Protein Clues Reveal Why Heart Risk Lingers After Bad Cholesterol Falls

For decades, lowering low-density lipoprotein cholesterol has been the central strategy in the fight against coronary heart disease, and it has saved countless lives. Yet cardiologists have long been troubled by an uncomfortable reality: even when treatment brings so-called bad cholesterol down to recommended levels, a substantial number of patients still go on to suffer heart attacks. A new study from Chalmers University of Technology in Sweden now offers some of the most detailed clues yet about where this residual risk comes from, and it points the way toward prevention strategies that are far more precisely targeted than today’s one-size-fits-all approach.

The research, published in the European Heart Journal, was led by Clemens Wittenbecher, Assistant Professor of Precision Medicine and Diagnostics at Chalmers, with postdoctoral fellow Jakub Morze as lead author. The team undertook an unusually ambitious measurement campaign: using blood samples from around 35,000 participants in the UK Biobank who had no previous history of heart disease, they measured nearly 3,000 different proteins circulating in the blood. They then combined this proteomic data with genetic information and long-term health records, allowing them to ask a deceptively simple question: what is happening in the bodies of people who remain at risk even after their cholesterol numbers look healthy?

To understand why the question matters, it helps to look at the scale of the problem. According to the World Health Organization, nearly 17.9 million people die from cardiovascular diseases worldwide every year, and heart attacks and strokes account for more than four out of five of those deaths. Coronary heart disease develops when fatty material accumulates in the blood vessels that supply the heart, a process known as atherosclerosis. If a plaque formed from this fatty material ruptures, a clot can rapidly form and block the vessel entirely, cutting off blood flow to the heart muscle. High blood cholesterol remains one of the most important modifiable risk factors for this process, which is why statins and other lipid-lowering therapies dominate modern prevention.

Cholesterol itself is not a villain. It is a fat-like substance that is essential for building cells and producing certain vitamins and hormones. The trouble arises when it is transported in excess. Cholesterol and other fats cannot travel freely through the watery bloodstream, so they are packaged into specialised particles called lipoproteins. Three classes of these particles share a structural surface protein called apolipoprotein B, or apoB, and when present in excess, all three can deposit cholesterol into the walls of blood vessels. Because of this shared capacity for harm, the cholesterol they carry is collectively labelled bad cholesterol, even though the particles themselves behave in distinctly different ways.

Low-density lipoprotein, or LDL, is the most abundant of these apoB-containing particles and carries the majority of cholesterol in the blood. Standard clinical tests measure the cholesterol inside these particles, but the Chalmers group’s previous work had already suggested that counting the particles themselves is a more effective way of predicting future heart disease. Beyond LDL, two other particles attracted the researchers’ attention. Triglyceride-rich lipoproteins, known as TRL, carry triglycerides, a major source of energy for the body, along with cholesterol; as triglycerides are removed from these particles, they leave behind remnants that can deposit cholesterol in artery walls. Lipoprotein(a), or Lp(a), is an LDL-like particle with an additional protein called apolipoprotein(a), and elevated levels of it are an established risk factor for coronary heart disease.

Crucially, the earlier work by the same research group had shown that TRL and Lp(a) appear to be more harmful per particle than LDL, and the two are believed to represent the main remaining risk particles for heart disease once LDL cholesterol has been brought down to a healthy level. What remained unclear was why. For this study, the team wanted to understand what happens beyond the simple accumulation of cholesterol in artery walls, whether different fat-carrying particles can damage blood vessels differently, and why the remaining risk persists in some people. Proteomics, the large-scale and systematic study of all the proteins present in a body fluid at a given moment, offered a way in.

Unlike genomics, which examines fixed DNA, proteomics captures the dynamic, working machinery of biology. Proteins build tissues, digest food, send hormonal signals and fight infections, and their composition shifts in response to diet, stress, aging and disease. Measuring them therefore provides something close to a real-time snapshot of how the body is actually functioning. By combining measurements of almost 3,000 blood proteins with genetic data and long-term health records, the researchers identified protein patterns that offer new clues about how lipid particles may damage arteries, and about which biological pathways are activated in the people who go on to develop disease.

The most striking discovery was an overlap. The protein patterns associated with the risk particles beyond LDL, namely TRL and Lp(a), pointed toward the future onset of heart disease, and the two particle types shared many of the same protein signatures and harmful biological effects despite being chemically distinct. These particles were shown to contain proteins that attract immune cells, a process that could contribute to inflammation and structural changes in the walls of blood vessels. In other words, TRL and Lp(a) may not merely deliver cholesterol to artery walls; they may actively recruit the immune machinery that drives atherosclerosis forward. The protein pattern for LDL, by contrast, was mainly associated with the build-up of cholesterol in artery walls, a more classical mechanism.

For Morze, the convergence between TRL and Lp(a) is one of the most interesting findings of the study. It suggests that these two particle types may affect some of the same inflammatory and vascular processes, which could help identify targets for more precisely directed prevention in the future. If TRL remnants and Lp(a) are indeed harming vessels through shared inflammatory pathways, then therapies aimed at those pathways, rather than at cholesterol alone, might address the risk that today’s treatments leave behind. The authors are careful to note the boundaries of the work: the study did not test a new treatment, and it did not establish a protein-based test ready for clinical use. Its contribution is mechanistic, mapping the biological processes that connect specific lipoproteins to arterial damage in a very large human cohort.

Wittenbecher emphasises that the established pillar of prevention stands firm. Lowering LDL cholesterol remains a cornerstone of cardiovascular protection, and nothing in the new findings changes that. What the study adds is a plausible explanation for the risk that remains beyond LDL, along with a research agenda for testing whether measuring or targeting the newly identified processes can improve prevention alongside existing treatments. The research was a genuinely international collaboration, with authors active at Chalmers and the University of Gothenburg in Sweden, Harvard Medical School and the Harvard T.H. Chan School of Public Health in the United States, AstraZeneca, the University of Copenhagen, the University of Minnesota, the Lundquist Institute at Harbor-UCLA, the University of Glasgow and a municipal hospital in Olsztyn, Poland. As proteomic profiling becomes faster and cheaper, studies of this kind may move from explaining residual risk to predicting it in individual patients, opening the door to a future in which heart disease prevention is tailored not just to a cholesterol number, but to the full molecular story unfolding in a person’s blood.

Subject of Research: Proteomic profiling of apolipoprotein B-containing lipoproteins to explain residual coronary heart disease risk beyond LDL cholesterol

Article Title: Beyond ‘bad’ cholesterol: new clues to the risk of heart disease

Article References: Beyond ‘bad’ cholesterol: new clues to the risk of heart disease. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: cardiovascular disease, LDL cholesterol, lipoprotein(a), triglyceride-rich lipoproteins, proteomics, atherosclerosis, UK Biobank, apolipoprotein B, inflammation, precision medicine, European Heart Journal, residual risk