Abstract Body: Cognitive impairment (CGI) is common in patients with cardiovascular diseases, contributing to morbidity and mortality, especially among people over the age of 64. Cardiogenic dementia has been suggested to characterize patients suffering from cognitive decline after heart disease. Clinical and experimental evidence further suggest that 35%-65% of patients with myocardial ischemia are affected by CGI which include memory and global cognitive deficits. Although increasing evidence suggests that neurological disorders, such as stroke underlying a brain-heart axis can lead to myocardial injury and cardiac dysfunction, the heart-brain axis remains to be completely understood.
To elucidate the potential effects of myocardial injury on the CGI and the underlying mechanism by which cardiac damage regulates brain dysfunction, we employed a rodent model of myocardial infarction (MI) generated by left coronary artery ligation and a cardiac-specific GFP⁺ Tg reporter mouse model to track the brain distribution of cardiac extracellular vesicles (EVs), combining in vitro imaging, cellular and molecular techniques. Here we demonstrate crosstalk between heart and brain via EVs, and glial cell uptake of GFP⁺ cardiac EVs (See Figure). Importantly, myocardial injury not only promotes the brain distribution of cardiac EVs, but also elicits a neuroinflammatory response in vitro and in vivo. Further molecular studies suggests that cardiac EVs are abundant with miR-21-5p, which was selectively upregulated in cardiac cells in the post-MI model and transported by EVs. We also confirmed that miR-21-5p overexpression in vitro caused a pro-inflammatory response in brain microglia.
Taken together these observations indicate that weeks following MI, cardiac-secreted EVs abundant with miRNAs communicate with the brain and are associated with microglial activation, which may be responsible for neuroinflammation and neurotoxicity leading to cognitive impairment.

Keywords: Myocardial injury; Cardiogenic dementia; Neuroinflammation; Extracellular vesicles; microRNAs

Funding source: This work was supported by the National Institution of Health R01HL153176 (IZ/CT); American Heart Association (AHA) Career Development Award (19CDA34520004) and AHA Transformational Program Award (https://doi.org/10.58275/AHA.24TPA1300008.pc.gr.198448) to CT.