Evaluation of metastatic cardiac calcification in a model of chronic primary hyperparathyroidism.
Recent reports have fueled an interest in the prevalence and significance of metastatic calcium deposition in patients with chronic hyperparathyroidism. Experimental data are limited by the lack of suitable in vivo animal models. We have developed a model of marked hypercalcemia and overproduction of parathyroid hormone using somatic gene transfer. Briefly, the process involves infection of cultured rodent fibroblasts (RAT-1 cells) with a retroviral expression vector that contains the gene encoding human parathyroid hormone. Fibroblasts are grown to confluence on collagen-coated dextran microcarrier beads and are injected into the peritoneal cavities of syngeneic Fisher rats. Human parathyroid hormone production in rat serum is quantified by an immunoradiometric assay for human parathyroid hormone (1-84), which does not recognize rat parathyroid hormone. These rats consistently show production of human hormone within a week. Levels increase progressively, often to 1 ng/ml within 60 days of injection. Serum calcium showed a concomitant rise to an average of 15.5 mg/dl. In this study, 13 rats that had been transplanted with parathyroid hormone-producing fibroblasts were killed 80 days after injection. Examination of the skeleton revealed demineralization and histopathologic sequelae of parathyroid hormone excess with extensive osteoclastic bone resorption. Examination of the hearts revealed calcification in five of 13 hearts. There was no involvement of major coronary arteries or conducting systems, but there was calcification of cardiac myocytes, primarily in subepicardial region. This model may permit an understanding of the mechanisms for sudden cardiac death in severe hypercalcemia.
Thompson
A R
AR
Endocrine Unit, Massachusetts General Hospital, Boston.
Fallon
J
J
Nussbaum
S
S
D000818:Animals; D002114:Calcinosis / Q000209:etiology* / Q000473:pathology; D002118:Calcium / Q000097:blood; D009202:Cardiomyopathies / Q000209:etiology / Q000473:pathology; D002908:Chronic Disease; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000637:transplantation; D006961:Hyperparathyroidism / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D010281:Parathyroid Hormone / Q000097:blood; D051381:Rats; D014162:Transfection
D010281:Parathyroid Hormone; D002118:Calcium