Growth Hormone, Acromegaly, and Heart Failure: An Intricate Triangulation

Luigi Saccà, Raffaele Napoli, Antonio Cittadini


Clin Endocrinol. 2003;59(6) 

In This Article

The Gene Reprogramming Theory

When the myocardium hypertrophies to face an increased mechanical load, extensive gene reprogramming occurs in the cardiomyocytes. Some genes are downregulated, whereas others are upregulated. A distinct feature of this process is the re-emergence of an ensemble of fetal genes that are normally quiescent in the adult myocardium. It was theorized that the hypertrophic cardiomyocytes are sentenced to death, as an inherent consequence of the new gene programme (Katz, 1994)

The gene reprogramming in heart failure involves changes in actin and myosin isoforms, re-expression of the atrial natriuretic factor in the ventricular wall, as occurs in the fetal life, and downregulation of the β1-adrenergic receptor (Swynghdaw, 1999). In addition, heart failure entails profound changes in the expression of the molecules that regulate calcium handling, consisting of downregulation of SERCA2, phospholamban and ryanodine receptors, whereas the Na+- Ca2+ exchanger is upregulated (Swynghdaw, 1999).

The changes in gene expression associated with GH-mediated cardiomyocyte growth have little, if anything, in common with the gene reprogramming of heart failure (Tanaka et al., 1998). In cultured cardiomyocytes, IGF-I induces expression of myosin light chain-2 and troponin I (Ito et al., 1993). At variance with heart failure, GH and IGF-I do not activate or even decrease the expression of atrial natriuretic factor, and skeletal and smooth muscle α-actin (Eppemberger-Eberhardt et al., 1997; Tanaka et al., 1998).

In the postinfarction rat model, treatment with GH reduced myocardial expression of β-myosin heavy chain, atrial natriuretic factor, α-smooth muscle actin, collagen I, collagen III and fibronectin (Yang et al., 1999). Interestingly, these changes were associated with improved rate of survival. In transgenic mice with GH overexpression, no change was observed in the atrial natriuretic factor content in the ventricular wall (Dirsch et al., 1998). In the rat model of GH excess due to GH-producing tumours, the myosin isoform spectrum is reshuffled,with a marked shift towards the V3 isoform (Timsit et al., 1990; Mayoux et al., 1993), similar to that observed in the failing heart of small rodents. Contrary to the traditional belief, it has been recently shown that a shift towards the V3 isoform also occurs in the failing human myocardium (Lowes et al., 1997). It is likely that, because of these changes in the myosin spectrum, the cardiomyocytes are able to face the overload emergency and to obey an energy-saving programme.

The evidence available indicates that two different gene patterns are induced by GH/IGF-I and heart failure. If the gene paradigm of heart failure holds true, the data indicate that chronic GH excess is unlikely to predispose to heart failure through a sequence of events led by gene reprogramming.