Pheochromocytoma-induced cardiomyopathy is modulated by the synergistic effects of cell-secreted factors.
BACKGROUND
Pheochromocytomas are rare tumors derived from the chromaffin cells of the adrenal medulla. Although these tumors have long been postulated to induce hypertension and cardiomyopathy through the hypersecretion of catecholamines, catecholamines alone may not fully explain the profound myocardial remodeling induced by these tumors. We sought to determine whether changes in myocardial function in pheochromocytoma-induced cardiomyopathy result solely from catecholamines secretion or from multiple pheochromocytoma-derived factors.


RESULTS
Isolated cardiomyocytes incubated with pheochromocytoma-conditioned growth media contracted at a higher frequency than cardiomyocytes incubated with norepinephrine (NE) only. Sprague-Dawley rats and black-6 mice were implanted with agarose-encapsulated pheochromocytoma (PC12) cells, dihydroxyphenylalanine decarboxylase knock-out PC12 cells deficient in NE (PC12-KO), or NE-secreting pumps. PC12 cell implantation increased left ventricular dilation by 35+/-6% and 9.6+/-1.4% and reduced left ventricular fractional shortening by 20+/-3% and 28+/-4% in rats and mice compared with animals dosed only with NE, respectively. Elimination of NE secretion in PC12-KO cells induced neither cardiac dilation (3.9%+/-1.8% increase versus control) nor changes in (1.9%+/-0.4% reduction) fractional shortening compared to controls.


CONCLUSIONS
Pheochromocytomas induce a greater degree of cardiomyopathy than equivalent doses of NE, suggesting pheochromocytoma-induced cardiomyopathy is not solely mediated by NE, rather pheochromocytoma secretory factors in combination with catecholamines act synergistically to induce greater cardiac damage than catecholamines alone.
Mobine
Hector R
HR
Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, E25-442, Cambridge, MA 02139, USA. mobine@mit.edu
Baker
Aaron B
AB
Wang
Libin
L
Wakimoto
Hiroko
H
Jacobsen
Kurt C
KC
Seidman
Christine E
CE
Seidman
J G
JG
Edelman
Elazer R
ER
D000310:Adrenal Gland Neoplasms / Q000150:complications* / Q000378:metabolism; D000818:Animals; D009202:Cardiomyopathies / Q000139:chemically induced / Q000175:diagnosis / Q000209:etiology* / Q000503:physiopathology; D002395:Catecholamines / Q000378:metabolism; D004195:Disease Models, Animal; D004452:Echocardiography; D005260:Female; D015870:Gene Expression; D006321:Heart / Q000503:physiopathology; D051379:Mice; D008815:Mice, Inbred Strains; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects; D009368:Neoplasm Transplantation; D009638:Norepinephrine / Q000172:deficiency / Q000378:metabolism / Q000494:pharmacology; D016716:PC12 Cells / Q000378:metabolism; D010673:Pheochromocytoma / Q000150:complications* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014407:Tumor Cells, Cultured
D002395:Catecholamines; D009638:Norepinephrine