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.

Inclusion criteria

• Good general health and, if aged 45 year or more, low to intermediate (<10%) atherosclerotic cardiovascular disease (ASCVD) risk category, based on clinical data measured within 12 months prior to enrolment.

Exclusion criteria

• History of severe chronic lung diseases such as chronic obstructive pulmonary disease or asthma as determined by participants' care providers.
• History of chest pain, irregular heartbeats, heart failure, heart attack, heart pacemaker or coronary bypass surgery.
• High cardiovascular risk (>10%) category on the ASCVD risk calculator or judged to be at high risk by study cardiologist, for those aged 45 years or older.
• History of stroke, dementia or other neurological condition
• Untreated high blood pressure (≥ 140 systolic, ≥ 90 diastolic)
• History of autoimmune or inflammatory rheumatic disease (e.g., rheumatoid arthritis, systemic lupus erythematosus, spondyloarthritis). Osteoarthritis alone is not an exclusion.
• History of immunodeficiency
• Diabetes (any type)
• Current medications: Long term medications that interact with atorvastatin (such as verapamil, digoxin and warfarin); Medications that affect heart rate variability including beta-blockers (such as atenolol, metoprolol, propranolol, and acebutolol), tricyclic antidepressants and selective serotonin reuptake inhibitors (such as amitriptyline, sertraline, fluoxetine or citalopram), or medications with anti-cholinergic action (such as promethazine or prochlorperazine); stimulant medications, such as those prescribed for ADHD (such as methylphenidate, dexamphetamine, lisdexamfetamine); anti-inflammatory, immunosuppressive or immune modulating medications including systemic corticosteroids (such as prednisolone, dexamethasone) and non-steroidal anti-inflammatory drugs (NSAIDS) (such as ibuprofen, naproxen or diclofenac)
• Currently smoking, or have smoked: more than one pack of cigarettes in the past year, or have smoked more than 100 packs of cigarettes in their lifetime
• Currently vaping or have vaped: more than 200 puffs in the last year, more than 20,000 puffs in their lifetime
• Currently pregnant, attempting to become pregnant or breastfeeding
• History of skin allergy to tape or electrodes
• Inability to travel to the study site