Highlights
- Serum neurofilament light chain (sNfL) is significantly associated with major vascular events (MVEs) in patients with atrial fibrillation (AF), independent of traditional risk factors.
- The SWISS-AF cohort study reveals that every doubling of sNfL concentration corresponds to a 35% increase in the risk of MVEs.
- Higher sNfL levels are linked to nonfatal stroke, cardiovascular death, heart failure-related hospitalization, and all-cause mortality, though not to myocardial infarction.
- sNfL represents a novel, multi-organ prognostic tool that may refine risk stratification in the complex AF patient population.
Background
Atrial fibrillation (AF) is a global epidemic associated with a substantially increased risk of stroke, heart failure, and death. While clinical risk scores like CHA2DS2-VASc have long guided anticoagulation therapy, they often fail to capture the full spectrum of systemic and cardiovascular vulnerability. Recently, the search for blood-based biomarkers has intensified, aiming to identify high-risk patients who might benefit from more intensive monitoring or therapeutic interventions.
Neurofilament light chain (NfL) is a structural protein uniquely expressed in the axonal cytoplasm of neurons. When axons are damaged due to neurodegenerative disease, trauma, or ischemia, NfL is released into the cerebrospinal fluid and subsequently into the bloodstream. While serum NfL (sNfL) has gained prominence as a marker for multiple sclerosis, Alzheimer’s disease, and stroke, its relevance in cardiovascular disease—specifically AF—has only recently come to light. Patients with AF are known to have higher sNfL levels than those in sinus rhythm, potentially reflecting silent brain infarcts or chronic cerebral hypoperfusion. However, whether sNfL can serve as a broader sentinel for cardiovascular outcomes remained an unanswered question until the publication of the SWISS-AF analysis.
Key Content
The SWISS-AF Cohort: Study Design and Methodology
The Swiss Atrial Fibrillation Cohort (SWISS-AF) study is a prospective, multicenter, observational study designed to assess the long-term outcomes and complications of patients with documented AF. The analysis conducted by Baskaran et al. included 2311 patients enrolled between 2014 and 2017 across 14 care centers in Switzerland. The cohort was characterized by an elderly population (mean age 73.2 years) with a male predominance (73%).
The primary exposure was the baseline concentration of sNfL, measured using an ultrasensitive single-molecule array (Simoa) assay, which allows for the detection of protein concentrations at sub-picogram levels. The primary endpoint was Major Vascular Events (MVEs), a composite of cardiovascular death, nonfatal stroke, and nonfatal myocardial infarction (MI). Secondary endpoints included heart failure hospitalizations and all-cause mortality. The median follow-up period was impressively long at 8.0 years, providing robust data for longitudinal assessment.
Association Between sNfL and Primary Outcomes
The study found a strong, linear association between elevated sNfL levels and the occurrence of MVEs. Over the follow-up period, 665 MVEs occurred. After adjusting for age, sex, renal function, and traditional cardiovascular risk factors, every doubling of sNfL was associated with an adjusted hazard ratio (aHR) of 1.35 (95% CI, 1.22-1.50) for MVEs. This suggests that sNfL provides prognostic information that is not fully captured by existing clinical variables.
Divergent Findings: Stroke vs. Myocardial Infarction
Interestingly, the association was not uniform across all components of the composite endpoint. Increasing sNfL was significantly associated with:
- Nonfatal Stroke: aHR 1.31 (95% CI, 1.09-1.57), reinforcing its role as a marker of neuronal injury.
- Cardiovascular Death: aHR 1.36 (95% CI, 1.20-1.54).
- All-cause Mortality: aHR 1.41 (95% CI, 1.27-1.56).
However, there was no significant association between sNfL levels and nonfatal myocardial infarction (aHR 1.04; P = .76). This divergence suggests that sNfL may be more reflective of vascular-driven neuro-axonal damage and general systemic frailty rather than coronary-specific atherosclerotic events.
Heart Failure and Systemic Vulnerability
One of the most striking findings was the association between sNfL and heart failure-related hospitalizations (aHR 1.25; 95% CI, 1.11-1.41). This suggests that sNfL may be a surrogate for systemic congestion or endothelial dysfunction that predisposes patients to cardiac decompensation. The link between a neuro-axonal protein and heart failure highlights the potential of sNfL as a marker of “biological aging” or multi-organ cross-talk in AF patients.
Expert Commentary
The findings from the SWISS-AF study represent a paradigm shift in how we view neuro-biomarkers. Traditionally, sNfL was pigeonholed as a neurology-specific tool. These data suggest it may actually function as a “barometer” of systemic vascular health in the AF population. Several mechanistic hypotheses may explain this:
- Silent Cerebral Damage: AF causes micro-emboli and chronic hypoperfusion, leading to cumulative axonal damage that sNfL detects before clinical symptoms appear.
- Endothelial Dysfunction: Systemic vascular disease affects both the blood-brain barrier and the coronary/systemic circulation. Elevated sNfL might indicate a pervasive endothelial failure.
- Comorbidity Burden: sNfL levels are known to rise with age and renal dysfunction, but even after adjustment, the association remains. It likely integrates the cumulative impact of various comorbidities (diabetes, hypertension) on organ systems.
Clinically, sNfL could potentially be integrated into a multi-marker risk score alongside NT-proBNP and high-sensitivity troponin. While those markers are heart-specific, sNfL adds a “neuro-vascular” dimension, identifying patients at high risk for death and stroke who might be missed by cardiac-only markers. However, a limitation of the study is its observational nature; we do not yet know if intervening on AF (e.g., earlier ablation or more aggressive anticoagulation) based on high sNfL levels will actually improve outcomes.
Conclusion
The SWISS-AF study establishes serum neurofilament light chain as a powerful and independent prognostic biomarker for a wide range of cardiovascular events and mortality in patients with atrial fibrillation. Its ability to predict cardiovascular death and heart failure hospitalizations, in addition to its known role in stroke monitoring, makes it a uniquely versatile tool for risk stratification. Future research should focus on whether sNfL levels change in response to AF treatments and whether such changes correspond to reduced clinical risk. For now, clinicians should recognize sNfL as an emerging marker of systemic vulnerability that bridges the gap between neurology and cardiology.
References
- Baskaran G, Krisai P, Kühne M, et al. Serum Neurofilament Light Chain and Cardiovascular Outcomes in Patients With Atrial Fibrillation. JAMA Cardiol. 2026;11(5):400-407. PMID: 41904963.
- Kuhle J, Kropshofer H, Haering DA, et al. Blood neurofilament light chain as a biomarker of MS disease activity and treatment response. Neurology. 2019;92(10):e1007-e1015.
- Polymeris AA, et al. Serum neurofilament light chain at stroke onset and functional outcome at 3 months. Neurology. 2020;94(8):e841-e850.