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

Luigi Saccà, Raffaele Napoli, Antonio Cittadini


Clin Endocrinol. 2003;59(6) 

In This Article

Myocardial Structure and Interstitial Remodelling

There are many similarities between heart failure and acromegaly with regard to the changes in myocardial structure. At the cellular level, heart failure is characterized by: (1) cardiomyocyte lengthening due to series addition of new sarcomeres and consequent fall in the short/long axis ratio; and (2) decrease in myocyte density due to both necrosis and apoptosis (Narula et al., 1996). Necrosis is followed by replacement fibrosis, whereas apoptosis entails restructuring of the ventricular wall with side-to-side slippage, wall thinning, and consequent cavity dilation (Anversa et al., 1993). Another prominent feature of the failing myocardium is the extensive interstitial remodelling. Particularly important is the decreased capillary density, which impairs oxygen and substrate exchanges. Indeed, in heart failure there is insufficient angiogenesis, probably because of thickening of the vessel wall and interstitial collagen accumulation (Tomanek, 1990). Because of these changes, cardiac growth in heart failure is referred to as pathological cardiac hypertrophy.

The presence of focal necrosis with replacement fibrosis and apoptosis of both cardiomyocytes and nonmyocytes has been recently documented in the acromegalic heart after many years of the disease (Frustaci et al., 1999). The magnitude of cardiomyocyte apoptosis is correlated with the deterioration of ventricular function and with the duration of acromegaly (Frustaci et al., 1999).

It is not easy to explain the structural myocardial changes occurring in advanced acromegaly as a direct consequence of GH/IGF-I per se. A variety of experimental studies point to a differentrole of GH/IGF-I with regard to myocardial cell biology. In the rat model of ischaemia-reperfusion myocardial injury, IGF-I reduced the extent of cell necrosis and apoptosis (Buerke et al., 1995). More important, in transgenic mice with IGF-I overexpression, cell apoptosis following myocardial infarction was largely prevented. This was associated with more favourable outcome in terms of ventricular dilation, reactive hypertrophy, diastolic wall stress, and overall ventricular performance (Li et al., 1997). Similar findings were obtained in a dog model of heart failure induced by rapid ventricular pacing (Lee et al., 1999a). Treatment with IGF-I partially prevented apoptosis and attenuated LV remodelling and dysfunction.

It is equally difficult to explain the interstitial remodelling of the acromegalic heart as a consequence of GH/IGF-Iexcess. Use of GH or IGF-I in animal models of heart failure activated a growth response in the cardiac tissue that was characterized by unchanged proportion of the myocardial collagen content (Cittadini et al., 1996; Duerr et al., 1995). In a more recent study, GH administration to rats with experimental infarction reduced the extent of interstitial myocardial fibrosis (Grimm et al., 1998). In particular, GH blunted the considerable increase of collagen I and fibronectin observed in the infarcted heart. In line with these observations, recent data showed that long-term administration of GH to normal rats, a model that simulates acromegaly, induced marked growth of the heart, but the fractional area of the collagen relative to myocytes remained unchanged. It was concluded that GH causes proportionate growth of the myocardium without formation of fibrosis (Bruel & Oxlund, 1999).

When GH or IGF-I was used in animal models of experimental heart failure, the myocardial capillary density was not affected (Duerr et al., 1995). In a recent study performed in pigs with heart failure secondary to rapid ventricular pacing, GH even restored to normal the reduced capillary density secondary to heart failure (Houck et al., 1999). Based on the observation that GH, in the short term, preserves the capillary density and does not induce fibrosis, the growth response to GH or IGF-I may be regarded as a physiological cardiac hypertrophy. This response is entirely different from that observed in heart failure or in the acromegalic failing heart.