Linking Heat Stress to Impaired Cardiac Repair: The ER Stress–Angiogenesis Axis as a Critical Barrier

Climate change has transformed extreme heat from a transient environmental perturbation into a persistent threat that worsens cardiovascular outcomes. Epidemiological studies show a lag between heat exposure and peaks in acute myocardial infarction (AMI) mortality, indicating a subclinical, latent vulnerability. This latent vulnerability likely originates at the level of the microvasculature, as cardiac microvascular endothelial cells (CMECs)-the heart's primary "thermal sensors"-are uniquely susceptible to proteotoxic stress. The existing literature suggests that this sensitivity may be mediated by thermodynamically gated activation of the activating transcription factor 6 (ATF6) branch of the unfolded protein response (UPR), which could function as a master switch that reprograms endothelial cells from a pro-repair to a maladaptive, anti-angiogenic phenotype. However, this mechanism is derived primarily from preclinical studies and lacks direct validation in humans. The resulting "endothelial memory" is sustained by epigenetic modifications and organelle uncoupling; it persists beyond the initial insult and impairs subsequent neovascularization. As a result, ischemia occurs later in a compromised microenvironment, promoting a fibrosis-conduction mismatch that drives infarct expansion and arrhythmic risk. Thus, the post-exposure latent phase emerges as a novel therapeutic window: Precision targeting of the ER stress-angiogenesis axis during this period offers a focused strategy to protect heat-vulnerable individuals.