Abstract Body (Do not enter title and authors here): Introduction: The heart responds differently to injury at different times of day. This has been shown in clinical and animal studies of myocardial ischemia reperfusion injury and in a rodent study of doxorubicin cardiotoxicity. Circadian disruption around the time of myocardial infarction has also been linked to more adverse cardiac remodeling. Clinical studies assessing the effects of diurnal rhythms on anthracycline cardiotoxicity are lacking. We hypothesize that anthracycline dosing time and sleep disruption can affect the risk for cardiotoxicity.
Methods: Using the All of Us database, we identified 1,973 patients with anthracycline exposure. We included patients with no heart failure or cardiomyopathy diagnostic codes before their first anthracycline dose. We defined our outcome of interest as the incidence of heart failure after the first dose. We calculated the percentage of anthracycline doses given at nighttime (between 6pm and 6 am) from the total number of doses. To assess the effects of sleep disruption we identified patients with a sleep disorder diagnosis before their first dose of anthracycline. We then fit univariate cox proportional hazards models and models that were adjusted for age at first dose and the presence of hypertension, diabetes, and hyperlipidemia before receiving the first anthracycline dose. We set our follow up time to start from the time of the first anthracycline dose to 10 years after and data was censored at the date of the last recorded EHR encounter.
Results: There were 194 incident cases of heart failure, and a mean follow up time of 5 years. Patients who received more than 50% of their anthracycline doses at night and patients with a prior sleep disorder diagnosis had a significantly higher risk of developing heart failure (HR: 1.92; 95% CI: 1.41-2.63 and HR:2.49; 95% CI: 1.79-3.47 respectively) The associations remained significant in the fully adjusted models (HR: 1.98; 95% CI: 1.45-2.70 and HR: 1.81; 95% CI: 1.27-2.56 respectively).
Conclusions: Patients receiving the majority of their anthracycline doses at night and patients with sleep disorder diagnoses are at a higher risk for developing heart failure. Day time dosing and addressing sleep disturbances could decrease the risk of anthracycline cardiotoxicity.