For decades, cardiologists have observed that heart attacks cause more damage when they occur during the day than when they happen at night — and understanding why could be key to treating the condition, a new study finds.
There are many theories as to why daytime heart attacks are more harmful; some point to daily fluctuations in stress hormones and blood pressure as possible culprits. But the role of the immune system has remained less clear.
More damaging by day
By analyzing clinical records from more than 2,000 heart attack patients, the team found that patients admitted during daytime hours showed higher neutrophil counts and greater heart damage, suggesting neutrophils themselves might play a role in worsening the injury. They then confirmed the same pattern in experiments with mice.
The researchers split their lab mice into two groups: one with normal neutrophil levels and one whose neutrophil levels were depleted with an antibody treatment. Then, they induced heart attack in the mice at different times of the day and night.
In the first set of mice, they observed a pronounced rhythm of greater heart injury in the morning than at night, similar to what was seen in the human data. However, in the mice with low neutrophil counts, this rhythm disappeared and the heart attacks caused less damage overall.
To test the idea further, the researchers genetically disabled a gene that helps control the circadian clock, a regulator of 24-hour cycles in the body. As they expected, the rhythm again disappeared and the overall heart damage was reduced in these modified mice.
Importantly, although depleting neutrophils hobbles the immune system, deleting just the clock gene didn’t impair the mice’s ability to fight infections, the scientists found.
“This makes the study really interesting,” Tim Lammermann, an immunologist at the University of Münster in Germany who was not involved in the work, told Live Science. That’s because it was always believed that immune protection and inflammatory damage caused by neutrophils “cannot be disconnected from each other.”
Putting neutrophils in ‘night mode’
Next, the scientists wanted to test whether there might be another way to control this gene and mimic the body’s natural nighttime calming of neutrophils without diminishing the cells’ numbers. They focused on a receptor on neutrophils called CXCR4, which typically responds to signals that slow down neutrophil activity at night.
They genetically engineered mice to carry really high concentrations of this receptor. This calmed the cells down even during the daytime, so the heart injury was again alleviated and the rhythmic pattern disappeared.
Finally, using a drug that activates this receptor, the researchers toned down neutrophil activity during the day, pushing the cells into their nighttime state. Treatment with this drug prior to heart attack reduced tissue damage and improved heart function weeks after the event, they found.
What’s more, in mouse models of sickle cell disease, in which neutrophils clog blood vessels and trigger rampant inflammation, the drug reduced blockages and improved blood flow.
It’s surprising that controlling just one type of immune cell offered significant protection against these inflammatory injuries, senior study author Andrés Hidalgo, an immunologist 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 uncovered an interesting pattern behind the neutrophil action: In skin wounds and heart tissue alike, daytime neutrophils tend to spread into neighboring uninjured areas, enlarging the injury site, Hidalgo explained. Calmer, nighttime neutrophils, on the other hand, stay confined to the center of the damaged zone.
The findings suggest there could be ways to fine-tune neutrophils and tone down their aggressiveness without compromising their defense capability. However, translating this approach to humans will require careful study. The ways in which CXCR4 signaling affects other types of cells would also need to be carefully considered, Lammermann cautioned.
A drug that calms down inflammation without compromising immunity would be the holy grail of immune therapy. However, human trials for such a drug would need to assess many factors, such as the timing of when it should be given in the event of a heart attack, and if there are any potential risks involved, he added.
This article is for informational purposes only and is not meant to offer medical advice.
