For decades, cardiologists have observed that heart attacks cause more harm when they occur during the day than when they occur at night, and understanding why this may be the key to treating the disease, new research shows.
There are many theories why daytime heart attacks more harmful; some point to daily fluctuations in stress hormones and blood pressure as possible culprits. But the role of the immune system remains less clear.
A more destructive day
After analyzing the clinical records of more than 2,000 heart attack patients, the team found that patients admitted during the day had higher neutrophil counts and more severe 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 as a result of antibody treatment. They then gave the mice heart attacks at different times of the day and night.
In the first group of mice, they observed a distinct pattern of more severe heart damage in the morning than at night, 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, the researchers genetically disabled a gene that helps control circadian clockregulator of 24-hour cycles in the body. As they expected, in these modified mice the rhythm disappeared again and overall heart damage was reduced.
Importantly, while depleting neutrophils weakens the immune system, deleting the clock gene alone did not impair the mice's ability to fight infections, the scientists found.
“It makes the research really interesting.” Tim Lammermannan immunologist at the University of Münster in Germany who was not involved in the work told Live Science. This is because it has always been believed that immune defense and inflammatory damage caused by neutrophils “cannot be separated from each other.”
Transferring neutrophils to “night mode”
The scientists then wanted to test if there was another way to control this gene and mimic the body's natural nighttime quiescence of neutrophils without reducing the number of cells. They focused on a neutrophil receptor called CXCR4, which normally responds to signals that slow neutrophil activity at night.
They have genetically modified mice that carry very high concentrations of this receptor. This calmed the cells even during the daytime, so the heart injury was relieved again and the rhythmic pattern disappeared.
Finally, using a drug that activates this receptor, the researchers reduced neutrophil activity during the day, putting the cells into a nocturnal state. They found that treatment with the drug before a heart attack reduced tissue damage and improved heart function several weeks after the event.
What's more, in mouse models of sickle cell disease, in which neutrophils clog blood vessels and cause rampant inflammation, the drug reduced the blockages and improved blood flow.
Surprisingly, controlling just one type of immune cell provides significant protection against these inflammatory damages, says the study's senior author. Andres Hidalgoan immunologist at Yale University, told Live Science.
Lammermann noted that the experiments with the drug were particularly significant because they provided evidence that the compound reduces the inflammatory response of neutrophils while preserving their protective mechanisms.
The researchers also discovered an interesting pattern of neutrophil action: In both skin wounds and heart tissue, daytime neutrophils tend to spread to adjacent uninjured areas, enlarging the site of injury, Hidalgo explained. On the other hand, quieter, nocturnal neutrophils remain in the center of the damaged area.
The results suggest there may be ways to fine-tune neutrophils and reduce their aggressiveness without compromising their protective ability. However, applying this approach to humans will require careful study. Lammermann cautioned that it is also necessary to carefully consider the ways in which CXCR4 signaling affects other cell types.
A drug that calms inflammation without compromising the immune system could be the Holy Grail of immune therapy. However, human trials of such a drug would have to evaluate many factors, such as when it should be given in the event of a heart attack and whether there are any potential risks, he added.
This article is for informational purposes only and is not intended to provide medical advice.
