Emma Larsson

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.

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.

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.

Acute kidney injury following severe trauma: Risk factors and long-term outcome.

BACKGROUND The trauma patient sustains numerous potentially harmful insults that may contribute to a notable risk of acute kidney injury (AKI). The aim of this study was to investigate the incidence of and to identify risk factors for AKI in severely injured trauma patients admitted to the intensive care unit (ICU). The patients were followed up for 1 year with respect to survival and end-stage renal disease. METHODS Trauma patients admitted to the ICU for more than 24 hours at a Level I trauma center were included. The outcome measure was AKI diagnosed Days 2 to 7 of ICU treatment. Regression analysis was performed to identify factors associated with AKI development. RESULTS A quarter of the patients (103 of 413) developed AKI within the first week of ICU admission. AKI was associated with increased 30-day (17.5% vs. 5.8%) and 1-year (26.2% vs. 7.1%) mortality. Risk factors for AKI were male sex, age, nondiabetic comorbidity, diabetes mellitus, Injury Severity Score (ISS) greater than 40, massive transfusion, and volume loading with hydroxyethyl starch (HES) within the first 24 hours. Unexpectedly, sepsis before AKI onset, admission hypotension, and extensive contrast loading (>150 mL) were not associated with AKI development. None of the surviving AKI patients had developed end-stage renal disease 1 year after injury. CONCLUSION AKI in ICU-admitted trauma patients is a common complication with substantial mortality. Diabetes, male sex, and severe injury were strong risk factors, but age, nondiabetic comorbidity, massive transfusion, and resuscitation with HES were also associated with postinjury AKI. Based on the results of the current study, volume resuscitation with HES cannot be recommended in trauma patients. LEVEL OF EVIDENCE Prognostic study, level III; therapeutic study, level IV.

More patients are treated for nonruptured abdominal aortic aneurysms, but the proportion of women remains unchanged.

BACKGROUND Large variations in the intervention rates for ruptured and nonruptured abdominal aortic aneurysm (AAA) over time have been reported, both decreasing and increasing numbers. Women have been reported to constitute an increasing proportion of patients treated for several manifestations of cardiovascular disease; whether a similar trend is true for AAA is not well understood. This study investigated recent temporal trends in a complete national register regarding the number and type of procedure performed for AAA, and outcome, with special emphasis on gender differences. METHODS Data for all individuals treated for nonruptured or ruptured AAA in Sweden (1990 to 2005) were obtained from the Swedish National Board of Health and Welfare (NBHW). A total of 14369 individuals were identified; 2327 (16%) were women. Date and type of intervention, date and cause of death, age, and sex were included in the statistical model. RESULTS There was a relative annual increase in interventions for nonruptured AAA; 4% for women (P < .0001) and 2% for men (P < .0001). No significant trends were observed for interventions for rupture during the observation period. No significant increase in the proportion of women was recorded for nonrupture (17%) or rupture (15%). Women had higher crude 30-day mortality rate than men after treatment for both nonruptured (5.7% vs 4.9%) and ruptured (41.9% vs 36.8%) AAA. In a logistic regression model, survival improved over time after intervention for nonrupture (P < .0001) and rupture (P < .0001). Increasing age (P < .0001 for both nonrupture and rupture) but not sex (P = .49 for non rupture and P = .42 for rupture) had a negative influence on mortality. CONCLUSION Interventions for nonruptured but not for ruptured AAA increased over time, with an expected rapid increase of endovascular repair in the nonruptured group. The unchanged fraction of women over time possibly reflects the true distribution of AAA between the sexes. The outcome after treatment for both nonruptured and ruptured AAA improved, as anticipated, over time. No increase in mortality among women was recorded after adjustment for age.

Quality of anaesthesia for Caesarean sections: a cross-sectional study of a university hospital in a low-income country

To evaluate the quality of anaesthesia for Caesarean sections at Muhimbili National Hospital, Dar es Salaam, Tanzania.

Causes of excessive late death after trauma compared with a matched control cohort

Studies on mortality following trauma have been restricted mainly to in‐hospital or 30‐day death. Mortality risk may be sustained several years after trauma, but the causes of late death have not been elucidated. The aim was to investigate mortality and analyse causes of late death after trauma.

Thioredoxin a novel biomarker of post-injury sepsis.

Background: Thioredoxin (TRX), an endogenous anti‐oxidant protein induced in inflammatory conditions, has been shown to increase in plasma and to be associated with outcome in septic patients. This biomarker has never been studied in a trauma setting. We hypothesized that TRX would be increased after trauma and associated with post‐injury sepsis. Methods: Single‐centre prospective observational study conducted at the intensive care unit (ICU) at the Karolinska University Hospital, Stockholm, Sweden, a level‐1 trauma centre. Eighty‐three severely injured trauma patients, 18 years or older, with an ICU stay of three days or more were included. Plasma samples were obtained on day 1 and 3 after informed consent. Clinical, physiological and outcome data were retrieved from the trauma and ICU research registries. Plasma samples were also obtained from 15 healthy subjects. In addition, a standardized porcine trauma model was conducted where a femur fracture followed by a controlled hemorrhage period were inflicted in four pigs. Results: In pigs, however not significant, there was a continuing increase in plasma‐TRX after femur fracture and sequential hemorrhage despite near normalisation of cardiac index and lactate levels. In patients, median injury severity score was 29 and 48 patients developed sepsis during their ICU stay. A three‐fold increase in initial TRX was seen in trauma patients when compared to healthy volunteers. Thioredoxin was significantly higher in patients in shock on admission, those subject to massive transfusion and in the most severely injured patients. No difference was seen between survivors and non‐survivors. Plasma‐TRX on day 1 was significantly increased in patients who later developed post‐injury sepsis. In a logistic regression analysis including TRX, C‐reactive protein, injury severity, massive transfusion, and admission blood pressure, TRX was the only variable independently associated with post‐injury sepsis. Conclusions: This study demonstrates that TRX is released into plasma in response to severe trauma and independently associated with post‐injury sepsis. The use of TRX as a biomarker in trauma patients needs further evaluation in larger studies. Level of evidence: Retrospective cohort study, level III. HIGHLIGHTSThioredoxin (TRX) in plasma is shown to be increased after traumatic injury.TRX levels correspond to injury severity, shock on arrival and massive transfusion.TRX is independently associated with later sepsis development.TRX shows promise as an early future biomarker for post‐injury sepsis.