Graphical Abstract.

Duchenne muscular dystrophy (DMD) is associated with progressive dilated cardiomyopathy eventually leading to heart failure as the main cause of death in DMD patients. A human cardiomyocyte (CM) model was developed from several independent dystrophin-deficient human pluripotent stem cell (hPSC) lines from DMD patients and hESC line with deletion of DMD gene generated by CRISPR/Cas9 technology. DMD hPSC were differentiated into CMs. DMD mutation-carrying cells are less prone to differentiate into CMs. DMD CMs further demonstrate an enhanced cell death rate. Ion channel expression was altered in terms of potassium (Kir2.1 overexpression) and calcium handling (DHPR overexpression). DMD-CMs exhibited mishandling of calcium demonstrated by increased time of calcium release. Further mechanical impairment (hypocontractility), bradycardia, increased beat rate variability, and blunted β-adrenergic response connected with remodeling of β-adrenergic receptors' expression was found in DMD-CMs (LTCC L-type calcium channel, cTnT - cardiac troponin T, Kir2.1 - potassium channel).