Patients undergoing open heart surgery in the afternoon have a lower risk of potentially fatal complications than those undergoing operations in the morning. The study found that events including heart attacks and heart failure were less common among those who had undergone a valve replacement operation in the afternoon.
The report says the finding appears to be linked to the ability of the heart tissue to recover after being starved of blood supply during surgery – an effect the researchers say is influenced by the cells’ biological or “circadian” clock.
While the study suggests patients might fare better if they undergo afternoon surgery, Professor David Montaigne, first author of the research from the University of Lille in France, said it also highlighted another approach to reduce complications. “We have to find a drug that can alter the circadian clock to induce a jet lag,” he said, noting that it could also help to improve patient outcomes for heart attacks and organ transplantation.
The report says Montaigne and colleagues report how they looked at the outcomes of 596 patients, half of whom had valve surgery in the morning, and half in the afternoon. While 18% of morning surgery patients experienced a major cardiac event – such as a heart attack or heart failure –in the following 500 days, only 9% of those who had afternoon surgery experienced such events. The team then randomly assigned 88 valve surgery patients to either morning or afternoon operations and monitored levels of a protein in their blood linked to heart tissue damage.
The results reveal that afternoon surgery patients had lower levels of the protein after their operation, suggesting about 20% less damage to the heart than those who underwent morning surgery.
Delving deeper, the team took biopsies from 14 morning surgery patients and 16 afternoon surgery patients, finding that tissue from the latter recovered better after being deprived of oxygen.
The report says further analysis found 287 genes within the cells that showed different levels of activity depending on whether the cells were from morning or afternoon patients – genes which have, in many cases, previously been linked to the circadian clock.
With a time-of-day effect also found in the recovery of mouse heart tissue, the team explored the impact of tinkering with the activity linked to one of the body clock genes, both using drugs and by looking at mice without the gene. Both approaches improved the recovery of the heart tissue at the time of day when it was typically worse.
Dr John O’Neill, an expert in circadian rhythms from the MRC Laboratory of Molecular Biology, said in the report that the research backed up previous work in mice and fruit flies that had explored the genes involved in the body clock – work which scooped a trio of scientists the Nobel prize for medicine earlier this month.
“The biological clock, the circadian rhythm, is in every single cell of the body, therefore it affects the biological activity of each cell type, commensurate with the function of those cells,” he said, adding that in healthy humans the heart is known to follow a daily pattern of activity and is not at its optimum performance in the morning. But, he noted, since systems including that of inflammation are also influenced by circadian rhythms, they too might play a role in the different outcomes for morning and afternoon surgeries.
What’s more, said O’Neill in the report, the study did not consider whether the surgeons performed the operation better in the afternoon, adding that more work was need to explore whether the findings would hold for patients at other hospitals, or for other types of surgery.
“It is not the case that every single medical intervention is necessarily going to be best dealt with in the afternoon,” he said, adding that the research did not mean that patients should try to “jet lag” themselves before surgery.
Professor Bryan Williams, chair of medicine at University College London, described the new research as fascinating and elegant, adding that the study builds on the fact that cardiovascular events, such as heart attacks, are more common in the morning. “What this research suggests is that an intrinsic body clock within cells of the heart may render these cells more susceptible to injury during cardiac surgery in the morning versus the afternoon,” he said.
But, the report says, Williams agreed that it was too soon to consider rescheduling heart surgeries to the afternoon, and that large-scale, robust clinical trials would be needed to probe the effect further. “This would be needed to change practice because the logistical implications of doing so would be huge and require definitive proof that there is a real benefit,” he said.
Background: On-pump cardiac surgery provokes a predictable perioperative myocardial ischaemia–reperfusion injury which is associated with poor clinical outcomes. We determined the occurrence of time-of-the-day variation in perioperative myocardial injury in patients undergoing aortic valve replacement and its molecular mechanisms.
Methods: We studied the incidence of major adverse cardiac events in a prospective observational single-centre cohort study of patients with severe aortic stenosis and preserved left ventricular ejection fraction (>50%) who were referred to our cardiovascular surgery department at Lille University Hospital (Lille, France) for aortic valve replacement and underwent surgery in the morning or afternoon. Patients were matched into pairs by propensity score. We also did a randomised study, in which we evaluated perioperative myocardial injury and myocardial samples of patients randomly assigned (1:1) via permuted block randomisation (block size of eight) to undergo isolated aortic valve replacement surgery either in the morning or afternoon. We also evaluated human and rodent myocardium in ex-vivo hypoxia–reoxygenation models and did a transcriptomic analysis in myocardial samples from the randomised patients to identify the signalling pathway(s) involved. The primary objective of the study was to assess whether myocardial tolerance of ischaemia–reperfusion differed depending on the timing of aortic valve replacement surgery (morning vs afternoon), as measured by the occurrence of major adverse cardiovascular events (cardiovascular death, myocardial infarction, and admission to hospital for acute heart failure).
Findings: In the cohort study (n=596 patients in matched pairs who underwent either morning surgery [n=298] or afternoon surgery [n=298]), during the 500 days following aortic valve replacement, the incidence of major adverse cardiac events was lower in the afternoon surgery group than in the morning group: hazard ratio 0·50 (95% CI 0·32–0·77; p=0·0021). In the randomised study, 88 patients were randomly assigned to undergo surgery in the morning (n=44) or afternoon (n=44); perioperative myocardial injury assessed with the geometric mean of perioperative cardiac troponin T release was significantly lower in the afternoon group than in the morning group (estimated ratio of geometric means for afternoon to morning of 0·79 [95% CI 0·68–0·93; p=0·0045]). Ex-vivo analysis of human myocardium revealed an intrinsic morning–afternoon variation in hypoxia–reoxygenation tolerance, concomitant with transcriptional alterations in circadian gene expression with the nuclear receptor Rev-Erbα being highest in the morning. In a mouse Langendorff model of hypoxia–reoxygenation myocardial injury, Rev-Erbα gene deletion or antagonist treatment reduced injury at the time of sleep-to-wake transition, through an increase in the expression of the ischaemia–reperfusion injury modulator CDKN1a/p21.
Interpretation: Perioperative myocardial injury is transcriptionally orchestrated by the circadian clock in patients undergoing aortic valve replacement, and Rev-Erbα antagonism seems to be a pharmacological strategy for cardioprotection. Afternoon surgery might provide perioperative myocardial protection and lead to improved patient outcomes compared with morning surgery.
David Montaigne, Xavier Marechal, Thomas Modine, Augustin Coisne, Stéphanie Mouton, Georges Fayad, Sandro Ninni, Cédric Klein, Staniel Ortmans, Claire Seunes, Charlotte Potelle, Alexandre Berthier, Celine Gheeraert, Catherine Piveteau, Rebecca Deprez, Jérome Eeckhoute, Hélène Duez, Dominique Lacroix, Benoit Deprez, Bruno Jegou, Mohamed Koussa, Jean-Louis Edme, Bart Staels