Chronic heat stress disrupts the sleep–heart–brain–immune Axis: A novel mechanistic hypothesis for autonomic and neuroimmune dysfunction

Rising global temperatures and more frequent, prolonged heatwaves are increasingly recognised as independent drivers of cardiovascular and neuropsychiatric morbidity, yet the mechanistic pathway linking ambient heat exposure to chronic disease remains incompletely defined. Existing frameworks largely treat autonomic dysregulation, sleep disruption, and low-grade systemic inflammation as parallel consequences of chronic heat stress (CHS). We propose an alternative, unifying hypothesis: that CHS acts primarily through a self-reinforcing “sleep–heart–brain–immune axis,” in which heat-induced sympathetic dominance progressively erodes slow-wave and REM sleep architecture; the resulting loss of deep sleep withdraws two protective mechanisms that normally depend on it glymphatic clearance of the brain and vagally mediated suppression of peripheral cytokine release via the cholinergic anti-inflammatory pathway; and the ensuing low-grade neuroinflammation and disturbed hypothalamic–pituitary–adrenal (HPA) axis/heat-shock-protein (HSP) chaperone availability feedback to further destabilize autonomic control, worsening both sleep fragmentation and cardiac sympathovagal imbalance. We synthesise convergent evidence from human and rodent heat-exposure studies of heart-rate variability, polysomnographic/EEG sleep architecture, brain–heart coupling, glymphatic clearance kinetics, and neuroendocrine-immune signalling to support this integrated model. However, the supporting evidence has been drawn from separate, non-integrated experimental paradigms; therefore, the proposed causal loop requires experimental validation. The proposed framework considers slow-wave sleep loss as a potential mediator of CHS-induced autonomic dysfunction and highlights the interconnected roles of vagal regulation and chaperone availability in maintaining sleep architecture and inflammatory homeostasis. This framework positions sleep restoration and vagal-tone modulation as potentially important, mechanistically linked therapeutic targets in heat-vulnerable stressed populations rather than treating cardiovascular, sleep, and neuroimmune outcomes as separate clinical problems.