In the Netherlands, approximately 1.7 million people have cardiovascular disease. This can have a major impact on the daily lives of patients. For example, people with heart failure, where the heart cannot pump blood properly, become tired and short of breath extremely quickly, and they often have difficulty climbing stairs or cycling. Sometimes heart disease leads to hospitalization or death. Because there is still a lot of uncertainty about the origins of various heart diseases, the Maastricht researchers from the CARIM research institute want to understand this better in order to prevent the disease and enable targeted treatment.
Genetic changes in the blood
Job Verdonschot, researcher and clinical geneticist in training, will study the genetic changes in blood cells to better understand heart failure. In heart failure, the heart no longer pumps blood properly. He investigates how changes in these genes contribute to an inflammatory response in the body that ultimately affects the heart muscle. Verdonschot explains: ‘We see that patients with heart failure often have dormant inflammation, but we still know little about the causes. It has recently been discovered that changes in the genes of blood cells may play a role. Although such genetic changes occur without problems in many people, we think that large changes cause inflammation and are therefore part of the disease mechanism.’ Verdonschot will therefore investigate how often these genetic changes occur in a large database of patients with diastolic heart failure. He also investigates inflammation in mice with this genetic change. ‘We want to find out whether anti-inflammatories can help reduce symptoms and slow the progression of heart failure in people with this mutation in the blood cells, and which anti-inflammatories are best to choose.’
Different types of inflammation
Vanessa van Empel, cardiologist and researcher, will investigate how heart failure can be prevented or slowed down. She also looks at the role of inflammatory reactions. ‘We want to know whether there are subgroups of patients with their own inflammatory mechanism, and whether that affects how the heart functions. If the inflammatory response is different, the best treatment may also be different.” Van Empel previously set up a large database with data from patients with heart failure for scientific research – the database with which Verdonschot also hopes to answer his research questions. She is now going to expand that database further: ‘We are going to call all patients in our database again for blood samples. We remove the white blood cells from there to further investigate the inflammatory response.’ The ultimate goal is to find a better treatment for heart failure.
Let the heart muscle repair itself
Leon de Windt, professor of molecular vascular biology, aims to help the heart muscle repair itself after a heart attack. ‘During a heart attack, the heart muscle is damaged because too little oxygen flows to it, usually due to a blocked blood vessel,’ says De Windt. ‘The problem is that the heart muscle cannot repair itself, so a heart attack causes permanent damage to the heart. But some animals, such as zebrafish and African spiny mice, can do this.’ De Windt wants to understand which genes are responsible for this ability of the heart muscle to repair itself. With this knowledge, he wants to develop a gene therapy and investigate whether it can improve the natural ability of the human heart to repair itself. He will test this on organoids, small versions of the human heart made from human stem cells, and on slices of human heart muscle.
Sudden worsening in heart failure
Miranda Nabben, assistant professor specialized in cardiac metabolism, focuses on the treatment of sudden worsening of heart failure. When patients with heart failure experience worsening of symptoms such as shortness of breath over a short period of time, this is called acute decompensation of heart failure. People often have to be admitted to hospital for this, but there is no good treatment yet. This is because the cause of the worsening is unclear, but there are indications. Nabben explains: ‘It appears that changes in certain metabolic proteins play an important role in the worsening of heart failure. A new drug that counteracts these protein changes has led to improved heart function in laboratory animals.’ Her research in rats with heart failure focuses on understanding the disruptions in these proteins. ‘We first want to understand the disease development and investigate how medicines can counteract these changes. We do this at different times to determine when the treatment is most effective.’ In addition to her research in rats, Nabben also uses organoids to study heart failure in human cells. ‘In this way we hope to find a drug that can reduce the deterioration of heart failure.’
Restoring the disturbed inflammatory response
Marleen van Greevenbroek, medical biologist and epidemiologist, will investigate how the body restores balance after an inflammatory response. A dormant inflammatory response appears to play a role in people who are properly treated for risk factors such as high blood pressure or high cholesterol, but who still develop cardiovascular disease. ‘Although medications can reduce the inflammatory response and thus prevent or repair vascular damage, they increase the risk of infections,’ explains van Greevenbroek. ‘That is why we do not focus on suppressing the inflammation, but on stopping the inflammation once it has done its job.’ She looks at special substances in the blood that can promote recovery after inflammation. These substances are called ‘specialized proresolvin mediators’. ‘We use data from the Maastricht Study to determine whether people who have many of these substances in their blood have a lower risk of cardiovascular disease. We also look at the genes involved in the production and function of these substances, to see whether they play a role in the risk of cardiovascular disease. Understanding the mechanism by which the body resolves an inflammatory response can help to further reduce the risk of cardiovascular disease.
ERA4Health promotes international research by providing subsidies to European collaborations, including in the field of cardiovascular diseases. The research by Job Verdonschot and Vanessa van Empel uses data from a large database that was provided with financial support from the Heart and Vascular Research Fund Limburg was constructed.
