When the Time is Right: Translational Approaches to Prevent Cardiac Dysfunction in Individuals at Risk

Heart failure is a chronic, progressive condition and a leading cause of morbidity and mortality worldwide. Despite advances in treatment, prevention remains essential, as cardiac damage becomes increasingly difficult to reverse once dysfunction and remodelling have developed. This thesis explores two factors that may determine when and in whom cardiac dysfunction develops: biological time and individual susceptibility. Together, these perspectives provide new insights into the prevention of cardiac dysfunction and the development of precision cardio-oncology. Circadian rhythms play an important role in cardiovascular physiology and influence the heart’s response to stress. Disruption of these rhythms is associated with cardiovascular disease, while the response to cardiotoxic treatment may also vary throughout the day. Anthracycline-induced cardiotoxicity appears to be time dependent, with early-morning administration emerging as a potentially more favourable treatment window. However, treatment timing affects more than cardiac toxicity alone. Differences in fatigue, neuroinflammation, systemic inflammation, and metabolic responses demonstrate that the optimal timing for cardioprotection may not coincide with the optimal timing for minimizing toxicity in other organs. These findings highlight the need for a whole-body perspective when developing chronotherapy. Cardiac vulnerability also differs substantially between individuals, with genetic background emerging as an important determinant. Cardiac tissue from patients carrying cardiomyopathy-associated genetic variants showed increased susceptibility to doxorubicin-induced injury, accompanied by impaired cellular stress responses and metabolic alterations. Dexrazoxane reduced doxorubicin-induced functional, structural, and metabolic injury, supporting its potential as a cardioprotective strategy in patients at increased risk. Importantly, patient-specific cardiac models demonstrated that ex vivo responses can reflect clinical cardiac dysfunction and may provide complementary information on treatment sensitivity and recovery. Together, these findings support a more personalized approach to the prevention of cardiac dysfunction, in which circadian characteristics and genetic susceptibility complement established risk factors. Such integration may improve risk stratification and inform the timing of treatment, cardioprotection, and cardiac monitoring, providing a foundation for preventive precision cardio-oncology.