Researchers at the University of Ottawa has found that a heart attack may trigger neurological disorders and cognitive decline, and have identified the reactive molecule methylglyoxal as a potential driver of neuroinflammation after myocardial infarction. The research, published in the journal Advanced Science, adds to a growing body of evidence that injury to the heart can directly alter brain function through the “heart-brain axis.”
“Methylglyoxal has been widely studied for its role in metabolic diseases, including diabetes, but much less is known about its function in other diseases. In a previous study, we discovered that methylglyoxal was produced by dying heart tissue after a heart attack. Based on this evidence, we predicted that methylglyoxal in the blood would target other organs and tissues, including the brain—and this is what we did indeed observe,” said senior author Erik Suuronen, PhD, a professor in the department of surgery and director of the BEaTs research program at the University of Ottawa Heart Institute.
The researchers found that methylglyoxal-derived advanced glycation end products (MG-AGEs) accumulated in the brains of mice within hours after myocardial infarction and remained elevated seven days later. This accumulation resulted in neuroinflammation, activation of microglia and macrophages, increased inflammatory signaling, and disruption of the blood-brain barrier.
The study examined five brain regions in female and male mice after they induced myocardial infarction. Brain tissue was collected at six hours and seven days after the cardiac event. Researchers measured levels of MG-H1, the major MG-derived advanced glycation end product, along with glyoxalase-1, inflammatory cytokines, receptors for AGEs, activated microglia, and macrophages.
The work builds on a multiple earlier research studies linking cardiovascular disease and neurological disorders. Prior clinical studies have found that myocardial infarction and heart failure are associated with increased risks of dementia, depression, anxiety, and cognitive impairment. Patients with depression after myocardial infarction also face a greater risk of future cardiovascular events.
The heart-brain axis is the bidirectional relationship between cardiac and neurological function similar to the gut-brain axis. Changes in heart function can influence the brain, while neurological disease can also affect cardiovascular health. While the biological factors relating to this interaction are still emerging, the new research indicates that methylglyoxal may be one factor contributing to this relationship.
MG is produced as a byproduct of glycolysis and can react with proteins, lipids, and DNA, contributing to cellular dysfunction. Conditions associated with myocardial infarction, such as ischemia, inflammation, oxidative stress, and metabolic shifts toward anaerobic glycolysis, promote MG production while limiting its detoxification.
The mouse studies showed that the brainstem had the highest accumulation of MG-H1 after myocardial infarction, followed by the cortex. These same regions also showed elevated expression of inflammatory markers and receptors associated with MG-mediated signaling. Male mice exhibited higher MG-AGE accumulation and greater neuroinflammation than females in several brain regions.
The team also documented increases in inflammatory markers including NF-κB, TNF-α, and activated microglia across multiple brain regions. The cortex and brainstem demonstrated the highest inflammatory responses. According to the authors, the findings suggest a “region-specific vulnerability to glycation-induced stress post-MI.”
The findings could have implications for better understanding how heart attacks contribute to long-term neurological disease risk, including dementia and Alzheimer’s disease. The researchers noted that MG-AGEs already have recognized roles in neurodegenerative disease and mental health disorders.
The researchers have already used the information from the study to develop a peptide designed to trap methylglyoxal and prevent cellular damage, as a potential new therapy. The peptide will be tested for its ability to protect the brain after myocardial infarction.
“Given the increased risk of subsequent heart attacks or death in heart attack patients who experience depression or anxiety, being able to alleviate these conditions could reduce subsequent major cardiac events and improve the lives of countless patients, filling an urgent unmet clinical need,” Suuronen says.
The researchers said future work will examine how MG-driven inflammation contributes to neuron death and behavioral changes after myocardial infarction. They also plan further research to better understand the glyoxalase detoxification system, including glyoxalase-1 activity and glutathione levels.
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