Science & Technology

Obesity paradox and circadian rhythm in heart failure

Disturbances in the circadian rhythm that change spontaneously in a 24-hour cycle are associated with heart disease, but it is unclear how it leads to this condition. A research team at Baylor Medical University and a collaborative research institute investigated the function of the protein Rev-erb α / β, an important component of the circadian clock, on the development of heart disease in animal models and human patients.

The team reports in the journal circulation Rev-erb α / β in cardiomyocytes mediates normal metabolic rhythms, allowing cells to prefer lipids as a source of energy during the daytime of animals, during rest time in animals. Removal of Rev-erb α / β disrupts this rhythm, reducing the ability of cardiomyocytes to use lipids at rest, leading to progressive dilated cardiomyopathy and fatal heart failure.

“We studied how the Rev-erb α / β gene affects the metabolism of the heart by knocking out the heart in mouse cardiomyocytes,” said Associate Professor of Medicine in the Endocrinology, Diabetes, and Metabolism sections. Dr. Chung Son said. Study of molecular and cell biology at Baylor. “The lack of genes resulted in progressive heart damage leading to heart failure.”

To learn how Rev-erb α / β mediates its effects, the team analyzed a comprehensive panel of gene and protein expression, metabolites and lipids, both in wake time and sleep time. Did. They found that the Rev-erb α / β gene was highly expressed only during sleep and its activity was associated with fat and sugar metabolism.

“The heart responds differently to different energy sources, depending on the time of day,” said Relay, co-author of Baylor’s assistant professor of molecular genetics and human genetics, molecular physiology, and biophysics.・ Dr. Chan explains. “During the rest period, which is night for humans and daytime for mice, the heart uses fatty acids released from fat as the main source of energy. During the active period, which is daytime for people and nighttime for mice. The heart has some resistance to dietary carbohydrates. Without Rev-erb α / β, the heart has metabolic disorders, restricted use of resting fatty acids, and excess sugar during active periods. I found it to be used. “

“If Rev-erb α / β knockout hearts couldn’t burn fatty acids efficiently during telogen, I suspected they didn’t have enough energy to defeat them. That energy deficiency is probably a change in the heart. It leads to progressive dilated cardiomyopathy, “said Sun, a member of the Dan L Duncan Comprehensive Cancer Center.

To test this hypothesis, researchers decided whether to repair fat defects. acid Use it to improve the condition.

“We know that the use of fatty acids can be controlled by metabolic pathways that sense lipids. When more lipids are given to Rev-erb α / β knockout mice, the lipid sensing pathways are activated and defects are nullified. As a result, we assumed that the heart could extract energy from lipids, “Sun explained.

Researchers fed Rev-erb α / β knockout mice one of two high-fat diets. One diet was mostly high in fat. The other was a high-fat / high-sucrose diet similar to the human diet that promotes obesity and insulin resistance. “A high-fat / high-sucrose diet partially reduced heart defects, but a high-fat diet did not,” Sun said.

“These findings support that metabolic defects that prevent heart cells from using fatty acids as fuels cause most of the cardiac dysfunction found in Rev-erb α / β knockout mice. It also shows that correcting metabolic disorders can improve the condition, “says Zhang.

Clinical significance in obesity paradox and time therapy

“There are three clinical implications from this study,” Sun said. First, we analyzed the molecular clock function of the heart tissue of patients with dilated cardiomyopathy who underwent heart transplantation and investigated whether the clock function was associated with the severity of cardiac dilation in humans. Tissue samples were taken at various times of the day to calculate the ratio of gene expression for the circadian Rev-erbα / β and Bmal1 genes, resulting in chronotype. Chronotype of the heart was found to correlate with the severity of cardiac dilation. “

“The second meaning is that obesity and insulin resistance, long-known clinical risk factors for heart failure, are paradoxized against heart failure within a specific time frame, perhaps by supplying fatty acids during telogen. It means that you can protect yourself, “Sun said.

Finally, researchers explored the potential for pharmacological manipulation of fatty acid and glucose metabolism to improve the condition. They found that while drug therapy could help restore altered metabolic pathways, it was important to give the drug in line with the internal circadian rhythm of the corresponding metabolic pathway. Treatment did not improve the condition of the heart if the drug was out of sync with the path it was trying to recover. “

These findings highlight the importance of chronotherapy, which is a circadian rhythm-based drug therapy schedule, not only in this study, but also in many other drug therapies.

“At least half of the top 100 most prescribed medications in the United States have targets related to circadian rhythms,” Zhang said. “This shows that these drugs need to be taken in a time-specific manner for them to be effective. Unfortunately, they are not. When scheduling dosing, circadian rhythms I would like to emphasize the importance of considering rhythm. “

Reference: “Chronotype Myocardial Rev-erb-mediated Diurnal Metabolic Rhythm and Obesity Paradox,” January 17, 2022, circulation..
DOI: 10.1161 / CIRCULATIONAHA.121.056076

Obesity paradox and circadian rhythm in heart failure Obesity paradox and circadian rhythm in heart failure

Back to top button