Statins Against Bushfire Smoke

Background and Rationale:

Climate-driven increases in landscape fire activity are substantially increasing population exposure to air pollution, the most important environmental driver of cardiovascular disease (CVD). The 2019-20 Australian bushfires exposed approximately 80% of the population to increased air pollution for several months, resulting in an estimated 429 excess deaths, 3,230 extra hospitalizations for cardiorespiratory problems, and 1,323 emergency presentations for asthma. Despite strong evidence linking air pollution to adverse cardiovascular outcomes, no intervention has been proven effective against bushfire smoke exposure in individuals. Oxidative stress, inflammation, and autonomic dysregulation are key mechanisms underlying these effects. Statins, beyond their cholesterol-lowering properties, have autonomic stabilizing, anti-inflammatory and antioxidant activity that may protect against cardiovascular impacts of air pollution. However, no clinical trials have tested this hypothesis.

Exposure Methodology:

The study utilizes the Climate Hut, a purpose-built facility at the University of Tasmania that allows controlled manipulation of air quality, temperature and humidity. The facility contains a small internal room with one transparent wall enabling observation and communication. Bushfire smoke is generated from eucalyptus fuel burned in a controlled combustion chamber, then diluted and delivered to maintain an average PM2.5 concentration of 300 μg/m³ during 2-hour exposure sessions. This concentration simulates community exposure during planned burns or bushfires and is comparable to smoke experienced at outdoor events with open fire heating. Filtered air sessions use HEPA filtration to remove particulate matter. Real-time monitoring of PM2.5, temperature, and humidity ensures consistent exposure conditions. Each participant undergoes both exposure conditions in randomized order, separated by ≥3 weeks washout period.

Intervention Protocol:

Stream 1 participants are randomized 1:1 to receive atorvastatin 80mg (supplied as two 40mg tablets) or identical placebo. The investigational product is supplied by SYNTRO Health in individual HDPE bottles containing 8 tablets per participant. Participants take 2 tablets on the morning of the day before each exposure visit and 2 tablets 1-2 hours before each exposure session. Stream 2 intervention group consists of participants who have been taking statin medication (primarily atorvastatin 40mg daily, or alternatives if myalgia occurred) for ≥12 months as part of the CAUGHT-CAD clinical trial or usual clinical care. The comparison group comprises statin-naïve individuals matched for age, sex, and cardiovascular risk profile.

Technical Measurements:

Heart rate variability is assessed through continuous 3-lead ECG monitoring (AMBPPro Research, Machinery Forum Medical Systems) throughout each 2-hour exposure. Time-domain measures (SDNN, RMSSD) and frequency-domain measures are calculated. Blood pressure is measured at 15-minute intervals using oscillometric monitoring. Pulse wave velocity is measured non-invasively using applanation tonometry (SphygmoCor, Atcor Medical) to assess carotid-femoral arterial stiffness pre- and post-exposure. Serum biomarkers including oxidized LDL, C-reactive protein, soluble ICAM-1 and VCAM-1, and serum amyloid A are quantified using multiplex protein assays (Abcam). Exploratory analyses include respiratory tract microbiome composition via 16S rRNA gene sequencing from nasopharyngeal swabs and urinary metabolites of PAH exposure (hydroxynaphthalenes, pyrene carboxylic acid) measured by LC-MS/MS.

Safety Monitoring:

Continuous ECG and regular blood pressure monitoring throughout exposure sessions enable real-time detection of cardiovascular changes. A study cardiologist (Prof Tom Marwick) is on-call for any medical concerns during exposure visits. An independent Medical Monitor (a cardiologist from the local hospital in Hobart) provides oversight of all adverse events. Pre-defined stopping criteria include sustained symptomatic tachycardia, bradycardia, arrhythmias, or blood pressure elevation requiring intervention. Participants are actively monitored for adverse events before, during, and immediately after exposure sessions, with passive collection continuing for 4 weeks post-exposure.

Sample Size and Analysis:

Each stream enrolls 50 participants (25 per treatment arm), providing 80% power to detect moderate effect sizes in the primary outcome (HRV changes) with α=0.05. Linear mixed-effects models will account for the crossover design, with each participant serving as their own control across exposure conditions. The primary comparison tests whether statin treatment modifies the change in HRV between filtered air and smoke exposure.

• Change in blood pressure (BP) associated with smoke exposure in the group treated with statins, compared with the group not treated with statins. [Срок оценки: BP is measured 15 minutely for 3 hours on two occasions at least 4 weeks apart. Once incorporating 2 hours of smoke exposure and once incorporating 2 hours of filtered air exposure.]
• Change in aortic vascular stiffness associated with smoke exposure in the group treated with statins, compared with the group not treated with statins. [Срок оценки: PWV is measured on two occasions at least 4 weeks apart, one immediately following 2 hours of smoke exposure and the other following 2 hours of filtered air exposure.]
• Difference in Oxidised Low-Density Lipoprotein (oxLDL) Levels Following Clean Air vs. Simulated Bushfire Smoke Exposure in Participants Treated with Statins Compared to Those Not Treated with Statins [Срок оценки: Following each 2-hour exposure session (clean air and simulated bushfire smoke), with sessions separated by at least 4 weeks.]
• Difference in High-Sensitivity C-Reactive Protein (hsCRP) Levels Following Clean Air vs. Simulated Bushfire Smoke Exposure in Participants Treated with Statins Compared to Those Not Treated with Statins [Срок оценки: Following each 2-hour exposure session (clean air and simulated bushfire smoke), with sessions separated by at least 4 weeks.]
• Difference in Soluble Intercellular and Vascular Cell Adhesion Molecule Levels (sICAM-1 and sVCAM-1) Following Clean Air vs. Simulated Bushfire Smoke Exposure in Participants Treated with Statins Compared to Those Not Treated with Statins [Срок оценки: Following each 2-hour exposure session (clean air and simulated bushfire smoke), with sessions separated by at least 4 weeks.]
• Difference in Serum Amyloid A (SAA) Levels Following Clean Air vs. Simulated Bushfire Smoke Exposure in Participants Treated with Statins Compared to Those Not Treated with Statins. [Срок оценки: Following each 2-hour exposure session (clean air and simulated bushfire smoke), with sessions separated by at least 4 weeks]
• Spatial Working Memory Score as Assessed by the CANTAB Spatial Working Memory Test During Clean Air vs. Simulated Bushfire Smoke Exposure [Срок оценки: During the second hour of each 2-hour exposure session (clean air and simulated bushfire smoke)]
• Cognitive Inhibition and Processing Speed Score as Assessed by the Modified Stroop Test During Clean Air vs. Simulated Bushfire Smoke Exposure [Срок оценки: During the second hour of each 2-hour exposure session (clean air and simulated bushfire smoke)]
• Self-Reported Anxiety Score as Assessed by the State-Trait Anxiety Inventory (STAI) During Clean Air vs. Simulated Bushfire Smoke Exposure [Срок оценки: During the second hour of each 2-hour exposure session (clean air and simulated bushfire smoke)]
• Postural Stability as Assessed by a Standing Balance Test (Floor and Foam Surfaces, Eyes Open and Closed) During Clean Air vs. Simulated Bushfire Smoke Exposure [Срок оценки: During the second hour of each 2-hour exposure session (clean air and simulated bushfire smoke)]
• Symptoms [Срок оценки: Collected immediately before and after environmental exposure sessions]
• Salivary cortisol [Срок оценки: Collected before and after each environmental exposure session]