Cardiovascular

The Nampt/NAD+ Axis may be a Potent Therapeutic Target for Atrial Fibrillation

NAD+ precursor decreases atrial fibrillation susceptibility and duration in mice

(magicmine | iStock)
By Noemi Canditi

Aging and obesity are prominent risk factors for the onset of atrial fibrillation, which is when the heart’s upper chambers (atria) beat out of coordination with the lower chambers (ventricles). Atrial fibrillation is the most common problem with the rate or rhythm of the heartbeat, affecting more than 33 million people worldwide. The enzyme nicotinamide phosphoribosyltransferase (Nampt), a regulator of the vital molecule nicotinamide adenine dinucleotide (NAD+) involved in metabolism and aging, is highly expressed in heart cells. Recent studies have demonstrated the dysfunction of Nampt in a variety of heart diseases, however, there have been no reports on the relationship between atrial fibrillation and Nampt.

A research team from the University of Tsukuba in Japan published an article in the International Journal of Molecular Sciences showing that in mice fed high fat diets to model obesity, Nampt levels decreased and atrial fibrillation susceptibility and duration increased significantly. Also, treatment with nicotinamide riboside (NR), which can rescue NAD+ levels, partially restored the atrial fibrillation perpetuation in mice fed high fat diets. These findings suggest that the Nampt/NAD+ axis may be a potent therapeutic target for atrial fibrillation.

NAD+ and Nampt are found in every cell in your body, and their levels decrease with aging and obesity. The Nampt/NAD+ axis has been shown to have protective roles against aging and obesity-related disorders, such as type 2 diabetes. Because the Nampt and NAD+ diminish in obesity and aging, the most important risk factors for atrial fibrillation, the investigators of this study examined whether the Nampt/NAD+ axis has an important role in the development of atrial fibrillation induced by obesity. To achieve that, they tried to clarify how the Nampt/NAD+ axis and diet interact to affect atrial fibrillation in mice.

In the study, the researchers saw that levels of Nampt were cut in half in atrial tissues in mice fed high fat diets compared to mice fed normal diets. When genetically modified mice with decreased Nampt were fed high fat diets, they had even lower levels of Nampt compared to mice fed normal diets in atrial tissues. Also, NAD+ levels in the atria were significantly decreased for mice fed high fat diets when they were either genetically unaltered or genetically modified to have decreased Nampt compared to the mice fed normal diets. Collectively, these findings show that diet affects the Nampt/NAD+ axis in mouse atria.


Mice fed high fat diets have reduced Nampt levels in atrial tissues. (A) Nampt levels were reduced by nearly 50% in mice fed high fat diets and genetically modified mice fed normal diets compared with mice fed normal diets, and were further decreased in genetically modified mice fed high fat diets. (B) There were significant decreases of NAD+/NADH ratio in the other three groups compared to the mice fed normal diets. Wt+ND, mice fed normal diets; NKO+ND, genetically modified mice with decreased Nampt fed normal diets; Wt+HFD, mice fed high fat diets; NKO+HFD, genetically modified mice with decreased Nampt fed high fat diets.

Mice fed high fat diets and genetically modified mice with decreased levels of Nampt had increased susceptibility and prolonged duration of atrial fibrillation without significant structural abnormalities in the heart. The prolonged effect on atrial fibrillation duration was further increased in genetically modified mice with decreased Nampt fed high fat diets.


Genetically modified mice with decreased Nampt and mice fed high fat diets have increased atrial fibrillation susceptibility and duration. (C) AF susceptibility was significantly increased in mice fed high fat diets, genetically modified mice fed normal diets, and genetically modified mice fed high fat diets compared with mice fed normal diets. (D) Atrial fibrillation duration was significantly longer in mice fed high fat diets and genetically modified mice fed normal diets and further prolonged in genetically modified mice fed high fat diets compared with mice fed normal diets. Wt+ND, mice fed normal diets; NKO+ND, genetically modified mice with decreased Nampt fed normal diets; Wt+HFD, mice fed high fat diets; NKO+HFD, genetically modified mice with decreased Nampt fed high fat diets.

To assess whether the NAD+ precursor NR can abolish arrhythmias, problems with the rate or rhythm of the heartbeat, induced by a high fat diet, the investigators compared mice fed normal diets, high fat diets, and NR supplemented high fat diets. NR treatment recovered the reduction in Nampt levels in mice fed high fat diets. The NAD+ levels were also recuperated by the NR treatment. The electrophysiological study revealed that, despite the lack of difference in atrial fibrillation susceptibility, treatment with NR decreases atrial fibrillation duration time to that seen with a normal diet.


NAD+ precursor NR increases Nampt amount and decreases atrial fibrillation duration. Treatment with NR restored atrial fibrillation susceptibility and duration in mice fed high fat diets. ND, mice fed normal diets; HFD, mice fed high fat diets; HFD+NR, mice fed high fat diets supplemented with NR.

“Our data showed that NR supplementation significantly increased Nampt and NAD levels in high fat diet fed mice,” said the investigators in their study. “Also, atrial fibrillation duration …significantly recovered by NR supplementation. Taking our data and previous findings together, NR may be a promising therapeutic agent for cardiovascular diseases, including atrial fibrillation, in clinical practice.”

Source

Feng D, Xu D, Murakoshi N, et al. Nicotinamide Phosphoribosyltransferase (Nampt)/Nicotinamide Adenine Dinucleotide (NAD) Axis Suppresses Atrial Fibrillation by Modulating the Calcium Handling Pathway. Int J Mol Sci. 2020;21(13):4655. doi:10.3390/ijms21134655

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