial locations, whereas causal correlation cannot be concluded from this study. Arterial development from different embryological cell origins could contribute to this effect [[17]]. Further knowledge and understanding of molecular pathological processes in arterial tissue of different locations is needed, particularly to discriminate between innate and acquired risk factors, to prevent aneurysm formation and disease progression. This could have a considerable impact on the follow-up care of affected patients.

In addition, improved knowledge of aneurysm location co-prevalence optimizes screening recommendations and may lead to early detection of coexisting aneurysms with appropriate therapy. According to the results of this study, in case of a diagnosed peripheral aneurysm below the aortic bifurcation, patients should receive extended screening of bilateral iliac, femoral und popliteal arteries. This would exceed the recent clinical practice guidelines, which recommend sole screening for PAA in AAA patients and vice versa [[1], [15]]. Similarly, patients with an internal carotid or subclavian artery aneurysm should receive extended screening of the remaining cervical vessels. Computed tomography-based screening for TAA in respective patients does not appear to be as important, also considering radiation exposure, although this should be explored in larger population studies. Considering the fact, that TAA screening (of the descending aorta in particular) is only accessible for cross sectional imaging, this information could be important regarding cost effectiveness in larger populations. Peripheral arteries, on the other hand, are well accessible to ultrasound.

The retrospective design of this study is susceptible to missing or undocumented data. A further limitation is possible incomplete screening for all arterial segments included, although screening modalities were highly standardized following the abovementioned guidelines. Full body computed tomography scans were not available for every patient included. Review of available imaging in case of unprecise medical records was performed by a single observer (experienced vascular surgeon). As patients were treated and enrolled from a vascular surgery department, certain prevalence of aneurysm locations (intracranial arteries, ascending aorta) was not or potentially underreported. Not all included patients received genetic testing and could thus confound the study group with an undiagnosed hereditary disorder of connective tissue.

Aneurysm correlation among peripheral arteries below the aortic bifurcation and supra-aortic is considerably high, whereas simultaneous aortic involvement is considerably low. Further and more detailed knowledge of iliac, femoral, and popliteal aneurysm prevalence and co-prevalence is needed, which could eventually lead to extended screening for respective patients. Furthermore, aneurysm formation and molecular pathological mechanisms in different arterial locations should be further investigated.

The electronic supplementary material (ESM) is available with the online version of the article at https://doi.org/10.1024/0301-1526/a001121.

• ESM 1. Correlation between arterial aneurysm locations (Table).

Conflicts of Interests: No conflicts of interest exist.