BREVOC Study: Exhaled VOCs for High-Risk Chest Pain in the ED

1. Research Background Since the concept of precision medicine was introduced, the innovation and optimization of clinical diagnostic technologies have become a central issue in medical research. Traditional diagnostic methods-including imaging, hematology, and histology-often rely on invasive procedures. While these techniques can provide highly accurate diagnostic information, they are associated with high costs, operational complexity, and potential risks of harm to patients, making them less suitable for rapid screening and dynamic monitoring. Therefore, the development of non-invasive, rapid, and cost-effective diagnostic technologies has become an urgent need in modern medicine.

As one of the most metabolically active organs, the lungs exchange metabolites produced by body tissues into the bloodstream, which are subsequently exhaled. Thus, exhaled breath can reflect the physiological and pathological states of the body. Historically, physicians identified certain diseases through changes in body odor-for instance, a fruity "rotten apple" smell in diabetic ketoacidosis or a fishy odor in patients with liver disease. At that time, the specific chemical composition underlying these odors was unknown. In 1971, Pauling et al. first applied gas chromatography to human exhaled breath analysis, identifying hundreds of volatile organic compounds (VOCs), thereby laying the foundation for breath analysis technology.

Acute chest pain is one of the most common presenting symptoms in emergency departments, with diverse etiologies and varying prognoses. Several life-threatening cardiovascular emergencies-such as acute coronary syndrome (ACS), acute pulmonary embolism (APE), and acute aortic syndrome (AAS)-typically present with acute chest pain and require prompt diagnosis and treatment in the emergency setting. However, not all chest pain cases are high risk. A considerable proportion of patients (e.g., those with intercostal neuralgia) have favorable outcomes and do not require extensive diagnostic testing or monitoring. Therefore, accurate risk stratification is critical: rapid recognition and management of high-risk chest pain, while avoiding overtreatment in low-risk cases, are essential to safeguard public health and reduce healthcare burden.

Breath analysis of exhaled VOCs has attracted increasing attention in recent years as a unique biomarker-based tool for early disease diagnosis and screening. VOCs are highly volatile organic molecules present not only in the environment but also generated through human metabolic processes. As endogenous metabolites, VOCs reflect health status and disease progression. Due to their non-invasive detection and high sensitivity, VOCs show great promise in early diagnosis, personalized treatment, and disease monitoring. Compared with traditional biomarker assays, breath analysis offers unique advantages. Instead of detecting a single molecule, VOC analysis can identify molecular patterns, providing more comprehensive and accurate diagnostic information. Current evidence has demonstrated strong associations between VOCs and various diseases-including cancer, respiratory disorders, and diabetes-highlighting their value in precision medicine.

Precision medicine emphasizes individualized treatment strategies tailored to patient-specific biological characteristics. Within this framework, VOCs-as biomarkers of physiological and pathological states-may hold significant clinical value in the early diagnosis, screening, and monitoring of acute chest pain. However, research on breath analysis for acute chest pain remains limited. Marzoog et al. demonstrated that VOCs could distinguish ischemic heart disease patients from controls using machine learning models, suggesting the potential application of breath analysis in acute cardiogenic chest pain. In 2024, the Chinese Chest Pain Consensus proposed incorporating novel metabolic markers, such as fatty aldehydes, into chest pain evaluation systems. Nevertheless, standardized studies on exhaled VOCs remain scarce.

Therefore, this study aims to apply exhaled VOC detection for the identification of high-risk acute chest pain patients, establish a database of VOC profiles, and evaluate the prognostic value of dynamic VOC changes. This research will, for the first time, systematically characterize the VOC profile of high-risk acute chest pain, analyze dynamic changes, and construct a VOC-based predictive scoring model for patient prognosis. These efforts are expected to provide novel strategies for individualized treatment, disease monitoring, and management in high-risk acute chest pain.

2. Research Objectives

1. Biomarker identification: Establish a VOC profile for high-risk acute chest pain patients and differentiate them from other chest pain etiologies.

   Aldehyde detection: Explore the role of exhaled aldehyde detection in high-risk chest pain; establish and validate an early diagnostic model using VOCs to optimize emergency triage.

2. Prognostic assessment: Evaluate the predictive value of VOC concentration changes for in-hospital mortality and major adverse cardiovascular events (MACE) in high-risk chest pain patients.
3. Novel indicators: Explore new diagnostic marker combinations superior to conventional biomarkers.

3. Research Methods Study Design This study is designed as a prospective cohort study. 3.1 Study Sites and Participants The study will be conducted in the Emergency Department (ED), Emergency Intensive Care Unit (EICU), and Intensive Care Unit (ICU) of Qilu Hospital, Shandong University. Eligible participants will include all patients presenting with acute chest pain to the ED.

3.2 Study Outcomes

1. Primary outcome: Discrimination between high-risk and low/intermediate-risk chest pain, assessed by area under the receiver operating characteristic curve (AUC-ROC), sensitivity, and specificity.

2. Secondary outcomes:

   1. Missed diagnosis rate (proportion of high-risk patients misclassified as low/intermediate risk by the model).
   2. ED length of stay and healthcare costs under model-guided triage.

   3. In-hospital mortality and incidence of MACE. 3.3 Statistical Analysis To ensure data accuracy, an Excel database will be established with dual-entry verification. Data will be analyzed using R software (version 4.3.2), with a two-tailed significance level of α = 0.05 (P \< 0.05 considered statistically significant).

      1. Descriptive analysis: Baseline characteristics and VOC concentrations will be summarized. Categorical variables will be expressed as frequencies or percentages. Continuous variables with normal or approximately normal distribution will be presented as mean ± standard deviation (SD). Skewed data will be reported as median (P25, P75). Between-group comparisons will use independent-samples t-tests, one-way analysis of variance (ANOVA), Mann-Whitney U test, or Kruskal-Wallis test, as appropriate. Categorical variables will be analyzed using chi-squared (χ²) test or Fisher's exact test.
      2. Feature selection: Characteristic VOCs will be screened, and a VOC scoring model will be developed using machine learning methods.
      3. Prognostic analysis: Prognostic factors will be evaluated using Cox proportional hazards regression.
      4. Trajectory analysis: VOC concentration dynamics will be modeled to explore temporal patterns.