Rebecka Hultgren

Genetic and environmental contributions to abdominal aortic aneurysm development in a twin population

BACKGROUND The contribution of hereditary and environmental factors to the development of abdominal aortic aneurysms (AAAs) is still partly unknown. The aim of this study was to analyze the role of these factors in a large population-based sample of twins. METHODS The Swedish Twin Registry, containing data on twins born in the country since 1886, was cross-linked with the Inpatient Registry, providing national coverage of discharge diagnoses coded according to the International Classification of Diseases (ICD). All twins with an infrarenal AAA were identified. Concordance rates and tetrachoric correlations were calculated for monozygotic (MZ) and dizygotic (DZ) twins. Tetrachoric correlations were calculated assuming an underlying normal distribution of liability, with multiple factors contributing additively and a threshold value that discriminates between AAA and no AAA. Higher concordance rates and correlations of liability in MZ twins than in DZ twins suggest that genetic factors influence disease development. Structural equation modeling techniques, Mx-analyses, were used to estimate the contributions of genetic effects as well as shared and nonshared environmental factors for development of AAA. RESULTS There were 172,890 twins registered at the time of the study including 265 twins (81% men; mean age 72 years; range, 48-94) with AAA. There were 7 MZ and 5 DZ concordant pairs as well as 44 MZ and 197 DZ discordant pairs with AAA. The probandwise concordance rates for MZ and DZ pairs were 24% and 4.8%, respectively. The tetrachoric correlations were 0.71 in MZ pairs and 0.31 in DZ pairs. The odds ratio (OR) was 71 (95% confidence interval [CI] 27-183) for MZ twins and 7.6 (95% CI 3.0-19) for DZ twins. In the structural equation models, genetic effects accounted for 70% (95% CI 0.33-0.83), shared environmental effects for 0% (95% CI 0-0.27), and nonshared environmental effects for 30% (95% CI 0.17-0.46) of the phenotypic variance among twins. CONCLUSION These data provide robust epidemiologic evidence that heritability contributes to aneurysm formation. Concordances and correlations were higher in MZ compared with DZ twins, indicating genetic effects. There was a 24% probability that an MZ twin of a person with AAA will have the disease. The twin of an MZ twin with AAA had a risk of AAA that was 71 times that of the MZ twin of a person without AAA. A heritability of 70% of the total trait variance was estimated. The remaining variance was explained by nonshared environmental factors with no support for a role of shared environmental influences.

A population-based case-control study of the familial risk of abdominal aortic aneurysm

BACKGROUND Several studies have reported a familial clustering of abdominal aortic aneurysm (AAA) supporting that AAA is an inheritable disease, but few population-based studies can be found. Possible gender differences regarding hereditary patterns have been reported. OBJECTIVE The aim of this study was to investigate the risk of developing an AAA for first-degree relatives of patients with AAA in Sweden and compare them with matched controls and their relatives. METHODS AND MATERIALS All persons (3183) born after 1932, diagnosed with AAA between 2001 and 2005, and a random selection of 15,943 age-, gender-, and region-matched controls were included. First-degree relatives of cases and controls were identified via the Multigeneration Register. Family history of AAA for cases and controls was assessed by linking the relatives to the Hospital Discharge Register and Cause of Death Register. The data were analyzed by conditional logistic regression. RESULTS The overall relative risk of AAA associated with family history compared to no family history was 1.9 (95% confidence interval [CI] 1.6-2.2). Comorbidities were more common among the cases than the controls (P < .0001) but the relative risks remained unchanged after adjustment for comorbidities. Stratification for absence or presence of comorbidities showed no significant difference between the two groups (P = .29). The relative risk of AAA for first-degree relatives was similar for women and men (P = .22 for gender differences), ie, the relative risk of AAA was not dependent on the gender of the index person. CONCLUSION In this nationwide survey, the relative risk of developing AAA for first-degree relatives to persons diagnosed with AAA was approximately doubled compared to persons with no family history. Neither the gender of the index person nor the first-degree relative influenced the risk of AAA.

miR-24 limits aortic vascular inflammation and murine abdominal aneurysm development

Identification and treatment of abdominal aortic aneurysm (AAA) remain among the most prominent challenges in vascular medicine. MicroRNAs (miRNAs) are crucial regulators of cardiovascular pathology and represent intriguing targets to limit AAA expansion. Here we show, by using two established murine models of AAA disease along with human aortic tissue and plasma analysis, that miR-24 is a key regulator of vascular inflammation and AAA pathology. In vivo and in vitro studies reveal chitinase 3-like 1 (Chi3l1) to be a major target and effector under the control of miR-24, regulating cytokine synthesis in macrophages as well as their survival, promoting aortic smooth muscle cell migration and cytokine production, and stimulating adhesion molecule expression in vascular endothelial cells. We further show that modulation of miR-24 alters AAA progression in animal models, and that miR-24 and CHI3L1 represent novel plasma biomarkers of AAA disease progression in humans.

Analysis of aortic wall stress and rupture risk in patients with abdominal aortic aneurysm with a gender perspective.

OBJECTIVE The most commonly used predictor of rupture of an abdominal aortic aneurysm (AAA) is the diameter; however, this does not estimate the true risk for each patient. Why women with AAAs have an increased growth rate, weaker aortic wall, and increased risk for rupture is yet unclear. It is likely that geometrical and biomechanical properties contribute to found gender differences. Several studies have shown that peak wall stress (PWS) and peak wall rupture risk (PWRR), predicted by a finite element (FE) analysis of AAAs derived from computed tomography (CT), is a better predictor of rupture than maximum diameter. The purpose of this study was to investigate if women with AAAs have an increased PWS and PWRR using an FE model compared to men. METHOD Fifteen men and 15 women (AAAs 4-6 cm) were included. AAA geometry was derived from CT scans, and PWS and PWRR were estimated using the FE method. Comparisons were made by t test and Mann-Whitney test. RESULTS Mean age (women 73 years old vs men 71 years old) and mean AAA diameter was similar (49.7 mm vs 50.1 mm) for women and men. PWS did not differ for women 184 and men 198 kPa. PWRR was 0.54 (0.28-0.85) for women and 0.43 (0.24-0.66) for men, P = .06. CONCLUSION This is the first analysis of stress and strength of the aneurysm wall with a gender perspective. The reported higher rupture risk for women has previously not been tested with geometrical and biomechanical properties. PWS did not differ, but the PWRR was slightly higher in women. However, the difference did not reach statistical significance, probably due to the small sample size. In summary, the results in the present study suggest that differences in biomechanical properties could be a contributing explanation for the higher rupture risk reported for female patients with AAAs.

High frequency of thoracic aneurysms in patients with abdominal aortic aneurysms.

Objective:To investigate the prevalence of thoracic aortic aneurysms (TAA) in patients with abdominal aortic aneurysms (AAA). Background:Different disease profiles between men and women treated for AAA have been reported. Reports regarding causes of death for treated AAA patients have shown an increased risk of death because of other aneurysms for women, possibly TAA. The prevalence of TAA in AAA patients is not well known. Methods:Data for AAA patients attending the outpatient clinic at a university hospital were analyzed (N = 1055). Patients who had undergone abdominal and thoracic computed tomography were included (n = 354). The diameter of the aorta was measured in the ascending, descending, and infrerenal aorta. Comorbid conditions were analyzed. Results:Mean age was 74 years, 23% were women. The presence of comorbid conditions did not differ between men and women except for a higher proportion of female smokers (P = 0.003). When sex-specific criteria were used, 100 patients (28%) had a TAA, 38 (48%) of the women compared with 62 (23%) of the men (P < 0.0001). Odds ratio for women compared with those of men to have a concurrent TAA was 3.09 (95% confidence interval, 1.84–5.22). Conclusions:More than one fourth of patients with AAA attending a regular outpatient clinic have a concomitant TAA, and women are particularly affected. During the last decades, the therapeutic options for TAA patients have changed considerably. Physicians need to increase the efforts to investigate also the thoracic aorta in AAA patients.

High prevalence of abdominal aortic aneurysms in brothers and sisters of patients despite a low prevalence in the population

OBJECTIVE Population-based screening for abdominal aortic aneurysms (AAAs) in elderly men is organized in many regions and countries in the Western world, and the prevalence of disease is reported to decline. Whether the prevalence among those with a family history also is declining is unknown. The primary purpose of this study was to assess the prevalence of AAAs among siblings of persons with AAAs and to investigate the proportion of siblings already diagnosed by opportunistic screening. METHODS Patients treated for AAAs from January 2008 through December 2010 (n = 412) in Stockholm, Sweden, were screened for siblings. Seven hundred seventy-nine siblings were identified. All siblings <80 years residing in Stockholm County were considered eligible and were invited to participate in the study (n = 174). Deceased siblings were not included in the study, regardless of the cause of death. One hundred fifty siblings were enrolled in the study after informed consent was provided. One hundred thirty-four siblings were screened for AAAs with ultrasound scan and maximum aortic, infrarenal, anteroposterior, external (outer-to-outer) aortic diameter was measured. Characteristics of siblings with and without AAAs were compared. RESULTS The mean age of the screened siblings was 66.4 years (standard deviation, 7.1). Of the siblings, 11% were found to have an AAA, 17% (n = 11) of the brothers, and 6% (n = 5) of the sisters. Only 11% of the siblings were screened for AAAs before the study. One of 16 siblings with AAAs was <65 years. Ever smoking was evident in 81% of the AAA siblings compared to 59% in the non-AAA siblings. Factors associated with increased risk of AAAs in the multivariate regression analysis were: male sex (odds ratio, 3.4; 95% confidence interval, 1.1-10.8; P = .04) and age >65 (odds ratio, 10.8; 95% confidence interval, 1.3-86.4; P = .03). Ever smoking was not statistically significant as a risk. CONCLUSIONS A strikingly high prevalence of AAAs in siblings was found as compared to the reported declining aneurysm prevalence in elderly men in the Western world. Systematic improvements regarding screening of first-degree relatives is mandated and selective screening of siblings is an underused tool to prevent death from aneurysm disease, both among men and women.

Treatment of Popliteal Aneurysm by Open and Endovascular Surgery: A Contemporary Study of 592 Procedures in Sweden

BACKGROUND Popliteal aneurysm (PA) is traditionally treated by open repair (OR). Endovascular repair (ER) has become more common. The aim was to describe time trends and compare results (OR/ER). METHODS The Swedish vascular registry, Swedvasc, has a specific PA module. Data were collected (2008-2012) and supplemented with a specific protocol (response rate 99.1%). Data were compared with previously published data (1994-2002) from the same database. RESULTS The number of operations for PA was 15.7/million person-years (8.3 during 1994-2001). Of 592 interventions for PA (499 patients), 174 (29.4%) were treated for acute ischaemia, 13 (2.2%) for rupture, 105 (17.7%) for other symptoms, and 300 (50.7%) were asymptomatic (31.5% were treated for acute ischaemia, 1994-2002, p = .58). There were no differences in background characteristics between OR and ER in the acute ischaemia group. The symptomatic and asymptomatic groups treated with ER were older (p = .006, p < .001). ER increased 3.6 fold (4.7% 1994-2002, 16.7% 2008-2012, p = .0001). Of those treated for acute ischaemia, a stent graft was used in 27 (16.4%). Secondary patency after ER was 70.4% at 30 days and 47.6% at 1 year, versus 93.1% and 86.8% after OR (p = .001, <.001). The amputation rate at 30 days was 14.8% after ER, 3.7% after OR (p = .022), and 17.4% and 6.8% at 1 year (p = .098). A stent graft was used in 18.3% for asymptomatic PA. Secondary patency after ER was 94.5% at 30 days and 83.7% at 1 year, compared with 98.8% and 93.5% after OR (p = .043 and 0.026). OR was performed with vein graft in 87.6% (395/451), with better primary and secondary patency at 1 year than prosthetic grafts (p = .002 and <.001), and with a posterior approach in 20.8% (121/581). CONCLUSIONS The number of operations for PA doubled while the indications remained similar. ER patency was inferior to OR, especially after treatment for acute ischaemia, and the amputation risk tended to be higher, despite similar pre-operative characteristics.

Women With Abdominal Aortic Aneurysms Have More Extensive Aortic Neck Pathology

BACKGROUND The proportion of women with abdominal aortic aneurysm (AAA) treated with endovascular aortic repair (EVAR) is lower than for open repair (OR). Unfavorable morphologic features for EVAR in women with AAA may explain this disproportion. The objective of this study was to identify morphologic features in AAA patients undergoing elective repair with special emphasis on gender differences. METHODS Patients undergoing elective repair from January 1, 2006 to December 31, 2008 at our universitys vascular unit were included in this study. Computed tomography (CT) angiograms were analyzed. Morphologic features considered unfavorable for EVAR rather than open repair (OR) included: infrarenal aortic neck <15 mm; angulation >60°; circumferential neck thrombus; neck width >32 mm; iliac arteries <7.5 mm; or presence of bi-iliac aneurysms. Complex aortic neck was defined as a neck length of <15 mm and one or more of the other aortic neck exclusion criteria. RESULTS One hundred seventy-two patients, including 140 men and 32 women, were treated during the study period, which included 99 with OR (21 women, 78 men) and 73 with EVAR (11 women, 62 men). Morphologic unsuitability for EVAR was 44% (75 of 172) and was not statistically different between women and men [47% (15 of 32) vs. 43% (60 of 140), P = 0.70]. Aortic neck pathology was the dominating feature for unsuitability for EVAR (69 of 75, 92%), and 85 of 172 patients had an unsuitable aortic neck. This rate was not different between women and men [19 of 32 (59%) vs. 66 of 140 (47%), P = 0.24]. Iliac unsuitability rates were 11% (19 of 172) and were not different between women and men [4 of 32 (12%) vs. 15 of 140 (11%), P = 0.76]. In patients unsuitable for EVAR, the proximal aortic necks showed more extensive aortic neck pathology in women than in men [8 of 15 (53%) vs. 13 of 60 (22%), P = 0.02]. More men had only short neck pathology [22 of 60 (37%) vs. 1 of 15 (7%), P = 0.03]. CONCLUSIONS Aortic neck pathology is the dominating cause of EVAR exclusion in both genders. A higher proportion of women have more pathologic neck anatomy. Future development of EVAR devices should focus on the complexity of the aortic neck, which will benefit all AAA patients, but especially women.

Female and Elderly Abdominal Aortic Aneurysm Patients More Commonly Have Concurrent Thoracic Aortic Aneurysm

BACKGROUND A recent report unexpectedly revealed that one-fourth of abdominal aortic aneurysm (AAA) patients also have an aneurysm in the thoracic aorta (TAA). It remains to be investigated which AAA patients have a higher risk of also developing TAAs. The aim of this study was to identify possible differences in the risk factor profile in AAA patients with or without a TAA. METHODS All AAA patients attending an outpatient clinic and investigated using an abdominal and thoracic computed tomography scan were included (n = 354). Image analysis and hospital chart review were conducted. The association between comorbidity and TAA was estimated by logistic regression and odds ratios (ORs) with 95% confidence intervals (CIs). Gender-specific and neutral criteria were used. Validation of excluded patients was performed. RESULTS Ninety-four (27%) of 354 AAA patients had a concurrent descending TAA (AAA/TAA). AAA/TAA patients were older than AAA patients (76 vs. 73 years). More women were identified in the AAA/TAA group (39% vs. 16%, P < 0.001). In the univariate logistic regression model, female gender (OR: 3.3, 95% CI: 1.9-5.6), hypertension (OR: 1.8, 95% CI: 1.1-3.0), and age (70-79 years-OR: 2.4, 95% CI: 1.3-4.6; 80-89 years-OR: 3.0, 95% CI: 1.5-6.0) were associated with concurrent TAA. In the multivariate model, only female gender and age were associated with TAA. CONCLUSIONS AAA patients, in general, should be offered examination of the thoracic aorta, and special attention needs to be paid to female AAA patients and AAA patients at high age, if the AAA patient is considered operable. Surveillance of AAA patients must improve to enhance identification of the large group of patients who have developed, or will develop, TAAs. Future strategies will, of course, address pathophysiological aspects of aneurysmal development in the thoracic and infrarenal aorta.

Randomized clinical trial of mast cell inhibition in patients with a medium-sized abdominal aortic aneurysm.

Abdominal aortic aneurysm (AAA) is thought to develop as a result of inflammatory processes in the aortic wall. In particular, mast cells are believed to play a central role. The AORTA trial was undertaken to investigate whether the mast cell inhibitor, pemirolast, could retard the growth of medium‐sized AAAs. In preclinical and clinical trials, pemirolast has been shown to inhibit antigen‐induced allergic reactions.