Inflammatory endotypes in cardiac amyloidosis: divergent cytokine- and neutrophil-driven pathways in AL and ATTR”

Background

Cardiac amyloidosis (CA) is an infiltrative cardiomyopathy caused by extracellular deposition of misfolded proteins leading to progressive heart failure. While inflammation is central in AA amyloidosis, its role in transthyretin (ATTR) and light-chain (AL) amyloidosis remains insufficiently characterized. Extracellular matrix remodeling, complement activation, and amyloid cytotoxicity suggest a pro-inflammatory component, but systemic inflammatory patterns in CA are poorly defined.

Purpose

To (1) demonstrate systemic inflammation in CA using routine serum inflammatory biomarkers; (2) identify distinct inflammatory pathways in AL and ATTR amyloidosis; and (3) evaluate the prognostic impact of inflammatory markers.

Methods

We retrospectively analyzed 1,000 patients with amyloidosis and heart failure (2021–2024), including ATTR (n=358), AL (n=94), and other cardiomyopathies (Other-CM, n=258). Calprotectin, interleukin-6 (IL-6), and serum amyloid A (SAA) were quantified by ELISA. Associations with echocardiographic parameters, cardiac biomarkers (NT-proBNP, troponin), hepatic and renal function, and bone scintigraphy (H/M ratio) were assessed. Survival analyses were performed using Cox regression models.

Results

ATTR patients most frequently exhibited elevation of all three markers (23.5%), with isolated calprotectin predominance (12.8%), supporting a local inflammatory phenotype. In AL amyloidosis, IL-6 showed the highest isolated prevalence (17.0%), with strong IL-6/SAA overlap (20.2%), indicating cytokine-driven systemic inflammation. Other-CM showed predominantly 1–2 elevated markers, suggesting moderate and heterogeneous inflammation.

In ATTR, calprotectin correlated with diastolic dysfunction, right ventricular remodeling, and LV morphology, while IL-6 was associated with NT-proBNP, troponin, bilirubin, H/M ratio, and diastolic indices. In AL, IL-6 strongly correlated with NT-proBNP, troponin, bilirubin, and renal dysfunction; SAA was associated with LV hypertrophy.

Inflammatory markers predicted mortality. IL-6 was independently associated with death in AL (HR=1.23, p=0.003) and showed a trend in ATTR. Calprotectin predicted mortality in ATTR (HR=1.37, p=0.047). SAA was predictive only in Other-CM (HR=2.12, p=0.037)( Figure1).

Conclusion

Cardiac amyloidosis exhibits subtype-specific inflammatory signatures. AL amyloidosis is characterized by systemic cytokine-driven inflammation (IL-6), whereas ATTR demonstrates predominantly local myocardial inflammation (calprotectin). Inflammatory biomarkers independently predict mortality and may refine risk stratification in CAFigure 1predictors factors of mortality