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Clock genes may play a role in how well a patient is able to tolerate myocardial ischemia–reperfusion during surgical aortic valve replacement (SAVR), with potential implications for timing of surgery, a series of French studies showed.

A single-center cohort of SAVR patients with severe aortic stenosis and preserved left ventricular ejection fraction was split into morning and afternoon surgery groups (298 patients each), which were then matched by propensity score by David Montaigne, MD, PhD, of the University of Lille, France, and colleagues.

Major adverse cardiovascular events (combined cardiovascular death, MI, and admission to hospital for acute heart failure) were . The rate was 9% in the first 500 days post-afternoon surgery versus 18% with morning SAVR (HR 0.50, 95% CI 0.32-0.77), although the study was underpowered to show that the time of day of SAVR had an effect on clinical outcomes.

"Afternoon surgery might provide perioperative myocardial protection and lead to improved patient outcomes compared with morning surgery," they suggested in the paper online in The Lancet.

Montaigne's group then performed a separate study (n=88) randomizing patients to morning or afternoon isolated SAVR. From transcriptomic analysis of myocardial samples, they discovered that perioperative myocardial injury assessed with the geometric mean of perioperative cardiac troponin T release was lower in afternoon group (179 ng/L versus 225 ng/L for morning group, estimated ratio of geometric means 0.79, 95% CI 0.68-0.93).

"They have shown for the first time, to my knowledge, in the human heart that time of the day affects the tolerance of cardiomyocytes to ischemia–reperfusion injury and the subsequent recovery of contraction," according to an accompanying commentary by Thomas Bochaton, MD, and Michel Ovize, MD, PhD, both of France's Hôpital Louis Pradel.

"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 ischemia-reperfusion injury clinical trial design and interpretation, the study by Montaigne and colleagues might already have some practical implications," Bochaton and Ovize said.

For one, it may be reasonable to say that high-risk patients should preferentially be operated on in the afternoon, the duo suggested.

Ex-vivo analysis of human myocardium showed morning-afternoon variation in hypoxia-reoxygenation tolerance; these lined up with transcriptional alterations in circadian gene expression with the nuclear receptor highest in the morning.

Rev-Erbα gene deletion or antagonist treatment reduced injury at the time of sleep-to-wake transition, separate mouse model experiments showed.

This "is a unique circadian gene belonging simultaneously to the molecular circadian clock and to nuclear receptor families. As such, by contrast with most other circadian genes, it is a relevant pharmacological target, and several small molecules acting through this receptor have been identified," the investigators commented.

"Rev-Erbα represses CDKN1a/p21 gene expression, resulting in cardiomyocytes more sensitive to hypoxic insults at times of low CDKN1a/p21 levels which coincides with high levels of Rev-Erbα," such as during the morning, the authors noted, calling Rev-Erbα a "master switch in myocardial hypoxia-reoxygenation tolerance."

"We provide the proof-of-concept that Rev-Erbα antagonism is potentially a useful strategy to limit ischemia–reperfusion injury."

Nonetheless, the investigators acknowledged that their findings require validation from multiple centers.

In the meantime, cardiac surgery with extracorporeal circulation continues to require cardioplegia and exclusion of the heart from the general circulation by aortic cross-clamping, according to Montaigne and colleagues -- the sequence of myocardial ischemia–reperfusion can't be avoided just yet.

Previous studies have suggested that the efficacy of several heart treatments hinges on the time of day in which they are given. This year's Nobel Prize in Physiology or Medicine was given to a group of researchers for their work on the behind circadian rhythms.