Cardiovascular

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.

TL;DR

The HOEPA study protocol describes a randomized, double-blind, placebo-controlled trial designed to investigate whether omega-3 eicosapentaenoic acid (EPA) supplementation mitigates acute cardiometabolic impairments in response to heat-ozone coexposure.

Key Findings

The HOEPA study will enroll 48 healthy adult participants to investigate cardiometabolic responses to combined heat and ozone exposure.

  • Total sample size is 48 healthy adult participants
  • Participants will be randomly assigned to either EPA supplementation or corn oil placebo
  • The trial is registered at ChiCTR with unique identifier ChiCTR2500099752
  • The study integrates a controlled human exposure framework with a randomized, double-blind, placebo-controlled nutritional intervention design

Participants will receive EPA supplementation at a dose of 3 g/day for 4 weeks followed by a washout stage.

  • EPA dose is 3 g/day
  • Supplementation duration is 4 weeks
  • Corn oil will serve as the placebo comparator
  • A washout stage follows the supplementation period
  • Erythrocyte membrane EPA levels will be measured longitudinally to verify supplementation uptake and to assess reversibility following washout

Controlled chamber exposures will use ozone at 200 ppb under heat conditions of 32°C to characterize acute cardiometabolic responses.

  • Ozone exposure concentration is set at 200 ppb
  • Heat condition is set at 32°C
  • Chamber conditions will be tightly regulated to ensure predefined exposure targets
  • The design characterizes acute responses and the potential protective effects of EPA supplementation

The primary outcome of the trial is activated partial thromboplastin time, with multiple secondary outcomes assessing cardiometabolic function.

  • Primary outcome is activated partial thromboplastin time (aPTT)
  • Key secondary outcomes include hemostatic and fibrinolytic responses, platelet function, vascular function, endothelial dysfunction, and oxidative stress
  • These outcomes are designed to characterize acute cardiometabolic impairments from combined environmental exposures

The study was motivated by evidence that global climate change is intensifying extreme heat events and may exacerbate ozone exposure, both independently associated with adverse cardiovascular and metabolic outcomes.

  • Heat events and ozone exposure have each been independently associated with adverse cardiovascular and metabolic health outcomes
  • The combined effects of heat and ozone coexposure and potential interventions remain 'poorly understood' according to the authors
  • The study addresses a gap in understanding both the combined exposure effects and individual-level mitigation strategies

The authors hypothesize that EPA supplementation will attenuate acute cardiometabolic impacts induced by heat-ozone coexposure.

  • The hypothesis focuses on EPA as a protective nutritional intervention against environmental stress
  • The study is designed to evaluate EPA supplementation 'as an individual-level strategy to mitigate environmental stress'
  • The study will assess whether EPA mitigates acute cardiometabolic impairments through mechanisms including effects on oxidative stress and endothelial function

What This Means

This research describes the design of a clinical trial called the HOEPA study, which aims to understand how being exposed to both high temperatures and air pollution (specifically ozone) at the same time affects heart and metabolic health. Climate change is making extreme heat more common and may also worsen ozone pollution, but scientists do not yet fully understand how these two environmental stressors work together to harm the body, or whether nutritional supplements might protect against these harms. The study will expose 48 healthy adults to ozone (at 200 parts per billion) in a warm environment (32°C) in a carefully controlled chamber setting, and measure a range of heart and blood-related outcomes including blood clotting time, blood vessel function, and markers of inflammation and oxidative stress. Half of the participants will take a fish oil supplement (eicosapentaenoic acid, or EPA, at 3 grams per day) for four weeks before the exposure, while the other half will take a placebo (corn oil). Neither participants nor researchers will know who received which treatment until the study is complete. Blood samples will be used to verify that participants actually absorbed the EPA supplement, and a washout period will allow researchers to track how long the supplement's effects last. The main measurement of interest is activated partial thromboplastin time, a measure of how quickly blood clots, which reflects cardiovascular risk. This research suggests that omega-3 fatty acid supplementation might offer a practical, individual-level way to protect people from the heart and metabolic harms caused by combined heat and air pollution exposure. If the hypothesis is confirmed, it could have important implications for protecting vulnerable populations during extreme heat events and periods of high air pollution, which are expected to become more frequent with climate change. The study protocol itself represents a methodological contribution, offering a rigorous framework for testing environmental health interventions in controlled human exposure settings.

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Citation

Li J, Wang T, Mi J, Liao W, Xu L, Wang Z, et al.. (2026). 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.. Journal of the American Heart Association. https://doi.org/10.1161/JAHA.126.050377