Heart attacks that occur at night are usually less serious than those that occur during the day. Today, a study explains a possible reason and opens the door to possible therapies.
Published in the Journal of Experimental Medicine, the research describes how a “ … internal clock” of neutrophils, a type of white blood cell that plays a key role in the immune response, regulates their aggressiveness throughout the day and determines the degree of damage they cause to the heart after a heart attack.
THE Neutrophils are part of the body’s first line of defense against infections and tissue damage.. However, its inflammatory activity, essential for eliminating damaged or infected cells, can also affect healthy tissues.
Decades of work have shown that almost half of heart damage following a heart attack is precisely due to its action. And this activity is not constant: it fluctuates throughout the day according to a circadian rhythm that makes them more destructive during the day.
The team of Andrés Hidalgo from the National Cardiovascular Research Center (CNIC) and the Yale University School of Medicine identified that neutrophils have an internal clock that regulates their degree of aggressiveness. During the night, these cells adopt a “less harmful», respecting healthy tissues more when they migrate towards the lesion. On the contrary, during the day they lose this directionality and can cause more collateral damage.
The analysis of thousands of patients from the 12 de Octubre Hospital, in collaboration with the Hector Buenoconfirmed this dynamic: nocturnal infarctions are less serious because neutrophils are less active and their response is more ordered during this period.
The first author of the study, Alejandra Aroca-Crevillén, explains that “at night, neutrophils move toward the damaged area while sparing healthy tissue. During the day, they lose this precision and injure areas that are not affected.
From these results, the researchers developed a pharmacological strategy to block the molecular clock of neutrophils and maintain them in a “nocturnal” state even during the day.
According to Hidalgo, the compound used “mimics a factor that the body produces primarily at night,” prompting neutrophils to reduce their toxic activity.
New mechanism
The study looks at this mechanism.
Hidalgo’s team demonstrated that an experimental drug, ATI2341, can inhibit neutrophil clock and thus reduce cardiac damage in animal models of heart attack. ATI2341 acts on a receptor on the surface of these cells and prompts them to behave as they would at night.
In daytime mode, neutrophils tend to accumulate at the edge of the cardiac wound, damaging surrounding healthy tissues and enlarging the lesion. On the other hand, in night mode, they concentrate in the center of the injured area, away from healthy tissues.
One of the most relevant observations is that manipulation of the circadian clock does not appear to compromise the immune system’s ability to fight infections.
Antimicrobial response
In fact, the study shows that in addition to protecting the heart, this strategy can improve antimicrobial response and reduce inflammatory complications in other pathologies, such as sickle cell disease.
“We were surprised to see – underlines Aroca-Crevillé – that blocking the circadian clock of neutrophils not only protects the heart, but also improves the defense against certain microbes and reduces embolisms associated with sickle cell anemia.”
The authors consider that these results open the door to therapies based on chronobiology of the immune system. Acting on the “circadian checkpoint” of neutrophils could make it possible to control inflammation without weakening the body’s natural defenses.
“This therapeutic strategy offers an advantage over other approaches that alter neutrophil function or numbers, thereby compromising the host’s ability to control infections or heal wounds,” says Hidalgo.
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