JMIR Publications

ABSTRACT

Background:

Hypertension is a chronic condition and a leading risk factor for cardiovascular disease, stroke, and premature mortality worldwide. While blood pressure (BP) monitoring-via office, home, or ambulatory measurements-remains the primary diagnostic tool, each method is limited by variability, device inaccuracy, and difficulties in detecting atypical BP patterns such as masked or white-coat hypertension. These challenges underscore the need for innovative, complementary diagnostic approaches.

Objective:

This systematic review and meta-analysis protocol aims to synthesize current evidence on the role of metabolomic profiling in the detection and understanding of hypertension. Specifically, it seeks to evaluate whether metabolomics can identify preclinical metabolic signatures, improve diagnostic accuracy, and elucidate pathophysiological mechanisms underlying hypertension, thereby complementing traditional BP monitoring.

Methods:

Electronic searches will be performed in three databases (PubMed, Scopus, and the Cochrane Central Register of Controlled Trials (CENTRAL)) from inception to March 2025. This systematic review will include studies involving adults (≥18 years) that investigate metabolomic biomarkers in hypertension using validated analytical platforms such as nuclear magnetic resonance (NMR) spectroscopy, gas chromatography-mass spectrometry (GC-MS) or liquid chromatography-mass spectrometry (LC-MS). Eligible studies must stratify participants into hypertensive, pre-hypertensive, or normotensive groups and report associations between metabolites and BP measurements. Two independent reviewers will conduct study selection, data extraction, and risk of bias assessment using the Cochrane Risk of Bias (RoB)2) and Risk of Bias in Non-randomised Studies of Interventions (ROBINS-I) tools, with evidence certainty evaluated via Grading of Recommendations Assessment, Development and Evaluation (GRADE). Meta-analysis will be performed where possible, using random-effects models and subgroup analyses to address heterogeneity.

Results:

As of March 2025, 399 studies were identified for screening. Screening, data extraction, and synthesis are ongoing, with analysis projected for completion by July 2025. This systematic review will report on diagnostic accuracy metrics (e.g., Area Under the Curve, sensitivity), key metabolites (such as stearidonate and hexadecadienoate), and pathway dysregulation linked to hypertension.

Conclusions:

Future research should prioritize longitudinal studies integrating serial metabolomic assessments and dynamic modeling to track hypertension progression. Comparative validation of metabolomic models against established clinical algorithms is critical for clinical integration, though challenges persist due to the limited routine measurement of key metabolites in standard care. Metabolomic-based tools should complement, not replace, traditional assessments, enhancing risk identification, patient stratification, and personalized interventions. Successful translation into clinical decision aids will require multidisciplinary collaboration among researchers, clinicians, and public health experts to address feasibility and implementation barriers. Clinical Trial: PROSPERO(CRD420251016289); https://www.crd.york.ac.uk/PROSPERO/view/CRD420251016289