New process Atrial fibrillation

Metabolic Remodeling: Atrial Fibrillation in a New Light

Atrial fibrillation is on the rise. The sharp increase in the number of cases of this arrhythmia, which is associated with an increased risk of stroke, is due in part to demographic changes and in part to Western lifestyles that have led to an epidemic of obesity. Although conventional therapies can slow the progression of the arrhythmia, they cannot reliably eliminate atrial fibrillation in most cases. A new - metabolic - perspective is promising. Research into altered cardiac metabolism opens up prospects for new therapies and is an example of translational research, which aims to rapidly translate basic research into clinical progress.

Mit herkömmlichen Therapien lässt sich ein Fortschreiten der Herzrhythmusstörung zwar verlangsamen, zuverlässig beseitigen lässt sich Vorhofflimmern aktuell jedoch in den meisten Fällen nicht. Vielversprechend ist eine neuer – ein metabolischer – Blickwinkel. Die Erforschung des veränderten Herzstoffwechsels eröffnet Perspektiven für neue Therapien und ist ein Beispiel für translationale Forschung, deren Ziel es ist, Grundlagenforschung zügig in klinischen Fortschritt umzumünzen.

David Bode is a resident physician at the Virchow Clinic of the Charité in Berlin and a clinical scientist at the DZHK. At the Max Rubner Center for Cardiovascular Metabolic Renal Diseases at the Charité - a partner site of the DZHK - Bode conducts research on atrial cardiomyopathies with a current focus on metabolic changes. Bode is the first author of a recent review on metabolic remodeling in atrial fibrillation*. 

Bode: That's right. This aspect has only come into focus in the last few years. There have been some promising studies, but there is still a lot to be discovered. This is a very exciting field of research at the moment. 

What exactly does metabolic remodeling mean?

Bode: In atrial fibrillation, the heart undergoes metabolic remodeling that plays a role in the development of the arrhythmia. We refer to these processes as remodeling. In atrial fibrillation, the remodeling occurs on three levels: structural, electrophysiological, and metabolic. In structural remodeling, the structure of the atria changes, including the incorporation of connective tissue. Electrophysiological remodeling changes the ion channels responsible for cardiac excitation, and metabolic remodeling changes metabolism. These are three aspects of a complex disorder and there are interactions between these three levels. Metabolic changes often precede structural and electrophysiological remodeling.
But remodeling is initially a positive adaptation?

Bode: Yes, it often begins with a physiological adaptation process. Over time, however, this can lead to permanent or only partially reversible changes that are detrimental and promote disease. How and when such a process can tip over - which is also important from a therapeutic point of view - has not yet been conclusively clarified. 

And what exactly are the metabolic changes in atrial fibrillation?

Bode: In atrial fibrillation, the chaotic electrical excitation of the atria causes the heart muscle cells to work harder. This leads to metabolic stress. As a result, the heart muscle cells change the way they obtain nutrients, which can lead to chronic remodeling processes in the atria, which in turn promote the arrhythmia. A vicious cycle!

"The funding from the DZHK makes my research possible in the first place. As part of the funding, I am released from clinical work and can pursue my research. In addition, the DZHK is a platform that creates a very sustainable network between scientists."

David Bode
Assistenzarzt am Virchow-Klinikum der Charité Berlin und DZHK Clinical Scientist.

The metabolic changes that occur in atrial fibrillation are complex and far from understood. However, some processes are relatively well understood. For example, large amounts of reactive oxygen species are produced in heart muscle cells. These reactive particles can damage ion channels and contribute to arrhythmias. To make this very clear: Metabolic remodeling is by no means unique to atrial fibrillation on the back of systemic metabolic diseases such as obesity. Rather, metabolic remodeling is a local pathological phenomenon that generally occurs in atrial fibrillation.

Bode: Yes, these are two different aspects. Systemic metabolic diseases such as obesity and diabetes mellitus can indeed lead to altered glucose, ketone, and lipid metabolism in the heart. However, AF itself also leads to metabolic remodeling independent of systemic disease.

Although research on metabolic remodeling in atrial fibrillation is still in its infancy, can we perhaps already foresee how this new perspective might change the treatment of atrial fibrillation?

Bode: That is the key question. Our group is involved in translational research, so we always have the question in the back of our minds: Can we perhaps derive new therapeutic approaches from our research findings? This can involve the development of innovative therapies, but also the new application of already established drugs, i.e. repurposing. 

Are there already new therapeutic approaches with regard to metabolic remodeling?

Bode: Interesting drugs include SGLT2 inhibitors and GLP1 receptor agonists, as well as the classic metformin, i.e. antidiabetic drugs that might be useful in AF even without diabetes. The mechanisms by which these drugs may have a beneficial effect on cardiac metabolism are very different. In order to be able to make reliable statements about their efficacy, we need controlled studies that show that the drug can have a positive effect on the frequency of atrial fibrillation or the course of the disease. One problem with established drugs is the financing of such studies, as manufacturers often do not consider it worthwhile to invest in new indications.


From today's perspective, when might it make sense to use metabolically active drugs in atrial fibrillation - for all patients, or is the path more in the direction of individualized therapy?

Bode: I see metabolic agents more as adjunctive therapy. Prophylactic use in high-risk patients is also conceivable. Conventional therapies such as ablation and antiarrhythmic drugs, flanked by lifestyle modifications, will remain important. By adding metabolically active drugs, we are attacking on an additional level and may increase the chances of success. 

*Bode D et Al: Metabolic remodelling in atrial fibrillation: manifestations, mechanisms and clinical implications. Nature Reviews Cardiology 2024. doi.org/10.1038/s41569-024-01038-6