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24.10.2025 15:29

Why energy transport in the heart fails in hypertrophic cardiomyopathy

Kirstin Linkamp Stabsstelle Kommunikation
Universitätsklinikum Würzburg

Oxidative stress deactivates creatine kinase at key points, causing the heart to lose its energy balance
In an international, multicentre study published in the journal Circulation, researchers from the Comprehensive Heart Failure Center Wuerzburg show why energy transport can fail in hypertrophic cardiomyopathy (HCM) and how reducing cardiac stress and oxidative stress can reduce arrhythmias.

Würzburg. Hypertrophic cardiomyopathy (HCM) is the most common hereditary heart disease. It causes the left ventricle to thicken, the heart muscle to contract too strongly and work too hard. This additional strain puts pressure on the cells' power plants, the mitochondria, and can increase the risk of dangerous cardiac arrhythmias. Creatine kinase plays a key role in maintaining the balance between energy consumption and production (energy homeostasis). This enzyme helps the heart to recycle energy quickly so that each heartbeat receives the energy it needs. A team from the Department of Translational Research at the Comprehensive Heart Failure Center Würzburg (CHFC) worked with national and international partners to investigate the role of creatine kinase in HCM. Their findings were published in the journal Circulation.

Strong heart contractions increase hydrogen peroxide in mitochondria – creatine kinase is switched off

"We found that overloading the heart muscle causes the mitochondria to produce more hydrogen peroxide. This reactive oxygen molecule normally occurs in small amounts as a by-product, but too much of it can stress or damage cells over time. In HCM, oxidative stress switches off creatine kinase at two important sites: at the filaments, where muscle strength is generated, and at the mitochondria, where energy is produced," explains Anton Xu, doctoral student at the CHFC and first author of the study. “This means that when creatine kinase is deactivated, the heart cannot maintain a constant supply of energy where it is most needed. This increases the risk of cardiac arrhythmia and causes additional stress.”

Myosin inhibitors reduce contractions and thereby protect creatine kinase from inactivation and prevent cellular arrhythmias

The team observed these changes in heart biopsies from patients with HCM and confirmed both the cause and the positive effect of a myosin inhibitor in several laboratory models. Myosin inhibitors reduce the interaction between the contractile proteins actin and myosin, which helps the heart muscle to better relax and contract with less strength. “In our studies, we observed that under the effect of the myosin inhibitor, hydrogen peroxide levels decreased, creatine kinase function was maintained and abnormal heart rhythms were reduced,” reports Dr Vasco Sequeira, last author of the study. ‘Our findings therefore suggest that treatments that reduce the workload on the heart and limit oxidative stress may help restore energy balance and improve treatment outcomes in HCM.”

Observe myosin motors in the heart in real time during each heartbeat

In the next step, the team will focus on an advanced form of cardiomyopathy: hypertrophic obstructive cardiomyopathy (HOCM). In this disease, a narrowing in the outflow tract of the left ventricle causes additional resistance to the blood flowing out of the heart. This means that the heart has to work even harder with every beat. Together with partners at the National Cerebral and Cardiovascular Centre in Osaka, the researchers from Würzburg aim to develop more realistic animal models. Using a specially-modified high-resolution X-ray system, they will then be able to observe the tiny myosin motors of the heart, i.e., the molecular machines responsible for contraction, in real time during each heartbeat at the Japanese Synchrotron Radiation Research Institute Spring 8 in Harima.

“This gives us an unprecedented view of how hard the heart is working, beat by beat, and allows us to investigate how well the smallest blood vessels supply the heart muscle with blood and how efficiently the cells produce and transport energy,” Vasco Sequeira explains enthusiastically.

Developing metrics to identify patients who will benefit from treatment

To better reflect reality, the team will also investigate metabolic stress, such as the negative effects of a high-fat diet. Subsequently, they will also examine whether reducing the obstruction-related strain on the heart muscle using myosin inhibitors restores the heart's energy transport, stabilizes its energy supply and reduces the risk of cardiac arrhythmia.
“Our goal is to develop simple measurements that will help doctors identify those patients with HOCM who are most likely to benefit from these relieving treatments,” summarizes Prof. Dr. Christoph Maack, Head of Translational Research and Spokesperson of the CHFC.

Multicentre collaboration and funding

In addition to Würzburg University Hospital (UKW), the following institutions were involved: National Cerebral and Cardiovascular Center (Japan); Monash University and the Victor Chang Cardiac Research Institute (Australia); Erasmus MC and Amsterdam UMC (Netherlands); University Medical Center Hamburg-Eppendorf/DZHK (Germany); University of Glasgow (UK); University of Porto (Portugal); and cooperation partners in the US, such as Mississippi State University and Vanderbilt University.

The work was supported by by national and international agencies, including the Deutsche Forschungsgemeinschaft (DFG), the German Centre for Cardiovascular Research (DZHK), the Japan Society for the Promotion of Science (JSPS), and others. Bristol Myers Squibb provided support related to the myosin inhibitor used in some experiments.

Image: How the heart’s “energy shuttle” is built. The image shows the 3D shape of mitochondrial creatine kinase (Mt-CK; protein structure code 4Z9M), an enzyme that helps move and buffer energy inside heart cells. The eight building blocks of the enzyme (monomers) are shown in different colors. The dark-blue spots mark where energy-carrying molecules (ATP, ADP) and creatine/phosphocreatine (Cr/PCr) bind. The red marks highlight three individual cysteine sites (Cys63, Cys67, and Cys90) that can be oxidized in hypertrophic cardiomyopathy. In the zoomed view, these cysteines lie ~6.5–14.8 Å apart (about 0.7–1.5 nm), which is too far to form stabilizing (disulfide) links; this implies that oxidation disrupts Mt-CK through other structural changes, for example by weakening how the enzyme docks onto membrane lipids.

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Wissenschaftliche Ansprechpartner:

Vasco Sequeira, sequeira_v@ukw.de
Christoph Maack maack_c@ukw.de

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Originalpublikation:

Anton Xu, David Weissman, Katharina J. Ermer, Edoardo Bertero, Jan M. Federspiel, Felix Stadler, Elisa Grünler, Melina Tangos, Sevasti Zervou, Mark T. Waddingham, James T. Pearson, Jan-Christian Reil, Smita Scholtz, Jan Dudek, Michael Kohlhaas, Alexander G. Nickel, Lucie Carrier, Thomas Eschenhagen, Michelle Michels, Cris Dos Remedios, Sean Lal, Leticia Prates Roma, Nazha Hamdani, Diederik Kuster, Inês Falcão-Pires, Christopher N. Johnson, Craig A. Lygate, Jolanda van der Velden, Christoph Maack, Vasco Sequeira. Hypercontractility and Oxidative Stress Drive Creatine Kinase Dysfunction in Hypertrophic Cardiomyopathy, Circulation (American Heart Associationi), October 2025, https://doi.org/10.1161/CIRCULATIONAHA.125.074120

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How the heart’s “energy shuttle” is built. The image shows the 3D shape of mitochondrial creatine ki ...

Copyright: Anton Xu et al., Circulation, October 2025 https://doi.org/10.1161/CIRCULATIONAHA.125.074120

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Key members of tThe team and colleagues from Würzburg University Hospital visiting their cooperation ...
Quelle: Katrin Streckfuß-Bömeke
Copyright: UKW

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