Improved insights in the pathogenesis of abdominal aortic aneurysm unlock new therapeutic avenues

This is an interesting meta- analysis of great relevance given that abdominal aortic aneurysm (AAA) is a life-threatening condition in which progressive aortic expansion may lead to rupture, which is associated with high mortality. Smoking and male sex are key risk factors. In the current European clinical practice guidelines population screening for AAA with ultrasound is recommended in all men >65 years of age. We are therefore facing a relevant public health issue, further highlighting the importance of this article.

In this manuscript, the authors leveraged genetic data across 17 studies with the following objectives: (1) perform a genetic discovery analysis for AAA with substantially higher numbers of participants with AAA than in previous studies (fivefold increase); (2) create and test the predictive power of a polygenic risk score (PRS) derived from this analysis; (3) prioritize causal genes and pathways leading to disease; (4) explore the spectrum of phenotypic consequences associated with AAA risk variants and (5) identify potential therapeutic targets that may help to prevent and treat AAA.

The article is perfectly developed and illustrated with tremendously attractive and interesting figures that graphically expose the biological mechanisms underlying genetic loci associated with AAA. From the identified AAA risk loci, it becomes evident that lipid metabolism, vascular development and remodeling, extracellular matrix dysregulation and inflammation are key mechanisms in AAA pathogenesis. Additionally, through a combination of colocalization experiments as well as analysis in human plasma and Pcsk9−/− AAA mouse models, the authors prioritized possible therapeutic targets for the treatment and prevention of AAA focusing on the above described disease mechanisms.

From a practical and treatment point of view, these findings suggest that treatments that are beneficial for traits that we have now proven to be related to AAA genetically (for example, atherosclerotic vascular disease and inflammatory conditions) should also be tested for their efficacy in AAA patients. In particular, the results strongly highlight the critical role of lipids and lipid metabolism in AAA pathogenesis, rendering them key therapeutic targets. 

Finally, another of the authors' results, which also gives the title to the manuscript, supports PCSK9 inhibition as a potential therapeutic strategy for AAA. In a porcine pancreatic elastase (PPE) infused AAA mouse model, genetic Pcsk9 ablation was shown to attenuate disease progression, suggesting that the relationship between PCSK9 and AAA warrants further investigation. In short, this is a large and very well-developed study with practical relevance that opens up new possible therapeutic targets for AAA, a frequent entity with high mortality.