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

Luigi Saccà, Raffaele Napoli, Antonio Cittadini


Clin Endocrinol. 2003;59(6) 

In This Article

Myocardial Mechano-Energetics

From a mechano-energetic point of view, heart failure is characterized by depression of intrinsic contractility and a major defect in the energy store system, consisting of depletion of phosphocreatine and reduced creatine kinase activity. Consequently, the transfer rate of high-energy phosphates between adenosine triphosphate (ATP) and phosphocreatine is attenuated (Ingwall, 1993). Additional mechano-energetic defects that occur in heart failure include: (i) calcium transients are slowed and intracellular diastolic calcium is elevated in failing cardiomyocytes and this accounts for the impaired contractility and relaxation (Gwathmey et al., 1987); (ii) myocardial efficiency, i.e. the ratio of cardiac work to oxygen consumption, is reduced (Laine et al., 1999); and (iii) the oxygen cost of contractility, which indicates the amount of energy needed for calcium handling, is increased (Hayashi et al., 1996). The mechanisms responsible for these abnormalities include elevated wall stress, sympathetic overactivity and impaired sarcoplasmic reticulum function, consequent to reduced expression of the specific Ca2+-ATPase pump (SERCA2; Gwathmey et al., 1987; Beuckelmann et al., 1992) and decreased density of ryanodine receptors (Naudin et al., 1991).

The effects of GH on myocardial energetics have been assessed in rats with GH-producing tumours - a model of relatively short-term GH excess. In this model, the force of contraction of the isolated papillary muscle or isolated myocardial fibres is increased. This occurs despite the fact that GH causes myosin heavy chain to shift towards the V3 isoform, which has lower ATPase activity than the usually prevalent V1 isoform (Timsit et al., 1990; Mayoux et al., 1993). This finding has been interpreted as an effect of GH to enhance the mechanical efficiency of the contractile apparatus. Accordingly, in isolated heart preparations, IGF-I enhances myocardial contractility without inducing changes in intracellular ATP content and high-energy phosphates (Cittadini et al., 1998).

The effects of long-term GH elevation on myocardial energetics have been assessed in transgenic mice overexpressing bovine GH (Bollano et al., 2000). When studied at the age of 8 months, these animals showed marked LV hypertrophy of the eccentric kind, similar to that occurring in advanced acromegaly. The LV remodelling was associated with marked depression of the indices of systolic function. Interestingly, the creatine phosphate/ATP ratio was decreased and associated with ultrastructural alterations of the cardiomyocyte mitochondria. These data are seemingly at variance with the reported improved energetic status in rats bearing GH-producing tumours (Timsit et al., 1990; Mayoux et al., 1993). However, there is a fundamental difference between the two models that may explain the discrepant results. Transgenic mice were studied when they were aged and after much longer exposure of the heart to high GH levels as compared with rats with GH-secreting tumours.

The reduction of wall stress caused by GH should be associated with lowered oxygen consumption by the myocardium. In an uncontrolled study of patients with heart failure treated with GH, myocardial oxygen consumption on effort was indeed reduced after GH treatment (Fazio et al., 1996). In a recent study, treatment of infarcted rats with GH improved the cardiac energy status, as shown by normalization of the phosphocreatine/ATP ratio. This observation is particularly relevant in view of the fact that an altered phosphocreatine/ATP ratio is a predictor of mortality in patients with heart failure (Neubauer et al., 1997).

Taken together, the data support the concept that, in the short term, GH and IGF-I activate an energy-saving programme, mediated by myosin shift towards the V3 isoform, improved calcium handling and reduced oxygen demand ( Table 3 ). Although GH reduces energy output, it favours the conversion of metabolic energy to external work and enhances the intrinsic ability of the myofilament to develop force. This results in improvement of LV mechanical performance. In heart failure, myocardial energy output is similarly reduced. However, the altered energy status is associated with abnormal calcium handling by the sarcoplasmic reticulum and seriously depressed intrinsic contractility. Ultimately, these events concur to make heart performance deteriorate.