Heart attacks are less harmful at night. A study hints at why.
For decades, cardiologists have observed that heart attacks cause more damage when they occur during the day than when they occur at night — and understanding why could be key to treating the disease, according to a new study.
There are many theories as to why the day heart attacks are more harmful; Some point to daily fluctuations in stress hormones and blood pressure as possible causes. But the role of the immune system remains less clear.
More damaging by day
Analyzing clinical records of more than 2,000 heart attack patients, the team found that patients admitted during the day had higher neutrophil counts and greater heart damage, suggesting that neutrophils themselves may play a role in worsening the injury. They then confirmed the same pattern in experiments on mice.
The researchers divided their laboratory mice into two groups: one with normal neutrophil levels and one whose neutrophil levels were depleted by antibody treatment. Then they induced heart attacks in the mice at different times of the day and night.
In the first group of mice, they observed a pronounced pattern of greater heart damage in the morning than in the evening, similar to what was observed in the human data. However, in mice with low neutrophil counts, this rhythm disappeared and heart attacks caused less damage overall.
To test this idea further, researchers genetically disabled a gene that helps control circadian clocka regulator of 24-hour cycles in the body. As they expected, the rhythm disappeared again and overall heart damage was reduced in these modified mice.
Importantly, although neutrophil depletion hampers the immune system, deleting the clock gene alone did not impair the mice’s ability to fight infections, the scientists found.
“That makes the study really interesting,” Tim Lammermannan immunologist at the University of Münster in Germany who was not involved in the work, told Live Science. Indeed, it has always been believed that immune protection and inflammatory damage caused by neutrophils “could not be dissociated from each other”.
Put neutrophils in “night mode”
Next, the scientists wanted to test whether there might be another way to control this gene and mimic the natural nighttime calming of neutrophils without decreasing cell numbers. They focused on a receptor on neutrophils called CXCR4, which typically responds to signals that slow neutrophil activity at night.
They genetically modified mice so that they carried very high concentrations of this receptor. This calmed the cells even during the day, so that the heart damage was alleviated again and the rhythmic pattern disappeared.
Finally, using a drug that activates this receptor, the researchers attenuated neutrophil activity during the day, pushing the cells into their nocturnal state. Treatment with this drug before a heart attack reduced tissue damage and improved heart function weeks after the event, they found.
Additionally, in mouse models of sickle cell disease, in which neutrophils block blood vessels and trigger widespread inflammation, the drug reduced blockages and improved blood flow.
It is surprising that controlling just one type of immune cell provides significant protection against these inflammatory lesions, says the study’s lead author. Andres Hidalgoimmunologist at Yale University, told Live Science.
Lammermann noted that the experiments with the drug were particularly significant, providing evidence that the compound reduced the inflammatory response of neutrophils while keeping their defense mechanisms intact.
The researchers also discovered an interesting pattern behind the action of neutrophils: In skin wounds as in heart tissue, daytime neutrophils tend to spread to nearby uninjured areas, thereby widening the injury site, Hidalgo explained. In contrast, quieter nocturnal neutrophils remain confined to the center of the damaged area.
The results suggest that there may be ways to fine-tune neutrophils and dampen their aggressiveness without compromising their defense capacity. However, translating this approach to humans will require careful study. How CXCR4 signaling affects other cell types should also be carefully examined, Lammermann cautioned.
A drug that calms inflammation without compromising immunity would be the holy grail of immunotherapy. However, human trials of such a drug would need to evaluate many factors, such as when it should be administered in a heart attack and whether there are any potential risks, he added.
This article is for informational purposes only and is not intended to offer medical advice.
