Traditional medicine could slow heart disease development.
Time halted during the European Football Championship last summer. When football player Christian Eriksen unexpectedly fell, passed away, and was resuscitated on live television, the buzzing anxiety that had filled the air vanished in a matter of seconds. And in no time, millions of people all over the globe were aware of the danger posed by cardiovascular diseases, the leading cause of mortality in the western world, according to the World Health Organization.
When the heart fails in young athletes, the condition ARVC is often to blame. Half of all cases of sudden cardiac arrest in athletes occurring during physical activity are thought to be caused by ARVC.
Researchers from the University of Copenhagen provide new insights into a process involved in the development of the disease in a recent study. In fact, they also present a viable treatment method, according to Professor Alicia Lundby, whose research team led the new study.
“We have identified a previously unknown disease mechanism in ARVC, which adds a completely new layer of information that no one knew about,” she says.
The previously unknown mechanism is a defect in the nucleus, deep within the heart cells that are responsible for heart muscle contraction. The defect sets off a chain reaction that leads to cell death.
“Based on the new insights we obtained, we identified a molecule that may be able to slow down disease progression,” says Alicia Lundby from the Department of Biomedical Sciences at the University of Copenhagen.
Alicia Lundby and her colleagues studied heart biopsies from healthy individuals and from patients suffering from hereditary ARVC. They performed a deep and so-called molecular profiling of the heart samples and identified the molecular differences between the hearts. Based on these measurements, they formulated hypotheses about the causes of the disease and tested them on mice models and stem cell-derived heart muscle cells.
The study was recently published in the journal Circulation.
Molecule from tulip tree as treatment?
The researchers found that by activating a specific molecule, sirtuin-3, they could slow down disease development. They, therefore, started a hunt for a molecule with that function.
And with honokiol, they found it. Honokiol is a natural product extracted from the bark and leaves of the tulip tree and has been used e.g. as a pain killer in traditional medicine in some parts of Asia.
“When we tested honokiol on our mouse model, it really did slow down the development of the disease. The same happened in our stem cell-derived heart cells. We do not know if it works the same with humans, but the fact that we can confirm the effect in two different models makes it very interesting,” says Alicia Lundby.
“It is really satisfying to take a project all the way from very basic science measurements, through interpretation of the results to coming up with a possible strategy to mitigate the disease progression and finally demonstrate that it works. To me, this is truly the essence of the type of research I am excited about, namely to shed light on the mechanisms behind heart disease such that we can propose novel treatment strategies,” she says.
“Doing the types of studies we do, analyzing several thousands of proteins at a time, is challenging when trying to understand what the changes we measure actually mean. This part of the work requires delving into the scientific literature. So you read and read and read. And talk to colleagues, think, and read some more. It is months of detective work. And it’s both stimulating and frustrating at times. Because it is certainly not straightforward.”
The hard work does not stop here. The researchers have already launched a follow-up study to examine their findings more closely.
“We believe our findings are significant, and we want to determine whether they can actually help patients. The next step for us is to determine whether the mechanism we identified is present in all ARVC patients,” says Alicia Lundby.
Reference: “Loss of Nuclear Envelope Integrity and Increased Oxidant Production Cause DNA Damage in Adult Hearts Deficient in PKP2: A Molecular Substrate of ARVC” by Marta Pérez-Hernández, Chantal J.M. van Opbergen, Navratan Bagwan, Christoffer Rasmus Vissing, Grecia M. Marrón-Liñares, Mingliang Zhang, Estefania Torres Vega, Andrea Sorrentino, Lylia Drici, Karolina Sulek, Ruxu Zhai, Finn B. Hansen, Alex Hørby Christensen, Søren Boesgaard, Finn Gustafsson, Kasper Rossing, Eric M. Small, Michael J. Davies, Eli Rothenberg, Priscila Y. Sato, Marina Cerrone, Thomas Hartvig Lindkær Jensen, Klaus Qvortrup, Henning Bundgaard, Mario Delmar and Alicia Lundby, 12 August 2022, Circulation.