Research published in the Journal of the American Heart Association Jan. 13 has concluded administering PCSK9 inhibitors to acute MI patients ahead of ischemia can mitigate the potential negative neurological effects that come with treatment.
In their study, Nattayaporn Apaijai, PhD, et al. note that acute MI doesn’t only block healthy blood flow to the heart. It also limits circulation to other vital organs, like the brain, and can cause irreparable damage.
“Immediate reperfusion therapy through primary percutaneous coronary intervention and fibrinolytic therapies is recommended for managing patients with acute MI in those presenting with ST-segment-elevation myocardial infarction,” Apaijai and colleagues at Chiang Mai University in Thailand wrote. “However, PCI may cause further deleterious effects on both the heart and brain, effects that are known as ischemic/reperfusion injury (I/R).”
Cardiac I/R causes brain damage characterized by increased inflammation, they explained. It also encourages beta-amyloid aggregation, tau hyperphosphorylation, reactive gliosis, a reduction of spine density and reduced cognition and neurogenesis.
Though they’re more popularly used in hyperlipidemic patients to lower cholesterol, Apaijai and co-authors said PCSK9 inhibitors have recently emerged as a possible preventive treatment against the brain damage so often induced by cardiac I/R. PCSK9 inhibitors were, after all, first identified in a neuronal apoptosis paradigm, suggesting they might be involved in neuronal injury and death.
Hypothesizing that PCSK9 inhibitors would attenuate brain damage by diminishing the instance of microglial/astrocytic hyperactivation, beta-amyloid aggregation and loss of dendritic spine, the researchers undertook a study of adult male Wistar rats. Rats were divided into four groups: controls; sham; rats who were administered PCSK9 inhibitors and suffered cardiac I/R; and rats who were administered PCSK9 inhibitors with no resulting cardiac I/R. The cardiac I/R cohort was further broken down based on when the rats received PCSK9 inhibitors—before ischemia, during ischemia or at the onset of reperfusion.
At the end of cardiac I/R protocol, Apaijai and colleagues removed rats’ brains to determine microglial and astrocytic activities, beta-amyloid aggravation and dendritic spine density.
The authors reported their findings confirmed that cardiac I/R caused a decreased number of CD11b+/CD45+low and increased CD11b+/CD45+high microglia, increased the activity of microglia and astrocytes, increased amyloid-beta production and decreased dendritic spine density.
“Pretreatment with PCSK9 inhibitors was the most effective regimen to protect the brain following cardiac I/R injury,” the team wrote. “Under physiological condition, PCSK9 inhibitors did not exert favorable outcomes on microglial and astrocytic activity, amyloid-beta levels and dendritic spine density. It is interesting that these favorable effects of PCSK9 inhibitors were found to be independent of the PCSK9 levels.”
Apaijai et al. said their findings showed pretreatment with PCSK9 inhibitors reduced all relevant parameters of microglial activation, suggesting there may be a role for the PCSK9 inhibitor in reducing inflammation in the brain following acute MI.
“Only the administration of PCSK9 inhibitors before ischemia effectively attenuated these deleterious effects on the brain following cardiac I/R,” they wrote. “This study suggests the possible therapeutic advantages of the use of PCSK9 inhibitors for hyperlipidemic individuals and a potential new strategy for the improvement of neurological outcomes following cardiovascular events.”