New study links high triglyceride levels to aortic aneurysm development and rupture

A paper published in Circulation brings together human genetics and experimental models to come to a simple conclusion: hypertriglyceridemia is not just a “companion” of cardiovascular disease, but a key driver of abdominal aortic aneurysm (AAA). In mouse models, very high TGs led to accelerated aneurysm growth, dissection, and even rupture, while lowering TGs (ASO to ANGPTL3) slowed progression. The mechanism is that fatty acids (palmitate) “break” the maturation of lysyl oxidase (LOX), an enzyme that “cross-links” elastin and collagen in the aortic wall; without normal LOX, the tissue becomes loose and vulnerable. In humans, Mendelian randomization confirmed a causal relationship between TG-rich lipoproteins and AAA risk.

Background of the study

Why AAA is an Unresolved Clinical Problem
Abdominal aortic aneurysm (AAA) is a "silent" condition with high mortality when ruptured; there are no effective drugs that reliably slow its growth. The strategy today is ultrasound screening in risk groups and surgery when the diameter threshold is reached. USPSTF recommendations: single screening in men aged 65-75 years who have ever smoked; in women without risk factors - not recommended.

What was tried before and why it didn't work
A number of "antidegradation" approaches (eg, doxycycline as a matrix metalloproteinase inhibitor) failed to slow the growth of small AAAs in RCTs, dampening hopes for simple anti-inflammatory/antimatrix therapy.

The role of lipids: the focus shifts to TG-rich particles
While LDL-C remains the key factor for coronary heart disease, for AAA, more and more data point to triglyceride-rich lipoproteins (TRL, remnants). Modern reviews and genetic studies (including Mendelian randomization) support a causal relationship between elevated TG/TRL and the risk of AAA. A new article in Circulation (2025) combined MR analyses and experiments and came to the same conclusion.

Vessel wall mechanics: where it’s “subtle”
The strength of the aorta is determined by the “cross-links” of collagen and elastin, for which lysyl oxidase (LOX) is responsible. The LOX family stabilizes the extracellular matrix; when it is deficient/inhibited, the aorta becomes loose and prone to expansion - which is confirmed by both reviews and experimental models.

Why ANGPTL3 is an attractive target
ANGPTL3 inhibits lipoprotein lipase; its inhibition dramatically reduces TG (and partly other lipids). There is already an approved anti-ANGPTL3 drug (evinacumab) and RNA approaches are being developed - that is, the "tools" for clinical testing of the "lower TG → inhibit AAA" hypothesis exist.

Context Summary
The field is shifting from “universal” anti-inflammatory ideas to the lipid-matrix axis: TRL/TG → disruption of matrix maturation and “cross-linking” (including via LOX) → weakening of the aortic wall → growth/rupture of AAA. Against this background, the work in Circulation logically tests causality with genetics and shows in models that TG correction can slow progression - this is the bridge between epidemiology and mechanism that was lacking to launch clinical trials.

What exactly did they do?

• Humans (genetics): applied Mendelian randomization, combining genomic, proteomic and metabolomic data - and obtained a causal signal: the higher the TG-rich lipoproteins and proteins/metabolites associated with TG metabolism, the higher the risk of AAA.
• Mechanism (cells/tissue): elevated TG and palmitate were shown to disrupt LOX maturation and reduce its activity → the aortic wall loses its “cross-links”, expands and tears more easily. Local overexpression of LOX in the aorta removed the “harm” of hypertriglyceridemia.
• Mice (AAA models):
  • in Lpl deficiency (extreme hypertriglyceridemia), most animals in the angiotensin II model died from aortic rupture;
  • Apoa5-/- (moderately high TG) - accelerated growth of AAA;
  • transgenic for human APOC3 (very high TG) - delamination and rupture.
• Therapeutic proof of concept: antisense oligonucleotide to ANGPTL3 dramatically reduced TG and inhibited AAA progression in transgenic APOC3 mice and in Apoe-/-.

Why is this important?

Abdominal aortic aneurysm is a silent and deadly condition: rupture often ends in death, and there are virtually no effective drugs to slow the growth of AAA (the basis is observation/screening and surgery when the threshold is reached). The new work for the first time strictly and multilinearly (genetics → mechanisms → models) shows that TG-rich lipoproteins are the key link in pathogenesis, and that their targeted reduction can become a drug strategy against AAA.

Details to look out for

• LOX as a "weak spot" of the aortic wall. Lysyl oxidase "cross-links" elastin and collagen fibers. The authors showed that palmitate interferes with LOX maturation, and this is a direct bridge from fat metabolism to the mechanical strength of the aorta. When LOX was artificially increased at the aneurysm site, the anti-aneurysmal effect returned, despite high TG.
• "Reverse evidence": pharmacological reduction of TG (ANGPTL3-ASO) inhibited AAA in two independent models, strengthening clinical plausibility.

What does this mean (potentially) for the clinic?

• New target - TG-rich lipoproteins. Work in recent years has shifted the focus of AAA from "pure LDL" to inflammation and matrix remodeling. Here, a hard TG link is added, with a clear mechanism via LOX. This opens up space for preventive/therapeutic trials of TG-lowering agents - from ANGPTL3 inhibition to other pathways for correcting TG metabolism.
• Biomarkers and risk stratification: If the association is confirmed in prospective cohorts, TG and TG-rich particle levels may be included in risk assessment algorithms and selection for closer surveillance in patients with small/moderate AAA.

Important Disclaimers

• Mice are not humans: ANGPTL3-ASO therapeutic effect and LOX repair shown in preclinical models; no clinical data yet. RCTs are needed to test whether TG reduction slows AAA growth in humans.
• MR - about causality, but "on average". Mendelian randomization reduces confounding factors, but speaks of a lifelong genetically determined increase in TG, and not of short-term fluctuations in a particular patient. Transfer to drug intervention requires an independent test.

Context: Why this discovery makes sense

The picture is: TG-rich lipoproteins → fatty acids (palmitate) → LOX defect → weak aortic wall → AAA growth/rupture. Previously, AAA was associated with inflammation, matrix degradation, and smooth muscle dysfunction; this new work places the lipid component right at the heart of these processes - and provides a tested intervention "button" (lowering TG).

Source: Liu Y. et al. Circulation (Publish Ahead of Print, August 5, 2025): “Hypertriglyceridemia as a Key Contributor to Abdominal Aortic Aneurysm Development and Rupture: Insights from Genetic and Experimental Models.” https://doi.org/10.1161/CIRCULATIONAHA.125.0747