Chronobiology in Aortic Diseases – “Is This Really a Random Phenomenon?”

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Abstract

Although acute aortic rupture or dissection is relatively uncommon, it ranks in third position among necropsy-confirmed causes of out-of-hospital sudden death in the general population. Similar to other acute cardiovascular events (e.g., acute myocardial infarction, sudden death, stroke, and pulmonary embolism) there is a growing body of evidence regarding temporal patterns in onset, characterized by circadian, seasonal and weekly variations for aortic aneurysms. On one hand, it is possible that these cardiovascular diseases share common underlying pathophysiologic mechanisms, e.g., increase in blood pressure, heart rate, sympathetic activity, basal vascular tone, vasoconstrictive hormones, and prothrombotic tendency.

On the other hand, the possibility exists that the connecting link is an internal disruption (dyssynchrony) of some molecular mechanisms intrinsic to the peripheral biological clock (that of cardiomyocyte is the most widely investigated). Such disruption may contribute to cardiovascular disease and biological rhythms – an intriguing hypothesis for future research.

Section snippets

Circadian rhythm and cardiovascular diseases

Chronobiology is a branch of biomedical sciences aimed at the study of biological rhythms. Biological rhythms exist at many levels in living organisms and, according to their cycle length, may be divided into: a) circadian (period of ~ 24 hours), b) ultradian (period < 24 hours), c) infradian (period > 24 hours). Circadian rhythms are the widely studied, and are driven by circadian clocks. Circadian clocks can be defined as a transcriptionally based molecular mechanism, based on both positive and

Circadian clocks and their role in cardiovascular diseases

The principal role of cellular biological clocks is driving circadian rhythms to adapt the organism to further needs in an anticipatory manner, thus providing selective advantage.9 However, it has been recently shown that external or internal disruption (dyssinchrony) of circadian control may result in overt diseases. For example, mice exposed to a 20-hour instead of 24-hour circadian rhythm show a complete disruption of sleep/wake behavior and a marked progression of myocyte hypertrophy and

Circadian variation

Our group observed a circadian variation, characterized by a main peak in the morning hours (at about 8 a.m.) and a secondary one in the evening) both for acute spontaneous rupture of abdominal aortic aneurysms26 and acute dissection of thoracic aorta.27 A few years after these first findings in a limited number of patients in the small town of Ferrara, Italy, the existence of a morning peak in the acute dissection of the aorta was confirmed also in Japan28 and in the twelve worldwide centers

Pathophysiology: possible insights of morning cardiovascular events

The similarity of temporal patterns of different acute cardiovascular and cerebrovascular events seems to suggest the possibility that they share common underlying pathophysiologic mechanisms. Several pathophysiologic phenomena, i.e., increase in blood pressure (BP), heart rate, sympathetic activity, basal vascular tone, vasoconstrictive hormones, prothrombotic tendency, platelet aggregability, plasma viscosity, and hematocrit, exhibit prominent circadian rhythms with phases positively

Other than circadian variation: seasons of the year

“Whoever wishes to investigate medicine properly, should proceed thus: in the first place to consider the seasons of the year, and what effects each of them produces for they are not all alike, but differ much from themselves in regard to their changes”…Hippocrates wrote, in 400 b.c., in his masterpiece treatise on Air, Waters and Places. According to a series of studies, fall and winter months represent a high-risk temporal frame for occurrence of aortic rupture or dissection,56., 57., 58., 59.

Other than circadian variation: day of the week

A few studies have investigated this temporal aspect (Table 3). Sumiyoshi28 found a small peak on Monday and a trough on Thursday and Friday, but the distribution was homogenous as a whole. The IRAD Registry study29 did not find any significant daily variation. Lasica31 and Benouaich69 reported peaks on Wednesday, but this was not statistically significant.

The only positive study was one that analyzed more than 4600 cases in the Emilia-Romagna region of Italy.93 A daily pattern, characterized

Dangerous weekends: myth or reality?

Bell & Redelmeier105 analyzed all acute care admissions from emergency departments in Ontario, Canada, between 1988 and 1997 (near four million admissions), and found that rupture of abdominal aortic aneurysms was associated with a significantly higher mortality in patients admitted during the weekend vs. patients hospitalized during the weekdays (42% vs. 36%, respectively; adjusted O.R 1.28). More recently, our group confirmed a highly significantly increased risk of death during

Conclusions

We have reviewed the growing evidence dealing with temporal aspects of onset of acute cardiovascular events, as well as the newest intriguing information about peripheral circadian clocks. Among these, the cardiomyocyte circadian clock has emerged as a molecular mechanism influencing multiple critical myocardial processes, since it appears to regulate heart rate, growth, triglyceride and glycogen metabolism, and contractility, as well as modulate the responsiveness of the myocardium to

Statement of Conflict of Interest

All authors declare that there are no conflict of interest.

Acknowledgments

The Authors thank Prof. Walter Ageno, MD, Dr. Francesco Dentali, MD, and Dr. Josè Vitale, MD, from the University of Insubria, Varese, Italy, for their precious help in providing anticipations of original unpublished material.

This work was supported, in part, by a scientific grant (FAR – Fondo Ateneo Ricerca) from the University of Ferrara, Italy.

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