New Study Explores Neutrophils’ Night Mode to Mitigate Heart Damage

Research conducted by a team from the Centro Nacional de Investigaciones Cardiovasculares (CNIC) and Yale University School of Medicine has revealed that heart attacks occurring at night tend to be less severe than those that happen during the day. The study, led by Dr. Andrés Hidalgo, has identified an internal clock in neutrophils, which are a type of white blood cell, that influences their activity levels and, consequently, the extent of heart damage following a myocardial infarction.

The findings suggest that by inhibiting the natural fluctuations of neutrophil activity, it may be possible to reduce the tissue damage they cause during heart attacks. The researchers developed a pharmacological approach using a drug called ATI2341. In experimental models, this drug blocked the internal clock in neutrophils, maintaining them in a less aggressive state typically associated with nighttime.

Dr. Hidalgo commented on the significance of their findings, stating, “Our study demonstrates that pharmacological delivery of a drug that activates a receptor on the surface of neutrophils induces their transition to a night-like, permissive state that alleviates the inflammatory response without interfering with antimicrobial defense.” This approach provides a potential advantage over traditional treatments that might reduce neutrophil numbers or functions, which can compromise the body’s ability to fight infections and heal wounds.

The research was published in the Journal of Experimental Medicine under the title “A circadian checkpoint relocates neutrophils to minimize injury.” The immune system plays a crucial role in defending the body against infections, especially since humans are diurnal, meaning they are active during the day and rest at night. This daily rhythm influences the immune response, leading to increased activity during the day when exposure to pathogens is more likely. Yet, this heightened activity can also result in significant tissue damage, particularly during events like heart attacks.

Years of research indicate that neutrophils are responsible for nearly half of the cardiac damage that occurs after a heart attack. Intriguingly, the inflammatory damage caused by these cells varies throughout the day, hinting at the existence of circadian mechanisms that regulate their activity.

When heart attacks occur during the day, neutrophils tend to congregate around the edges of the injury site, potentially damaging surrounding healthy tissue. In contrast, during nighttime, these cells are more likely to gather at the center of the wound, thereby sparing healthier areas. This phenomenon raises important implications regarding the timing of heart attacks and their subsequent damage.

The research team, including Dr. Hidalgo, collaborated with the Multidisciplinary Translational Cardiovascular Research Group at CNIC, led by Dr. Héctor Bueno. They analyzed data from thousands of patients at Hospital 12 de Octubre and confirmed that lower neutrophil activity at night correlates with reduced severity of heart attacks that occur during that time.

In their experiments, the researchers also established that, similar to humans, mice experience greater cardiac damage following a heart attack in the early morning, driven by increased neutrophil activity. By employing the CXCR4 agonist ATI2341, which inhibits the neutrophil clock, they saw a reduction in myocardial tissue damage. The drug acts by mimicking a factor produced mainly at night, effectively tricking neutrophils into maintaining a less harmful behavior.

The study’s first author, Dr. Alejandra Aroca-Crevillén, emphasized the protective effect observed during nighttime, stating, “At night, neutrophils migrate to the damaged area while sparing healthy tissue.” The team’s findings suggest that targeting the neutrophil clock could offer a straightforward and effective method to mitigate the adverse effects of these cells during cardiovascular events without sacrificing the body’s ability to combat infections.

Importantly, the researchers noted that the protective effects of ATI2341 were specific to neutrophils with intact CXCR4 receptors. Their experiments demonstrated that the compound did not impair the immune response against bacterial and fungal infections, indicating a potential pathway for new therapies aimed at controlling inflammation without compromising immune function.

This study opens new avenues for therapeutic strategies based on chronobiology, which studies how biological processes are influenced by time. By understanding and harnessing the circadian rhythms of the immune system, researchers may be able to protect the heart and other organs from inflammatory damage while keeping the body’s natural defenses intact.

The implications of this research are profound, providing a framework for developing treatments that could significantly enhance outcomes for patients experiencing heart attacks and possibly other inflammatory conditions.