People with cardiac amyloidosis have heart problems and/or neurological problems that can lead to death. Early detection of human heart problems would mean earlier treatment and less damage. A patient with the hereditary variant of TTR amyloidosis who was examined at UMC Utrecht about this: “An MRI scan has shown that the nerves that control my heart show abnormalities caused by amyloidosis. For now I only experience neuropathic problems. Fine motor skills are affected and I have pain in my hands and feet.”
Human heart
In amyloidosis there is precipitation of various so-called precursor proteins. These can cause the accumulation of proteins in the body. This damages organs and the function of organs. The human heart is usually one of the organs by which you can tell that something is wrong. It becomes stiffer and it is more difficult to relax, resulting in fatigue and shortness of breath, for example.
“Conduction and rhythm disturbances can also occur and eventually fatal heart failure is possible. It’s an insidious process; there can be ten years between mild and serious complaints,” says Marish Oerlemans, cardiologist and one of the initiators. “The sooner you know that someone has the disease, the sooner you can intervene to stop or at least slow down the aggravation.”
Laboratory
A university medical center offers the advantage that, in addition to doctors, fundamental researchers also work there. They are able, for example, to acquire knowledge in the laboratory that helps improve patient care. Among them is biomedical scientist Alain van Mil, who heads a research group within the Circulatory Health Research Center. Van Mil and Oerlemans have known each other for years.
Van Mil: “Oerlemans told me about the challenges of TTR amyloidosis. Could my research group perhaps develop cell models to better understand the disease? We are able to reproduce human tissue and imitate diseases. We start with a human cell, for example a blood cell or skin cell. We can reprogram them into an induced pluripotent stem cell (iPS cell). You can derive other cell types from such a cell. Cardiac muscle cells, for example.” Oerlemans’ request resulted in the development of 3D heart tissue models for TTR amyloidosis research.
3D cardiac tissue models of human heart
Van Mil: “With 2D you only use one cell layer and one cell type. A 3D piece of tissue is much closer to the human heart. These are 3D models on a chip, so that you can, for example, also create circulation of blood, containing proteins, and see what the influence is on the heart.” Once a model is ready, the researchers can add TTR and map its effect on heart tissue.
It research with the 3D heart models is possible thanks to financial support from pharmaceutical companies and the Amyloidosis Netherlands Foundation. John Rusman is a board member of the foundation: “Everyone would be happy if the disease could be diagnosed earlier. That would be pure profit. Hence the support of the foundation.”
Few millimeters
The models are miniscule, partly because of the cost. The smallest model is less than half a millimeter, the ‘largest’ a few millimeters. Van Mil: “In about three weeks we can make beating young heart muscle cells from iPS cells. A heart does not only consist of heart muscle cells.
That is why we also make endothelial cells (layer of cells on the inside of heart and blood vessels) and fibroblasts (main cells of the connective tissue). We ‘organize’ all cells in such a way that together they strongly resemble heart tissue. We manage to make such an advanced heart model within a month.”
Special office hours
The multidisciplinary consultation hour for patients with TTR amyloidosis that has been running since 2019 has been set up to put the patient first. The patient is simultaneously seen by a neurologist, cardiologist and, if necessary, a hematologist. Oerlemans: “We now know that people with a suspicion of TTR amyloidosis are referred to us sooner on average than when there were no consultation hours. In the event of a diagnosis, the patient can therefore also be treated earlier for health problems.”
Three years ago, the University of Twente (UT) received financing in the form of a loan of 250,000 euros for early phase projects. The company develops 3D heart models that can reliably imitate human heart functions
