Growth hormone and risk for cardiac tumors in Carney complex

Abstract

Carney complex (CNC) is a multiple neoplasia syndrome that is caused mostly by PRKAR1A mutations. Cardiac myxomas are the leading cause of mortality in CNC patients who, in addition, often develop growth hormone (GH) excess. We studied patients with CNC, who were observed for over a period of 20 years (1995-2015) for the development of both GH excess and cardiac myxomas. GH secretion was evaluated by standard testing; dedicated cardiovascular imaging was used to detect cardiac abnormalities. Four excised cardiac myxomas were tested for the expression of insulin-like growth factor-1 (IGF-1). A total of 99 CNC patients (97 with a PRKAR1A mutation) were included in the study with a mean age of 25.8 ± 16.6 years at presentation. Over an observed mean follow-up of 25.8 years, 60% of patients with GH excess (n = 46) developed a cardiac myxoma compared with only 36% of those without GH excess (n = 54) (P = 0.016). Overall, patients with GH excess were also more likely to have a tumor vs those with normal GH secretion (OR: 2.78, 95% CI: 1.23-6.29; P = 0.014). IGF-1 mRNA and protein were higher in CNC myxomas than in normal heart tissue. We conclude that the development of cardiac myxomas in CNC may be associated with increased GH secretion, in a manner analogous to the association between fibrous dysplasia and GH excess in McCune-Albright syndrome, a condition similar to CNC. We speculate that treatment of GH excess in patients with CNC may reduce the likelihood of cardiac myxoma formation and/or recurrence of this tumor.

Keywords: acromegaly; growth hormone; insulin-like growth factor-I (IGF-I); myxoma; tumor.

Figure 1

Cardiac myxoma and growth hormome (GH) excess in 99 patients with Carney Complex (CNC): 60.9% (n = 28 of 46) of the patients with GH excess had a cardiac myxoma, compared to 35.9% (n = 19 of 53) of those who did not have GH excess (p = 0.0160). Patients with a history of GH excess were more likely to develop a cardiac mass versus those without GH excess during their lifetime (OR = 2.78, 95% CI: 1.23–6.29, p = 0.0139).

Figure 2

Kaplan-Meier Curve of penetrance (time to first myxoma) grouped by presence or absence of growth hormone (GH) excess, restricted to those age 21 or older at the time of GH testing. Those with GH excess had a median time to first myxoma of 34.5 years (95% CI: 28.7–46.2) compared to 45.2 years [95% CI: 33.4-(undefined upper bound)] in those without GH excess (p =0.0709).

Figure 3

IGF-1 mRNA and protein expression in cardiac myxomas. Samples were four different CNC associated cardiac myxomas (M1–M4) and normal control heart (C). A. IGF-1 mRNA expression levels were determined by RT-qPCR performed in triplicate. Error bars represent the S.E.M. and show that IGF-1 expression is clearly up-regulated in myxomas on the mRNA (p = 0.002). B. Western blot showing the protein expression of IGF-1.