Acromegaly, inflammation and cardiovascular disease: a review

Abstract

Acromegaly is characterized by Growth Hormone (GH) and Insulin-like Growth Factor 1 (IGF-1) excess. Uncontrolled acromegaly is associated with a strongly increased risk of cardiovascular disease (CVD), and numerous cardiovascular risk factors remain present after remission. GH and IGF-1 have numerous effects on the immune and cardiovascular system. Since endothelial damage and systemic inflammation are strongly linked to the development of CVD, and have been suggested to be present in both controlled as uncontrolled acromegaly, they may explain the presence of both micro- and macrovascular dysfunction in these patients. In addition, these changes seem to be only partially reversible after remission, as illustrated by the often reported presence of endothelial dysfunction and microvascular damage in controlled acromegaly. Previous studies suggest that insulin resistance, oxidative stress, and endothelial dysfunction are involved in the development of CVD in acromegaly. Not surprisingly, these processes are associated with systemic inflammation and respond to GH/IGF-1 normalizing treatment.

Keywords: Acromegaly; Cardiovascular disease; Cytokines; Growth hormone; Inflammation; Insulin-like growth Factor-1.

Figure 1.

Schematic overview of the effect of GH/IGF-1 excess on cardiovascular disease-related morbidity. In Growth Hormone (GH)/Insulin-like Growth Factor 1 (IGF-1) excess, the pro-atherosclerotic mitogen-activated protein kinase (MAPK)-mediated effects are suggested to predominate over the beneficial phosphoinositide 3-kinase (PI3K)-Akt-mediated effects, which renders a negative impact on the cardiovascular system. This balance is also modified by circulating inflammatory, metabolic and endocrine factors, and by age, ethnicity, genetics and environmental modulation (diet, behavior). CVD: cardiovascular disease; AT: adipose tissue; OSAS: obstructive sleep apnea syndrome; IL: interleukin; IFN-γ: interferon gamma; APP: acute phase proteins; FMD: flow-mediated dilatation; PWV: pulse wave velocity; IMT: intima-media thickness; CVA: cerebrovascular accident.

Figure 2.

The relations between GH, IGF-1, Klotho, inflammation and atherosclerosis. The upper panel depicts the normal physiological situation. Thick arrows depict enhanced effects, whereas thin arrows depict suppressed effects. The balance between GH and IGF-1 is maintained by a negative feedback loop, which also includes Klotho. GH stimulates the production of physiological levels of sKlotho, and sKlotho stimulates GH secretion (direct and via inhibition of the negative feedback loop via IGF-1). A high ratio of soluble (sKlotho) to membrane-bound Klotho (mKlotho) induces inflammation, insulin resistance and atherosclerosis. Healthy muscle and AT inhibit atherosclerosis. Physiological IGF-1 levels have anti-inflammatory and atheroprotective effects via PI3K, whereas GH predominantly has atherogenic effects via MAPK. In the lower panel, the situation in active acromegaly is depicted. In active acromegaly, excessive autonomous GH secretion leads to increased IGF-1 and sKlotho levels, and decreased mKlotho expression. The negative feedback of IGF-1 on GH secretion is disturbed. Both GH and sKlotho induce insulin resistance via ectopic intramuscular adipose tissue (IMAT) deposition and adipose tissue (AT) inflammation. The pro-inflammatory transformed AT and muscle secrete pro-inflammatory cytokines, which stimulate development and persistence of atherosclerosis. The anti-inflammatory and anti-atherogenic effects of mKlotho are overruled by the insulin-antagonizing effects of sKlotho. The potential short-term beneficial effects of GH, Klotho and IGF-1 are overruled by long-term effects of GH and IGF-1 excess: stimulation of pro-inflammatory cytokines, insulin resistance and atherosclerosis. In addition, dyslipidemia, oxidative stress and endothelial dysfunction, increased vascular resistance and hypercoagulability contribute to the development of atherosclerosis.

Figure 3.

GH/IGF-1 excess is suggested to cause endothelial damage via increased oxidative stress, microvascular inflammation and VSMC proliferation. Additional contributing factors are concomitant hormonal deficiencies and metabolic disturbances.

Figure 4.

The relation between GH, IGF-1 and class I acute phase proteins (APP). In the upper panel, the situation for normal to high-normal (physiological) IGF-1 levels is depicted with black arrows. There is a balance between GH-induced pro-inflammatory cytokine production and APP. Healthy muscle and adipose tissue (AT) inhibit inflammation. In the lower panel, the situation in GH/IGF-1 disturbances is depicted. The pink arrows display the situation in states of low to very low IGF-1 levels, where inflammation in AT induces pro-inflammatory cytokine production and the inhibitory effects of GH on class I APP are attenuated, rendering high levels of both pro-inflammatory cytokines and class I APP.The green arrows display the situation in active acromegaly, where both GH excess and pro-inflammatory transformed AT and muscle induce pro-inflammatory cytokine production, but GH also suppresses class I APP production, rendering higher levels of pro-inflammatory cytokines combined to lower levels of class I APP.