Discovery Hints at Why Cardiac Death Risk Is Highest in Early Morning
Febraury 24, 2012 (Cleveland, Ohio) — Researchers have identified a molecule that links circadian rhythms to ventricular arrhythmias in an animal model, with the results providing a greater understanding as to why certain cardiovascular events, specifically those with an underlying arrhythmogenic etiology, occur in the early-morning hours .
In the study, published online February 22, 2012 in Nature, the researchers, led by Dr Darwin Jeyaraj (Case Western Reserve University School of Medicine, Cleveland, OH), report that cardiac ion-channel expression and QT-interval duration exhibit an endogenous circadian rhythm that is under the control of the transcription factor Krüppel-like factor 15 (Klf15).
"The study showed that this factor, Klf15, regulates the electrical activity of the heart, and second, we linked it to the endogenous 24-hour rhythms, the so-called daily biological clock," senior investigator Dr Mukesh Jain (University Hospitals Case Medical Center and Case Western Reserve University) told heartwire . "If there is a singular line that encapsulates the work, it's that Klf15 is the first link between the biological clock and arrhythmogenesis."
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In an interview, Jain explained that the incidence of sudden cardiac death, including both the hereditary and acquired forms of heart disease, exhibits a diurnal variation, with the occurrence of sudden death increasing within a few hours of waking in the morning and a second peak observed in the evening. MI, various arrhythmias, and even ruptures of the aortic aneurysm also tend to occur in the morning or in the early waking hours. Other biological parameters, including blood pressure, heart rate, vascular tone, and QT interval, also exhibit diurnal variation.
Calling Klf15 a "fascinating molecule," one that is conserved across species and is expressed in muscle tissue, Jain noted that his laboratory first identified the transcription factor about 10 years ago and published studies showing that animals deficient in Klf15 develop heart failure and aortic aneurysms. In the present study, the researchers wanted to determine whether Klf15 also regulated electrical activity and, given that heart failure and aortic aneurysms exhibited this diurnal pattern, also sought to determine whether Klf15 linked electrical regulation with the body's biological clock.
"There is something provocative about why these events should happen at certain times of the day, and it has been talked about, conjuring up all kinds of theories as to why this might happen," said Jain.
In their study, the researchers identified a specific ion channel under the control of Klf15. They showed the transcription factor controls the expression of voltage-gated potassium (Kv) channel-interacting protein 2 (KChIP2), a protein that is needed to create the transient outward potassium current. In linking Klf15 to the circadian rhythm, they examined 5kb of the promoter region of Klf15 and identified binding sites for CLOCK and BMAL1, two transcription factors that are involved in the circadian clock. In in vivo loss- and gain-of-function mouse models, they found that deficiencies or excesses of Klf15 can cause the loss of rhythmic QT variations, abnormal repolarization, and ventricular arrhythmias.
Regarding the next steps, Jain said his group would like to determine whether Klf15 can regulate other processes and whether it might also be responsible for the occurrence of heart failure and aneurysm during certain times of the day. Down the road, the group would also like to determine whether mutations in Klf15 might be observed in patients at high risk for sudden death or even in healthy populations, as this might help illuminate some of the seemingly unexplainable cases of sudden cardiac death.
"There are two patient populations, broadly speaking, that are susceptible to sudden death," Jain told heartwire . "One is those with known heart disease, but I also really want to highlight that there is a whole swath of patients, some of whom are quite young and in the prime of their life, for whom we don't have an explanation. We would like to look at Klf15 mutations or polymorphisms not only in populations like heart-disease patients; I think we have to look at it quite broadly."
Klf15 also offers has some diagnostic potential, and that would include developing chemical compounds to manipulate Klf15 to reduce the risk of sudden cardiac death.