David Montaigne (University of Lille, France) and others report in The Lancet that performing heart valve replacement in the afternoon was associated with better outcomes compared with performing it in the morning.
Previous research has suggested that cardiovascular events, such as myocardial infarction, that happen in the morning may be associated with a higher risk of the damage, compared to afternoon events, but reasons have remained unclear. Therefore, to review the link a link between a person’s circadian clock and their risk of heart damage and major cardiac events after heart surgery, Montaigne et al conducted a four-part study—consisting of: 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.
Results
In the observational study, which ran from January 2009 to December 2015, the 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.
Implications
To better understand why there were these differences in outcomes for morning and afternoon surgery, Montaigne et al tested 30 heart tissue samples from a subgroup 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.
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. 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.
