December 8, 2025

Serum cFAS Shows Promise as a Diagnostic Marker in PAD and CLTI

December 8, 2025—In a retrospective study evaluating circulating fatty acid synthase (cFAS) as a biomarker for peripheral artery disease (PAD), Abu-Amer et al found that elevated cFAS levels were independently associated with both PAD and chronic limb-threatening ischemia (CLTI), with higher concentrations correlating with greater disease severity. Results were published in JACC: Basic to Translational Science.¹

KEY FINDINGS

Serum cFAS levels were significantly higher in patients with PAD and CLTI compared with healthy controls, with the highest concentrations observed in CLTI.
Two diagnostic cutoffs (≥ 340 pg/mg for PAD/CLTI and ≥ 490 pg/mg for CLTI) demonstrated moderate sensitivity and specificity, supporting cFAS as a potential screening and staging biomarker.
Elevated cFAS remained independently associated with PAD and CLTI after adjusting for age, diabetes, lipid levels, renal function, and medication use.
cFAS correlated with ABI and Rutherford classification, suggesting utility in reflecting disease severity.

Investigators analyzed serum samples and clinical data from 347 individuals enrolled in a vascular surgery biobank between 2014 and 2023. Participants were categorized as healthy controls (n = 34), PAD (n = 164), or CLTI (n = 149) based on ankle-brachial index (ABI) measurements and Rutherford classification. Exclusion criteria included advanced kidney or liver disease, alcohol abuse, prior inclusion in earlier cFAS studies, and unverified PAD status. Serum cFAS was quantified using ELISA, normalized to total protein content, and compared across groups. Lipid panels and cardiovascular risk factors were also evaluated.

The primary objective was to assess whether serum cFAS could distinguish individuals with PAD or CLTI from controls. Secondary aims examined whether cFAS could stratify disease severity and provide incremental diagnostic value beyond traditional measures such as low-density lipoprotein (LDL) levels or ABI. Receiver operating characteristic (ROC) analyses were used to identify optimal diagnostic cutoffs, and multivariable logistic regression accounted for age, diabetes, lipid levels, renal function, and medication use.

Median serum cFAS levels rose progressively across groups: 46.9 pg/mg in controls, 326.2 pg/mg in PAD, and 423.8 pg/mg in CLTI (P = .002). cFAS concentrations were markedly elevated in both PAD and CLTI compared with controls, with the highest levels in CLTI. ROC analysis identified a threshold of ≥ 340 pg/mg for distinguishing PAD/CLTI from controls (area under the receiver operating curve [AUC], 0.679), yielding 52.4% sensitivity and 79.9% specificity. A higher cutoff of ≥ 490 pg/mg helped differentiate CLTI from PAD or controls (AUC, 0.553). After adjustment, cFAS remained independently associated with PAD/CLTI (adjusted odds ratio [OR], 1.05; 95% CI, 1.01-1.09; P = .015) and showed a borderline association with CLTI alone (adjusted OR, 1.11; P = .055).

Additional findings included inverse correlations between cFAS and ABI and positive correlations with Rutherford score, supporting the relevance of cFAS as a severity marker. Lipid values (LDL, high-density lipoprotein, total cholesterol) were lower among PAD and CLTI patients, but this was likely a reflection of statin use and not an indicator of disease status. cFAS levels were not influenced by statins, aspirin, diabetes, or carotid disease, suggesting potential diagnostic independence from traditional risk factors.

Study limitations noted by the investigators included the reliance on a surgically enriched biobank population, having a younger healthy control group, potential recall bias, limited representation of asymptomatic PAD, and small sample size for CLTI severity stratification. Prospective studies with serial sampling are needed to evaluate whether cFAS changes with revascularization or predicts major adverse limb events.

This study identifies serum cFAS as a promising diagnostic and risk-stratification biomarker for PAD and CLTI. Elevated cFAS distinguished disease presence and severity better than LDL cholesterol or ABI in this cohort, supporting its potential use as a noninvasive clinical tool and laying groundwork for future validation.

1. Abu-Amer W, Shorbaji K, Meade R, et al. Serum cFAS content correlates with incidence of peripheral arterial disease. JACC Basic Transl Sci. Published online November 12, 2025. doi: 10.1016/j.jacbts.2025.101411

ENDOVASCULAR TODAY ASKS...

Study investigator Mohamed A. Zayed, MD, with Washington University School of Medicine in St. Louis, Missouri, provides additional insights into the results of this study and how serum cFAS could affect diagnostic algorithms for PAD/CLTI in clinical practice.

How do you envision serum cFAS being integrated into current PAD diagnostic workflows, particularly given the limitations of ABI and reliance on symptom-based identification?

Serum cFAS could serve as an early, noninvasive biochemical screening tool that complements ABI, particularly in patients for whom physiologic testing is unreliable due to calcified vessels or atypical symptoms. By providing an objective molecular signal of vascular metabolic dysfunction, cFAS can help identify disease earlier in the trajectory—well before manifestations of severe arterial insufficiency. In primary care and high-risk clinics, cFAS could be used to triage patients for confirmatory imaging or ABI testing, helping reduce underdiagnosis. Ultimately, integrating cFAS into routine blood panels could modernize PAD detection by shifting reliance away from symptom-driven recognition toward a more proactive molecular screening.

What clinical scenarios or patient populations do you believe would benefit most from early cFAS testing?

Patients with diabetes, chronic kidney disease, or medial arterial calcification—groups in whom ABI is notoriously unreliable—stand to benefit substantially from early cFAS testing. Individuals with atypical leg symptoms or functional limitations that mask claudication could also be identified earlier using a molecular signal rather than symptom reporting. Screening high-risk but asymptomatic populations, such as smokers or those with a strong family history of atherosclerotic disease, may help uncover subclinical PAD before limbs become threatened. Additionally, vascular surgery and wound care clinics could use cFAS to identify patients at greatest risk of progression toward CLTI.

Given that cFAS remained independently associated with PAD and CLTI after adjusting for traditional risk factors, how might this biomarker complement or outperform existing markers such as LDL or inflammatory indicators?

Unlike LDL or inflammatory markers, which reflect systemic metabolic or immune activity, cFAS appears to capture a metabolic phenotype directly related to atheroprogression. Because cFAS levels are not confounded by statin use, diabetes, or aspirin therapy, it provides diagnostic independence from traditional risk factors that often obscure true disease burden. cFAS complements ABI by offering a biochemical dimension of disease severity that correlates with Rutherford classification, something existing markers (including LDL) do not reliably achieve. Together, these characteristics suggest that cFAS could outperform current biomarkers in identifying patients with active atherosclerotic limb disease and stratifying their risk.

What steps are needed to translate cFAS testing into a clinically validated, widely available assay, and what challenges do you foresee in implementing it in routine practice?

The next steps include multicenter prospective studies, analytical validation of standardized assays, and CLIA/FDA regulatory pathways to ensure accuracy and reproducibility across laboratories. Establishing population-based reference ranges and actionable biomarker thresholds are essential for broad adoption. Challenges include integrating a novel biomarker into existing clinical workflows and educating clinicians on its interpretation and utility. Nonetheless, given its strong mechanistic basis and early diagnostic promise, these hurdles are surmountable with coordinated academic, industry, and regulatory collaboration.

In your opinion, does serum cFAS have a future role in predicting adverse limb outcomes, such as progression to CLTI or need for intervention? Are there any plans for prospective studies to evaluate its prognostic value?

Given the strong correlation between elevated cFAS levels, ABI reduction, and higher Rutherford class, it is highly plausible that cFAS will serve as a prognostic marker for progression to CLTI or need for revascularization. A dynamic biomarker reflecting active vascular metabolic dysfunction may be particularly powerful in predicting which patients will deteriorate despite guideline-directed therapy. Our group is actively designing prospective longitudinal studies with serial cFAS measurements to assess whether changes over time correlate with limb events, wound healing, and postintervention outcomes. These studies will be critical for determining whether cFAS can guide personalized surveillance and therapeutic decision-making in PAD.

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