Study emphasises importance of scheduling medication(s) according to circadian rhythm
The circadian rhythm is a target for most medications on the US market, yet most drugs are not prescribed in a time-specific way to be most effective. A research team from Baylor College of Medicine (Baylor), Texas, has recently shown how a disrupted circadian rhythm affects heart disease development in animal models and human patients – homing in on a key protein that mediates a normal metabolic rhythm in cardiomyocytes (heart cells).
In mice models, the presence of the protein Rev-erbα/β, a key component of the circadian clock, enables the cells to prefer lipids as a source of energy during the animal’s resting time, or daytime for mice. On the other hand, removing Rev-erbα/β disrupts this rhythm, reduces the cardiomyocytes’ ability to use lipids in the resting time and leads to progressive dilated cardiomyopathy and lethal heart failure.
Analysis revealed that the Rev-erbα/β gene is highly expressed only during the sleep hours for both the mice and human subjects, and its activity is associated with fat and sugar metabolisms.
“The heart responds differently to different sources of energy, depending on the time of the day,” said Dr. Lilei Zhang, assistant professor of molecular and human genetics and of molecular physiology and biophysics at Baylor. “In the resting phase, which for humans is at night and for mice in the day, the heart uses fatty acids that are released from fats as the main source of energy. In the active phase, which is during the day for people and at night for mice, the heart has some resistance to dietary carbohydrates. We found that without Rev-erbα/β, hearts have metabolic defects that limit the use of fatty acids when resting, and there is overuse of sugar in the active phase.”
“We suspected that when Rev-erbα/β knockout hearts cannot burn fatty acids efficiently in the resting phase, then they don’t have enough energy to beat. That energy deficiency would probably lead to changes in the heart that resulted in progressive dilated cardiomyopathy,” added Dr. Zheng Sun, associate professor of medicine, section of endocrinology, diabetes and metabolism and of molecular and cellular biology at Baylor.
Later tests carried out to see if restoring the defect in fatty acid use would improve the condition revealed that a “high-fat/high-sucrose diet partially alleviated the cardiac defects, but the high-fat diet did not.”
“These findings support that the metabolic defect that prevents the heart cells from using fatty acids as fuel is causing the majority of the cardiac dysfunction we see in the Rev-erbα/β knockout mice. Importantly, we also show that correcting the metabolic defect can help improve the condition,” Zhang said.
The Baylor researchers also touched on the possibility of pharmacologically manipulating fatty acid and sugar metabolism to improve the cardiac condition. They found that while medications can help restore altered metabolic pathways, it was important to give the drugs aligned with the internal circadian rhythm of the corresponding metabolic pathways. If the drugs were given out-of-sync with the pathway they were intended to restore, the treatment failed to improve the cardiac condition.
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