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

Luigi Saccà, Raffaele Napoli, Antonio Cittadini


Clin Endocrinol. 2003;59(6) 

In This Article

Role of Metabolic Factors

The ability of GH to antagonize insulin's action has long been known and explains why acromegaly is complicated by severe insulin resistance and sometimes by overt diabetes. In patients with active acromegaly, basal insulin concentration shows two- to threefold elevations (Bolinder et al., 1986; Hansen et al., 1986). However, insulin's action to promote glucose uptake by the skeletal muscle is impaired (Møller et al., 1992; Capaldo et al., 2000).

One of the mechanisms by which GH lowers insulin sensitivity is its free fatty acia (FFA)-mobilizing effect, with consequent activation of the glucose-FFA competition cycle. The increased availability of FFA may also exert relevant effects on myocardial energetics and performance. If themyocardium is flooded with FFA and this becomes the prevalent substrate, the energy requirement for myocardial internal work (essentially calcium handling) rises consistently (Korvald et al., 2000). This is the so-called 'oxygen-wasting' effect of lipids and represents an unfavourable condition, both energetically and functionally. However, when patients with heart failure were treated with GH, there was no change in the myocardial respiratory quotient, indicating that GH does not affect the substrate metabolic preference (Fazio et al., 1996). This conclusion is supported by recent studies that explored GH's effect on myocardial glucose uptake in human subjects, using positron emission tomography (Botker et al., 2000). At variance with systemic insulin resistance, GH did not antagonize the stimulatory effect of insulin on myocardial glucose disposal. This finding lends support to the conclusion that GH excess is not able to induce a substrate shift in the myocardium.

Insulin excess stimulates the growth of cardiomyocyte and nonmyocyte cells, with consequent functional abnormalities. Diabetes is a well-recognized cause of cardiac dysfunction and congestiveheart failure, even in the absence of coronary artery disease, hypertension and valvular defects (Kannel et al., 1974). The failing diabetic heart is hypertrophic with LV dilation and clear evidence of both diastolic and systolic LV dysfunction (Joffe et al., 1999). A distinct feature of diabetic cardiomyopathy is the appearance of both interstitial myocardial fibrosis and diastolic dysfunction at a very early stage of the disease, when the only abnormality is insulin resistance and hyperinsulinaemia (Celentano et al., 1995; Mizushige et al., 2000).

Given the characteristics of diabetic cardiomyopathy, the question arises as to whether the chronic insulin resistance and hyperinsulinaemia of acromegaly may play a contributory role in the development of cardiac disease. This possibility is realistic, particularly with regard to myocardial interstitial fibrosis. However, it should be noticed that the time-course of diabetic cardiomyopathy is different from that of acromegalic heart disease. In acromegaly, the initial event is the marked growth of cardiac tissue, which is associated for several years with little or no functional abnormality (Fazio et al., 2000). On the other hand, what predominates in the early stage of diabetic cardiomyopathy is cardiac dysfunction with a modest increase in cardiac mass.

Because of the increased FFA turnover and oxidation, patients with acromegaly have reduced body fat mass. Conversely, the anabolic property of GH with regard to amino acids accounts for the increased lean body mass. Interestingly, when patients with visceral obesity were treated with GH for up to 9 months, there was a reduction of visceral adipose tissue associated with a more favourable lipoprotein profile (Joannsson et al., 1997). Because visceral adiposity is considered a vascular risk factor, GH excess, if anything, may be expected to work against the intervention of this risk factor.

Besides acting as an FFA mobilizing agent, GH exerts other important effects on lipid metabolism. Serum triglyceride levels and lipoprotein(a) are increased in active acromegaly (Davidson, 1987; Wildbrett et al., 1997; Arosio et al., 2000). In addition to changes in the carbohydrate and lipid profile, acromegalics show some abnormalities of the coagulation and fibrinolytic systems. In particular, hyperfibrinogenaemia (Wildbrett et al., 1997; Sartorio et al., 2000) and increased levels of plasminogen activator inhibitor type I (Sartorio et al., 2000) have been reported in acromegalic patients.

Collectively, the metabolic changes reported in acromegaly are compatible with an increased cardiovascular risk profile due to: (i) insulin resistance and hyperinsulinaemia; (ii) abnormal lipid profile; and (iii) prothrombotic pattern.