Inhibition of plasmin-mediated TAFI activation may affect development but not progression of abdominal aortic aneurysms

Objective: Thrombin-activatable fibrinolysis inhibitor (TAFI) reduces the breakdown of fibrin clots through its action as an indirect inhibitor of plasmin. Studies in TAFI-deficient mice have implicated a potential role for TAFI in Abdominal Aortic Aneurysm (AAA) disease. The role of TAFI inhibition on AAA formation in adult ApoE-/- mice is unknown. The aim of this paper was to investigate the effects of TAFI inhibition on AAA development and progression. Methods: Using the Angiotensin II model of AAA, male ApoE-/- mice were infused with Angiotensin II 750ng/kg/min with or without a monoclonal antibody inhibitor of plasmin-mediated activation of TAFI, MA-TCK26D6, or a competitive small molecule inhibitor of TAFI, UK-396082. Results: Inhibition of TAFI in the Angiotensin II model resulted in a decrease in the mortality associated with AAA rupture (from 40.0% to 16.6% with MA-TCK26D6 (log-rank Mantel Cox test p = 0.16), and 8.3% with UK-396082 (log-rank Mantel Cox test p = 0.05)). Inhibition of plasmin-mediated TAFI activation reduced the incidence of AAA from 52.4% to 30.0%. However, late treatment with MA-TCK26D6 once AAA were already established had no effect on the progression of AAA in this model. Conclusions: The formation of intra-mural thrombus is responsible for the dissection and early rupture in the angiotensin II model of AAA, and this process can be prevented through inhibition of TAFI. Late treatment with a TAFI inhibitor does not prevent AAA progression. These data may indicate a role for inhibition of plasmin-mediated TAFI activation in the early stages of AAA development, but not in its progression

Pioneering techniques in abdominal aortic surgery and endovascular aortic repair

The history and evolution of abdominal aortic aneurysm repair highlights the wider evolution of surgery from traditional open operative techniques to modern minimally invasive procedures. From their first recording in ancient Egypt, through surgical techniques such as aortic ligation, polyethylene wrapping, and external compression, and to the work of Astley Cooper and Rudolph Matas pioneering modern day open surgical repair, abdominal aortic aneurysm treatment remains a highly debated area. The introduction of endovascular techniques by Parodi provided the footing for the most significant recent step forward in vascular surgery however; randomized controlled trials comparing open and endovascular techniques suggest that a minimally invasive approach may not confer any long term survival advantage. Endovascular surgery is quickly evolving to overcome the problems placed by more challenging aortic anatomy with results from fenestrated endovascular aortic repair and endovascular aneurysm sealing looking promising however, prevention remains better than cure. The future of aneurysm treatment should involve public health strategies targeting smoking and other common cardiovascular risk factors to reduce the incidence of AAA as well as the concomitant risk of rupture

Mortality from thoracic aortic diseases and associations with cardiovascular risk factors

Background— Temporal trends in mortality from thoracic aortic disease are unclear. This study examined trends in mortality from thoracic aortic aneurysm (TAA) and aortic dissection (AD) with the aim of identifying associations with trends in established cardiovascular risk factors. Methods and Results— TAA and AD mortality (1994–2010) using International Classification of Diseases codes was extracted from the World Health Organization mortality database and age standardized. World Health Organization InfoBase and International Mortality and Smoking Statistics provided risk factor data. Eighteen World Health Organization member states were included (Europe=13, Australasia=2, North America=2, Asia=1). Ecological regression was performed of temporal trends in cardiovascular risk factors (1946–2010) and independent correlations to mortality trends. TAA and AD mortality trends show substantial heterogeneity but are generally declining. TAA mortality has increased in Hungary, Romania, Japan, and Denmark, and AD mortality has increased in Romania and Japan; therefore, the mortality decline is not universal. A linear relationship exists between trends in systolic blood pressure, cholesterol, and body mass index and mortality from TAA. Body mass index demonstrated a negative linear association with female AD mortality, whereas trends in systolic blood pressure demonstrated a positive linear relationship with male AD mortality. Trends in smoking prevalence were not associated with TAA or AD mortality trends. Conclusions— This population-level ecological regression provides evidence that mortality secondary to TAA and mortality secondary to AD are both in decline. Differences between countries could be explained by population-level changes in common cardiovascular risk factors. Public health measures could further reduce mortality from TAA and AD

Mortality From Thoracic Aortic Diseases and Associations With Cardiovascular Risk Factors

Background— Temporal trends in mortality from thoracic aortic disease are unclear. This study examined trends in mortality from thoracic aortic aneurysm (TAA) and aortic dissection (AD) with the aim of identifying associations with trends in established cardiovascular risk factors. Methods and Results— TAA and AD mortality (1994–2010) using International Classification of Diseases codes was extracted from the World Health Organization mortality database and age standardized. World Health Organization InfoBase and International Mortality and Smoking Statistics provided risk factor data. Eighteen World Health Organization member states were included (Europe=13, Australasia=2, North America=2, Asia=1). Ecological regression was performed of temporal trends in cardiovascular risk factors (1946–2010) and independent correlations to mortality trends. TAA and AD mortality trends show substantial heterogeneity but are generally declining. TAA mortality has increased in Hungary, Romania, Japan, and Denmark, and AD mortality has increased in Romania and Japan; therefore, the mortality decline is not universal. A linear relationship exists between trends in systolic blood pressure, cholesterol, and body mass index and mortality from TAA. Body mass index demonstrated a negative linear association with female AD mortality, whereas trends in systolic blood pressure demonstrated a positive linear relationship with male AD mortality. Trends in smoking prevalence were not associated with TAA or AD mortality trends. Conclusions— This population-level ecological regression provides evidence that mortality secondary to TAA and mortality secondary to AD are both in decline. Differences between countries could be explained by population-level changes in common cardiovascular risk factors. Public health measures could further reduce mortality from TAA and AD