Ryan E. Temel, PhD

Triglyceride-rich lipoproteins and abdominal aortic aneurysm growth and progression

 Abdominal aortic aneurysm (AAA) is a life-threatening condition in which progressive dilatation of the abdominal aorta leads to rupture. With ~2.3 million prevalent cases, AAA afflicts ~4% of the U.S. population ≥ 65 years of age and is responsible for ~10,000 deaths annually. Open or endovascular surgical repair is the only intervention shown to prevent AAA growth and progression to rupture; no pharmacological therapies exist to slow aneurysm growth and avert the need for operative repair.

Our collaborator, Dr. Scott Damrauer, recently led an international collaborative study to identify genetic variants associated with AAA.  The genome-wide association study (GWAS) of 39,221 individuals with and over 1 million without AAA identified a central role for lipoprotein biology. Multiple lines of human genetic evidence suggest triglyceride-rich lipoproteins (TRL) are a potential key mediator of AAA susceptibility. TRL enter circulation from an endogenous pathway via the liver as very low-density lipoprotein (VLDL) and from an exogenous pathway via the intestine as chylomicrons. In plasma, TRL undergo rapid catabolism by lipoprotein lipase (LPL) into remnant particles that are proposed to promote atherosclerosis and inflammation. Preliminary data from our collaborative group that implicate TRL in AAA pathobiology include: (1) genetic causal inference experiments prioritizing TRL containing non-high-density lipoprotein cholesterol (nonHDL-c) over low-density lipoprotein
cholesterol (LDL-c) as the most likely causal lipid fraction promoting susceptibility to AAA; (2) a genome-wide significant association between a missense variant in LPL (LPL p.Asn318Ser) associated with increased TRL and AAA risk; (3) genetic data implying a causal relationship between increased plasma apolipoprotein A5 (ApoA5) levels (a key regulator of LPL and circulating TRL) and decreased susceptibility to AAA; (4) results from angiotensin II (AngII)-infused mice showing elevated TRL lead to development, growth, and rupture of AAA.

Based on human genetic and animal mechanistic evidence, several therapies specifically targeting the TRL pathway are in various stages of clinical development. Because reducing TRL is thought to be beneficial for cardiovascular health, emerging targets include plasma proteins that activate (e.g. ApoA5, ApoC2) or inhibit (e.g. ANGPTL3/4/8, ApoC3) LPL. Clinical trials of emerging therapies targeting these regulators have demonstrated potent reductions in plasma TRL, although their effect on cardiovascular outcomes remains to be determined. The effect of TRL-targeted therapies on AAA remains unexplored.

The true therapeutic opportunity for pharmacological treatment of AAA lies in prevention of aneurysm growth and progression in individuals with established small aneurysms. Despite our strong preliminary data suggesting a potential role of TRL in the susceptibility to AAA initiation, the relationship of TRL to AAA growth and progression to rupture is unknown. Furthermore, mechanistic data linking TRL to either AAA susceptibility or growth is non-existent. These key knowledge gaps temper enthusiasm for large-scale trials that will be necessary to position emerging TRL-targeted therapies to treat established AAA by preventing aneurysm growth and rupture. To elaborate data and build evidence to support clinical trials, we are testing the central hypothesis that TRL concentration and composition contribute to both AAA susceptibility and growth in humans and AAA mouse models.