Eating late night snacks can protect the heart? The truth behind is "biorhythm"

The prevalence of heart disease is growing as people live longer lives. Heart failure has emerged as a critical medical issue. Many studies have shown in the past that obesity is a risk factor for heart failure, but the discovery of the "obesity paradox" has made the truth even more confusing, which refers to the clinical observation that patients with heart failure with higher BMI have a better prognosis than those with lower BMI. It is not clear through which mechanism obesity affects the prognosis of heart failure.

In animal models, diet-induced obesity can improve heart failure in certain conditions, but diet-induced obesity can also impair cardiac function, for example, a chronic high-fat diet can lead to diabetic cardiomyopathy.

This defiance of logic reveals a secret mechanism behind this event. A landmark research just published online in the prominent international journal Circulation reveals that the "obesity paradox" may be related to cardiac rhythm.

Rev-erbα/β is a cellular nuclear receptor that plays a key role in the regulation of biological rhythms. Researchers first constructed a Rev-erbα/β knockout (KO) mouse model in which the mouse heart does not express functional Rev-erbα/β proteins. The knockout model was used to study the effect of Rev-erbα/β on cardiac function compared to the control group.

KO mice showed no significant abnormalities in circadian rhythms of exercise, energy expenditure, respiration, and food intake, and their left ventricular size, wall thickness, and systolic function were normal until 2.5 months of age.

However, at 4.5 months of age, KO mice began to show impaired cardiac systolic function and an increase in left ventricular diameter, but no significant wall thickening was observed. By 6 months of age, the ejection fraction of their hearts had decreased to 20%-30%, and the left ventricle was further dilated. Similar systolic dysfunction and cardiac dilatation were seen in female KO mice.

Also, cardiac systolic dysfunction in KO mice was associated with elevated ANP and BNP expression. Compared to controls, inflammatory genes were not upregulated in the hearts of KO mice at 2 months of age but were elevated at 4.5 months of age. Most KO mice died at 6 ~ 8 months of age.

Most of the organs of these KO mice were largely morphologically normal, except for cardiac lesions. Therefore, the researchers concluded that cardiomyocyte-specific knockdown of Rev-erbα/β could lead to progressive systolic dysfunction, triggering dilated cardiomyopathy and lethal heart failure.

Given that Rev-erbα/β is closely related to circadian rhythms, the team next performed rhythm experiments on mice, dividing their day into a resting period (light) and an active period (dark). Since mice and humans have opposite circadian rhythms, their resting and active periods are equivalent to human night and day, respectively.

The researchers took myocardial tissue from mice every 4 hours for sequencing analysis. The results revealed that the differential genes downregulated in KO mice were mainly enriched in metabolic pathways, especially the fatty acid oxidation pathway. This suggests that Rev-erbα/β occupies a central position in myocardial energy metabolism.

Another major finding was that the fatty acid oxidation pathway in the KO mouse heart lost its rhythmicity and showed a persistently depressed state. However, the gluconeogenic pathway genes showed peak expression during the active phase in mice. This may be because the restriction of fatty acid energy supply forces compensatory enhancement of gluconeogenesis.

The researchers speculated that if impaired fatty acid oxidation leads to increased carbohydrate demand in KO mice and consequent heart failure, it might be possible to alleviate the cardiac systolic dysfunction by increasing the ability of fatty acid oxidation to reduce their over-reliance on gluconeogenesis.

Thus, they supplemented mice in the active phase with a high-fat, sugar-free diet. However, high fat did not improve the pattern of energy metabolism in the heart, nor did it improve cardiac function. This suggests that increasing lipid supply during the active phase does not, by itself, improve cardiac dysfunction in KO mice.

So they switched to supplementing the mice with a high-fat diet during the resting period, equivalent to giving humans a high-fat energy supplement at night. Not surprisingly, the mice showed poor signs of blood glucose and insulin levels, and obesity rates increased dramatically. However, fatty acid oxidation was restored in the KO mice!

This suggests that providing more fatty acids for myocardial oxidative metabolism during the resting period partially mitigates the damage in the hearts of KO mice. Of course, as a double-edged sword, this can also lead to the development of obesity.

This led the researchers to propose a possible explanation for the "obesity paradox" that impaired fatty acid metabolism plays a role in the development of heart failure. Obese people provide more fatty acids to the heart at rest, which can improve the heart's fatty acid metabolism and thus partially mitigate heart damage.

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