Carl-Magnus Wahlgren

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.

Endovascular Treatment of Mycotic Aortic Aneurysms A European Multicenter Study

Background— Mycotic aortic aneurysm (MAA) is a rare and life-threatening disease. The aim of this European multicenter collaboration was to study the durability of endovascular aortic repair (EVAR) of MAA, by assessing late infection–related complications and long-term survival. Methods and Results— All EVAR treated MAAs, between 1999 and 2013 at 16 European centers, were retrospectively reviewed. One hundred twenty-three patients with 130 MAAs were identified. Mean age was 69 years (range 39–86), 87 (71%) were men, 58 (47%) had immunodeficiency, and 47 (38%) presented with rupture. Anatomic locations were ascending/arch (n=4), descending (n=34), paravisceral (n=15), infrarenal aorta (n=63), and multiple (n=7). Treatments were thoracic EVAR (n=43), fenestrated/branched EVAR (n=9), and infrarenal EVAR (n=71). Antibiotic was administered for mean 30 weeks. Mean follow-up was 35 months (range 1 week to 149 months). Six patients (5%) were converted to open repair during follow-up. Survival was 91% (95% confidence interval, 86% to 96%), 75% (67% to 83%), 55% (44% to 66%), and 41% (28% to 54%) after 1, 12, 60, and 120 months, respectively. Infection-related death occurred in 23 patients (19%), 9 after discontinuation of antibiotic treatment. A Cox regression analysis demonstrated non-Salmonella–positive culture as predictors for late infection–related death. Conclusions— Endovascular treatment of MAA is feasible and for most patients a durable treatment option. Late infections do occur, are often lethal, and warrant long-term antibiotic treatment and follow-up. Patients with non-Salmonella–positive blood cultures were more likely to die from late infection. # CLINICAL PERSPECTIVE {#article-title-32}Background— Mycotic aortic aneurysm (MAA) is a rare and life-threatening disease. The aim of this European multicenter collaboration was to study the durability of endovascular aortic repair (EVAR) of MAA, by assessing late infection–related complications and long-term survival. Methods and Results— All EVAR treated MAAs, between 1999 and 2013 at 16 European centers, were retrospectively reviewed. One hundred twenty-three patients with 130 MAAs were identified. Mean age was 69 years (range 39–86), 87 (71%) were men, 58 (47%) had immunodeficiency, and 47 (38%) presented with rupture. Anatomic locations were ascending/arch (n=4), descending (n=34), paravisceral (n=15), infrarenal aorta (n=63), and multiple (n=7). Treatments were thoracic EVAR (n=43), fenestrated/branched EVAR (n=9), and infrarenal EVAR (n=71). Antibiotic was administered for mean 30 weeks. Mean follow-up was 35 months (range 1 week to 149 months). Six patients (5%) were converted to open repair during follow-up. Survival was 91% (95% confidence interval, 86% to 96%), 75% (67% to 83%), 55% (44% to 66%), and 41% (28% to 54%) after 1, 12, 60, and 120 months, respectively. Infection-related death occurred in 23 patients (19%), 9 after discontinuation of antibiotic treatment. A Cox regression analysis demonstrated non-Salmonella–positive culture as predictors for late infection–related death. Conclusions— Endovascular treatment of MAA is feasible and for most patients a durable treatment option. Late infections do occur, are often lethal, and warrant long-term antibiotic treatment and follow-up. Patients with non-Salmonella–positive blood cultures were more likely to die from late infection.

Human Carotid Plaque Calcification and Vulnerability

Background: Inflammation is a key mechanism in human atherosclerotic plaque vulnerability and disruption. The objective was to determine the differential gene expression of pro- and anti-inflammatory factors in the fibrous cap and shoulder region of noncalcified and calcified carotid endarterectomy plaques. Methods: Thirty carotid endarterectomy plaques were classified as type Va (noncalcified, n = 15) and type Vb (calcified, n = 15) in accordance with the American Heart Association consensus. Using laser capture microdissection, fibrous cap and shoulder regions were excisedfrom frozen sections. Gene expression of pro- [interleukin 1 (IL-1), IL-8 and monocyte chemoattractant protein 1 (MCP-1)] and anti-inflammatory (IL-10) factors, and bone formation (bone morphogenetic protein 6 and osteocalcin) mediators were quantitated by real-time PCR. Protein levels were determined using Western blotting. Results: Mean percent carotid stenosis and calcification area were 79 and 5% in Va-plaques (40% symptomatic) and 77 and 42% in Vb-plaques (20% symptomatic). Macrophages infiltrating the region of the fibrous cap and the shoulder were more numerous in non-calcified plaques compared with calcified plaques (p < 0.01]. mRNA expression of MCP-1 and IL-8, and protein levels of IL-8 were also greater in Va plaques compared to Vb plaques (p < 0.05). Protein levels and mRNA expression of osteocalcin were greater in Vb compared to Va plaques (p < 0.05). Conclusions: Fibrous cap inflammation is more likely to occur in noncalcified than in calcified plaques. These findings suggest that carotid atherosclerotic plaque calcification is a structural marker of plaque stability.

Endovascular Treatment in Postthrombotic Syndrome

Background: The postthrombotic syndrome is a chronic complication of deep venous thrombosis that leads to considerable pain and suffering to patients. We evaluated our experience of endovascular treatment for patients with chronic postthrombotic femoroiliocaval venous disease. Materials and Methods: From January 2003 through December 2007, 50 patients (51 limbs; 60% women; mean age 45 years; range: 24-74 years) with chronic postthrombotic venous disease were referred to our institution for interventional assessment. All patients underwent duplex ultrasonography as well as ascending and descending venography. The CEAP (clinical, etiologic, anatomic, and pathophysiologic classification) clinical scores were class 0 (no signs) in 2% of limbs, class 3 (edema) in 63%, class 4a (pigmentation or eczema) in 18%, class 5 (healed venous ulcer) in 14%, and class 6 (active venous ulcer) in 4%. The etiology was secondary (postthrombotic) in all patients. The anatomical distribution of reflux and obstruction were deep veins in 63% and a combination of deep and superficial veins in 37%. The underlying pathophysiology due to obstruction of the deep venous outflow with no reflux was found in 25% of limbs, only reflux was found in 14%, and a combination of obstruction and reflux was found in 61%. Results: There were 21 limbs in 20 (38%) patients that underwent endovascular and/or surgical treatment. One limb underwent femoral endovenectomy and 1 limb superficial femoral vein to deep femoral vein transposition. In all, 19 limbs were scheduled for endovascular treatment. The technical success rate was 84%, 3 limbs with iliac vein occlusions could not be recanalized. A total of 11 patients (11 limbs) underwent solely endovascular intervention and 4 patients (5 limbs) underwent endovascular intervention combined with femoral endovenectomy. The endovascular and surgical procedures were performed with no perioperative or postoperative mortality as well as no major bleeding or cardiac, pulmonary, or renal 30-day complications. Early thrombosis (<30 days) of the stented iliac veins occurred in 3 limbs which were lysed and restented successfully. The mean follow-up time was 23 months (range: 1-69 months). Primary and assisted-primary/secondary patency rates at 12 months were 61% and 81%, respectively. The Venous Clinical Severity score was 9.1 (range: 5-15) before endovascular treatment and 6.0 (range: 3-13) after the treatment (P < .0001). There were 30 patients (62%) with symptoms attributable to venous dysfunction or with deep venous pathology that did not undergo interventional treatment after workup. These patients continued with appropriate thromboprophylaxis and elastic compression stockings. Conclusion: Endovascular treatment of chronic postthrombotic femoroiliocaval venous disease is a safe technique that can be performed with acceptable patency rates in this challenging patient population.

Outcomes of endovascular abdominal aortic aneurysm repair compared with open surgical repair in high-risk patients: Results from the Swedish Vascular Registry

BACKGROUND The management of infrarenal aortic aneurysms in high-risk patients remains a challenge. Endovascular aneurysm repair (EVAR) is associated with superior short-term mortality rates but unclear long-term results and has not been shown to improve survival in patients unfit for open repair (OR). The aim of this population-based study was to evaluate the outcome after elective EVAR compared with OR in a high-risk patient cohort. METHODS Prospectively collected data from January 2000 to December 2006 were retrieved from the Swedish Vascular Registry. The high-risk cohort was defined as age >or=60 years, American Anesthesiologists Association (ASA) class 3 or 4, and at least one cardiac, pulmonary, or renal comorbidity. These criteria were met by 217 of 1000 EVAR patients and 483 of 2831 OR patients. Primary end points were 30-day and 1-year all-cause mortality. Kaplan-Meier curves for survival and multivariate Cox regression analyses were performed. RESULTS The crude 30-day and 1-year all-cause mortality rates for EVAR vs OR for the whole treatment group (n = 3831) were 1.8% vs 2.8% and 8.0% vs 7.2%, respectively. In the high-risk cohort (n = 700), EVAR patients were approximately 2 years older and renal insufficiency and diabetes mellitus were more common, and smoking was more prevalent in the OR group. About two-thirds of EVAR procedures were performed at university hospitals and one-half of OR procedures were performed at county hospitals. In the high-risk cohort, there was no difference in mortality at 30-days (EVAR, 4.6% vs OR, 3.3%), but OR had lower 1-year mortality (8.5% vs 15.9%; P = .003). More bleeding complications occurred in the EVAR group, but more pulmonary complications occurred in the OR group; however, there was no difference in cardiac, cerebrovascular, or renal complications. The mean follow-up was 3.4 years. EVAR was associated with increased mortality risk after adjusting for age, ASA class, and comorbidities (hazard ratio, 1.50; 95% confidence interval, 1.07-2.12; P = .02). Kaplan-Meier survival analysis showed a lower mortality rate for patients undergoing OR, which remained during follow-up (P = .001). CONCLUSIONS Elective OR of aortic aneurysms seems to have a better outcome compared with EVAR in this specific, population-based, high-risk patient cohort after adjusting for covariates. We cannot confirm the benefit of EVAR from previous registry studies with a similar high-risk definition. In clinical practice, OR may be at least as good as EVAR in high-risk patients fit for surgery.

Genetic Influences on Peripheral Arterial Disease in a Twin Population

Objective—To analyze the contribution of genetic and environmental factors to the development of peripheral arterial disease (PAD) in a large population-based sample of twins. Methods and Results—The understanding of genetics in PAD is still limited. From the Swedish Twin Registry and the national patient discharge registry, 1464 twins with PAD were identified, including 33 monozygotic (MZ) and 42 dizygotic (DZ) concordant pairs and 298 MZ and 1008 DZ discordant pairs. Traditional cardiovascular risk factors were significantly more prevalent in twins with PAD than in those without PAD. Concordances and correlations were higher in MZ compared with DZ twins, indicating genetic influences in PAD. The risk of PAD for persons whose twin had PAD compared with persons whose twin did not have PAD, estimated as an odds ratio, was 17.7 (95% CI, 11.7 to 26.6) for MZ twins and 5.7 (95% CI, 4.1 to 7.9) for DZ twins. In the structural equation models, Mx analyses, genetic effects accounted for 58% (95% CI, 50% to 64%) and nonshared environmental effects for 42% (95% CI, 36% to 50%) of the phenotypic variance among twins. Conclusion—Heritability is an important component, along with unique environmental factors, for the development of PAD. The proportion of the overall PAD heritability attributed to the heritability of cardiovascular risk factors needs to be resolved. Traditional risk factors could explain a major proportion of PAD heritability. A better understanding of the genetics in PAD could identify individuals at increased risk who may benefit from targeted therapies.

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.

Thrombolysis for lower extremity bypass graft occlusion

BACKGROUND Thrombolysis is a common method in the treatment of lower extremity bypass graft occlusion. The purpose of this study was to investigate the results of thrombolytic therapy in the management of acute bypass graft occlusion and to identify risk factors for technical failure and amputation. METHODS All patients at two tertiary referral centers undergoing thrombolysis for acute graft occlusion in the lower limb between January 1, 2000 and December 31, 2008 were retrospectively reviewed. Factors associated with technical failure of thrombolytic therapy, major amputation, and mortality were determined with multivariate analysis, and long-term outcomes were assessed with the Kaplan-Meier method and log-rank test. RESULTS During the study period, 123 patients underwent thrombolysis for acute bypass graft occlusion. Mean age was 69 years (range, 27-91 years); 38% were women. Sixty-seven percent had synthetic grafts. Acute critical leg ischemia (74%) was the dominating symptom preceding thrombolytic treatment. In 29% of cases, no adjunctive interventions were required, whereas 21% underwent open surgery, 39% endovascular intervention, and 11% underwent a hybrid procedure. Technical failure of thrombolysis occurred in 18 patients. Presence of ischemic heart disease (P = .013), older grafts (P = .014), and synthetic grafts (trend; P = .092) were associated with success of thrombolysis, and ischemic heart disease remained as an independent factor in the multivariate analysis for technical success of thrombolysis (P = .04; odds ratio 4.0; 95% confidence interval [CI; 1.1-15.1]), whereas there was a trend for older grafts (P = .089). Mean follow-up was 38 months (range, 0-119 months). The major amputation rate was 11% (14/123) at 1 month and 25% (31/122) at 1 year. In a Cox regression model, technical failure (P = .031; hazard ratio [HR] 2.58, 95% CI [1.0-6.08]), higher age (P = .004; HR 1.06, 95% CI [1.02-1.10]), and synthetic graft as opposed to vein graft (P = .050; HR 2.63, 95% CI [1.0-6.9]) remained as independent factors associated with major amputation. The amputation-free survival rate was 89% and 75% at 1 and 12 months, respectively. Higher age (P < .001; HR 1.06, 95% CI [1.03-1.09]) and acute limb ischemia (P = .007; HR 2.40, 95% CI [1.26-4.56]) remained as independent adverse factors associated with amputation-free survival. CONCLUSIONS Our findings support the use of thrombolysis in the treatment of acute bypass graft occlusion in the lower limb given its acceptable short- and long-term amputation-free survival rates. Technical failure and higher age were factors associated with major amputation. Synthetic grafts appeared to have a somewhat increased likelihood of technically successful thrombolysis compared with vein grafts, but on the other hand, they exhibited an increased risk of amputation during follow-up.

The role of coagulation and inflammation after angioplasty in patients with peripheral arterial disease.

PurposeRestenosis remains a frequent complication after angioplasty in peripheral arterial disease. Inflammation plays a critical role in the vascular response to injury. Effective medical treatment to improve patency after angioplasty is still elusive. The aims of this prospective clinical study were to investigate changes in blood coagulation and inflammatory markers after angioplasty and their significance for restenosis.MethodsThirty-four patients with peripheral arterial disease underwent angioplasty of the iliac and superficial femoral arteries. Ten patients undergoing diagnostic angiography were included in the study as controls. Plasma levels of tissue factor, prothrombin fragment 1 + 2, D-dimer, P-selectin, C-reactive protein (CRP), and fibrinogen were analyzed before and after angioplasty. Patients were followed up with angiography after 6 months to assess restenosis.ResultsCRP was elevated the day after angioplasty (6.6 mg/l, p = 0.0001) and tended to peak after 1 week (11 mg/l, p = 0.09). There was a significant increase of D-dimer and P-selectin 1–4 hr after angioplasty (0.4 mg/l, p = 0.001 and 68 ng/ml, p = 0.05, respectively). None of the biochemical markers was a statistically significant predictor of restenosis.ConclusionWe have observed a much more prolonged inflammatory response than previously noted, but only minor changes in coagulation activity after angioplasty. The biochemical markers, before and after angioplasty, were not related to restenosis. Further studies are needed to delineate the molecular mechanisms behind these observations and their involvement in thrombosis and restenosis. If these pathways are further defined, improved treatment strategies, including antithrombotic treatments and statins, could be tailored to modulate postprocedural inflammation.