Metabolite Identified as Blood Pressure Biomarker in Large Cohort

The Challenge: Identify Pathogenic Pathways Associated with Hypertension

High blood pressure (BP), estimated to affect more than 1 billion people globally, stands as a major modifiable risk factor for cardiovascular diseases, accounting for a significant percentage of stroke and ischemic heart disease cases and a substantial portion of global deaths. Despite the availability of various hypertension treatments, a significant number of patients fail to reach target BP levels due to the complexity of individualized BP regulatory mechanisms. This challenge is compounded by a lack of significant progress in developing new hypertension medications over the past decade. Identifying novel biological pathways through approaches like metabolomics holds promise in uncovering new drug targets or refining treatment strategies for hypertension. Despite successful genome-wide association studies in pinpointing common genetic variants linked to BP, they’ve yielded limited new pathways. Recent advances in metabolomics offer a unique glimpse into individual metabolic profiles, potentially unveiling previously unknown disease pathways.

Metabolon Insight: Associate Metabolites with Blood Pressure

The researchers conducted a comprehensive screening of metabolites unrelated to a specific target to uncover those connected to BP by analyzing data on dietary intake and mortality within a sizable female twin group in the UK. The results were confirmed in two separate human populations from Germany and England and in an animal model.

The Solution: Screen Metabolites in a Large Cohort

The research involved screening 280 metabolites in the discovery TwinsUK cohort, leading to the identification of 77 metabolites significantly associated with systolic or diastolic blood pressure (SBP or DBP). After narrowing down to 15 independent metabolites and addressing correlations and confounding factors through various analyses, further investigation concentrated on exploring their associations with all-cause mortality.

Among the three metabolites (dihomo-linoleate (20:2n6), hexadecanedioate, and caffeine) significantly associated with mortality in TwinsUK, only hexadecanedioate exhibited consistent and significant associations with both high blood pressure and mortality, suggesting a potentially sustained detrimental effect related to elevated levels of this metabolite. In contrast, the other two metabolites, despite positively correlating with BP, did not show increased mortality risk. Additional survival analyses on similar acids did not demonstrate significant associations with mortality, indicating the specificity of hexadecanedioate’s impact.

The study showed generalizability by replicating the results for hexadecanedioate in different cohorts that included both male and female subjects, including those on hypertension treatment. The findings persisted even when individuals from the TwinsUK cohort on BP-lowering medications were included.

In vivo experiments conducted on rats supported the causal role of hexadecanedioate in regulating BP. The experiments revealed a consistent increase in BP following hexadecanedioate intake, particularly indicating a vascular mechanism as the association between hexadecanedioate and blood pressure. The analysis of hexadecanedioate’s metabolism revealed its generation during fatty acid ω-oxidation and subsequent metabolism through β-oxidation in peroxisomes. Its levels were negatively correlated with carnitine in the data.

The Outcome: Reveal Potential Mechanisms of Pathogenicity

The study suggests potential mechanisms through related pathways that could explain the association between hexadecanedioate and BP regulation. Notably, it links the disruption of fatty acid metabolism, specifically ω-oxidation, to increased vascular tone, potentially leading to hypertension.

The Metabolon Global Discovery Panel helped identify hexadecanedioate as a potential key metabolite associated with blood pressure regulation, suggesting a novel avenue for understanding and potentially addressing hypertension. Further studies are required to fully comprehend the underlying mechanisms and causal pathways.