| Detailed histological and ultrastructural studies were conducted on transgenic (TG) mice over-expressing the human activating transcription factor 3 (ATF3) gene, targeted to the heart by using an a-myosin heavy chain promoter. The transgenic mice showed biatrial enlargement when compared with nontransgenic (nTG) control of the same strain, with no apparent gross anatomical or ultrastructural changes in the ventricles. Visible atrial calcification occurred in 56% of the TG mice but none of the nTG mice. Gross anatomical changes were observed after 2–4 weeks of age and continued throughout the 67 weeks of the experiment. The hearts of TG mice were approximately 4 times heavier, and the myocytes about 2.3 times larger, than those of nTG mice. Chondroid metaplasia associated with mural thrombosis was observed in Muridae here for the first time to my knowledge. These processes accelerated changes in the atria of TG mice during a 12-week period and were responsible for mineralization of thrombi in the atrial chamber. Proliferation of connective tissue, circular collagen bundles with fibroblasts around mineralized areas, and dilated vascular spaces in the myocardial layer were followed eventually, by ossification. In this advanced stage, most myocytes had degenerated, as was proven by myofibril preparation and SDS-PAGE. Destruction of atrial myocytes was attributed to mineralization of mitochondria and vacuolization. Very few myocytes in the right atrium also underwent apoptosis, detected by the TUNEL assay, in a 36-week-old TG mouse. Electron microscopic examination showed that atria from the TG mice had papillar-pleated nuclear membranes and blebbing nuclei. Digestion of cytoplasmic components led to pseudohypertrophy of the TG mouse atrium. Hypertrophic myocytes showed degeneration and destruction of such cytoplasmic components as myofibrils, mitochondria, and Z-lines. However, comparison of TG and nTG mice showed that aging was not a factor in the structural alterations. |
