Finding the real culprit between circadian rhythm and « out of hours effect » to explain the higher myocardial infarction size among patients with symptom onset occurring at night.

Circ Res. 2012 Apr 27;110(9):e67; author reply e68.
Fournier S, Muller O.

To the Editor:
We read with great interest the recent publication by Reiter et al about circadian dependence of infarct size and left ventricular function after ST elevation myocardial infarction. Although this article is clinically relevant, we think that a few points of the utmost importance have not been taken into account. Therefore, we have some comments about this article.
Although the authors show that door-to-needle time is not significantly different in patients with symptom onset between 00:00 and 05:59 (group 1 based on the Suárez-Barrientos group classification), no data in the article show that performances of the medical team or of the interventional cardiologist are the same during the night. During the night (when medical team size is usually smaller), different mean procedure times, different mean thrombolysis in myocardial infarction scores at the end of the procedures, or different mean numbers and sizes of used stents could cause an important bias because of an “out of hours effects.” In fact, previous publications have already shown a poorer prognosis for people undergoing primary percutaneous coronary intervention for ST elevation myocardial infarction during the night, and this article does not enable differentiation between higher cardiomyocyte vulnerability to ischemia at this time of the day and a lower performance of the medical team, both of which could explain higher creatine kinase levels. Similarly, authors could have studied the variations of creatine kinase levels depending on hours of symptom onset, taking into account weekends only (out of hours system at every hour of the day during a weekend).
Furthermore, and interestingly enough, patients in the night group (between 00:00 and 05:59) had significantly lower rates of aspirin in their medical treatment. This information is of the utmost importance when evaluating the size of a myocardial infarction.
Finally, recent publications have shown a link between melatonin levels and the size of a myocardial infarction. To assess circadian variations of ischemic burden among these patients, it would have been important to take into account the circadian variation of melatonin level.
Evidence of higher ischemic burden for patients with symptom onset occurring at night grows and confirms recent observations based on animal models that have shown that the cardiomyocyte circadian clock affects the heart response to various stressors, including ischemia/reperfusion, by modulating multiple cardioprotective signaling pathways.However, to affirm that day time at symptom onset clearly influences the size of myocardial infarction in patients with ST elevation myocardial infarction undergoing primary percutaneous coronary intervention, it is mandatory to be able to distinguish the difference between circadian rhythm and the out of hours effect.

References

  • Fournier S, Muller O. Finding the real culprit between circadian rhythm and “out of hours effect” to explain the higher myocardial infarction size among patients with symptom onset occurring at night. Circ Res. 2012 Apr 27;110(9):e67; author reply e68. PMID: 22539760.