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Afternoon surgical AVR confers fewer cardiac events
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Patients with severe aortic stenosis who underwent surgical aortic valve replacement in the afternoon had a lower risk for perioperative myocardial injury than those who underwent surgery in the morning, according to a study published in The Lancet.
“Currently, there are few other surgical options to reduce the risk of postsurgery heart damage, meaning new techniques to protect patients are needed,” David Montaigne, MD, of the University of Lille in France, said in a press release. “Out study found that postsurgery 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.”
Fewer events after morning surgery
A variety of studies were conducted to determine whether the time when cardiac surgery is performed affects clinical consequences. In a prospective cohort study, researchers analyzed data from 596 patients with severe aortic stenosis and preserved left ventricular ejection fraction less than 50% who underwent surgical AVR in the morning (n = 298) or afternoon (n = 298) between 2009 and 2015.
Patients were followed up for 500 days after surgery, when medical records were reviewed and interviews were performed to assess for major adverse cardiac events such as MI, CV death and admission to the hospital for acute HF.
There were fewer major adverse cardiac events in patients who underwent surgery in the afternoon vs. the morning (HR = 0.5; 95% CI, 0.32-0.77). For every 11 patients, one major adverse cardiac event was prevented among those in the afternoon group compared with the morning group (95% CI, 7-30).
Mechanism for fewer events
The randomized study involved 88 patients who underwent isolated surgical AVR for aortic valve stenosis with preserved LVEF between January 2016 and February 2017. Those with conditions such as diabetes, renal insufficiency and a history of atrial fibrillation or atrial flutter were excluded. Patients were assigned to undergo surgery in the morning (n = 44) or the afternoon (n = 44), and were followed up until they were discharged for a median of 12 days. Medical records were then reviewed for the occurrence of clinical events.
Perioperative myocardial injury based on perioperative cardiac troponin T release was lower in patients who underwent surgery in the afternoon (179 ng/L; 95% CI, 161-198) compared with the morning (225 ng/L; 95% CI, 199-255). The estimated geometric means ratio for the afternoon group to the morning group was 0.79 (P = .0045).
Right atrial biopsies were taken from the first 22 patients assigned morning or afternoon surgery. The myocardium showed an intrinsic morning-afternoon variation of hypoxia-reoxygenation tolerance that was associated with transcriptional alternations of the circadian gene expression. The nuclear receptor Rev-Erb alpha was highest in the morning.
“The association between perioperative ischemia-reperfusion injury and medium-term clinical outcomes remains correlative,” Montaigne and colleagues wrote. “Moreover, time of the day probably interferes with different systemic processes and as such might affect other organs (eg, kidneys and immune cells). Based on our findings, a large, prospective, multicenter, randomized trial designed to investigate clinical outcomes in patients undergoing either morning or afternoon cardiac surgery is warranted.”
“The authors have clearly shown that circadian rhythm is of clinical importance in aortic valve replacement surgery,” Thomas Bochaton, MD, PhD, of Centre Hospitalier Universitaire de Lyon in France, and Michel Ovize, MD, PhD, of the Hôpital Louis Pradel and Université de Lyon, wrote in a related editorial. “Beyond the fact that it brings a new effect-modifying factor into the complexity of ischemia-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.” – by Darlene Dobkowski
Disclosures: Montaigne, Bochaton and Ovize report no relevant financial disclosures.
Perspective
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Frank A. J. L. Scheer, PhD
This elegant and comprehensive study uses different approaches (randomized human trial, and ex vivo and in vitro human and rodent experimental studies) to show that time of day of cardiac surgery has relevance for serious adverse CV events.
Work by us and others had shown that the human circadian system influences CV risk factors, with peaks during the biological morning in systemic factors involved in blood clotting, such as prothrombotic factor PAI-1. Work by Martin E. Young, DPhil, and others had shown in animal studies that cardiomyocytes themselves have clocks and that they have relevance for, eg, infarct size after a cardiac insult.
The current study expands these observations and shows that serious adverse cardiac events are worse after morning compared to afternoon cardiac surgery, and — in a randomized study — that cardiac surgery scheduled in the afternoon compared to in the morning results in reduced short-term perioperative myocardial injury.
They further show by ex vivo and in vitro studies a role of Rev-Erb alpha, a core clock molecule, in modulating hypoxia-reoxygenation injury, and that inhibiting Rev-Erb alpha has a beneficial effect. The combination of approaches and strength of evidence make this an outstanding study.
This study is exceptional in showing not only mechanistic evidence, but also direct translatable value for clinical practice.
The initial randomized trial in 88 patients merits large-scale replication in a multicenter trial with long follow-up of hard endpoints.
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