Study Identifies Remnant Cholesterol as Key Contributor to Peripheral Artery Disease Risk: Study

The findings suggest that remnant cholesterol may be the primary cholesterol fraction responsible for the heightened risk of PAD, emphasizing the need for targeted preventive and therapeutic strategies.

PAD is a condition characterized by narrowed arteries, primarily in the lower limbs, due to atherosclerosis, leading to reduced blood flow. It can cause symptoms like leg pain, mobility issues, and, in severe cases, tissue damage or amputation. While LDL cholesterol has long been associated with atherosclerosis, emerging evidence suggests that remnant cholesterol, a component of triglyceride-rich lipoproteins, may play a more crucial role in PAD development.

In light of this, Benjamin Nilsson Wadström, Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom, and colleagues investigated whether elevated remnant cholesterol and LDL cholesterol independently contribute to the risk of peripheral artery disease.

For this purpose, the researchers developed genetic scores using variants near genes that directly influence remnant and LDL cholesterol levels, identified through a genome-wide association study in the UK Biobank. They applied univariable and multivariable Mendelian randomization to assess the causal effects of elevated cholesterol levels on the odds of developing peripheral artery disease (38,414 cases, 758,308 controls) and coronary artery disease (221,445 cases, 770,615 controls).

The study revealed the following findings:

• A 1 mmol/L (39 mg/dL) increase in remnant cholesterol was linked to a 2.72-fold higher risk of PAD in univariable analysis and a 2.16-fold higher risk in multivariable analysis.
• A 1 mmol/L (39 mg/dL) increase in LDL cholesterol was associated with a 1.37-fold higher risk of PAD in univariable analysis and a 1.14-fold higher risk in multivariable analysis.
• For CAD, a 1 mmol/L (39 mg/dL) increase in remnant cholesterol was associated with a 2.92-fold higher risk in univariable analysis and a 1.86-fold higher risk in multivariable analysis.
• A 1 mmol/L (39 mg/dL) increase in LDL cholesterol resulted in a 1.67-fold higher risk of CAD in univariable analysis and a 1.44-fold higher risk in multivariable analysis.
• When scaled to 1 SD increments, univariable ORs for PAD were 1.37 for remnant cholesterol and 1.29 for LDL cholesterol.
• Multivariable ORs for PAD with 1 SD increments were 1.28 for remnant cholesterol and 1.11 for LDL cholesterol.
• Univariable ORs for CAD with 1 SD increments were 1.40 for remnant cholesterol and 1.51 for LDL cholesterol.
• Multivariable ORs for CAD with 1 SD increments were 1.22 for remnant cholesterol and 1.34 for LDL cholesterol.

"The findings suggest that elevated remnant cholesterol plays a direct causal role in increasing the risk of peripheral artery disease, independent of LDL cholesterol levels. In contrast, the impact of elevated LDL cholesterol on PAD risk appears largely dependent on concurrent elevations in remnant cholesterol," the authors wrote.

"These results highlight remnant cholesterol as a key contributor to PAD development. Further research is needed to explore the underlying biological mechanisms and identify targeted therapeutic strategies for the prevention and treatment of PAD," they concluded.

Reference:

Wadström, B. N., Borges, M. C., Wulff, A. B., Smith, G. D., Sanderson, E., & Nordestgaard, B. G. (2025). Elevated Remnant and LDL Cholesterol and the Risk of Peripheral Artery Disease: A Mendelian Randomization Study. Journal of the American College of Cardiology, 85(12), 1353-1368. https://doi.org/10.1016/j.jacc.2024.12.033