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

Luigi Saccà, Raffaele Napoli, Antonio Cittadini


Clin Endocrinol. 2003;59(6) 

In This Article

Vascular Reactivity

A prominent feature of heart failure is impaired vascular reactivity (Kubo et al., 1991; Drexler et al., 1992). This consists of attenuated vasodilation in response to acetylcholine (ACh), pointing to an endothelium-dependent defect secondary to a loss of bioactive endothelial nitric oxide (NO). On the other hand, the vasodilator response to nitroprusside, an endothelium-independent vasodilator, is preserved (Hirooka et al., 1994). Endothelial dysfunction is not a mere scientific curiosity but represents one of the mechanisms that account for the reduced peripheral blood flow and impaired physical exercise in patients with heart failure. In addition, endothelial dysfunction may be the initiating event of atherosclerosis (Reddy et al., 1994). Indeed, a functionally intact endothelium is antiatherogenic because it inhibits a variety of processes, including leucocyte adhesion, platelet aggregation and smooth muscle cell proliferation. These are the reasons why endothelial dysfunction is one of the determinants of heart failure progression.

The question whether acromegaly is associated with abnormality of vascular reactivity has not been investigated in depth. An early study from transgenic mice overexpressing GH demonstrated extensive remodelling ofthe large arteries and the mesenteric vessels, with increased wall-to-lumen ratio - a condition limiting the vascular reserve and predisposing to hypertension (Dilley & Schwartz, 1989). More recent studies in acromegalic patients showed abnormalities in the peripheral microcirculation, consisting of reduced capillary density and tortuosity of the capillary loops. These abnormalities were documented in active acromegaly and tended to regress after successful therapy (Schiavon et al., 1999).

If GH excess results in such abnormalities in the vascular system, how can we explain the cardiac hyperkinetic syndrome (high cardiac output and decreased peripheral vascular resistance) of early intermediate stage acromegaly? It is not easy to answer this question. To add complexity to an already complex issue, in acromegalic patients with a documented hyperkinetic syndrome, the mean blood flow in the brachial artery may even be lower than in healthy subjects, whereas the forearm vascular resistance is increased (Chanson et al., 1998). This seemingly contradictory finding suggests that the circulatory dysfunction in acromegaly is much more complex than so far thought and points to marked heterogeneity in the distribution of cardiac output and regional vascular resistance.

Based on these data, it is difficult to understand whether, in a chronic setting, GH excess affects the peripheral circulation in a way that predisposes or contributes to heart failure. On the other hand, the short-term effects of GH and IGF-I on the vascular system argue against a causal role ofthese growth factors in vascular dysfunction. In vitro studies showed that IGF-I stimulates NO production by human endothelial cells (Tsukahara et al., 1994). In addition, infusion of IGF-I into the brachial artery of human subjects causes marked increment in forearm blood flow and a fall in forearm vascular resistance (Fryburg, 1996).

Two very recent clinical studies into the role of GH in the control of vascular reactivity provide new insights into the question. In the first, patients with GH deficiency showed impaired vascular reactivity, due to a complex defect that involves the entire pathway of NO-mediated vasodilation (Capaldo et al., 2001). On the other hand, vascular function was normal in GH-deficient patients treated with GH. The data support a physiological role for GH in the maintenance of vascular homeostasis.

The second study revealed a beneficial effect of GH treatment in vascular reactivity in heart failure (Napoli et al., 2002). Patients with dilated cardiomyopathy were treated with GH for 3 months. Before treatment, as expected, these patients showed marked impairment of endothelium-dependent vasodilation, while the endothelium-independent component, assessed by infusing the NO donor nitroprusside, was well preserved. After GH treatment, the endothelial dysfunction was completely reversed and even the endothelium-independent vasodilation was improved. Concomitantly, GH restored the defective release of both nitrite and cGMP from the forearm vessels. The data support the idea that GH exerts protective effects on the endothelium by preserving one of its key functions, i.e. the generation of NO and the activation of the cGMP pathway. The data also suggest that GH, by this endothelial mechanism, might have a favourable impact on the progression of heart failure.