Electro-metabolic coupling in multi-chambered vascularized human cardiac organoids

Multi-chambered vascularized human cardiac organoids produced under anisotropic stress and integrated with sensors facilitate the study of electro-metabolic coupling in arrythmia. The study of cardiac physiology is hindered by physiological differences between humans and small-animal models. Here we report the generation of multi-chambered self-paced vascularized human cardiac organoids formed under anisotropic stress and their applicability to the study of cardiac arrhythmia. Sensors embedded in the cardiac organoids enabled the simultaneous measurement of oxygen uptake, extracellular field potentials and cardiac contraction at resolutions higher than 10 Hz. This microphysiological system revealed 1 Hz cardiac respiratory cycles that are coupled to the electrical rather than the mechanical activity of cardiomyocytes. This electro-mitochondrial coupling was driven by mitochondrial calcium oscillations driving respiration cycles. Pharmaceutical or genetic inhibition of this coupling results in arrhythmogenic behaviour. We show that the chemotherapeutic mitoxantrone induces arrhythmia through disruption of this pathway, a process that can be partially reversed by the co-administration of metformin. Our microphysiological cardiac systems may further facilitate the study of the mitochondrial dynamics of cardiac rhythms and advance our understanding of human cardiac physiology.

Automated summary

Multi-chambered vascularized human cardiac organoids generated under anisotropic stress and equipped with sensors provide a platform for studying electro-metabolic coupling in arrhythmia. These organoids, which mimic human cardiac physiology, enable simultaneous measurement of oxygen uptake, extracellular field potentials, and cardiac contraction at high resolutions. The study reveals the importance of electro-mitochondrial coupling in cardiac rhythms and demonstrates the arrhythmogenic behavior induced by disruption of this pathway. This research improves our understanding of human cardiac physiology and offers potential applications in drug development and personalized medicine.