Why heart attacks can still happen even when bad cholesterol is low

Heart disease remains one of the world's leading causes of death. According to the World Health Organization (WHO), cardiovascular diseases kill nearly 17.9 million people worldwide each year, with heart attacks and strokes responsible for more than 80% of those deaths. Coronary heart disease develops when fatty deposits containing cholesterol (cholesterol) build up inside the arteries that supply blood to the heart. If left untreated, the condition can eventually cause a heart attack.

Reducing LDL cholesterol, commonly known as "bad cholesterol," is a proven way to lower the likelihood of a heart attack. However, bringing LDL cholesterol into the recommended range does not eliminate the danger. Some patients continue to develop coronary heart disease despite successful treatment, suggesting that other particles transporting fats through the bloodstream play an important role. Until recently, the biological reasons behind this remaining risk were not well understood.

"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, lead author and a postdoctoral fellow at Chalmers University of Technology, in Sweden.

What Is Bad Cholesterol?

Cholesterol is a substance similar to fat that circulates in the bloodstream. The body needs it to build cells and manufacture certain vitamins and hormones. Problems can arise when too much cholesterol accumulates in blood vessel walls, creating deposits called plaques.

These plaques can narrow arteries and interfere with blood flow. If a plaque ruptures, a blood clot may form quickly and completely obstruct the affected vessel, potentially triggering a heart attack or stroke.

Because cholesterol and other fats cannot travel through the blood on their own, they are transported by specialized particles known as lipoproteins. Three major classes of these particles contain a surface protein called apolipoprotein B (apoB). When too many of these particles circulate in the blood, they can deliver excess cholesterol into artery walls. The cholesterol they carry is commonly referred to as "bad cholesterol."

Looking Beyond Bad Cholesterol

To investigate these unanswered questions, the scientists used proteomics analysis to examine how three types of fat-carrying particles (LDL, TRL and Lp(a)) affect the body and may contribute to heart disease. This approach allowed the team to investigate biological changes associated with the particles rather than focusing exclusively on the cholesterol they carry.

All three types can contribute to cholesterol deposits inside artery walls, although LDL, which stands for low-density lipoprotein, is the most common. In a previous study, the same research group found that counting harmful lipoprotein particles was the most effective way to predict future heart disease risk.

The researchers also identified two particularly important contributors beyond LDL: triglyceride-rich lipoproteins, or TRL, and lipoprotein(a), known as Lp(a). Their earlier findings suggested that each of these particles poses a greater risk individually than an LDL particle. As a result, TRL and Lp(a) are considered major contributors to the cardiovascular danger that can persist even after LDL cholesterol has been successfully reduced.

What Is Proteomics Analysis?

Proteomics is the systematic, large-scale examination and measurement of proteins within cells, tissues, or body fluids at a particular point in time.

While genomics investigates a person's relatively stable DNA, proteomics focuses on proteins, which are constantly responding to changes inside the body. These molecules help construct tissues, process food, transmit hormonal messages, and defend against infections.

Because protein patterns shift in response to factors such as diet, stress, aging, and disease, analyzing them can provide a snapshot of current biological activity. Proteomics can help researchers identify biomarkers, diagnose medical conditions, and track how patients respond to treatment.

Blood Proteins Reveal Hidden Heart Disease Risks

The new investigation focused on proteins, which perform countless essential functions throughout the body. Unlike genetic information, which remains largely unchanged, protein levels and activity can respond to diet, stress, aging, and illness. Studying these changes can therefore provide valuable insights into the body's current biological condition.

Researchers analyzed measurements of nearly 3,000 proteins found in blood samples and compared the results with genetic information and long-term health records. This combination helped them identify protein patterns associated with different lipoprotein particles and provided clues about how those particles might contribute to damage inside the arteries.

One of the most striking discoveries involved TRL and Lp(a). Although these are distinct types of particles, their associated blood protein patterns showed substantial similarities. Those overlapping patterns also appeared to be linked to the later development of heart disease.

The researchers found that these particles carried proteins capable of attracting immune cells, potentially encouraging inflammation and changes in the structure of blood vessel walls. This suggests that TRL and Lp(a) may contribute to cardiovascular disease through some of the same biological processes, rather than simply depositing cholesterol in the arteries.

LDL showed a different pattern. Its associated proteins were primarily connected to cholesterol accumulation in artery walls, highlighting an important distinction between the ways these three types of particles may contribute to heart disease.

"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."

How LDL, TRL, and Lp(a) Affect Heart Health

The three types of lipoproteins examined in the study, LDL, TRL, and Lp(a), transport different amounts of cholesterol and other fats through the bloodstream. Each contains the structural protein apolipoprotein B, or apoB.

All three can contribute to atherosclerosis, a condition in which fatty material accumulates inside blood vessel walls. As these deposits develop, they increase the risk of coronary heart disease.

LDL: Low-density lipoprotein transports most of the cholesterol circulating in the blood. An LDL cholesterol measurement indicates how much cholesterol is contained within these particles.

TRL: Triglyceride-rich lipoproteins transport cholesterol along with triglycerides, which the body uses as an important energy source. As triglycerides are removed from these particles, the remaining fragments can deposit cholesterol inside artery walls. In this study, the TRL measurements primarily reflected liver-produced particles called VLDL and the remnants they leave behind.

Lp(a): Lipoprotein(a) resembles an LDL particle but contains an additional protein known as apolipoprotein(a). Higher levels of Lp(a) are already recognized as an established risk factor for coronary heart disease.

Could the Discovery Lead to Better Heart Disease Prevention?

By identifying biological pathways associated with cardiovascular risk beyond LDL cholesterol, the findings offer researchers new possibilities for developing more personalized prevention strategies. In particular, the shared inflammatory and blood vessel effects linked to TRL and Lp(a) could become promising areas for further investigation.

However, the research did not evaluate a new treatment or establish a blood protein test ready for routine clinical use. Additional studies will be needed to determine whether measuring these biological processes, or developing treatments that target them, can improve protection against heart disease.

"Lowering LDL cholesterol remains a cornerstone of prevention," says Clemens Wittenbecher, who led the study and is Assistant Professor of Precision Medicine and Diagnostics at Chalmers. "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."

The results reinforce the importance of controlling LDL cholesterol while revealing why cholesterol reduction alone may not address every source of cardiovascular risk. Understanding the additional ways blood particles affect arteries could ultimately help scientists develop more precise approaches to protecting heart health.

Study Details and Research Institutions

The study, "Apolipoprotein B-containing lipoproteins: distinct roles in atherosclerosis revealed by plasma proteomic profiling," was published in the European Heart Journal.

The research authors are Jakub Morze, Elias Björnson, Michael Y Mi, Martin Adiels, Giorgio E Melloni, Gonçalo Rosas da Silva, Andrzej Rynkiewicz, Nicholas A Marston, Marta Guasch-Ferré, Michael Y Tsai, Jerome I Rotter, Robert E Gerszten, Qi Sun, Frank B Hu, Rikard Landberg, Göran Bergström, Chris J Packard, Jan Borén and Clemens Wittenbecher.

At the time of the research, the authors were affiliated with Chalmers University of Technology and the Institute of Medicine at the University of Gothenburg, Sweden; Harvard Medical School, USA; AstraZeneca, Sweden; Municipal Hospital in Olsztyn, Poland; University of Copenhagen, Denmark; University of Minnesota, USA; The Lundquist Institute at Harbour-UCLA Medical Center in Torrance, USA; Harvard T.H. Chan School of Public Health in Boston, USA; and the University of Glasgow, UK.