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Page 6 of 14 Broadwin et al. Vessel Plus 2023;7:25 https://dx.doi.org/10.20517/2574-1209.2023.103

Figure 1. Enrichment analysis of molecular functions in (A) ischemia effect, (B) diet effect, (C) EV effect in normal diet, and (D) EV
effect in HFD.

maturation in angiotensin system maturation”, “development EGFR signaling pathway”, and “inhibitor of
ephrin receptors” [Figure 2D].

We employed cluster analysis to identify loci that were altered by ischemia compared to the control and
then reverted by EV treatment. In both normal and high-fat diets, there were several such clusters (as
highlighted by brown rectangle in Figure 4). This can potentially indicate the direct deleterious epigenetic
effect of ischemia on cardiomyocyte methylome that is partly recoverable by EV therapy.

While there were numerical differences between groups, there were no statistically significant differences in
myocardial perfusion in either the ischemic myocardial segments or the non-ischemic segments either at
rest and when paced [Figure 5].

DISCUSSION
There is evidence of epigenetic change in response to cardiac ischemia. Cardiac events have been shown to
significantly alter whole-genome methylation patterns in patients’ blood samples, and our own previous
research has demonstrated the effect of cardiopulmonary bypass (CPB) on the methylome of skeletal
muscle [20,26] . Alterations in the methylome have been associated with increased cardiac risk. For example, in
the Framingham Offspring Study, alterations in DNA methylation were used to identify biomarkers
[27]
associated with the risk of cardiovascular events . Cardiac myocytes themselves have been shown to have