Pheochromocytoma-Induced Cardiomyopathy is Modulated by the Synergistic Effects of Cell-Secreted Factors: Mobine. Cell-Secreted Factors in Pheo-Induced CM

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 pheochromocytomaderived factors. Methods and Results—Isolated cardiomyocytes incubated with pheochromocytomaconditioned growth media contracted at a higher frequency than cardiomyocytes incubated with norepinephrine only. Sprague-Dawley rats and Black-6 mice were implanted with agaroseencapsulated pheochromocytoma (PC12) cells, DOPA decarboxylase knock-out PC12 cells deficient in norepinephrine (PC12-KO), or norepinephrine-secreting pumps. PC12 cell Address correspondence to: Hector R. Mobine, Massachusetts Institute of Technology, 77 Massachusetts Avenue, E25−442, Cambridge, MA 02139. Tel.: 617−258−8895; Fax: 617−253−2514; E-mail: [email protected]. The autonomic nervous system is an important regulatory system in heart failure. Circulating catecholamines are markers of and causal contributors to progression of myocardial disease. In this regard the pheochromocytoma state presents a fascinating form of catecholamine excess. Pheochromocytomas induce a devastating cardiomyopathy but a paradox remains in understanding the means by which these tumors induce cardiotoxicty. Previous work attributed the induction of cardiomyopathy by pheochromocytomas to the hemodynamic and direct toxic effects that follow the hypersecretion of catecholamines. Yet, only a fraction of patients with these tumors are hypertensive and cardiac toxicity does not correlate with catecholamine levels. We show that catecholamine excess can induce heart failure but only at doses of catecholamines sufficiently high to induce hypertension and tachycardia. Pheochromocytoma cell implants in contrast induce cardiomyopathy even when they secrete low levels of catecholamines that alone have no effect. These cell implants produce early and profound cardiac dilation and loss of contractility without hemodynamic changes. In this paper we demonstrate for the first time that it is the synergistic effect of the total secretory cocktail that induces cardiomyopathy, not catecholamines alone. Infusion of catecholamines alone cannot recapitulate the pheochromocytoma's profound toxic effects. This work represents the first controlled and reproducible model of pheochromocytoma-induced cardiomyopathy and demonstrates that the effects of pheochromocytomas are induced by the synergistic effect of cell-secreted factors, not catecholamine excess alone. These results further our understanding of the general notion of myocardial disease generation, the course of cardiomyopathies and the particular toxicity of pheochromocytomas and secretory tumors. Disclosures: None NIH Public Access