Early transverse tubule involvement in cardiomyocytes in hereditary transthyretin amyloidosis: a possible cause of cardiac events.

BACKGROUND: Cardiac involvement is one of the most frequent and fatal manifestations of hereditary transthyretin (ATTRv) amyloidosis. This study sought to clarify the pathogenesis of ATTRv amyloidosis, specifically, how transthyretin (TTR) amyloid begins to deposit in cardiomyocytes and how this deposition progresses in these cells. METHODS: We analyzed autopsy cardiac tissues from five patients with ATTRv amyloidosis by using confocal microscopy with thioflavin S staining and immunofluorescence and electron microscopy to demonstrate the pattern of TTR amyloid deposition in cardiomyocytes. RESULTS: We demonstrated predominant amyloid deposition in the transverse tubules (t-tubules) of cardiomyocytes at the early stage of TTR amyloid deposition. Also, a pattern of the progression of amyloid deposition from deeply invaginated extracellular matrix, that is, t-tubules, to cell surface extracellular matrix, that is, basement membrane, was noted. Three-dimensional confocal microscopic images revealed the abnormal architecture of the t-tubules with nodular swelling, branching, and confluence in the cardiomyocytes with amyloid deposition. Double immunofluorescence staining with anti-TTR antibody and CACNA1C antibody demonstrated reduced voltage-dependent calcium channels around amyloid deposition. CONCLUSIONS: Our pathological study demonstrated that t-tubule involvement is an early event in cardiomyocytes in the pathogenesis of ATTRv amyloidosis. This finding may indicate that disruption of t-tubules in cardiomyocytes may contribute to the pathogenesis of cardiac events including heart failure and arrhythmia.