Investigating the role of inflammation in heart failure, laying the foundation for future discoveries
Understanding how the heart produces energy, and what happens when that process doesn檛 work as it should, is at the centre of new research underway at 91亚色.
Dr. Qutuba Karwi is an assistant professor of cardiovascular sciences in the Discipline of BioMedicine at the Faculty of Medicine.
淲hat I檓 really interested in is how the heart generates its energy and how that changes in cardiometabolic diseases like heart failure, obesity and type 2 diabetes, he said.
Newfoundland and Labrador has the highest incidence of cardiometabolic disease in Canada.
淭he issue is how the heart relaxes after each contraction.
While Dr. Karwi was drawn to the opportunity to conduct research in a province where the issue is keenly felt, he says the problem is a global one.
淣ewfoundland and Labrador is not unique, he said. 淭hese diseases are increasing everywhere.
Dr. Karwi recently received a $1,009,800 Canadian Institutes of Health Research (CIHR) project grant to investigate the role of inflammation in the development and progression of a particular type of heart failure: heart failure with preserved ejection fraction, or HFpEF.
淲hen people hear heart failure, the first thought that comes to mind is that the heart is not pumping as it should, he said. 淏ut in HFpEF, this is not the issue. The issue is how the heart relaxes after each contraction.
No targeted treatments
If impaired or damaged, the heart doesn檛 relax properly and can檛 fill with blood efficiently, leading to reduced circulation throughout the body.
Nearly half of all heart failure patients worldwide will also have HFpEF, but there are currently no targeted treatments, due in part to a lack of models to help properly study the disease.
淲e don檛 have a drug that can treat HFpEF specifically, said Dr. Karwi. 淚nstead, we are using what we use to treat other types of heart failure, and the outcomes are not optimal.
His research focuses on inflammation and the role of immune cells called macrophages, which are known to contribute to HFpEF-related cardiac dysfunction.
Dr. Karwi says the interesting thing about macrophages and immune cells in general is that the way they generate their energy to function dictates their activity.
淪o, if that檚 the case, how about we modify how those immune cells generate their energy in an attempt to change their behaviour, in particular to lessen their detrimental effects in HFpEF?
Dr. Karwi檚 team is now using a sophisticated mouse model of HFpEF that combines obesity and hypertension, two major comorbidities of the condition.
Instead of focusing on glucose and fat as dominant fuels for immune cells, they are investigating the role of ketones. Mice are provided with high-fat diets to induce obesity and are subjected to hypertension.
Genetic tools also allow the researchers to directly modify keytone metabolism in cardiac macrophages and observe the effects on disease progression.
淲e have some evidence to suggest that when we increase keytone metabolism in those immune cells, we actually modify their activity and their polarization, Dr. Karwi said. 淎nd we can lessen the severity of heart failure or HFpEF.
Prevention and treatment
The CIHR funding will allow the lab to significantly expand their work, support personnel and enable long-term studies that examine both prevention and treatment strategies at different stages of disease development.
Dr. Karwi also hopes the project will lay the foundation for future discoveries.
淚 think we will be able to identify a number of novel targets we can look at later on and take forward. We檙e really excited about it.