The Role of Cardiac Fibrosis and Fibroblast Activation in Amyloid Light Chain (AL) Amyloidosis

Q: What are the key findings of this study?

Amyloidogenic light chains upregulated 378 myocardial genes including COL1A1, COL3A1, and POSTN, increased type III collagen ratio, and directly induced fibroblast activation.

Q: What is the clinical evidence from this study?

Population: Cardiac amyloid light chain (AL) amyloidosis (n=21). Intervention: Amyloidogenic light chain (AL-LC) pathology and in vitro AL-LC stimulation vs. Healthy donor controls, non-AL heart failure tissues, and unstimulated or non-cardiac AL-LC-treated fibroblasts. Primary outcome: Myocardial transcriptomic/histological fibrosis profiling (Type I collagen ratio) and in vitro fibroblast-to-myofibroblast transition (p=<0.001).

Q: What question did this study set out to answer?

To elucidate the cellular and transcriptomic mechanisms driving cardiac fibrosis and fibroblast activation in light chain (AL) amyloid cardiomyopathy.

Shingo Narita; Johanna Jimenez; Nixuan Cai; Hiroki Kitakata; Sharmila Dorbala; Y. Joseph Woo; Kevin M. Alexander; Ronglih Liao

doi:10.1016/j.jacbts.2026.101653

August 27, 2026JACC Basic to Translational ScienceOpen Access

The Role of Cardiac Fibrosis and Fibroblast Activation in Amyloid Light Chain (AL) Amyloidosis

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Key result

Amyloidogenic light chains drive myocardial fibrosis by activating fibroblasts and halving type I collagen ratio.

P<0.001
n=21

Why the study?

The precise pathophysiological mechanisms underlying fibrosis in cardiac AL amyloidosis remain largely unexplored.

Does pathogenic amyloidogenic light chain (AL-LC) directly induce cardiac fibroblast activation and extracellular matrix remodeling in cardiac AL amyloidosis?

Key Points

To elucidate the cellular and transcriptomic mechanisms driving cardiac fibrosis and fibroblast activation in light chain (AL) amyloid cardiomyopathy.
Bulk RNA sequencing was conducted on human left ventricle midwall samples from patients with cardiac AL amyloidosis, non-AL heart failure, and healthy donor controls (n = 3 per group).
Transcriptomic findings were validated using reverse transcription-qPCR (n = 5) and Western blotting (n = 4) in human cardiac tissue.
Cultured cardiac fibroblasts were stimulated with pathogenic amyloidogenic light chain (AL-LC) in vitro to examine fibroblast-to-myofibroblast transition.
Transcriptome profiling revealed 378 upregulated genes (log2FC > 1, Padj < 0.05) in cardiac AL amyloidosis versus healthy controls, with key fibrosis drivers including COL1A1, COL3A1, and POSTN.
Multi-group comparison detected 53 cardiac AL amyloidosis-dependent upregulated genes, confirming distinct enrichment of extracellular matrix organization, collagen fibril organization, and mesenchymal differentiation pathways.
Histology and Western blotting confirmed significant accumulation of type III collagen and periostin in cardiac tissue, while in vitro AL-LC exposure directly triggered partial fibroblast-to-myofibroblast transition.

Structured PICO

Does pathogenic amyloidogenic light chain (AL-LC) directly induce cardiac fibroblast activation and extracellular matrix remodeling in cardiac AL amyloidosis?

P

Population

21 human myocardial tissue samples (7 cardiac AL amyloidosis, 6 non-AL heart failure, and 8 healthy controls) and cultured human ventricular cardiac fibroblasts stimulated with purified patient-derived amyloidogenic light chains.

E

Exposure

Pathogenic amyloidogenic light chain (AL-LC) exposure in vivo (human cardiac AL amyloidosis myocardium) and in vitro stimulation of human ventricular cardiac fibroblasts with purified AL-LC (1, 3, 10, and 30 μg/mL for 48 hours).

C

Comparator

Healthy donor heart tissues (n=8) and non-AL heart failure tissues (n=6) for tissue analyses; unstimulated negative control, TGF-β1 (10 ng/mL) positive control, and AL-LC from a patient without cardiac involvement (Con-LC, 10 μg/mL) for in vitro analyses.

O

Outcome

Differential expression of fibrosis-related genes and proteins (bulk RNA-seq, RT-qPCR, Western blot for COL1A1, COL3A1, POSTN, FN1), histological collagen composition (Masson's trichrome, Congo red, Picrosirius red for type I vs type III collagen ratio), and in vitro fibroblast-to-myofibroblast transition measured by α-SMA expression at 48 hours.surrogate

Main Result

Absolute Event Rate: 44% vs 88%

p-value: p=<0.001

Limitations

Small sample size with only 7 cardiac AL amyloidosis tissue samples (6 explanted hearts and 1 autopsy)
Most patients had advanced heart failure (5 of 7 Mayo stage IV) and 6 of 7 had received prior chemotherapy, reflecting late-stage post-treatment pathophysiology
Potential confounding from chemotherapy-related cardiotoxicity and cardiac fibrosis cannot be completely excluded
Absence of in vivo and clinical validation of fibroblast activation mechanisms, particularly at early disease stages
Small sample size (only 7 cardiac AL amyloidosis tissue samples from 6 explanted hearts and 1 autopsy)
Findings primarily reflect late-stage, post-treatment pathophysiology as 5 of 7 patients had Mayo stage IV disease and 6 of 7 received prior chemotherapy
Chemotherapy-related cardiotoxicity and cardiac fibrosis cannot be completely excluded
Absence of in vivo animal model and clinical validation of fibroblast activation mechanisms at early disease stages

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Implication

This translational study demonstrates that amyloidogenic light chains directly induce cardiac fibroblast-to-myofibroblast transition and type III collagen-predominant fibrosis in AL cardiomyopathy, revealing potential diagnostic biomarkers and antifibrotic therapeutic targets.

Abstract

Recent studies suggest that interactions between collagen and amyloid fibril may influence amyloid formation, matrix remodeling, and disease progression in cardiac amyloid light chain (AL) amyloidosis. However, the precise pathophysiological mechanisms underlying fibrosis remain largely unexplored. Here, we performed transcriptome analysis of myocardial samples from patients with AL amyloidosis and identified upregulation of fibroblast activation genes, such as collagen type I/III and periostin. Histology showed predominantly type III collagen fibrosis, accompanied by cardiac fibroblasts present within the interstitial myocardium, including areas with amyloidogenic light chain (AL-LC). We further demonstrated a partial fibroblast-to-myofibroblast transition (FMT) in vitro by stimulating cardiac fibroblasts with AL-LC. This indicates that pathogenic AL-LC directly induces fibroblast activation and that matrix remodeling accelerates during amyloid fibril deposition. This extensive cellular and molecular characterization provides novel insights into the essential role of fibrotic pathology in AL cardiomyopathy and may enable the discovery of biomarkers and therapeutic targets.

Discussion

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Cite This Study

Narita et al. (2026) studied Cardiac amyloid light chain (AL) amyloidosis (n=21). Amyloidogenic light chain (AL-LC) pathology and in vitro AL-LC stimulation vs. Healthy donor controls, non-AL heart failure tissues, and unstimulated or non-cardiac AL-LC-treated fibroblasts was evaluated on Myocardial transcriptomic/histological fibrosis profiling (Type I collagen ratio) and in vitro fibroblast-to-myofibroblast transition (p=<0.001). Amyloidogenic light chains upregulated 378 myocardial genes including COL1A1, COL3A1, and POSTN, increased type III collagen ratio, and directly induced fibroblast activation.

synapsesocial.com/papers/6a92bf3c8e5d7d1fc0c123f9 https://doi.org/10.1016/j.jacbts.2026.101653

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The Role of Cardiac Fibrosis and Fibroblast Activation in Amyloid Light Chain (AL) Amyloidosis

Key Points

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

The Role of Cardiac Fibrosis and Fibroblast Activation in Amyloid Light Chain (AL) Amyloidosis

Key Points

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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