Seidman, JonathanSeidman, ChristineWang, Adam2026-06-2420262026-06-242026Wang, Adam. 2026. Dissecting Disease Mechanisms of Cardiac Amyloidosis at the Single Cell Level. Bachelors Thesis, Harvard University Engineering and Applied Sciences.32575743https://dash.harvard.edu/handle/1/42742209Cardiac amyloidosis is a heart disease characterized by protein misfolding and deposition in the heart that leads to progressive dysfunction and heart failure. Questions remain regarding the precise mechanisms of pathology in amyloidosis; the transcriptomic landscape of this disease remains completely uncharacterized. Thus, this thesis used single-nucleus RNA sequencing (snRNA-seq) to assess the transcriptomic expression of the two predominant forms of cardiac amyloidosis, light-chain (AL) and transthyretin (ATTR) amyloidosis, in comparison with control and dilated cardiomyopathy tissue. We isolated 535,405 nuclei across 113 cardiac tissue samples to identify disease-specific patterns of cellular composition, transcriptional states, and inferred intercellular communication. Both AL and ATTR were associated with cardiomyocyte depletion and expansion of endothelial and fibroblast populations, consistent with broad multicellular remodeling; however, the two diseases exhibited distinct dominant signaling programs. AL amyloidosis was characterized by widespread inflammatory and stress-response signaling across multiple cell types. This included global upregulation of THBS1 and enrichment of macrophage and fibroblast states consistent with acute injury-associated signaling. In contrast, ATTR amyloidosis displayed more immunomodulatory and profibrotic remodeling programs. This included endothelial upregulation of CD200 with corresponding CD200R1 expression in resident macrophage populations, as well as expression of transcriptional features consistent with macrophage–fibroblast fibrotic signaling. These findings support distinct multicellular models of cardiac amyloidosis: an acute inflammatory injury program in AL and a more chronic immunomodulatory, fibrotic remodeling program in ATTR. Overall, this work provides a transcriptomic framework for understanding subtype-specific disease pathology in cardiac amyloidosis and highlights candidate pathways for future mechanistic and spatial validation.application/pdfenGeneticsMedicineThesis or Dissertation2026-06-24