Genetically elevated Lp(a) dysregulates vascular redox signalling via eNOS uncoupling and predicts cardiac mortality in advanced coronary disease (Arterioscler Thromb Vasc Biol 2026)

Original title: Lipoprotein(a) and Vascular Redox State in Patients With Advanced Coronary Atherosclerosis

Arterioscler Thromb Vasc Biol · 30 October 2025 · 8

Polkinghorne MD, Badi I, Baragetti A, Chauhan J, Xie C, Wahome E, Akoumianakis I, Foran D, Patel P, de Araujo E, Kotanidis CP, Krasopoulos G et al.

This study measured plasma Lp(a) and an LPA genetic risk score (LPA GRS) in 1,027 patients with advanced coronary artery disease undergoing cardiac surgery, combining this with RNA sequencing and vascular superoxide measurement in internal mammary artery tissue over a median follow-up of 5.07 years. Higher plasma Lp(a) (P = 0.03) and LPA GRS (P = 0.01) were associated with elevated arterial superoxide, driven mainly by eNOS uncoupling from reduced tetrahydrobiopterin availability rather than NADPH oxidase activity (P = 0.13), and independent of ApoB or systemic inflammatory and oxidative markers. Both LPA GRS (HR 3.615, 95% CI 1.044-12.515, P = 0.043) and high plasma Lp(a) (HR 3.286, 95% CI 1.003-10.767, P = 0.049) predicted cardiac mortality, an association that was vascular superoxide-dependent. This is the first demonstration that genetically determined Lp(a) drives dysregulated vascular redox and nitrosative signalling in atherosclerotic patients, a mechanistic link to hard outcomes.

Original abstract

Background: Lp(a) (lipoprotein[a]) is associated with cardiovascular disease, but neither the causal nature nor the underlying mechanisms are fully documented. This study investigated whether Lp(a) triggers atherogenesis by dysregulating vascular redox-sensitive inflammatory state.

Methods: Plasma Lp(a) was measured in 1027 patients with advanced coronary artery disease undergoing cardiac surgery. These patients were genotyped, and a modified LPA genetic risk score (LPA GRS) determining Lp(a) levels was generated. RNA sequencing and vascular superoxide measurements were performed in internal mammary arteries, and the contribution of NOXs (NADPH oxidases) and uncoupled eNOS (endothelial nitric oxide synthase) was determined. The median follow-up was 5.07 years.

Results: Increased plasma Lp(a) (P=0.03) and LPA GRS (P=0.01) were associated with elevated arterial superoxide in the overall patient population, an effect that was driven by nondiabetics. This effect was primarily due to eNOS uncoupling via reduced vascular BH4 (tetrahydrobiopterin) bioavailability. There was no significant impact of Lp(a) variability on vascular NOX-derived superoxide (P=0.13). RNA sequencing of arterial tissue revealed dysregulation of nitrosative and inflammatory signaling in high Lp(a) patients although there was no association with systemic biomarkers of inflammation (ie, hsCRP [high-sensitivity C-reactive protein]; P=0.82) or oxidative stress (ie, malondialdehyde; P=0.61). Finally, both LPA GRS (hazard ratio, 3.615 [95% CI, 1.044-12.515]; P=0.043) and high plasma Lp(a) (hazard ratio, 3.286 [95% CI, 1.003-10.767]; P=0.049) were associated with elevated risk for cardiac mortality. This association was vascular superoxide-dependent, implying that redox-sensitive inflammatory signaling may be a link between Lp(a) and cardiovascular risk. All the above associations were independent of plasma ApoB (apolipoprotein-B).

Conclusions: This study demonstrates for the first time that a genetically determined increase in plasma Lp(a) results in dysregulated vascular redox/nitrosative signaling in patients with atherosclerosis.

Summary written by lp-a.org from the published abstract; figures as published. Page updated 17 August 2026. Methods.