Age-related wild type transthyretin amyloidosis (ATTRwt) is a systemic condition that is characterized by deposition of amyloidogenic fibrils of misfolded transthyretin (TTR) in various organ systems. This disease manifests as an infiltrative cardiomyopathy hallmarked by extracellular deposition of misfolded TTR fibrils in the cardiac tissue, leading to cardiac dysfunction and heart failure with preserved ejection fraction (HFpEF); this disease is underdiagnosed and may affect 25% of elderly men and women. We hypothesize that deposition of amyloidogenic TTR fibrils alters cardiomyocyte contractility and sarcomere structure via modulation of cell growth due to altered microenvironmental features such as substrate stiffness. Recombinant TTR fibrils were deposited on glass substrates or substrates mimicking the stiffness of the healthy myocardium (10kPa). Neonatal rat ventricular myocytes exhibited decreased rate of linear contractility via line scan kymography and altered cytoskeletal structure when exposed to deposited TTR fibrils, with greater maladaptive effects seen on 10kPa substrates. Isolated adult mouse atrial cardiomyocytes plated on TTR fibril-containing substrates had attenuated calcium transient amplitude and a prolonged decay constant, consistent with lower amplitude. We also hypothesize that deposited TTR fibrils induce cardiac fibroblast activation and promote progression of fibrosis. Isolated cardiac fibroblasts grown on TTR-coated glass showed a reorganization of the F-actin cytoskeleton, with preferential distribution to the cell periphery. Barrier removal tests after confluence resulted in significantly faster migration velocity of fibroblasts cultured on TTR fibrils. Increased reduction of MTS tetrazolium by a colorimetric assay suggests a significant TTR-related increase in the proliferation rate of cells. Together, results suggest that amyloidogenic TTR fibrils may affect cardiac myocyte and fibroblast structure and function through both chemical and mechanical pathways. As recently approved therapies for ATTRwt are cost-prohibitive and are intended to slow disease progression only, better understanding of disease mechanisms may elucidate novel therapeutic targets.