Validating fatty acid binding protein 3 as a diagnostic and prognostic biomarker for peripheral arterial disease: a three-year prospective follow-up study

Zamzam, Abdelrahman; Syed, Muzammil H.; Rotstein, Ori D.; Eikelboom, John W.; Klein, David J.; Singh, Krishna K.; Abdin, Rawand; Qadura, Mohammad

doi:10.1016/j.eclinm.2022.101766

Cited by 5 publications

(5 citation statements)

References 49 publications

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“…Thus, EVs can be treated like any other component measured in blood, such as neurofilaments or fatty acids, whose increasingly relevant roles in disease susceptibility may provide therapeutic targets or prognostic/diagnostic markers [ 47 , 48 , 49 ]. EV assessment in large cohorts could further analyze their involvement in complex diseases through the colocalization of GWAS signals for EV levels and diseases and Mendelian randomization [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

Effect of Genetic Factors, Age and Sex on Levels of Circulating Extracellular Vesicles and Platelets

Orrù

Virdis

Marongiu

et al. 2023

IJMS

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Extracellular vesicles (EVs) mediate cell interactions in biological processes, such as receptor activation or molecule transfer. Estimates of variation by age and sex have been limited by small sample size, and no report has assessed the contribution of genetic factors to levels of EVs. Here, we evaluated blood levels of 25 EV and 3 platelet traits in 974 individuals (933 genotyped) and reported the first genome-wide association study (GWAS) on levels of these traits. EV levels all decreased with age, whereas the trend for their surface markers was more heterogeneous. Platelets and CD31dim platelet EVs significantly increased in females compared to males, although CD31 expression on both platelets and platelet EVs decreased in females. Levels of the other EV subsets were similar between sexes. GWAS revealed three statistically significant genetic signals associated with EV levels in the F10 and GBP1 genes and in the intergenic region between LRIG1 and KBTBD8. These add to a signal in the 3′UTR of RHOF associated with CD31 expression on platelets that was previously found to be associated with other platelet traits. These findings suggest that EV formation is not a simple, constant adjunct of metabolism but is under both age-related and genetic control that can be independent of the regulation of the levels of the cells from which the EVs derive.

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Section: Discussionmentioning

confidence: 99%

Effect of Genetic Factors, Age and Sex on Levels of Circulating Extracellular Vesicles and Platelets

Orrù

Virdis

Marongiu

et al. 2023

IJMS

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“…Despite its strong correlation with limb loss and mortality, PAD often receives inadequate treatment [ 3 ]. A potential approach to addressing this issue involves the identification of biomarkers to aid in the prognosis of PAD patients [ 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

“…Given that PAD is characterized by muscle ischemia, myokines may act as biomarkers for PAD development and progression [ 6 ]. Our group has previously identified several biomarkers for PAD, including fatty acid binding proteins [ 5 , 7 , 8 , 9 , 10 ], inflammatory proteins [ 11 ], and Cystatin C [ 12 ]; however, the investigation of myokines as PAD biomarkers has been limited. Myokines, including fibroblast growth factor-23 (FGF-23) [ 13 ], tumour necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) [ 14 ], interleukin-7 (IL-7) [ 15 ], and monocyte chemoattractant protein-1 (MCP-1) [ 16 ], among others, have been implicated in cardiovascular diseases.…”

Section: Introductionmentioning

confidence: 99%

The Identification and Evaluation of Interleukin-7 as a Myokine Biomarker for Peripheral Artery Disease Prognosis

Li,

Shaikh,

Zamzam

et al. 2024

JCM

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Background/Objectives: Myokines have been demonstrated to be associated with cardiovascular diseases; however, they have not been studied as biomarkers for peripheral artery disease (PAD). We identified interleukin-7 (IL-7) as a prognostic biomarker for PAD from a panel of myokines and developed predictive models for 2-year major adverse limb events (MALEs) using clinical features and plasma IL-7 levels. Methods: A prognostic study was conducted with a cohort of 476 patients (312 with PAD and 164 without PAD) that were recruited prospectively. Their plasma concentrations of five circulating myokines were measured at recruitment, and the patients were followed for two years. The outcome of interest was two-year MALEs (composite of major amputation, vascular intervention, or acute limb ischemia). Cox proportional hazards analysis was performed to identify IL-7 as the only myokine that was associated with 2-year MALEs. The data were randomly divided into training (70%) and test sets (30%). A random forest model was trained using clinical characteristics (demographics, comorbidities, and medications) and plasma IL-7 levels with 10-fold cross-validation. The primary model evaluation metric was the F1 score. The prognostic model was used to classify patients into low vs. high risk of developing adverse limb events based on the Youden Index. Freedom from MALEs over 2 years was compared between the risk-stratified groups using Cox proportional hazards analysis. Results: Two-year MALEs occurred in 28 (9%) of patients with PAD. IL-7 was the only myokine that was statistically significantly correlated with two-year MALE (HR 1.56 [95% CI 1.12–1.88], p = 0.007). For the prognosis of 2-year MALEs, our model achieved an F1 score of 0.829 using plasma IL-7 levels in combination with clinical features. Patients classified as high-risk by the predictive model were significantly more likely to develop MALEs over a 2-year period (HR 1.66 [95% CI 1.22–1.98], p = 0.006). Conclusions: From a panel of myokines, IL-7 was identified as a prognostic biomarker for PAD. Using a combination of clinical characteristics and plasma IL-7 levels, we propose an accurate predictive model for 2-year MALEs in patients with PAD. Our model may support PAD risk stratification, guiding clinical decisions on additional vascular evaluation, specialist referrals, and medical/surgical management, thereby improving outcomes.

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“…Unfortunately, these have not translated to routine clinical practice partly because of non-specificity to PAD, as they are also elevated in patients with other cardiovascular conditions such as coronary or cerebrovascular disease [ 36 , 37 ]. Recently, several biomarkers specific to PAD have been identified in the research setting, including fatty acid binding protein 3 (FABP3) [ 38 , 39 , 40 , 41 ]. This blood- and urine-based biomarker was demonstrated to be independently associated with the diagnosis of PAD and the prognosis of PAD-related adverse events, including major amputation and the need for surgical intervention [ 38 , 39 , 40 , 41 ].…”

mentioning

confidence: 99%

“…Recently, several biomarkers specific to PAD have been identified in the research setting, including fatty acid binding protein 3 (FABP3) [ 38 , 39 , 40 , 41 ]. This blood- and urine-based biomarker was demonstrated to be independently associated with the diagnosis of PAD and the prognosis of PAD-related adverse events, including major amputation and the need for surgical intervention [ 38 , 39 , 40 , 41 ]. The validation of these biomarkers for clinical implementation is ongoing and holds promise for improving PAD awareness.…”

mentioning

confidence: 99%

Increasing Awareness for Peripheral Artery Disease through the Identification of Novel Biomarkers

Li,

Syed,

Qadura

2023

Biomolecules

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Validating fatty acid binding protein 3 as a diagnostic and prognostic biomarker for peripheral arterial disease: a three-year prospective follow-up study

Cited by 5 publications

References 49 publications

Effect of Genetic Factors, Age and Sex on Levels of Circulating Extracellular Vesicles and Platelets

Effect of Genetic Factors, Age and Sex on Levels of Circulating Extracellular Vesicles and Platelets

The Identification and Evaluation of Interleukin-7 as a Myokine Biomarker for Peripheral Artery Disease Prognosis

Increasing Awareness for Peripheral Artery Disease through the Identification of Novel Biomarkers

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