Abstract Background Myocardial biopsy is a critical procedure for the definitive diagnosis of cardiac diseases. Although it has the potential beyond diagnosis to provide invaluable information that gives us insights into the underlying disease mechanisms, unfortunately, these important data are often underutilized in clinical practice. Transcriptomics or proteomics studies of cardiac biopsy samples are not many mainly due to their small sizes and the difficulty of analyzing formalin-fixed paraffin-embedded (FFPE) samples. Recent advances in spatial transcriptomics technologies have revolutionized our ability to map gene expression patterns preserving the spatial context of the tissue. Moreover, some newer technologies are compatible with very small FFPE samples. Purpose In this study, we utilized spatial transcriptomics to analyze myocardial biopsy samples from patients with cardiac amyloidosis to elucidate the spatial gene expression profiles and gain novel insights underlying the disease. Methods Endomyocardial biopsy was conducted for the diagnosis of clinically suspected cardiac amyloidosis. After the diagnosis was confirmed by detecting the presence of ATTR (amyloid transthyretin) deposits, the remaining FFPE samples were used in this study. FFPE blocks obtained from control and cardiac amyloidosis were sectioned and processed following the manufacturer’s protocol for the 10x Genomics Visium HD. Generated libraries were sequenced by DNBSEQ-G400 (MGI). Sequencing data were processed using Space Ranger (10x Genomics) and analyzed by the R package Seurat. Results The most prominent feature of cardiac amyloidosis samples was the upregulation of multiple mitochondrial genes encoding the mitochondrial respiratory chain. NPPA (encoding atrial natriuretic peptide) expression was higher, reflecting the heart failure status of cardiac amyloidosis. IGFBP7, a cytokine secreted from failing cardiomyocytes, was increased in cardiac amyloidosis. GPX3, the key enzyme to detoxify hydrogen peroxide, was inducted. In addition, fibroblast marker genes and genes related to apolipoproteins and the complement system were elevated in cardiac amyloidosis compared to control samples. Further, genes reported to be associated with amyloidosis in other organs were also upregulated, suggesting the common pathophysiology of amyloid deposits in various organs. TTR was not detected in any cardiac samples, in line with previous observations showing that ATTR is produced in the liver, but not in the heart. Conclusion Spatial transcriptomics of cardiac amyloidosis samples uncovered gene signature shared by other forms of heart failure as well as amyloidosis in other organs. Our findings have the potential to advance our understanding of the disease mechanism and to lead to the development of more precise diagnostic and therapeutic strategies. This research also highlights the usefulness and impact of spatial transcriptomics in cardiovascular research.
Sawaki et al. (Sat,) studied this question.