Myocardial mitochondrial morphology and oxidative phosphorylation capacity in wild-type transthyretin amyloid cardiomyopathy.

BACKGROUND: The effects of amyloid deposition on myocyte mitochondrial morphology and oxidative function in wild-type transthyretin cardiac amyloidosis (ATTRwt) are poorly understood. METHODS: Endomyocardial biopsies of patients with ATTRwt were investigated with electron microscopy to determine mitochondrial structure, numbers, and size. High-resolution respirometry was used to determine mitochondrial oxidative phosphorylation. Amyloid load was assessed using both the stereological counting method, cardiac resonance imaging, and echocardiography. Regression analysis was performed to assess associations between amyloid load variables and oxidative phosphorylation capacity. RESULTS: In 52 patients with ATTRwt, the proportion of morphologically normal mitochondria was 48% [30-74], and the oxidative phosphorylation capacity was 84.2 ± 30.1 pmol O2/(mg*s). The mitochondrial area was significantly associated with mitochondrial oxidative phosphorylation capacity (Estimate 289 [CI95: 52-526, p = 0.02] per 1 um2 area). Stratification by median echocardiography structural variables demonstrated significantly lower mitochondrial numbers, size, and oxidative function with increased wall thickness. Stratification by cardiac magnetic resonance-derived extracellular volume (n = 32) and stereology-derived amyloid load (n = 29) medians demonstrated no significant differences in numbers, morphology, or function. Regression analysis found no significant associations between amyloid load variables and oxidative phosphorylation capacity. CONCLUSION: Cardiac mitochondrial structure is affected, and oxidative phosphorylation capacity is low in ATTRwt. Echocardiography grouping was able to demonstrate differences in mitochondrial numbers, size, and oxidative function with increasing wall thickness. Regression analysis was unable to demonstrate significant associations between measures of amyloid load and mitochondrial oxidative phosphorylation capacity.