How doctors and other people can make drugs more effective especially against heart diseases, new study reveals.

Circadian rhythm disruption, which occurs naturally on a 24-hour cycle, has been linked to heart disease, but the exact mechanism is unknown.

A study team led by Baylor College of Medicine and collaborators examined the role of the protein Rev-erbα/β, a critical component of the circadian clock, in the development of heart disease in animal models and human patients.

The researchers write in the journal Circulation that Rev-erbα/β in cardiomyocytes mediates a regular metabolic rhythm that allows the cells to choose lipids as a source of energy during the animal’s resting time, which is daytime for mice. Removing Rev-erbα/β disturbs this rhythm, lowers the ability of cardiomyocytes to employ lipids during rest, and leads to progressive dilated cardiomyopathy and fatal heart failure.

“We studied how the Rev-erbα/β gene influenced the metabolism of the heart by knocking it out specifically in mouse cardiomyocytes,” says co-corresponding author Dr. Zheng Sun. “Lacking the gene resulted in progressive heart damage that led to heart failure.”

To determine how Rev-erbα/β exerted its effects, the researchers examined gene and protein expression as well as a comprehensive panel of metabolites and lipids throughout both awake and sleeping hours.

The Rev-erbα/β gene is significantly expressed exclusively during sleep hours, and its activity is linked to fat and sugar metabolisms, according to the researchers.

“The heart responds differently to different sources of energy, depending on the time of the day,” adds co-corresponding author Dr. Lilei Zhang. “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,” says Sun.

To test this theory, the researchers noted whether fixing the deficiency in fatty acid usage would improve the disease.

“We know that fatty acid use can be controlled by lipid-sensing metabolic pathways. We hypothesized that if we fed the Rev-erbα/β knockout mice more lipids, maybe the lipid-sensing pathways would be activated, override the defect and consequently the heart would be able to derive energy from lipids,” Sun explains.

The Rev-erbα/β knockout mice were fed one of two high-fat diets. One of the diets was primarily high-fat. The other was a high-fat, high-sugar diet, which was similar to human diets that induce obesity and insulin resistance.

“The high-fat/high-sucrose diet partially alleviated the cardiac defects, but the high-fat diet did not,” Sun adds.

“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,” according to Zhang.

“There are three clinical implications from this work,” says Sun, adding, ”First, we analyzed the molecular clock function in heart tissues of patients with dilated cardiomyopathy who had received heart transplants to explore whether the clock function was associated with the severity of cardiac dilation in humans. Tissue samples were taken at different times of the day and the ratio of the gene expression of the circadian genes Rev-erbα/β and Bmal1 was calculated providing a chronotype. We found that the heart chronotype correlates with the severity of cardiac dilation.”

“The second implication is that obesity and insulin resistance, long-known clinical risk factors for heart failure, can be paradoxically protective against heart failure, within a certain time window, probably by providing fatty acids in the resting phase,” according to the aurthors.

Finally, the researchers looked at the prospect of improving the disease by pharmacologically modifying fatty acid and sugar metabolism. They discovered that while drugs can help restore the altered metabolic pathways, it’s crucial to provide the treatments at the same time as the metabolic pathways’ internal circadian rhythm. If the meds were administered out of sync with the pathway they were supposed to restore, the treatment had no effect on the heart condition.

These findings focus on the importance of chronotherapy, or the timing of drugs according to the circadian rhythm, not only in this study, but for many other treatments as well.

“Of the top 100 most prescribed drugs in the U.S., at least half of them have a target that is connected to a circadian rhythm,” says Zhang, adding, “this indicates that for these drugs to be effective, they need to be taken in a time-specific way. Unfortunately, they are not. We want to emphasize the importance of taking the circadian rhythm into consideration when scheduling medications.”

Source: 10.1161/CIRCULATIONAHA.121.056076

Image Credit: Getty

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