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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-1506
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 1 115-120
Copyright © 2006 by The Endocrine Society

Sympathovagal Imbalance in Acromegalic Patients

Eugenia Resmini, Massimo Casu, Vittoriana Patrone, Giovanni Murialdo, Federico Bianchi, Massimo Giusti, Diego Ferone and Francesco Minuto

Department of Endocrinology and Metabolism and Center of Excellence for Biomedical Research (E.R., F.B., M.G., D.F., F.M.), Division of Internal Medicine (M.C., V.P., G.M.), University of Genova, 16132 Genova, Italy

Address all correspondence and requests for reprints to: Dr. Francesco Minuto, Department of Endocrinology and Metabolism, University of Genova, Viale Benedetto XV, 6; 16132 Genova, Italy. E-mail: minuto{at}unige.it.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Context: Sympathovagal imbalance is a common finding in diabetes and is considered to be a cardiovascular risk factor. No data are available on sympathovagal balance (SB) in acromegalic patients.

Objective: The objective of this study was to evaluate SB in acromegalic patients.

Patients: Twenty nondiabetic, nonhypopituitary, acromegalic patients (13 women and seven men; mean age ± SEM, 51.30 ± 3.09 yr) were compared with age-matched subjects (21 normal subjects, 20 patients with type 1 diabetes mellitus, and 15 patients with type 2 diabetes mellitus).

Interventions: Autonomic tests, used to evaluate SB, were performed by power spectral analysis of heart rate variability in clinostatism (c) and orthostatism (o), using a frequency domain method. Power spectral analysis identifies peaks of power: high frequency (HF), which expresses vagal activity, and low frequency (LF), which expresses sympathetic activity.

Results: Acromegalic patients displayed significantly lower LFc/HFc (P = 0.002) and LFo/HFo (P < 0.001) ratios than normal subjects. HFo was significantly higher in acromegalic patients than in normal subjects (P < 0.001) and patients with type 1 diabetes mellitus (P = 0.004), but no different from that in type 2 diabetes mellitus patients (P = 0.069). In untreated acromegalic patients, the alterations found in the whole group were confirmed; no statistically significant differences were found between untreated acromegalic patients and those treated with somatostatin analogs. Similarly, the same alterations found in the whole group were evident in the controlled acromegalic patients, and no significant differences were found between controlled and uncontrolled patients.

Conclusion: Our study evidenced that sympathovagal imbalance in acromegalic patients, due to vagal hypertone, is difficult to reverse and is not influenced by medical therapy. This could be a new cardiovascular risk factor.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
A SIGNIFICANT RELATIONSHIP has been reported between autonomic nervous system imbalance and cardiovascular mortality, including sudden cardiac death (1, 2, 3).

Electrocardiographic RR intervals fluctuate cyclically, modulated by ventilation, baroreflexes, and other genetic and environmental factors that are mediated through sympathetic and parasympathetic signals (4). The evaluation of RR intervals yields a useful index of global heart rate variability (HRV) from Holter recordings (5). Of the different methods of measuring HRV, spectral analysis has a greater ability to differentiate vagal and sympathetic modulation of the heart rate (6, 7).

Experimental evidence of an association between a propensity to lethal arrhythmias and signs of either increased sympathetic or reduced vagal activity has prompted the development of quantitative markers of autonomic activity. HRV represents one of the most promising such markers (8) and is also a useful tool in the diagnosis of cardiovascular pathologies (9, 10). HRV is becoming a measure of autonomic nervous system balance.

Long-term, 24-h recording can be used to assess autonomic nervous responses during normal daily activities in conditions of health or disease. Short-term electrocardiogram (ECG) recordings (5–15 min) made under controlled conditions, lying supine or standing or tilted upright, can elucidate physiological, pharmacological, or pathological changes in autonomic nervous system function. This method, which provides a simple, noninvasive analysis based on the processing of spontaneous oscillations in heart rate, is useful in assessing the risk of cardiovascular death or arrhythmic events (8).

Sympathovagal imbalance is a common finding in diabetes, and the utility of standard cardiovascular tests in diagnosing cardiac autonomic neuropathy in diabetes has been well documented (11, 12, 13). Evidence of the importance of autonomic control of the cardiovascular system together with the cardiovascular dysfunction linked to diabetic autonomic neuropathy support the hypothesis of a role of autonomic neuropathy in the increased cardiovascular morbidity and mortality observed in diabetic patients (14). The early subclinical detection of autonomic dysfunction is therefore important for risk stratification and subsequent management (10).

Cardiovascular complications are the most important cause of increased morbidity and mortality in acromegalic subjects, and a specific cardiomyopathy has been well documented in these patients (15, 16, 17, 18). However, no data are available on sympathovagal balance (SB) in acromegalic patients.

There are few experimental data on the effect of GH excess on HRV; in transgenic mice overexpressing bovine GH, as a model for human acromegaly, GH appears to have marked effects on autonomic tone by reducing sympathetic nervous system function, possibly via reduced noradrenaline stores (19).

For these reasons, we decided to evaluate SB in acromegalic patients compared with normal subjects and diabetic patients, a population with a well-known sympatovagal imbalance, as a sort of pathological control.

In this study we demonstrate that acromegalic patients present with a sympathovagal imbalance similar to that found in diabetic patients. Because this is a cardiovascular risk factor in the latter subjects, we hypothesize that it may also be a cardiovascular risk factor in acromegalic patients.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients and protocol

Twenty nondiabetic, nonhypopituitary, acromegalic patients (13 women and seven men; mean age, 51.30 ± 3.09 yr; age range, 21–71 yr) were studied under different clinical conditions. In all acromegalic patients, the values of oral glucose tolerance testing and hemoglobin A1C excluded diabetes mellitus.

One patient had been newly diagnosed and was not receiving any treatment; five were receiving primary medical therapy with somatostatin analogs. Of the remaining 14 patients, four had undergone transsphenoidal neurosurgery only, five had undergone transsphenoidal neurosurgery after primary therapy with somatostatin analogs (from 1–3 yr earlier), one had transsphenoidal neurosurgery, followed by radiotherapy, and thereafter received medical therapy with somatostatin analogs, and four had undergone transsphenoidal neurosurgery and thereafter received medical therapy with somatostatin analogs.

Disease activity was evaluated by means of oral glucose tolerance testing, with a single blood sample at the 120th min (20), and the basal value of IGF-I, according to the Consensus Conference criteria (21). For subsequent statistical analysis, the patients were classified according to whether they were receiving medical treatment with somatostatin analogs at the beginning of the study (treated and untreated) and according to clinical control, based on the Consensus criteria (controlled and uncontrolled) (21).

None of the acromegalic patients received therapy known to interfere with the autonomic system. All acromegalic patients had a basal ECG and echocardiography performed during the study.

In patients treated with somatostatin analogs, tests were performed about midway between two injections. The protocol was approved by the local ethics committee, and written informed consent was obtained from the patients.

Results were compared with those found in 21 normal subjects (mean age, 56.95 ± 1.96 yr), 20 patients with type 1 diabetes mellitus (T1DM; mean age, 48.40 ± 3.2 yr), and 15 patients with type 2 diabetes mellitus (T2DM; mean age, 55.40 ± 1.9 yr).

The diagnosis of T1DM or T2DM was made according to the guidelines of the American Diabetes Association (22).

Analytical methods

Serum GH levels were determined with a chemiluminescent immunoradiometric assay (Immulite, Diagnostic Products Corp., Los Angeles, CA). The analytical sensitivity of this assay was 0.01 µg/liter, and the precision was less than 7% in the standard curve range. The standard curve is calibrated against World Health Organization First International Reference Preparation 80/505 (1 mg = 2.6 IU). All data have been validated in our laboratory.

IGF-I was measured by RIA using immunochemicals and tracer provided by BioSource (Nivelles, Belgium). The sensitivity of the assay is 150 µg/liter (0.2 nmol/liter); the intra- and interassay coefficients of variation are 6% and 7.5%, respectively.

To avoid interference from binding proteins, single plasma EDTA samples were treated with acid ethanol, according to Daughaday et al. (23).

IGF-I was measured under basal conditions on initial testing and reported as SD scores for age, calculated on data obtained from more than 4000 normal subjects of both sexes from 0–100 yr of age, grouped into decades of age.

HRV analysis

Autonomic tests were performed by power spectral analysis of HRV in clinostatism (c) and orthostatism (o), using a frequency domain method. HRV is a measure of autonomic nervous system balance.

An electrocardiographic recording of R-R intervals was made at 1000 h in a quiet room reserved for this purpose, at least 1 h after venipuncture for routine hormonal evaluation. Subjects were placed supine on a mechanically driven tilt-table and instructed to relax, stay awake, breathe regularly, and not to speak. After supine resting for about 10 min to stabilize blood pressure and heart rate, clinostatic R-R intervals were acquired. Immediately thereafter, the patient was passively brought into the upright position by raising the table over a 30-sec period, and the recording was repeated.

For both clinostatic and orthostatic postures, the electrocardiogram was consecutively recorded for 330 sec by means of an electrocardiograph connected to a PC equipped with software which sampled the analogical signal at about 200 Hz using an analogic/digital converter. Each R-R interval was measured in milliseconds and memorized as a tachogram (R-R interval duration vs. number of heartbeats). Two series of data, corresponding to clinostatic (tachogram A) and orthostatic (tachogram B) R-R intervals, were analyzed in all subjects using a parametric method based on the autoregressive model for the quantification of HRV signals.

The main power densities in the high frequency (HF; 0.15–0.4 Hz) and low frequency (LF; 0.04–0.15 Hz) bands were identified for each density spectrum. In addition, LF/HF ratios were calculated in both clinostatism and orthostatism. An LF/HF greater than 1 is evidence of a normal SB.

Power spectral analysis identifies three peaks of power: a peak of HF, which expresses vagal activity; a peak of LF, which expresses sympathetic activity; and a peak of very LF, which is of uncertain significance. LF and HF are quantitative indicators of neural control of the sinoatrial node; in particular, the LF component is a marker of sympathetic modulation, whereas the HF component is a marker of vagal modulation.

LF/HF is regarded as an index of sympathovagal balance in the frequency domain (4, 24, 25).

All HRV parameters were measured in square milliseconds.

QT

The QT was obtained from the basal ECG. The most commonly used QT correction (QTc) formula is the one postulated by Bazett in 1920 (QTc = QT/RR1/2). In our study the QTc was calculated with the Bazett formula (26). The normal QTc is generally accepted to be less than or equal to 440 msec.

Echocardiography

All echocardiographic studies were performed on the same day as the autonomic study and used a Acuson Sequoia ultrasound machine (Siemens, New York, NY). Echocardiograms were obtained at rest, with patients supine in the left lateral position, using standard parasternal and apical views. The overall monodimensional left ventricular (LV) measurements and the bidimensional (apical four- and two-chamber) views were obtained according to the recommendations of the American Society of Echocardiography (27). All tracings were obtained and read by a single observer who was blinded to the clinical characteristics of the patients under observation. LV mass was derived using the formula described by Devereux and associates: LV mass (grams) = 0.80 x 1.04 [(VSTd + LVIDd + PWTd)3 – (LVIDd)3] + 0.6, where VSTd is ventricular septal thickness at end diastole, LVIDd is LV internal dimension at end diastole, and PWTd is LV posterior wall thickness at end diastole. LV mass was corrected for height2.7 and expressed in units of grams per meter2.7. The presence of LV hypertrophy was defined for LV mass corrected for height2.7 greater than 51 g/m2.7 in both males and females (28). None of the patients showed dyssynergic areas that would invalidate the theoretical assumptions behind the cardiac mass calculations.

Statistical analysis

Mann-Whitney U tests for unpaired data were used for data comparison between patients and healthy controls. Comparison within groups was made using the nonparametric Wilcoxon test.

Graphics were elaborated by the Sigmaplot 9.0 program (Systat Software, Inc., Richmond, CA).


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Clinical and cardiological data observed in the acromegalic patients divided according to medical treatment and clinical control are reported in Table 1Go. The acromegalic patients had, on the average, normal QT, normal heart rate, normal ejection fraction, and LV hypertrophy.


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  		TABLE 1. Clinical and cardiological data for the acromegalic patients enrolled in the study, grouped according to medical treatment and to clinical control

 
Evaluation of SB within the single groups revealed a significant decrease in HF on passing from c to o in both normal subjects (HFc, 20.24 ± 3.54; HFo, 7.76 ± 1.48; P = 0.002) and in T1DM patients (HFc, 26.90 ± 4.65; HFo, 13.95 ± 2.44; P = 0.013). A significant increase in LF/HF on passing from c to o was observed in normal subjects (LFc/HFc, 2.01 ± 0.29; LFo/HFo, 6.62 ± 1.70; P = 0.001) and in T1DM patients (LFc/HFc, 0.85 ± 0.16; LFo/HFo, 2.25 ± 0.57; P = 0.013), but not in acromegalic patients (LFc/HFc, 0.77 ± 0.91; LFo/HFo, 1.14 ± 0.25) or in T2DM patients (LFc/HFc, 0.96 ± 0.16; LFo/HFo, 1.09 ± 0.20).

Comparison of the results of sympathovagal balance between the groups showed that acromegalic patients displayed significantly lower LF/HF ratios than normal subjects both in c (acromegalic patients, 0.77 ± 0.91; normal subjects, 2.01 ± 0.29, P = 0.002) and in o (acromegalic patients, 1.14 ± 0.25; normal subjects, 6.62 ± 1.70; P < 0.001). HF in orthostatism was significantly higher in acromegalic patients (30.00 ± 4.39) than in normal subjects (7.76 ± 1.48; P < 0.001) and in T1DM patients (13.95 ± 2.44; P = 0.004), but was not different from that in T2DM patients (21.06 ± 6.31; P = 0.069; Figs. 1Go and 2Go).



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  		FIG. 1. Box and whisker plots of LF/HF in both c and o in the various study groups. The lines in the boxes represent the median; the boxes are the 25–75th percentile range, and the whiskers are the 10–90th percentile range. *, P < 0.05; **, P < 0.01; ***, P < 0.001.

 


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  		FIG. 2. Box and whisker plots of LF and HF in both c and o in the various study groups. The lines in the boxes represent the median; the boxes are the 25–75th percentile range, and the whiskers are the 10–90th percentile range. *, P < 0.05; **, P < 0.01; ***, P < 0.001.

 
According to medical treatment, untreated acromegalic patients had significantly higher HFc (41.40 ± 7.07; P = 0.035) and HFo (34.30 ± 7.17; P = 0.001) and significantly lower LFc/HFc (0.81 ± 0.15; P = 0.012) and LFo/HFo (0.78 ± 0.16; P < 0.001) ratios than normal subjects (see previous paragraph); HFo was also significantly higher than that in T1DM patients (13.95 ± 2.44; P = 0.010), but was not different from that in T2DM patients (21.06 ± 6.31). Treated acromegalic patients had significantly lower LFc/HFc (0.73 ± 0.10; P = 0.007) and LFo/HFo (1.50 ± 0.45; P < 0.001) than normal subjects and significantly higher HFo (25.70 ± 5.10) than normal subjects (P = 0.001) and T1DM patients (P = 0.039), but showed no difference from T2DM patients.

According to clinical control, controlled acromegalic patients had a lower LFc/HFc, at the limits of significance (0.99 ± 0.17; P = 0.05), a definitely lower LFo/HFo (1.01 ± 0.16; P < 0.001), and significantly higher HFo (29.88 ± 8.14; P = 0.011); no differences were seen compared with T1DM and T2DM patients. Uncontrolled acromegalic patients had significantly higher HFc (40.83 ± 5.59; P = 0.013) and HFo (30.08 ± 2.43; P < 0.001) and significantly lower LFc/HFc (25.83 ± 4.96; P = 0.001) and LFo/HFo (1.22 ± 0.40; P = 0.000). HFc (40.83 ± 5.59; P = 0.048) and HFo (30.08 ± 2.43; P = 0.005) were also significantly higher than in T1DM patients, but did not differ from those recorded in T2DM patients.

No statistically significant differences were found between treated and untreated acromegalic patients or between controlled and uncontrolled acromegalic patients.

In T1DM patients, LFc (19.07 ± 4.43; P = 0.018), LFc/HFc ratio (0.85 ± 0.16; P = 0.004), HFo (13.95 ± 2.44; P = 0.030), and LFo/HFo ratio (2.25 ± 0.57; P = 0.001) differed significantly from the corresponding values recorded in normal subjects.

T2DM patients displayed significantly different values of LFc (18.00 ± 3.27; P = 0.036), LFc/HFc ratio (0.96 ± 0.16; P = 0.011), LFo (17.93 ± 4.50; P = 0.039), HFo (21.06 ± 6.31; P = 0.013), and LFo/HFo ratio (1.09 ± 0.20; P = 0.000) from those in normal subjects. No significant differences emerged between the two groups of diabetic patients.


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
In normal subjects in c, LF prevails over HF, indicating a prevalence of sympathetic activity. On passing from c to o, a mechanism of postural adaptation occurs, producing a decrease in vagal activity (HF) and an additional increase in sympathetic activity (LF) (29).

Diabetic subjects with autonomic dysfunction are reported to display sympathovagal imbalance (7, 11, 12, 30), which is particularly evident in o, as we found in our diabetic patients. This is considered to be a cardiovascular risk factor in these subjects (10, 14).

It is well known that cardiovascular complications increase morbidity and mortality in acromegalic subjects (31), and a specific cardiomyopathy due to the effect of GH and IGF-I excess has been well documented in these patients (15, 16, 17, 18). Indeed, there is accumulating evidence of specific structural and functional changes in the heart in acromegaly (17). Coexisting factors, such as hypertension, glucose intolerance, and coronary heart disease, have a potential role in the progression of acromegalic cardiomyopathy, but other factors could be involved.

In this study we assessed whether the autonomic system could be involved as a cardiovascular risk factor in the increased mortality for cardiovascular accidents in these patients as it is in diabetic subjects.

Our data also showed significant alterations in HRV parameters in acromegalic patients. The LF/HF ratios, in particular, in both c and o were drastically reduced compared with normal subjects and, on the average, were lower than those in diabetic patients, although not significantly so. The decrease in HF that occurs on passing from c to o in normal subjects is still evident in T1DM patients, but not in T2DM patients or in acromegalic patients. In conclusion, the increased vagal activity observed in c in acromegalic patients is not attenuated by o.

To rule out a possible influence of somatostatin analogs on the sympathovagal balance, the acromegalic patients were analyzed according to medical treatment; no significant differences in SB were found between treated and untreated subjects. In the untreated group, the alterations found in the whole group of acromegalic patients were confirmed. Indeed, LF/HF ratios in both c and o and HFo were significantly different from the values recorded in normal subjects and patients with T1DM; moreover, HFc was significantly higher than that in normal subjects. In conclusion, medical treatment with somatostatin analogs does not seem to be responsible for the autonomic dysfunction found in acromegalic patients.

With regard to clinical control, the same alterations found in the whole group were evident in the controlled patients, and no significant differences between controlled and uncontrolled patients were found. Controlled patients showed significantly higher vagal activity in o than normal subjects; HFo in o did not decrease as it should. In single cases, a clear sympathovagal imbalance was also found in subjects who had been controlled for years, suggesting that this complication of the disease is difficult to reverse.

Severe arrhythmias can cause sudden death in acromegaly (15). Abnormalities of cardiac rhythm have been described, mostly at peak physical exercise (32, 33, 34), but these are less documented than the other cardiovascular complications, and often the causes of arrhythmias are not known (15).

A majority of acromegalic patients have LV hypertrophy, which changes the ECG pattern and prolongs the QT, but this is not enough to explain the arrhythmic profile of acromegaly. It has been found that acromegalic subjects present structural cardiac changes that could partially explain the increased risk of dysrhythmias (35), but very few data on the prevalence and severity of cardiac dysrhythmias in these patients are available (32, 33, 34).

No arrhythmias could be identified in our acromegalic patients during the ECG measurement. Moreover, ejection fraction and heart rate were normal. LV hypertrophy was found, but this did not determine a QT enlargement; indeed, QT was normal in all patients. For this reason we can hypothesize that a sympathovagal imbalance, which is known to be a risk factor for arrhythmias, could engender a risk of arrhythmias in acromegalics also. Additional studies are needed to better clarify this point.

The autonomic nervous system appears to play an important role in the pathophysiological mechanism of vasovagal syncope (36, 37, 38). Recent data have shown that vagal sinus modulation is increased at rest in subjects with vasovagal syncope (39). The vasovagal imbalance is believed to be the most common cause of syncope, especially if there is no evidence of underlying structural cardiac or cardiovascular disease (40).

No data are available on the risk of syncope in acromegalic patients. Sympathovagal imbalance would suggest that acromegalic subjects may be at risk of syncope, but this needs to be confirmed by epidemiological data on a sufficiently large number of subjects through more detailed cardiological studies.

In conclusion, our study evidenced a sympathovagal imbalance due to vagal hypertone in acromegalic patients. This imbalance, which was not determined by medical therapy with somatostatin analogs and which is difficult to reverse, could be a new cardiovascular risk factor in acromegaly.

Autonomic dysfunction together with cardiac autonomic neuropathy could be other important clinical complications of acromegaly. This issue needs to be clarified as soon as possible to reduce the cardiovascular risk of these patients.

Additional studies are needed to ascertain the clinical meaning and the role of sympathovagal imbalance in acromegalic subjects and to establish whether in acromegaly there is only a specific cardiac autonomic neuropathy or a more general autonomic dysfunction that could involve many organs, as documented for diabetes mellitus. Moreover, it will be important to identify the future specific target for treatment in the therapy of autonomic dysfunction in acromegaly.


   Acknowledgments
 
We thank Dr. GianPaolo Bezante for his critical review of the cardiological data. The outstanding collaboration of the patients who participated in this study is also acknowledged


   Footnotes
 
This work was supported by Ministero dell’Istruzione, dell’Università e della Ricerca (2002067251-001) and the University of Genova.

Preliminary data from this study were presented at the 87th Annual Meeting of The Endocrine Society, San Diego, CA, June 4–7, 2005.

First Published Online November 1, 2005

Abbreviations: c, Clinostatism; ECG, electrocardiogram; HF, high frequency; HRV, heart rate variability; LF, low frequency; LV, left ventricular; o, orthostatism; QTc, QT correction; SB, sympathovagal balance; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus.

Received July 8, 2005.

Accepted October 20, 2005.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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