Short Term Disruption of Diurnal Rhythms Following Murine Myocardial Infarction Adversely Affects Long Term Myocardial Structure and Function
Rationale: Patients in Intensive Care Units (ICU) are disconnected from their natural environment. Synchrony between environmental diurnal rhythms and intracellular circadian rhythms is essential for normal organ biology; disruption causes pathology. Whether disturbing rhythms post myocardial infarction (MI) exacerbates long-term myocardial dysfunction is not known.
Objective: Short term diurnal rhythm disruption immediately post-MI impairs remodeling and adversely affects long term cardiac structure and function in a murine model.
Methods and Results: Mice were infarcted by left anterior descending coronary artery ligation (MI model) within a 3-hour time window, randomized to either a normal diurnal or disrupted environment for 5 days, then maintained under normal diurnal conditions. Initial infarct size was identical. Short term diurnal disruption adversely impacted body metabolism and altered early innate immune responses. In the first 5 days, crucial for scar formation, there were significant differences in cardiac myeloperoxidase, cytokines, neutrophil and macrophage infiltration. Homozygous clock mutant mice exhibited altered infiltration post-MI, consistent with circadian mechanisms underlying innate immune responses crucial for scar formation. In the proliferative phase, 1 week post-MI, this led to significantly less blood vessel formation in the infarct region of disrupted mice; by day 14 echocardiography showed increased left ventricular dilation and infarct expansion. These differences continued to evolve with worse cardiac structure and function by 8 weeks post-MI.
Conclusions: Diurnal rhythm disruption immediately post-MI impaired healing and exacerbated maladaptive cardiac remodeling. These preclinical findings suggest that disrupted diurnal rhythms such as found in modern ICU environments may adversely affect long term patient outcome.
- Received November 6, 2013.
- Revision received March 20, 2014.
- Accepted March 31, 2014.