Increased mROS Generation Associates With Cardiovascular Risk in BioHEART‐CT PBMCs

TL;DR

The study found that mitochondrial reactive oxygen species in blood cells may weakly relate to heart disease risk in some groups, but not consistently enough to serve as a reliable biomarker.

Contribution

This study provides preliminary evidence of cell-type-specific mROS associations with cardiovascular risk factors in a small exploratory cohort.

Findings

Lymphocyte mROS showed a moderate association with coronary artery calcium score in males.

Monocyte mROS had a modest inverse association with hypertension.

No distinct CCBE1 gene expression signature was found in PBMCs.

Abstract

Coronary artery disease (CAD) remains a leading cause of morbidity and mortality worldwide, and identifying accessible blood‐based biomarkers is therefore a clinical priority. Given the involvement of oxidative stress and immune cell dysfunction in atherosclerosis, we investigated whether mitochondrial reactive oxygen species (mROS) production in peripheral blood mononuclear cells (PBMCs) is associated with CAD. This exploratory study analyzed PBMCs from 40 BioHEART‐CT participants with or without CT‐defined CAD using MitoSOX‐based flow cytometry. In parallel, single‐cell RNA sequencing (scRNA‐seq) was conducted in the same individuals to investigate differential expression of CCBE1, a recently implicated gene in cardiovascular disease, across PBMC populations. Overall, mROS levels in PBMCs and their major cellular subtypes did not show consistent or meaningful associations with CAD status or with modifiable cardiovascular risk factors. Small, subgroup‐specific signals—such as moderate association between lymphocyte mROS and coronary artery calcium score in males, and a modest inverse association between monocyte mROS and hypertension—were exploratory and not uniform across analyses. scRNA‐seq analysis did not identify a distinct CCBE1 expression signature in PBMCs. These findings indicate that PBMC‐derived mROS is unlikely to serve as a useful cross‐sectional biomarker of CAD in stable populations.

What is the current knowledge on the topic?
○Peripheral blood mononuclear cells (PBMCs) contribute to atherosclerosis, and mitochondrial dysfunction with excessive reactive oxygen species (ROS) generation has been implicated in cardiovascular disease. However, the role of mitochondrial ROS (mROS) in PBMC subsets as a biomarker for CAD has not been clearly established.
What question did this study address?
○This study examined whether PBMC‐derived mROS levels are associated with CAD, measured by coronary artery calcium scoring, and explored whether single‐cell transcriptomics could identify a distinct gene expression signature (specifically CCBE1) related to CAD in PBMCs.
What does this study add to our knowledge?
○The study provides preliminary evidence that lymphocytic mROS production may be associated with coronary artery calcium burden in male participants, suggesting a potential link between PBMC mitochondrial redox status and CAD. Additionally, elevated monocyte mROS showed a modest and exploratory association with lower odds of hypertension. These findings indicate potential cell type–specific differences in redox responses, but the observed associations have small effect sizes and require validation. No distinct CCBE1 signature was observed in PBMCs, helping refine future directions for biomarker discovery.
How might this change clinical pharmacology or translational science?
○These findings suggest that PBMC mROS profiling could contribute to understanding CAD‐related redox phenotypes. However, the current data are insufficient to support biomarker utility. If future studies with larger and longitudinal studies confirm these preliminary associations, PBMC redox phenotyping may have the potential to complement existing approaches for CAD risk assessment and for identifying individuals who could benefit from therapies targeting oxidative stress.

What is the current knowledge on the topic?
○Peripheral blood mononuclear cells (PBMCs) contribute to atherosclerosis, and mitochondrial dysfunction with excessive reactive oxygen species (ROS) generation has been implicated in cardiovascular disease. However, the role of mitochondrial ROS (mROS) in PBMC subsets as a biomarker for CAD has not been clearly established.

Peripheral blood mononuclear cells (PBMCs) contribute to atherosclerosis, and mitochondrial dysfunction with excessive reactive oxygen species (ROS) generation has been implicated in cardiovascular disease. However, the role of mitochondrial ROS (mROS) in PBMC subsets as a biomarker for CAD has not been clearly established.

What question did this study address?
○This study examined whether PBMC‐derived mROS levels are associated with CAD, measured by coronary artery calcium scoring, and explored whether single‐cell transcriptomics could identify a distinct gene expression signature (specifically CCBE1) related to CAD in PBMCs.

This study examined whether PBMC‐derived mROS levels are associated with CAD, measured by coronary artery calcium scoring, and explored whether single‐cell transcriptomics could identify a distinct gene expression signature (specifically CCBE1) related to CAD in PBMCs.

What does this study add to our knowledge?
○The study provides preliminary evidence that lymphocytic mROS production may be associated with coronary artery calcium burden in male participants, suggesting a potential link between PBMC mitochondrial redox status and CAD. Additionally, elevated monocyte mROS showed a modest and exploratory association with lower odds of hypertension. These findings indicate potential cell type–specific differences in redox responses, but the observed associations have small effect sizes and require validation. No distinct CCBE1 signature was observed in PBMCs, helping refine future directions for biomarker discovery.

The study provides preliminary evidence that lymphocytic mROS production may be associated with coronary artery calcium burden in male participants, suggesting a potential link between PBMC mitochondrial redox status and CAD. Additionally, elevated monocyte mROS showed a modest and exploratory association with lower odds of hypertension. These findings indicate potential cell type–specific differences in redox responses, but the observed associations have small effect sizes and require validation. No distinct CCBE1 signature was observed in PBMCs, helping refine future directions for biomarker discovery.

How might this change clinical pharmacology or translational science?
○These findings suggest that PBMC mROS profiling could contribute to understanding CAD‐related redox phenotypes. However, the current data are insufficient to support biomarker utility. If future studies with larger and longitudinal studies confirm these preliminary associations, PBMC redox phenotyping may have the potential to complement existing approaches for CAD risk assessment and for identifying individuals who could benefit from therapies targeting oxidative stress.

These findings suggest that PBMC mROS profiling could contribute to understanding CAD‐related redox phenotypes. However, the current data are insufficient to support biomarker utility. If future studies with larger and longitudinal studies confirm these preliminary associations, PBMC redox phenotyping may have the potential to complement existing approaches for CAD risk assessment and for identifying individuals who could benefit from therapies targeting oxidative stress.

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