Scott M. Damrauer, MD
In the course of a series of investigations linked to the genetics of aneurysmal disease, Scott M. Damrauer, MD, a vascular surgeon at the Hospital of the University of Pennsylvania and the Corporal Michael Crescenz VA Medical Center, and the Chair of Clinical Research for Penn Surgery, has been leading and/or participating in clinical trials with the goal of identifying new therapeutic targets for abdominal aortic aneurysms (AAA).
AAAs Mortality and Morbidity
Generally, a diameter of >3.0 cm in any segment of the abdominal aorta is considered an aortic aneurysm. The majority of AAAs (~85%) occur between the renal and common iliac arteries. Most are asymptomatic, a precipitant of elevated risk for dissection and rupture. In the United States, AAA rupture has a >50% mortality even when patients survive to present in the emergency room.
Demographics, Indications, and Lapses in Current Management
Smoking, male sex, hypertension, and age are the leading risk factors for abdominal aneurysm. Current Society for Vascular Surgery screening guidelines recommend screening via duplex ultrasonography in men aged 65-75 years who are past or current smokers. Beyond this population, incidental findings from imaging for unrelated conditions are the leading source of diagnosis for AAAs.
The narrow indication for diagnosis of AAA is a source of concern. A recent large retrospective study found that 23% of individuals hospitalized for AAA in the US were women (many of whom smoke, and have generally worse outcomes from AAA rupture), and that more than >16% of affected persons were younger than 65 years of age.
Further complicating matters is the current absence of medical therapy to prevent or treat the progression of aortic aneurysm. To date, human clinical trials have found no consistent evidence of efficacy for angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, matrix metalloproteinase inhibitors, and statins. Thus, for diagnosed individuals and those presumed to be at risk, management consists of longitudinal surveillance of aneurysm size. Elective surgical intervention is indicated when the risk of rupture exceeds that of repair, generally at ~5.5 cm in diameter.
Given these circumstances, an urgent needs exists for medical AAA prophylaxis and management—an effort that has been a focus of genetic research for many years.
A role for PCSK9 Inhibitors
A genetic basis for aneurysmal disease first appeared in the 1970s with the discovery of familial abdominal aortic aneurysm, a finding verified in genetic trials with the eventual identification of 24 genomic risk loci for AAA.
Suspecting the potential for elaboration on these investigations (and given that a substantial portion of AAA heritability remains unknown), Dr. Damrauer recently led a large genome-wide association meta-analysis of clinical and genetic data to identify and investigate the genetic determinants of AAA. Ultimately, this study confirmed the 24 previously identified AAA genetic risk loci, but also identified 141 independent AAA-associated variants in 121 loci, and uncovered 97 previously unreported genetic loci for AAA. Of note, 42 of the 121 loci identified were associated with lipids, indicating the involvement of lipid metabolism, vascular development and remodeling, extracellular matrix dysregulation and inflammation as key mechanisms in AAA pathogenesis.
Following a series of analyses to further define the risk loci, and motivated by strong evidence for the role of lipid metabolism in AAA, Damrauer and colleagues then used Mendelian randomization to establish the central role of nonhigh-density lipoprotein cholesterol in AAA and identified an opportunity to repurpose proprotein convertase, subtilisin/kexin-type 9 (PCSK9) inhibitors.
The PCSK9 (proprotein convertase subtilisin/kexin type 9) gene is the source of an eponymous protein that provides instructions for regulating the amount of cholesterol in the bloodstream.
Agents that block the action of PCSK9 have the capacity to lower blood LDL-particle concentrations, and may have a therapeutic role in the effective management of aneurysmal disease. This hypothesis is supported by a study conducted by the investigators in which mice with PCDK9 loss of function were observed to have a significant decrease in expansion of the abdominal aortic diameter by comparison to wild-type mice following porcine pancreatic elastase (PPE) infusion. At this time, Dr Damrauer is investigating the effects of PCSK9 inhibition on the progression of diagnosed AAA.
Study Sources
Published in Nature Genetics, the article Genome-wide association meta-analysis identifies risk loci for abdominal aortic aneurysm and highlights PCSK9 as a potential therapeutic target involved a multinational team of contributors, including Dr. Damrauer, who both supervised and was corresponding co-author for the report.
To identify genetic variants associated with AAA, the researchers performed a meta-analysis of 17 individual genome-wide association studies (GWAS) from 14 discovery cohorts in the AAAgen Consortium. The study was partially funded by the US Department of Veterans Affairs Office of Research and Development and relied heavily on data from the VA Million Veteran Program. The analysis comprised 39,221 individuals with AAA from diverse backgrounds. Other contributing sources included the UK Aneurysm Growth Study, DBDS Genomic Consortium.