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

Luigi Saccà, Raffaele Napoli, Antonio Cittadini


Clin Endocrinol. 2003;59(6) 

In This Article

Is Cardiac Hypertrophy the Culprit?

Acromegaly provides a unique model of cardiac hypertrophy, in which the initial event is not an increased mechanical load imposed to the heart but a pure, not teleological growth stimulus. As detailed in the previous sections, because of LV unloading and the lack of haemodynamic failure, the acromegalic heart is not exposed to the action of any of the classic mechanisms that operate in chronic heart failure. This prompts the hypothesis that acromegalic heart disease is simply the inescapable consequence of the unrestrained cardiac growth induced by the elevated GH levels. It should be emphasized that, in acromegaly, GH levels are constantly elevated, at variance with the physiological secretion and pharmacological treatments, characterized by a spike-decline pattern. Whether this difference has any relevance to cardiac growth and function is not known.

The question whether cardiac hypertrophy by itself is the prelude to heart failure has long been debated. Today, there is a widely shared belief in the cardiological literature that cardiac hypertrophy, even if physiological or compensatory in the beginning, is destined to become detrimental and to open the door to heart failure. Epidemiological studies have established that LV hypertrophy is a powerful and independent risk factor for a variety of cardiovascular sequelae, including congestive heart failure (Levy et al., 1990). This view is supported by the clinical observation that all therapeutic measures that prolong survival of patients with heart failure do simultaneously induce partial regression of cardiac hypertrophy.

Correlational data do not necessarily imply a mechanistic link between cardiac hypertrophy and subsequent failure. In addition, there seems little doubt that the continuous effect of LV overloading and the activation of the neurohormonal system are a sine qua non for hypertrophy to evolve towards failure. For instance, in patients with valvular aortic defects, who undergo reparative surgery, a rapid reduction of LV hypertrophy occurs, initially due to regression of myocyte hypertrophy and later to regression of interstitial fibrosis. This is accompanied by dramatic improvement of LV function and exercise performance (Davies et al., 1995). Similar findings were obtained in patients with heart failure treated with a mechanical assist device. After a few months of LV unloading by device application, cardiomyocyte function was substantially resumed (Dipla et al., 1998). These observations support the idea that cardiac hypertrophy evolves towards failure only when the initial insult is constantly active. If, as a consequence of medical or surgical interventions, the ventricular overload and the neurohormonal activation are attenuated, disease progression is halted.

This paradigm would not contradict the hypothesis that acromegaly is a progressive model of hypertrophy, eventually culminating in heart failure. In this model, the cardiotoxic and cardioremodelling effects of LV overload and neurohormonal activation are replaced by the incessant growth stimulus. For several years, this causes physiological cardiac hypertrophy without any apparent functional damage. For reasons yet to be completely understood, at one point in time, cardiac growth turns into a maladaptive process. It is important to note that, in the long run, the growth response to GH involves all myocardial components, particularly the interstitial compartment, causing profound structural remodelling of the myocardial tissue. In addition, in acromegaly, like in heart failure, there is ongoing apoptosis of myocytes and nonmyocyte cells (Frustaci et al., 1999), despite the documented antiapoptotic effect of IGF-I (Buerke et al., 1995; Li et al., 1997; Lee et al., 1999a). The role of apoptosis has been the object of intense disputes, mainly because of its low frequency. However, given the long duration of acromegaly, it is conceivable that even a low-frequency phenomenon may eventually gain quantitative relevance.

In conditions of GH excess, the contractile performance of cardiomyocytes is enhanced (Timsit et al., 1990; Cittadini et al., 1998). Even when tested in animal models of heart failure, GH confirmed its ability to improve cardiomyocyte function (Duerr et al., 1995; Cittadini et al., 1997; Houck et al., 1999; Tajima et al., 1999). In heart failure, the opposite is true: cardiomyocytes undergo impaired performance as the early stage of the disease and this contributes to the LV pump failure. The consequence is a vicious cycle where the ensuing LV dilation begets further LV dysfunction. In other words, if the theory holds true that the growth effect of GH is directly responsible for acromegalic heart disease, the data available support the view that the transition to failure is mediated by interstitial remodelling and apoptosis, and not by primary impairment of cardiomyocyte contractility.

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