Abstract Background Following cardiac injury, whether the heart is permanently damaged or regenerating, distal organs are subjected to changes in physiological function. It remains largely unknown whether a cardiac lesion can affect gametes and transmit heritable changes to subsequent generations. Here, we report the influence of paternal cardiac injury on the following generation. Methods We studied the intergenerational influence of neonatal cardiac injury in the mouse, an animal model capable of regenerating the heart after early life injury. Neonatal male mice were subjected to ventricular cryoinjury, crossed at adulthood, and their sires were compared with litters derived from uninjured male mice. We used echocardiography, histology, and single nuclei RNA-sequencing to thoroughly characterize cardiac morphology, composition, function, and response to cardiac insult. Results We show that paternal cardiac injury affects the heart morphology of offspring under physiological conditions. Furthermore, in response to the same injury, the F1 generation derived from injured fathers shows better systemic and cardiac recovery, with non-pathological left ventricular enlargement and improved cardiac function during the regenerative process. This is accompanied by the activation of the immune system healing program at 3 weeks post-injury, together with enhanced transcription of genes associated with physiological hypertrophy. Conclusions The memory of a paternal neonatal lesion can be transmitted to offspring and improve their recovery from a cardiac insult.

A paternal cardiac lesion induces cardiac adaptation in offspring