October 27, 2017
Through a combination of studies, researchers have linked circadian rhythms to myocardial injury and major cardiovascular events after aortic-valve replacement.
In an observational cohort of 298 matched pairs, the relative risk of major adverse cardiac events was halved in patients who underwent on-pump valve-replacement surgery in the afternoon rather than in the morning (hazard ratio 0.50; P=0.0021).
Among 88 patients in a randomized study, the postoperative cardiac troponin T area under the curve was significantly lower with afternoon vs morning valve surgery (179 ng/L vs 225 ng/L; estimated geometric means ratio 0.79; P=0.045).
The researchers went on to conduct transcriptional analysis of myocardial samples from the randomized patients, revealing 287 "clock genes" whose expression varied significantly by time of day.
Further, using an investigational antagonist or genetically knocking out Rev-Erbα, the nuclear receptor for a clock gene that protects cardiomyocytes from cell death, reduced cardiac ischemia-reperfusion injury in mice, Prof David Montaigne (University of Lille, France) and his colleagues report October 26, 2017 in the Lancet.
"We don't want to give the impression that people should not get an operation in the morning, because it is lifesaving, but my suggestion is you might want to stratify the operation by risk and rather schedule the higher-risk patients in the afternoon than in the morning," senior author Prof Bart Staels (Institut Pasteur de Lille, France) told theheart.org | Medscape Cardiology.
Even before drugs are available to regulate the circadian clock, "one might propose that high-risk patients should preferentially be operated on in the afternoon," agree Drs Thomas Bochaton and Michel Ovize (Hôpital Louis Radel, Lyon, France) in an accompanying commentary.
They add, "Whether or not clock genes modulate cell death directly and whether they affect ischemia 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."
Mice studies have shown a biorhythm in ischemia-reperfusion injury tolerance, but results are mixed for such a biorhythm in humans. Several studies have shown larger infarct sizes or more heart failure after ST-segment-elevation MI (STEMI) occurring in the early morning rather than later in the day; however, the largest multicenter study to date failed to show a time-of-day effect on STEMI, the researchers note.
To investigate the influence of circadian rhythms after cardiac surgery, the researchers prospectively examined 596 consecutive patients with aortic stenosis and preserved ejection fraction undergoing aortic-valve replacement at a single center between 2009 and 2015.
The reduction in adverse cardiac events observed in patients who underwent surgery in the afternoon (~3 PM) vs the morning (~9 AM) was driven by a lower relative risk for immediate perioperative MI (13% vs 6%; P=0.048; HR not reported) but also significantly fewer hospitalizations for acute heart failure over a median follow-up of 500 days (HR 0.36; P=0.038).
"It was quite surprising to see that we have also heart-failure issues longer down the line when the patient is already out of the hospital," Staels said. "We don't have a good explanation for it, and there are different ways to follow up on it, but one hypothesis is that it might be related to epigenetic programming of different cell types involved in the remodeling of the heart after reperfusion injury."
Notably, contraction recovery after hypoxia-reoxygenation challenge was significantly better in the myocardial samples of patients who underwent afternoon surgery in the randomized trial.
In addition, Rev-Erbα and its target gene BMAL1/ARNTL showed antiphasic, time-of-day variations in expression, with BMAL1/ARNTL mainly expressed during the afternoon when Rev-Erbα levels are low.
"Thus, the human myocardium displays an intrinsic morning-afternoon variation in hypoxia-reoxygenation tolerance concomitantly with transcriptional alterations in circadian-gene expression," the researchers write.
According to Bochaton and Ovize, this is the first time in the human heart that time of day has been shown to affect the tolerance of cardiomyocytes to ischemia-reperfusion injury and subsequent contraction recovery.
Although Rev-Erbα provides a possible pharmacologic target, Staels said no compounds are currently available for clinical practice. In addition, while their observational study "is of good quality and in a large population, it was drawn from a single center, and our findings need to be confirmed in other cohorts."
Bochaton and Ovize write "these new data are convincing" but also call for additional research, noting the single-center observational data and small randomized trial.
"This study will certainly foster basic research to improve our understanding of the effects of circadian rhythm on ischemia-reperfusion injury and could lead to the design of future protective therapies," they add.
The researchers and editorialists report no relevant financial relationships.