Study Protocol for a Randomized Controlled Trial Investigating Acute Cardiometabolic Responses to Heat–Ozone Coexposure and the Interventional Role of Omega‐3 Eicosapentaenoic Acid: The HOEPA Study

Background Global climate change is intensifying extreme heat events and may exacerbate ozone (O 3 ) exposure, both of which have been independently associated with adverse cardiovascular and metabolic health outcomes, yet their combined effects and potential interventions remain poorly understood. Methods The HOEPA (Cardiovascular Health Effects of Combined Exposure to High Temperature and Ozone and the Intervention Effects and Mechanisms of EPA Nutritional Supplementation) study will investigate whether omega‐3 eicosapentaenoic acid (EPA) supplementation mitigates acute cardiometabolic impairments in response to heat–O 3 coexposure, by integrating a controlled human exposure framework with a randomized, double‐blind, placebo‐controlled nutritional intervention trial. A total of 48 healthy adult participants will be randomly assigned to receive EPA (3 g/d) or corn oil as a placebo for 4 weeks, followed by a washout stage. The primary outcome will be activated partial thromboplastin time. Key secondary outcomes will assess hemostatic and fibrinolytic responses, platelet function, vascular function, endothelial dysfunction, and oxidative stress. The outcomes will be assessed following controlled exposure to O 3 (200 ppb) under heat conditions (32 °C) to characterize acute responses and the potential protective effects of EPA. Chamber conditions will be tightly regulated to ensure predefined exposure targets. Erythrocyte membrane EPA levels will be measured longitudinally to verify supplementation uptake and to assess reversibility following washout. We hypothesize that EPA supplementation will attenuate acute cardiometabolic impacts induced by heat–O 3 coexposure. Conclusion This study design is intended to provide a rigorous experimental framework for elucidating acute cardiometabolic responses to combined heat and O 3 exposure and for evaluating the potential of omega‐3 EPA supplementation as an individual‐level strategy to mitigate environmental stress. Registration URL: https://www.Chictr.org.cn ; Unique Identifier: ChiCTR2500099752.