Circadian rhythms in cardiovascular disease, from bench to bedside
The earth turns around its own axis every 24 hours. As a result, life on our planet experiences daily changing circumstances such as dark/light and temperature variation. To anticipate to these changes, plants, animals, and humans possess a circadian clock that regulates 24-hour rhythms of multiple processes and functions.
Circadian rhythms have been studied throughout history and already in the late 1970s, the molecular circadian clock was discovered. Its importance has been widely recognised; in 2017 the Nobel prize in physiology or Medicine was awarded to 3 circadian pioneers. So far however, biomedical research has largely ignored 24-hour rhythms. The pathophysiological role of the molecular clock has been studied in a few diseases and in most treatments, and we do not know whether time-of-day has any influence.
Traditionally, research about circadian rhythms focused on the central circadian clock of the brain which regulates 24-hour rhythms via hormones and the autonomic nervous system. In the last few decades, the focus of research switched to the peripheral, molecular clock that is present in almost all body cells including cardiovascular cell types such as cardiomyocytes. Studies showed that these peripheral clocks play a major role in the cardiovascular system: they regulate approximately 10% of the cardiac transcriptome and proteome and as a result, cardiovascular functions such as electrophysiology, metabolism, and coagulation vary throughout the day. Most importantly, circadian clocks are associated with cardiovascular disease such as myocardial infarction and arrhythmias: circadian rhythmicity is involved in the incidence, pathophysiology and outcome of these acute events.
In this thesis, we investigated this role of circadian rhythms in cardiovascular disease. To link preclinical, molecular information of the molecular clock to the cardiovascular patient, we developed an in vitro model of the heart mimicking functional 24-hour rhythms. We discovered that circadian clocks and 24-hour rhythms are present in stem cells of the heart. Specifically, we found that stem cell functions that are important for cardiac repair/regenerative medicine such as apoptosis, proliferation, and the excretion of paracrine factors, fluctuate throughout the day.
Next, we studied the role of the circadian clock in 2 common cardiac diseases, myocardial infarction and ventricular arrhythmias. Our study in an in vivo model of myocardial infarction showed that 24-hour rhythms are present in both ischaemia and reperfusion damage. In a clinical study investigating ventricular arrhythmias, we found a 24-hour rhythm in ventricular repolarisation. We developed a new clinical parameter, QT diurnality, that quantifies this rhythm. In patients at risk of ventricular arrhythmias, we showed that patients with a high QT diurnality suffer from ventricular arrhythmias. We expect that in the near future, implementation of QT diurnality enables the prediction of ventricular arrhythmias in patients at risk.
The data described in this thesis link pre-clinical studies of the molecular clock to the cardiovascular patient and shows that the circadian clock is not only involved in the pathophysiology and incidence of the cardiac disorder, but is also an important factor in prediction and treatment of cardiovascular disease.
B.C. du Pré
Departments of Medical Physiology and Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, the Netherlands.
E-mail: Dupre@startmail.com
Aimée Sakes won the first prize, Jouke Bokma the second prize and Bastiaan du Pré the third prize.