Vitamin K2 Dependent Matrix Gla Protein Relating to Abdominal Aortic Aneurysm and Overall Mortality: A Combined Case Control and Cohort Study.

OBJECTIVE: Inactivation of matrix Gla protein (MGP), using vitamin K antagonists or vitamin K deficiency results in increased vascular calcification, which has been associated with increased risk of symptomatic or ruptured abdominal aortic aneurysm (AAA). Insufficient activation of MGP leads to increased levels of undercarboxylated forms of MGP, measured as a dephosphorylated, undercarboxylated MGP (dp-ucMGP) in plasma. This study aimed to investigate whether the level of inactivated MGP influenced the risk of having an AAA, the risk of AAA progression, and overall mortality. METHODS: This combined case control and cohort study was based on data from the randomised, clinically controlled Viborg Vascular (VIVA) screening trial. Cases (n = 487) with an AAA and controls (n = 189) with neither peripheral artery disease nor AAA, had their plasma quantified for dp-ucMGP. Plasma levels were compared with the presence of an AAA, AAA growth rate, need for repair, and overall mortality. dp-ucMGP was divided into tertiles in regression analyses. RESULTS: The plasma levels of dp-ucMGP were higher for AAA cases compared with controls (median of 517 pmol/L vs. 495 pmol/L, p = .036). Adjusted analyses regarding dp-ucMGP being predictive of AAA, AAA growth rate, and need for repair all failed to show correlation. Overall mortality for AAA cases exhibited a significant association for the third tertile of dp-ucMGP with a hazard ratio of 2.55 (95% CI 1.29 - 5.05) compared with the first tertile. Overall mortality for controls was not correlated with dp-ucMGP plasma levels. CONCLUSION: dp-ucMGP did not correlate with the risk of having an AAA, AAA growth rate, or risk of surgery. For people with an AAA, dp-ucMGP was correlated with an increased mortality risk for the highest tertile of dp-ucMGP. This could suggest a role for prophylactic measures with vitamin K2 supplements to people at risk of AAA.

Diabetes Is Not Associated with the Risk of Rupture Among Patients with Abdominal Aortic Aneurysms - Results From a Large Danish Register Based Matched Case Control Study From 1996 to 2016.

OBJECTIVE: Numerous studies have shown a paradoxical protective effect of diabetes on the development and progression of abdominal aortic aneurysm (AAA). The aim of this study was to investigate whether the protective role of diabetes on AAA extends to rupture, given the presence of an AAA. METHODS: This was a register based case control study. Patients with ruptured AAA (RAAA) were matched 1:1 with patients undergoing elective surgery for AAA by sex, age, and year of diagnosis. Multiple conditional logistic regression was performed to estimate the odds ratio (OR) associating a diagnosis of diabetes with RAAA. No protocol was registered. RESULTS: From 1996 to 2016, there were 6293 potential people with RAAA. A total of 898 people with a RAAA were excluded since no matching controls existed. This left 5 395 cases in the study. The cases had a median age of 75, and 85.4% were men. Diabetes was defined by hospital diagnosis or the redemption of antidiabetic prescriptions within one year. Comparing cases with controls and the presence of diabetes, a significant crude OR of 0.82 (95% confidence interval [CI] 0.71-0.95) was found. When adjusting for confounders OR increased to 0.97 (CI 0.83-1.14). Stratifying by age and year of diagnosis did not change the results markedly. OR associating RAAA with diabetes was significantly elevated in women (adjusted OR 1.82 [CI 1.17-2.81]). Of the 5395 cases, the overall 30 days mortality was 58% (n = 3145). Using Cox regression, a crude hazard ratio (HR) of 1.06 (CI 0.93-1.22) was found for the 30 day mortality and having diabetes compared with not having diabetes. Adjusting for index year, male sex, and age had little effect on this estimate (HR 1.11 [CI 0.97-1.28]). CONCLUSION: Diabetes was not found to protect against RAAA, given the presence of an AAA. Furthermore, diabetes did not increase the risk of dying within 30 days of RAAA.

Metformin treatment does not affect the risk of ruptured abdominal aortic aneurysms.

OBJECTIVE: Diabetes counteracts formation and rupture of abdominal aortic aneurysms, possibly through arterial matrix accumulation. Use of metformin, on the other hand, reduces arterial accumulation of matrix molecules. Consequently, we hypothesized that metformin treatment may reverse the protective role of diabetes on the development and course of aneurysms, that is, that metformin would be associated with aneurysm rupture among individuals with diabetes. METHODS: Using nationwide Danish registry data, we performed a nested case-control study on the association between long-term use of metformin and ruptured abdominal aortic aneurysm (RAAA). The source population was defined as all individuals in Denmark with diabetes. Cases were all individuals within the source population who were hospitalized with a primary diagnosis of RAAA. For each case, 10 controls matched by age and sex were randomly selected from the source population by risk set sampling. The main exposure measure was a cumulative dispensing of 1000 g of metformin between January 1995 and the index date. RESULTS: We identified 362 cases of RAAA during 1998 to 2013, of which 83.7% occurred in men with a median age of 74 years. In total, 22.4% of the case population were long-term metformin users compared with 28.8% of the controls. We found a statistically nonsignificant protective effect of long-term metformin use toward RAAA with crude odds ratio (OR) of 0.74 (confidence interval, 0.54-1.00). When adjusted for covariates, OR increased to 0.84 (confidence interval, 0.61-1.17). None of the subgroups had ORs deviating substantially from the main result. CONCLUSIONS: Metformin use does not increase the risk of RAAA among individuals with diabetes.

Survival, Prevalence, Progression and Repair of Abdominal Aortic Aneurysms: Results from Three Randomised Controlled Screening Trials Over Three Decades.

AIM: The prevalence and mortality of abdominal aortic aneurysms (AAA) has been reported to decline. The aim of this study is to compare survival, prevalence, and repair rate of AAA in Denmark in the 1990s, the 2000s and the 2010s - and to examine any change in factors known to influence the prevalence. METHODS: Baseline status and up to 5-year outcomes of 34,079 general population men aged 65-74 were obtained from three RCTs; the Viborg study (1994-1998, n=4,860), the Viborg Vascular (VIVA) trial (2008-2011, n=18,748), and the Danish Cardiovascular (DANCAVAS) trial (2015-2018, n=10,471). After the millennium (VIVA and DANCAVAS) men with AAA were further offered low dose aspirin and statins. Follow-up data were not available for the DANCAVAS trial yet. RESULTS: Across the three decades, the AAA prevalence was 3.8% (Reference), 3.3% (p<0.001) and 4.2% (p=0.882), the proportion of smokers were 62%, 42% and 34% (p<0.001) amongst men with AAA, but AAA risk associations with smoking increased during the decades suggesting increased tobacco consumption of smokers. In addition, the proportions of attenders with ischemic heart disease or stroke increased significantly. The aneurysmal progression rate in the 1990s was 2.90 vs 2.98 mm/year in the 2000s (p=0.91). The need for preventive AAA repair increased insignificantly in the 2000s (Age adj. HR= 1.29, 95% C.I.: 0.95; 1.71, p=0.10), and mortality of men with screen-detected AAA was lower in the 2000s compared to the 1990s (Age-adj. HR= 0.28, 95% C.I.: 0.22; 0.36, p<0.001). CONCLUSION: The Danish prevalence of AAA today compares to the nineties. Unchanged aneurysmal progression rates combined with improved survival of men at risk of AAA leave them in longer time to develop an AAA, be diagnosed and to need later aneurysmal repair or experience rupture. CLINICAL TRIAL REGISTRATIONS: Viborg study: No possibility of registration in the nineties. VIVA: NCT00662480, URL: https://clinicaltrials.gov/show/NCT00662480, DANCAVAS: ISRCTN12157806, URL: http://www.isrctn.com/ISRCTN12157806.

Arachidonic Acid, but Not Omega-3 Index, Relates to the Prevalence and Progression of Abdominal Aortic Aneurysm in a Population-Based Study of Danish Men.

BACKGROUND: Animal models support dietary omega-3 fatty acids protection against abdominal aortic aneurysm (AAA), but clinical data are scarce. The sum of red blood cell proportions of the omega-3 eicosapentaenoic and docosahexaenoic acids, known as omega-3 index, is a valid surrogate for long-term omega-3 intake. We investigated the association between the omega-3 index and the prevalence and progression of AAA. We also investigated associations between AAA and arachidonic acid, an omega-6 fatty acid that is a substrate for proinflammatory lipid mediators. METHODS AND RESULTS: We obtained blood samples from 498 AAA patients (maximal aortic diameter ≥30 mm) within a population-based ultrasound-screening trial in men and from 199 age-matched controls who screened negative. We determined the fatty acids of red blood cells by gas chromatography. During a median follow-up of 4.85 years, 141 AAA patients reached criteria for vascular surgical repair. Participants were high consumers of omega-3 (average omega-3 index: 7.6%). No significant associations were found for omega-3 index. In contrast, arachidonic acid in AAA patients was higher than in controls (P<0.001), and individuals in the upper tertile of arachidonic acid at baseline had higher probability of having AAA (odds ratio: 1.309; 95% confidence interval, 1.021-1.678; P=0.033). AAA patients at the upper tertile of arachidonic acid at baseline had a 54% higher risk of needing surgical repair during follow-up (hazard ratio: 1.544; 95% confidence interval, 1.127-2.114; P=0.007). CONCLUSIONS: Omega-3 index is unrelated to men with AAA from a country in which fish consumption is customarily high. Arachidonic acid is associated with AAA presence and progression. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00662480.