Genome-wide association meta-analysis identifies risk loci for abdominal aortic aneurysm and highlights PCSK9 as a therapeutic target.

Abdominal aortic aneurysm (AAA) is a common disease with substantial heritability. In this study, we performed a genome-wide association meta-analysis from 14 discovery cohorts and uncovered 141 independent associations, including 97 previously unreported loci. A polygenic risk score derived from meta-analysis explained AAA risk beyond clinical risk factors. Genes at AAA risk loci indicate involvement of lipid metabolism, vascular development and remodeling, extracellular matrix dysregulation and inflammation as key mechanisms in AAA pathogenesis. These genes also indicate overlap between the development of AAA and other monogenic aortopathies, particularly via transforming growth factor ß signaling. Motivated by the strong evidence for the role of lipid metabolism in AAA, we used Mendelian randomization to establish the central role of nonhigh-density lipoprotein cholesterol in AAA and identified the opportunity for repurposing of proprotein convertase, subtilisin/kexin-type 9 (PCSK9) inhibitors. This was supported by a study demonstrating that PCSK9 loss of function prevented the development of AAA in a preclinical mouse model.

Preoperative geriatric assessment, a promising tool to improve outcomes in aortic pathology interventions.

BACKGROUND: Due to population aging and the spread of endovascular techniques for aortic diseases, there has been an increase in older population intervened. Objectively assessing patient's global status becomes mandatory in advanced ages, as impaired functional status and frailty are associated with higher postoperative mortality rates. The aim of this paper is to evaluate the impact of a systematic geriatric preoperative assessment on the outcomes of aortic interventions. METHODS: All patients above 60 years old with surgical indication for aortic disease between September 2016 and May 2019 underwent a standardized geriatric assessment. It analyzed physiological reserve, frailty, and life expectancy. An algorithm was created for its application before intervention indication. Variables registered were patient's data, type of aortic disease, type of intervention, geriatric assessment result, mortality and follow-up time. A bivariate analysis was performed. RESULTS: One hundred forty-four patients were included. Geriatric report was unfavorable for intervention in 6.25% (N.=9). From these, 88% (N.=8) were finally rejected for intervention. In those undergoing aortic intervention (N.=127) there was a 7% mortality rate (N.=9) and in the no-intervention group (N.=17) mortality rate raised up to 35% (N.=6). No aortic-related mortality was reported. A relevant association between an unfavorable geriatric report and mortality was found "OR 0.036 (CI 0.0082-0.155)." A protective relationship between any aortic intervention and mortality was found, with OR 0.139 (CI 0.043-0.447). CONCLUSIONS: Geriatric assessment is a valid tool to estimate life expectancy and patient's physiological status. An unfavorable report correlates with short-term non-aortic mortality independently of undergoing intervention. This has a high clinical relevance, and it highlights its practical applicability to improve aortic surgery indication's quality and optimize resource investment.

The TAGA Study: A Study of Factors Determining Aortic Diameter in Families at High Risk of Abdominal Aortic Aneurysm Reveal Two New Candidate Genes.

A variety of disorders are known to be related with aortic geometry, among them abdominal aortic aneurysm (AAA). This work aims to present the main determinants of abdominal aortic diameter in a new cohort of families at high risk of AAA. The Triple-A Genomic Analysis (TAGA) study comprises 407 individuals related in 12 families. Each family was collected through a proband with AAA. We calculated heritability and genetic correlations between abdominal aortic diameter and clinical parameters. A genome-wide linkage scan was performed based on 4.6 million variants. A predictive model was calculated with conditional forest. Heritability of the abdominal aortic diameter was 34%. Old age, male sex, higher height, weight, creatinine levels in serum, and better lung capacity were the best predictors of aortic diameter. Linkage analyses suggested the implication of Epidermal Growth Factor Receptor (EGFR) and Betacellulin (BTC) genes with aortic diameter. This is the first study to evaluate genetic components of variation of the aortic diameter in a population of AAA high-risk individuals. These results reveal EGFR, a gene that had been previously implicated in AAA, as a determinant of aortic diameter variation in healthy genetically enriched individuals, and might indicate that a common genetic background could determine the diameter of the aorta and future risk of AAA.