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The challenge of stiff hearts

The Christensen group at IEMR aims to increase our understanding of the processes that lead to cardiac stiffening and to develop new treatments for this major challenge.

An increasing number of people develop classic symptoms and signs of heart failure, such as shortness of breath and fluid retention, despite having normally contracting hearts. Many of these patients, particularly women and elderly, suffer from a stiff heart caused largely by cardiac fibrosis.

“As effective therapies for cardiac fibrosis are currently lacking and urgently needed, it is our vision to understand the molecular mechanisms governing these changes and develop the next generation of therapeutic approaches. In line with this, we have recently been able to improve cardiac function by inhibiting an enzyme that acts on proteoglycans”, says professor Geir Christensen. This new therapeutic approach has been granted patents in US and Europe. 

Membrane proteins activate fibroblasts

The heart increases its stiffness mainly due to an increase in connective tissue (extracellular matrix) surrounding the heart muscle cells (cardiomyocytes) (see Figure, Fibrosis in the hypertrophic heart). Particularly in elderly women and people with diabetes or high blood pressure, more matrix is produced in the heart. This matrix is mainly produced by fibroblasts, which are small cells embedded in the matrix. A central question is what activates these cells to produce more extracellular matrix.

Fibrosis in the hypertrophic heart (Adapted from Herum KM 2017 J Clin Med and Christensen G 2019 Matrix Biol).

It is our vision to understand the molecular mechanisms governing cardiac stiffening, and develop the next generation of therapeutic approaches.
Professor Geir Christensen

The Christensen group has shown that alterations in the amounts of proteins located in the fibroblast cell membrane have a critical impact on activation of fibroblasts. They have recently published a study by Andreas Romaine et al that addressed this issue. The study shows that membrane proteins termed integrins and proteins coated with sugars (proteoglycans) interact to promote activation of fibroblasts (see Figure). Further work is now performed in collaboration with University of Manchester. The work utilizes state-of-the art mass spectrometry of membrane proteins. Specific subgroups of quiescent and activated fibroblasts are used to further identify membrane proteins involved in activation of fibroblasts leading to stiff hearts.

New studies on the proteoglycans

Some proteoglycans are located in the extracellular matrix outside the cells. One such proteoglycan is lumican. In a recent study, Chloe Rixon et al. show that lumican is closely co-located with collagen, which is the main constituent of the matrix. We are currently examining how lumican participates in the organisation and regulation of the amounts of collagen in the heart. In ongoing work with PhD student Athiramol Sasi, the Christensen group has also shown that another proteoglycan, versican, is substantially increased in patients with heart failure and potentially important for fibrosis development. Maria Vistnes, MD, has been central in developing the new treatment mentioned above where inhibition of an enzyme that degrades proteoglycans is used to treat heart failure in a rodent model.

 

Read more about the Christensen groups work