For almost 60 years, measuring cholesterol levels in the blood has been the best way to identify individuals at high risk of cardiovascular disease. In a new study, led by Chalmers University of Technology in Sweden and Harvard University in the USA, researchers have shown comprehensively that a combination of two lipoprotein markers, measured in a simple blood test, can give more accurate information about individual risk of heart disease than the current blood cholesterol test, potentially saving lives.

According to the World Health Organization (WHO), cardiovascular diseases (CVDs) are the leading cause of death globally. Most cases could be prevented by addressing behavioural and environmental factors such as smoking, unhealthy diet or physical inactivity. It is therefore important to detect the risks as early as possible so that effective prevention techniques or management can begin.

“This is the largest study of its kind to date and the results show for the first time the relative importance of the three major families of lipoprotein for the potential risk of heart disease”, says Jakub Morze, lead author of the study and a postdoctoral fellow at Chalmers.

Good and bad cholesterol

One of the major indicators and controllable risk factors for cardiovascular disease is high blood cholesterol. Cholesterol is a fat-like substance in the blood that is essential for building cells and producing certain vitamins and hormones. However, when levels are too high, it can accumulate in the walls of blood vessels, forming deposits known as plaques. If a plaque ruptures, a clot can rapidly form and block the vessel entirely, leading to heart attack or stroke.

Cholesterol and other fats are carried through the blood by specialised particles called lipoproteins, which are divided into four main classes. Three of these classes have a special protein on their surface called apolipoprotein B (apoB). When present in excess, these lipoproteins can deposit cholesterol in the walls of blood vessels. Because of this, the cholesterol they carry is often called "bad cholesterol." In contrast, the fourth main class helps remove excess cholesterol from the bloodstream and transports it back to the liver—this is often referred to as "good cholesterol" because of its beneficial role.

Testing for lipoprotein carriers rather than the cholesterol itself

When assessing for near-term risk of heart disease, a doctor needs to determine whether the levels of “bad cholesterol” particles are high enough to be harmful. Currently, this is done by measuring a blood sample for levels of cholesterol. However, since cholesterol cannot circulate or cause damage without its lipoprotein carrier, researchers have increasingly focused on measuring the lipoproteins that carry the ‘bad cholesterol’, as a likely better indicator of future cardiovascular disease risk.

“It was previously unclear if two patients with the same total level of “bad cholesterol”, but that differ in their carrier characteristics (lipoprotein type, size, lipid content), have the same risk of heart disease. So, the aim of this study was to determine the importance of these different parameters,” says Jakub Morze.

Number of lipoprotein carriers matters most

The researchers analysed blood samples from over 200,000 people in the UK Biobank who had no history of heart disease, to measure the number and size of different cholesterol-carrying lipoproteins in the blood. They focused specifically on lipoproteins that carry a protein called apoB, which is found on all the “bad cholesterol” carriers. By following participants for up to 15 years, they examined which patterns of lipoprotein types and sizes were most strongly linked to future heart attacks. Key findings were validated in a separate Swedish cohort study called ‘Simpler’. This combination of advanced blood profiling, large-scale prospective data, and independent replication allowed for the most comprehensive assessment of how ‘bad cholesterol’ lipoproteins contribute to the development of heart disease.

“We found that apoB is the best marker when testing for risk of heart disease. Since apoB indicates the total number of “bad cholesterol” particles measuring it offers a more accurate test than standard cholesterol measures. That does not mean conventional tests are ineffective; they generally perform well. However, in about one in twelve patients, standard cholesterol tests may underestimate heart disease risk, which is important to consider, since 20 – 40 percent of all first-time occurrences of CVD are fatal. By switching to apoB testing, we can improve that accuracy and potentially save lives” says Jakub Morze.

Another key marker

The researchers concluded that the total number of ‘bad cholesterol’ lipoproteins was the most important factor to consider when testing for future risk of heart disease. Other factors such as size or type of lipoprotein did not affect the potential risk overall.

However, the study also showed that another ‘bad cholesterol’ lipoprotein, called lipoprotein(a) is an important part of the puzzle and should also be tested for. Its levels are genetically inherited in most individuals and represent less than 1 percent of all “bad cholesterol” lipoproteins on average in the general population. However, in some individuals these values are extremely high, significantly raising heart disease risk.

“Our results indicate that apoB particle count could eventually replace the standard blood cholesterol test in research and healthcare worldwide and that lipoprotein(a) also needs to be tested for to get a better picture of lipid-related CVD risk. The blood test for these two markers is commercially available now and would be cheap and easy enough to implement,” says Clemens Wittenbecher, one of the authors of the study and Assistant Professor of Precision Medicine and Diagnostics at Chalmers.


More about the study

In this study, ‘The relative importance of particle count, type, and size of apoB-containing lipoproteins in the development of coronary artery disease’, published in the European Heart Journal, the researchers observed and analysed data from more than 200,000 people within the UK Biobank, who had no prior history of heart disease, using a technique called nuclear magnetic resonance (NMR) spectroscopy.

The researchers for this study were Jakub Morze, Giorgio E Melloni, Clemens Wittenbecher, Mika Ala-Korpela, Andrzej Rynkiewicz, Marta Guasch-Ferre, Christian T. Ruff, Frank B. Hu, Marc S. Sabatine and Nicholas A. Marston.

They were active at the following institutions at the time of the study: Chalmers University of Technology and Sahlgrenska Academy at the University of Gothenburg, Sweden; SGMK University, Poland; Brigham and Women’s Hospital and Harvard Medical School, USA; University of Oulu and Biocenter Oulu, Finland; University of Eastern Finland; University of Copenhagen, Denmark; Harvard T.H. Chan School of Public Health, USA.