The first potential drug treatment for abdominal aortic aneurysms (AAA) may be on the horizon, thanks to research led in the UK by the University of Leicester and part-funded by the British Heart Foundation (BHF). A sequence of studies suggested that drugs already used in genetic or resistant hypercholesterolaemia might be repurposed to treat early AAA.
The possibility of medical therapy was hailed as a "huge breakthrough" that could offer patients living with the condition a viable option to slow the development of AAA and avert a catastrophic outcome.
Most AAA cases are discovered incidentally or by screening, which in the NHS is offered to men over age 65. About 4% are found to have AAA. The team noted that there are currently no treatments that can stop an aneurysm developing or expanding. The mortality of ruptured AAA is around 80%, causing over 2200 deaths in the UK each year.
Risk of Rupture Must be Balanced Against Risks of Surgery
The mainstay of management is longitudinal surveillance, "until the aneurysm size reaches the point at which the risk of rupture exceeds the risk of repair", the researchers noted. According to the Vascular Society, the rupture risk is less than 1% per annum for aneurysms less than 5.5cm in diameter, which is lower than the risks of surgery. Above this size, surgery, either open or endovascular repair, may be considered.
Most aneurysms grow slowly, about 3mm annually, and are usually monitored by ultrasound scans every 3 to 6 months. This disease surveillance period "may last several years", the researchers said, and represents "an ideal opportunity to intervene and prevent disease progression".
Effective Treatment Would be a "Huge Breakthrough"
Matthew Bown , BHF professor of vascular surgery at the University of Leicester, who led the UK research team, explained: "Despite being relatively common, the only option we can offer patients with AAA is regular monitoring potentially followed by surgery if their aneurysm becomes too large.
"An effective treatment that could slow or even stop an AAA developing would be a huge breakthrough for people living with the condition. But, so far, this has proved elusive. We're hopeful that our findings can provide the foundation to propel us towards the first drug treatment for AAA."
For their study, published in Nature Genetics, the international research team performed a genome-wide association meta-analysis of 17 studies from 14 discovery cohorts, with multiple aims to:
- Expand knowledge of genomic risk loci for AAA
- Create and test the predictive power of a polygenic risk score derived from this analysis
- Prioritise the causal genes and pathways
- Explore the spectrum of phenotypic consequences associated with AAA risk variants
- Identify potential therapeutic targets to help prevent and treat AAA
Genetic Variants Explained Risk Beyond Known Clinical Risk Factors
The total sample included 39,221 individuals with AAA – a fivefold higher number than previous studies. The analysis identified 141 involved genetic variants, including 97 risk loci never previously linked to AAA. From this, the team derived a polygenic risk score that explained the risk beyond known clinical risk factors.
Genes at AAA risk loci suggested that key mechanisms in AAA pathogenesis involved lipid metabolism, vascular development and remodeling, extracellular matrix dysregulation, and inflammation.
One of the genes encoded for a protein called PCSK9, and the team demonstrated that higher levels of PCSK9 were associated with increased AAA risk. They reasoned that PCSK9 inhibitors, already used to treat hypercholesterolaemia by boosting low density lipoprotein (LDL) cholesterol removal, might be repurposed as a treatment for AAA.
They therefore used Mendelian randomisation to establish the "central role" of non-high-density lipoprotein cholesterol in AAA. They then demonstrated in a preclinical mouse model that simulating the effect of PCSK9 inhibitors to cause loss of PCSK9 function slowed aneurysm growth, so could be an effective treatment.
Discovery Could Lead to Clinical Trials "Within the Next Few Years"
The researchers said that they hoped their discovery could lead to clinical trials of these drugs in people with AAA "within the next few years". With knowledge of the "significant number of new genes" they identified, and their linked biological processes, "it might be possible to repurpose more drugs as treatments for AAA", they added.
Professor James Leiper from the University of Glasgow Institute of Cardiovascular and Medical Sciences, and BHF associate medical director, said: "The consequences of an abdominal aortic aneurysm bursting are catastrophic and, more often than not, this will cost a patient their life. People with an AAA live day-to-day with this looming threat."
Repurposing drugs already in use can "dramatically shorten the time it takes for findings to go from discovery to patient trials", he added. While testing in large groups of patients will be needed before PCSK9 inhibitors can be recommended, these results "offer hope to thousands of AAA patients that their long wait for a treatment may soon be over."