Researchers at Chalmers University of Technology, in Sweden, shed new light on the remaining risk of heart disease, even after the known risk factor of 'bad' cholesterol is brought down to a healthy level. In a new study, key biological pathways – and an understanding of how the body is affected – were identified for the particles believed to contribute to the remaining disease risk. The results pave the way for more closely targeted prevention in heart disease which ultimately may save more lives.
According to the World Health Organization (WHO), nearly 17.9 million people die from cardiovascular diseases worldwide every year, with heart attacks and strokes accounting for more than four out of five of those deaths. Coronary heart disease, which can lead to a heart attack if untreated, develops when fatty material (cholesterol) accumulates in the blood vessels supplying the heart. Therefore, high blood cholesterol is a key risk factor for this.
Lowering 'LDL cholesterol', often called "bad cholesterol"*, substantially reduces the risk of heart attacks. Yet some people still develop coronary heart disease even when treatment brings their 'LDL cholesterol' down to a recommended level. Other particles that carry fats through the blood can contribute to this remaining risk, but until now the reason why has been unclear.
"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.
Understanding the key risk particles
For this study, the researchers used proteomics analysis* to uncover patterns, and new understandings of how three different fat-carrying particles (LDL, TRL and Lp(a))* affect the body and potentially lead to heart disease.
All of these particles can deposit cholesterol in artery walls. However, LDL, or low-density lipoprotein, is the most abundant of these particles. A previous study by the same research group identified that measuring the count of these harmful particles was the most effective way of predicting future heart disease risk.
Beyond LDL, there are two other important particles, known as TRL, or triglyceride-rich lipoprotein and Lp(a), or lipoprotein(a). In the same previous study, these were shown to be more harmful per particle than LDL, and they are believed to represent the main 'remaining risk particles' for heart disease; even after LDL cholesterol is brought down to a healthy level.
Clues found in protein patterns
Proteins are essential to different functions of the body, and they change based on diet, stress, aging, or disease, so analysing them provides a real-time snapshot of the status of body functions related to health. The researchers combined measurements of almost 3,000 blood proteins with genetic data and long-term health records. They identified blood protein patterns that offer new clues as to how the lipid particles may damage arteries.
An overlap was found in the protein patterns of the 'risk particles' beyond LDL, which appeared to indicate a link to the future onset of heart disease. These particles were also shown to contain proteins that attract immune cells, which could contribute to inflammation and a change in the structure of blood vessel walls. Despite being different types of particles, TRL and Lp(a) shared many of the same protein patterns and harmful biological effects.
The protein pattern for LDL was mainly associated with the build-up of cholesterol in the artery walls.
"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 findings provide a basis for investigating more precise approaches to prevention. The study itself did not test a new treatment or establish a protein test for clinical use.
"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."
More about the study:
The study, Apolipoprotein B-containing lipoproteins: distinct roles in atherosclerosis revealed by plasma proteomic profiling , has been published in the European Heart Journal.
The 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.
They were active at the following institutions at the time of the study: Chalmers University of Technology and Institute of Medicine at the University of Gothenburg, Sweden; Harvard Medical School, USA; AstraZeneca, Sweden; Municipal Hospital, Olsztyn, Poland; University of Copenhagen, Denmark; University of Minnesota, USA; The Lundquist Institute at Harbour-UCLA Medical Center, Torrance, USA; Harvard T.H. Chan School of Public Health, Boston, USA; University of Glasgow, UK.
