Molecular mechanism causing severe cardiac arrhythmia identified

Researchers from the UPC’s Computational Biology and Complex Systems Group (BIOCOM-SC) and the Heart Rhythm Analysis and Control Group (ANCORA) and other international scientists have identified one of the molecular mechanisms underlying cardiac alternans. It is an alteration of heart rhythm that is critical to the induction of ventricular fibrillation, a potentially fatal arrhythmia. The discovery was published in the journal Circulation Research (AHA Journals) and paves the way for new pharmacological treatments.

May 21, 2021

Cardiovascular disease is one of the leading causes of death worldwide, accounting for nearly 18 million deaths annually. In Spain and Catalonia, it accounts for almost a third of all deaths. It also causes a significant reduction in quality of life. An international team of researchers, led by Professor SR Wayne Chen from the University of Calgary (Canada) and composed of the Heart Rhythm and Contraction Group of the Institute of Biomedical Research of Barcelona (IIBB-CSIC) and of the Research Institute of the Santa Creu i Sant Pau Hospital (IIB Sant Pau) and the UPC’s Computational Biology and Complex Systems Group (BIOCOM-SC) and Heart Rhythm Analysis and Control Group (ANCORA), have identified one of the molecular mechanisms underlying cardiac alternans, which is an alteration of heart rhythm that is critical to the induction of ventricular fibrillation, a potentially fatal arrhythmia.

Cardiac alternans was first described in the late 19th century as an alteration in the pulse (hence the name pulsus alternans), alternating strong and weak beats. Almost a century later this alteration was found to be related to susceptibility to ventricular fibrillation, in which heart cells suddenly stop beating synchronously resulting in death within a few minutes in many cases. Since then, work has been done to find out the molecular mechanisms responsible for this arrhythmia, which would open the door to developing new pharmacological treatments.

Computational models for studying alternans

The UPC’s BIOCOM-SC has been long using computational models to study the onset of cardiac alternans. Cross-disciplinary collaborations have allowed the group to develop computational techniques for studying related physiological scenarios. Blas Echebarría, a researcher from the BIOCOM-SC who is the principal investigator of the computational part of the study, explains that “it is known that, in most cases, alternans are due to irregularities in intracellular calcium. Mathematical models predicted that alternans could appear due to alterations in ryanodine receptors (RyR), the protein that regulates intracellular calcium release.”

But the molecular mechanism behind this alteration has been the subject of debate over the past decade, in which researchers have suggested a number of causes of RyR dysfunction. Leif Hove-Madsen, a researcher at the IIBB-CSIC and the IIB Sant Pau, points out that “ryanodine receptors are a protein that is located in intracellular membranes, where large amounts of calcium are stored. The RyR behaves like a gate that, when opened, releases the stored calcium and triggers heart contraction. However, if calcium deposits are overloaded, the opening becomes uncontrolled and leads to irregular calcium release and cardiac arrhythmias. This study has managed to identify the key molecular mechanism regulating the opening of this gate.”

Thus, Professor Wayne Chen, from the University of Calgary, and one of the leading experts on ryanodine receptors, suggested that this alteration in RyR function could be due to its binding to another protein (calmodulin or CaM), which regulates its function. To confirm this, Professor Chen designed an experiment in collaboration with Hove-Madsen. He changed the function of CaM by introducing modified adenoviruses into mice to produce either the protein in its normal state or mutations in the protein that increased or decreased its function, and observing whether this decreased or increased the susceptibility to alternans.

The data have been analysed by the UPC’s ANCORA, led by the researcher Raúl Benítez, using statistical techniques. Benítez explains that “the results of these experiments clearly show that a decrease in CaM expression is correlated to a decreased susceptibility to alternans.”

Experimentally, however, it is not possible to observe what happens with the RyR, so there is always the possibility that CaM is affecting another regulatory mechanism and that there is an alternative explanation for this effect. To confirm whether the effect of CaM on the RyR is responsible for this change, the researchers from the BIOCOM-SC used a computational model that describes in detail the interaction between CaM and the RyR and its effect on cardiac dynamics. The results of the mathematical model agree perfectly with the experimental observations. As Echebarría and Hove-Madsen explain, “the mathematical model coincides so closely with the experiments that we can be quite certain that this is the actual mechanism.”

The researchers do not rule out that there might be other mechanisms causing alternans. Nevertheless, the identification of a clear molecular mechanism causing cardiac alternans should contribute to the development of pharmacological treatments for this arrhythmia. In this sense, basic science and cross-disciplinary work are fundamental.

This discovery on ventricular dysfunctions comes from the study on atrial fibrillation and the development of atrial models, funded by the Spanish Ministry of Science and Innovation, the Government of Catalonia and the La Marató de TV3 Foundation. “Thanks to the knowledge generated in these projects, we had the opportunity to develop the ventricular model in collaboration with Professor Chen”, concludes Echebarría.