**Author Listing - Lead/ Submitting Author (we will be communicating with this individual): Name, Institution, City and State where the work was done. Co-authors will be added in a separate section.**
Xiaokang Wu, MD, PhD
1. Stanford Cardiovascular Institute, Stanford University, Stanford, CA 94305, USA
2. Department of Medicine, Division of Cardiology, Stanford University, Stanford, CA 94305, USA

**Main Body of the Abstract**
Transthyretin cardiac amyloidosis (ATTR-CM) is an often-underdiagnosed, progressive cardiomyopathy that can lead to heart failure and death. Gradual deposition of amyloid fibrils, consisting of transthyretin (TTR), within the myocardium causes cardiac thickening and dysfunction. Robust in vivo models are needed to elucidate the precise pathogenic mechanisms of ATTR-CM. We developed a murine TTR knockout model expressing the human V122I TTR variant. We observed increased human TTR levels in plasma compared to controls (110 ± 10 ng/ml vs. 28 ± 12 ng/ml; p = 0.0008) with preserved cardiac function (FS%: 20 ± 6 for ATTR vs. 23 ± 5 for control; p = 0.8162). Histopathological analyses revealed the amyloidogenic deposits within murine hearts, confirmed by Congo Red and Thioflavin T staining. Transmission electron microscopy confirmed immature and mature amyloid fibrils in ATTR (Figure 1). Subsequent RNA-sequencing of the murine hearts unveiled distinct transcriptomic profiles similar to findings that we observed in human ATTR hearts, particularly highlighting inflammation-related pathways such as TNF, T-cell, and B-cell signaling. Up-regulation of inflammatory markers, including CXCL1/2/3 and CCL20, was also observed. Moreover, an increased level of CCL5 (MFI ATTR: 801 ± 105; Control: 426 ± 64; p = 0.0061, N = 3) was confirmed via luminance-based immunoassay. These chemokines are critical for directing leukocytes to inflammation sites. In summary, our humanized ATTR mouse model suggests a potential role for inflammation in the pathogenesis of ATTR amyloidosis. Further studies are needed to decipher the precise interactions between inflammation and ATTR-CM.



**Author Listing - Lead/ Submitting Author (we will be communicating with this individual): Name, Institution, City and State where the work was done. Co-authors will be added in a separate section.**
**Xiaokang Wu, MD, PhD**
1. Stanford Cardiovascular Institute, Stanford University, Stanford, CA 94305, USA
2. Department of Medicine, Division of Cardiology, Stanford University, Stanford, CA 94305, USA

**Main Body of the Abstract**
Transthyretin cardiac amyloidosis (ATTR-CM) is an often-underdiagnosed, progressive cardiomyopathy that can lead to heart failure and death. Gradual deposition of amyloid fibrils, consisting of transthyretin (TTR), within the myocardium causes cardiac thickening and dysfunction. Robust _in vivo_ models are needed to elucidate the precise pathogenic mechanisms of ATTR-CM. We developed a murine TTR knockout model expressing the human _V122I_ TTR variant. We observed increased human TTR levels in plasma compared to controls (110 ± 10 ng/ml vs. 28 ± 12 ng/ml; p = 0.0008) with preserved cardiac function (FS%: 20 ± 6 for ATTR vs. 23 ± 5 for control; p = 0.8162). Histopathological analyses revealed the amyloidogenic deposits within murine hearts, confirmed by Congo Red and Thioflavin T staining. Transmission electron microscopy confirmed immature and mature amyloid fibrils in ATTR (**Figure 1**). Subsequent RNA-sequencing of the murine hearts unveiled distinct transcriptomic profiles similar to findings that we observed in human ATTR hearts, particularly highlighting inflammation-related pathways such as TNF, T-cell, and B-cell signaling. Up-regulation of inflammatory markers, including CXCL1/2/3 and CCL20, was also observed. Moreover, an increased level of CCL5 (MFI ATTR: 801 ± 105; Control: 426 ± 64; p = 0.0061, N = 3) was confirmed via luminance-based immunoassay. These chemokines are critical for directing leukocytes to inflammation sites. In summary, our humanized ATTR mouse model suggests a potential role for inflammation in the pathogenesis of ATTR amyloidosis. Further studies are needed to decipher the precise interactions between inflammation and ATTR-CM.



Deciphering the pathogenesis of transthyretin cardiac amyloidosis in a humanized mouse model  OB11 (#324)

We invite you to attend the XIX International Symposium on Amyloidosis to be held in Rochester, MN.

This symposium is organized as a hybrid meeting (with the focus on in-person) held from Sunday, May 26 through Thursday, May 30, 2024.

Together with the ISA Board and members of Mayo Clinic, a very attractive scientific hybrid program is being planned. The program will cover a variety of types of systemic amyloidosis: ATTR (hereditary and wild-type), AL (light-chain), AA and less frequent forms. There will be key lectures, specific symposia including those company sponsored, oral presentations and poster sessions of accepted abstracts.

COURSE DESCRIPTION
This program will provide a comprehensive review of state-of-the-art education in systemic amyloidosis: basic science, pathophysiology, diagnosis, current and emerging treatments. Scientific presentations will include competitive oral and poster abstracts. The rapid evolution of scientific discovery and expanding treatment options has created tremendous interest in the field and this meeting will fill and important gap in educating scientists and clinicians.