on February 10, 2009
Published online before print February 10, 2009, doi: 10.1161/CIRCHEARTFAILURE.108.813261
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Original Article |
Pheochromocytoma-Induced Cardiomyopathy is Modulated by the Synergistic Effects of Cell-Secreted Factors
1 Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology;
2 Department of Genetics, Harvard Medical School;
3 Department of Genetics, Harvard Medical School and Howard Hughes Medical Institute;
4 Harvard-MIT Division of Health Sciences and Cardiovascular Division, Brigham & Women's Hospital
5 E-mail: mobine{at}mit.edu
Background—Pheochromocytomas are rare tumors derived from the chromaffin cells of the adrenal medulla. While 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.
Methods and Results—Isolated cardiomyocytes incubated with pheochromocytoma-conditioned growth media contracted at a higher frequency than cardiomyocytes incubated with norepinephrine only. Sprague-Dawley rats and Black-6 mice were implanted with agarose-encapsulated pheochromocytoma (PC12) cells, DOPA decarboxylase knock-out PC12 cells deficient in norepinephrine (PC12-KO), or norepinephrine-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 to animals dosed only with norepinephrine. Elimination of norepinephrine secretion in PC12-KO cells induced neither cardiac dilation (3.9±1.8% increase vs. 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 norepinephrine, suggesting pheochromocytoma-induced cardiomyopathy is not solely mediated by norepinephrine, rather pheochromocytoma secretory factors in combination with catecholamines act synergistically to induce greater cardiac damage than catecholamines alone.
Key Words: cardiomyopathy • catecholamines • heart failure • norepinephrine
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