Body Clock Link To Sudden Cardiac Death Revealed In Molecular Mechanism

A study led by Case Western Reserve University in the US has revealed the first molecular evidence of a link between the circadian rhythm or the body clock and sudden cardiac death. The researchers, who did their investigations in mice, hope their discovery will lead to new diagnostic tools and therapies to prevent or treat vulnerability to sudden cardiac death in humans. They reported their findings online in the journal Nature on Wednesday.

Previous studies had suggested a link between sudden cardiac death and circadian rhythm, in both acquired and hereditary forms of heart disease, but none had yet, until this discovery, revealed the underlying molecular explanation.

The lead author of the study is Dr Darwin Jeyaraj, assistant professor of medicine at Case Western Reserve University School of Medicine, and a cardiologist at Harrington Heart & Vascular Institute at University Hospitals Case Medical Center. He told the press:

"Our study identifies a hitherto unknown mechanism for electrical instability in the heart. It provides insights into day and night variation in arrhythmia susceptibility that has been known for many years."

Ventricular arrhythmias, or abnormal heart rhythms, are the most common cause of sudden cardiac death, which is the primary cause of death from heart disease. 

These abnormal heart rhythms occur most frequently in the morning waking hours, and there is also a smaller peak of activity in the evening.

Jeyaraj and colleagues discovered that a protein called Krüppel-like Factor 15 (Klf15, which is encoded by the KLF15 gene), links the body clock or circadian rhythm to the heart's electrical activity, and also regulates this electrical activity. 

(Too little KLF15 is seen in patients with heart failure, while too much causes the kind of electrocardiography (ECG) changes seen in patients with a genetic heart rhythm disorder known as Brugada syndrome.)

They write:

"Specifically, we show that cardiac ion-channel expression and QT-interval duration (an index of myocardial repolarization) exhibit endogenous circadian rhythmicity under the control of a clock-dependent oscillator, krüppel-like factor 15 (Klf15)."

(Prolonged QT interval is a biomarker of arrhythmia. It is the time between the start of the Q and the end of the T wave in the heart's electrical cycle, a measure of depolarization and repolarization of the left and right ventricles).

The researchers say too much or too little Klf15 disrupts the heart's electrical cycle, thereby increasing vulnerability to arrhythmias:

"Deficiency or excess of Klf15 causes loss of rhythmic QT variation, abnormal repolarization and enhanced susceptibility to ventricular arrhythmias," they write and suggest their findings show that "circadian transcription of ion channels" is a mechanism for generating arrhythmia in the heart.

One possible way forward with this knowledge is to investigate medications that regulate and stabilize Klf15 levels, particularly at certain times of the day, when sudden death is more common.

While the study proves that circadian rhythms are an important factor in sudden cardiac death, it also raises the possibility that there may be other factors. So there is a need for further studies to see how other components of the body clock may affect the electrical stability of the heart.

Senior author Dr Mukesh K. Jain, professor of medicine, Ellery Sedgwick Jr. Chair, and director, Case Cardiovascular Research Institute at Case Western Reserve University School of Medicine, suggested: 

"We are just scratching the surface."

"It might be that, with further study, assessment of circadian disruption in patients with cardiovascular disease might lead us to innovative approaches to diagnosis, prognosis, and treatment. In particular, such therapies could be beneficial for patients with heart failure or hereditary mutations where nocturnal death is common," said Jain, who is also chief research officer, Harrington Heart & Vascular Institute at University Hospitals Case Medical Center.

Sudden cardiac death due to electrical instability is a leading cause of death in the United States, where around 325,000 people die from it every year. 

Funds from the Heart Rhythm Society, National Institutes of Health, and Leducq Foundation helped pay for the study.