Exploring Cardiac Memory in hiPSC-derived cardioids: the cardiac side of MELAS syndrome

Metabolic diseases have an incidence of 0.5% in newborns and can lead to dramatic dysfunction in high energy-demanding organs, with the heart representing an illustrative example. Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) offer a unique platform for investigating cardiac manifestations of metabolic diseases and elucidating the establishment of vitious mechanisms, such as cardiac memory. Cardiac memory is an electrocardiographic anomaly whereby the T-wave remembers previous sinus or paced rhythms, thus modifying the ventricular repolarization. One of the metabolic diseases which might be affected by cardiac memory is Metabolic Encephalopathy with Lactic Acidosis and Stroke-like episodes (MELAS) syndrome. Indeed, cardiac memory may occur following the preventive implantation of a pacemaker in patients diagnosed with MELAS, mostly presenting conduction defects. This doctoral thesis describes the development and validation of OptTrack software for kinematic evaluation across a range of pathological phenotypes, encompassing mechanical and electrical deficiencies. Among the phenotypes studied, MELAS syndrome samples exhibited complete impairment ranging from electrophysiology to metabolism. These observations could translate into the shortening of substrate refractory period, optimal for causing arrhythmia. Additionally, considering the augmented cardiac fatigue, the patients would suffer from impaired contractility. This research project represents one of the first in-depth study of the cardiac manifestations of MELAS syndrome, given the lack of in-vivo measurements and models, which compels this research to further delineate this pathology.