Coronary microvascular dysfunction may be related to IGF-1 in acromegalic patients and can be restored by therapy

Highlights

• Acromegaly increases the risk of cardiovascular mortality.

• We aimed to determine the influence of acromegaly on coronary microvascular function.

• We studied 40 acromegalic patients without clinical evidence of cardiovascular disease.

• We assessed coronary flow reserve as a marker of coronary microvascular function.

• IGF-1 independently correlates with the coronary microvascular impairment.

Abstract

Background and aims

Acromegaly increases the risk of cardiovascular mortality. Data on the cardiovascular risk in asymptomatic acromegaly are limited. In particular, data on coronary microvascular abnormalities are lacking. We assessed coronary flow reserve (CFR) as a marker of coronary microvascular function in asymptomatic acromegaly.

Methods

We studied 40 acromegalic patients (23 male, age 52 ± 11 years) without clinical evidence of cardiovascular disease, and 40 control subjects matched for age and sex. Coronary flow velocity in the left anterior descending coronary artery was detected by transthoracic Doppler echocardiography, at rest, and during adenosine infusion. CFR was the ratio of hyperaemic to resting diastolic flow velocity.

Results

CFR was lower in patients than in controls (2.9 ± 0.8 vs. 3.7 ± 0.6, p < 0.0001) and was abnormal (≤2.5) in 13 patients (32.5%) compared with any control subjects (0%) (p < 0.0001). CFR was inversely related to insulin-like growth factor 1 (IGF-1) levels (r = −0.5, p < 0.004). In patients with CFR≤2.5, IGF-1 was higher (756 [381–898] μg/l versus 246 [186–484] μg/l, p < 0.007) whereas growth hormone (GH) levels were similar (6.3 [2.8–13.7] μg/l versus 5 [2.8–8.9] μg/l, p = 0.8). In multivariable linear regression analysis, IGF-1 was independently associated with CFR (p < 0.0001). In multiple logistic regression analysis, IGF-1 independently increased the probability of CFR≤2.5 (p = 0.009). In four patients with active disease (all with CFR<2.5), treatment with somatostatin analogues normalized CFR. However the other four patients with active disease were not responder.

Conclusions

Acromegalic patients have coronary microvascular dysfunction that may be restored by therapy with somatostatin analogues. IGF-1 independently correlates with the coronary microvascular impairment, suggesting the pivotal role of this hormone in explaining the increased cardiovascular risk in acromegaly.

Introduction

Acromegaly is a relatively rare disease characterized by growth hormone (GH) and insulin-like growth factor (IGF)-1 excess often associated with a GH-secreting pituitary adenoma [1]. Systemic complications of GH/IGF-1 excess include acromegalic cardiomyopathy, characterized by concentric biventricular hypertrophy and diastolic dysfunction and finally heart failure [2,3]. Acromegalic cardiomyopathy is a specific pathological entity partly unrelated to hypertension, diabetes and dyslipidemia. Indeed GH/IGF-1 excess remains as an independent and determining factor in the development of left ventricular hypertrophy, as it is more associated with this condition than hypertension [4]. Moreover, the most common mechanisms of death in acromegalic patients are cardiac in nature [2].

Coronary risk factors like hypertension, diabetes mellitus, and dyslipidemia are frequent in acromegaly, thus providing a possible link between the disease and vascular abnormalities [5]. Moreover, IGF-1 is a potent mitogen for vascular smooth muscle cells (VSMC) [6] and stimulates the endothelial expression of adhesion molecules [7], a feature of endothelial dysfunction. On the other hand, IGF-1 stimulates nitric oxide production from both the endothelium and VSMC [8]. However, data about the specific role of GH/IGF-1 on atherosclerosis in acromegalic patients are few and controversial [[5], [6], [7], [8]].

It is not well known whether GH or IGF-1 alterations, per se, may compromise cardiovascular function. Several investigations have documented acromegaly-associated endothelial dysfunction and subclinical cardiac dysfunction [8,9]. Indeed the reversal of cardiovascular dysfunction after successful treatment of acromegaly further supports the concept of a specific role of GH or IGF-1 in the pathogenesis of cardiovascular disease [10].

We aimed to determine the influence of acromegaly on coronary microvascular function, assessed by coronary flow reserve (CFR) by transthoracic Doppler echocardiography (TDE), in patients with asymptomatic acromegaly without evidence for epicardial coronary artery disease (CAD) as assessed by multislice computed tomography (MSCT) coronary angiography.