Protein Signatures Reveal Why Heart Disease Risk Persists After LDL Cholesterol Is Controlled

A new study from Chalmers University of Technology has identified biological pathways that may explain why some people still develop coronary heart disease after their “bad” LDL cholesterol has been brought down to a recommended level. The research points to two other fat-carrying particles, TRL (triglyceride-rich lipoprotein) and Lp(a) (lipoprotein(a)), as likely contributors to this remaining risk, and uses protein analysis to show how they may affect the body differently than LDL does.

“For this study, we wanted to understand what happens beyond the accumulation of cholesterol in artery walls, whether different fat-carrying particles can damage the blood vessels differently and why the remaining risk of heart disease still occurs,” says Jakub Morze, first author of the study published in European Heart Journal.

The researchers used proteomics analysis to examine patterns across three particles, LDL, TRL, and Lp(a), combining measurements of almost 3,000 blood proteins with genetic data and long-term health records. Since proteins change based on diet, stress, aging, or disease, analyzing them offers a real-time snapshot of the body’s status, and the team used this approach to uncover new clues about how each particle may damage arteries.

The analysis found an overlap in the protein patterns associated with TRL and Lp(a), a link that appeared connected to the future onset of heart disease. Both particles were shown to contain proteins that attract immune cells, which could contribute to inflammation and changes in the structure of blood vessel walls. By contrast, the protein pattern associated with LDL was mainly tied to the buildup of cholesterol in artery walls, rather than these inflammatory effects.

“The overlap for TRL and Lp(a) is one of the most interesting findings,” says Morze. “It suggests that these particles may affect some of the same inflammatory and vascular processes. This could help identify targets for more precisely directed prevention in the future.”

The study did not test a new treatment or establish a protein test for clinical use, but the findings lay groundwork for future research into more targeted prevention strategies.

“Lowering LDL cholesterol remains a cornerstone of prevention,” explained senior author Clemens Wittenbecher. “Our findings point to biological processes that may help explain some of the risk that remains beyond LDL. The next step is to establish whether measuring or targeting these processes can improve prevention alongside existing treatments.”