Study combines observational study, randomised trial, tissue analysis and research in mice to investigate the link between time of day of surgery and health outcomes
Outcomes for open heart surgery could potentially be improved by moving surgery to the afternoon, rather than in the morning, according to a study published in The Lancet which identifies a link between a person's circadian clock and their risk of heart damage and major cardiac events after heart surgery.
The study also provides early insights into the mechanism behind this link, identifying nearly 300 genes linking the circadian clock - the internal body clock that controls when people sleep, eat and wake up - to heart damage.
Following open heart surgery, some patients may develop heart damage impacting on the heart's ability to pump blood, resulting in poor outcomes including onset of heart failure and a heightened risk of death.
Previous research has suggested that cardiovascular events such as myocardial infarction (heart attacks) that happen in the morning may be associated with a higher risk of the damage, compared to afternoon events, but reasons have remained unclear.
The study published today consisted of four parts: an observational study looking at the association between time of day of surgery and outcomes; a randomised controlled trial to investigate whether there was a causal link between time of day of surgery and outcomes; a human tissue analysis to identify genes involved in the circadian effect on heart surgery; and a mouse model further investigating the biological mechanism and a potential therapeutic approach.
"Currently, there are few other surgical options to reduce the risk of post-surgery heart damage, meaning new techniques to protect patients are needed," says author Professor David Montaigne, University of Lille, France. "Our study found that post-surgery heart damage is more common among people who have heart surgery in the morning, compared to the afternoon. Our findings suggest this is because part of the biological mechanism behind the damage is affected by a person's circadian clock and the underlying genes that control it. As a result, moving heart surgery to the afternoon may help to reduce a person's risk of heart damage after surgery."
In the observational study, which ran from January 2009 to December 2015, researchers tracked the medical records of 596 people who had heart valve replacement surgery (half had surgery in the morning, half in the afternoon) for 500 days to monitor for any major cardiac events such as a heart attack, heart failure or died from heart disease.
People who had surgery in the afternoon had a 50% lower risk of a major cardiac event, compared to people who had surgery in the morning (28/298 [9.4%] compared to 54/298 [18.1%]) - this could equate to one major event being avoided for every 11 patients who have afternoon surgery.
In the randomised controlled trial, which took place from January 2016 to February 2017, 88 patients were randomly scheduled for heart valve replacement surgery in the morning or afternoon (half had morning surgery and the other half had afternoon surgery) and their health was monitored until they left hospital. There were no deaths in either group and the average time in hospital was 12 days. However, patients who had afternoon surgery had lower levels of heart tissue damage after surgery, compared to morning surgery patients.
To understand why there were these differences in outcomes for morning and afternoon surgery, the researchers tested 30 heart tissue samples from a sub-group of patients from the randomised controlled trial (14 from the morning surgery group, and 16 from the afternoon surgery group). In laboratory tests on the tissue, they found that the afternoon surgery samples more quickly regained their ability to contract when put in conditions that replicated the heart refilling with blood.
A genetic analysis of these samples also showed that 287 genes linked to the circadian clock were more active in the afternoon surgery samples, compared to the morning surgery samples. This suggests that the heart is subject to the body's circadian clock, and the surgical outcomes reflect the heart's poorer ability to repair in the morning than in the afternoon.
To further understand the mechanism, the researchers deleted and replaced the relevant genes in a mouse to study how this affected the sleep-to-wake transition. They also provided a proof of concept for future drug development by demonstrating the cardio-protective activities of a drug targeting the nuclear receptor and clock protein Rev-erba. Developing drugs which modulate these genes could help protect the heart during surgery. However, they note that the mechanism will require further confirmation in humans.
The authors note that the study will need to be replicated in larger trials to fully understand the association between the circadian clock and damage after heart surgery, and to confirm their findings. They also note that the research needs to be replicated in high-risk patients with diabetes and kidney failure, as they are at higher risk of heart disease and poor outcomes, and were not included in this study.
Writing in a linked Comment, Professor Michel Ovize, Hôpital Louis Pradel, France, says: "In addition to the central clock located in the CNS, each organ and cell type has its own internal (peripheral) clock. Gene-expression analysis - mainly performed in rodents but also in human beings - has shown a rhythmic expression of clock genes in the heart... Whether or not clock genes modulate cell death directly and whether they affect ischaemia injury or reperfusion injury remain to be established. Nevertheless, the authors have clearly shown that circadian rhythm is of clinical importance in aortic valve replacement surgery. Beyond the fact that it brings a new effect-modifying factor into the complexity of ischaemia-reperfusion injury clinical trial design and interpretation, the study by Montaigne and colleagues might already have some practical implications. Even before we have drugs available to regulate the circadian clock, one might propose that high-risk patients should preferentially be operated on in the afternoon."
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NOTES TO EDITORS
This study was funded by Fondation de France, Fédération Française de Cardiologie, EU-FP7-Eurhythdia, Agence Nationale pour la Recherche ANR-10-LABX-46, and CPER-Centre Transdisciplinaire de Recherche sur la Longévité. It was conducted by researchers from University of Lille, Inserm, University Hospital CHU Lille, and Institut Pasteur de Lille.
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