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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 2 628-633
Copyright © 2000 by The Endocrine Society

Original Studies

Abnormal Heart Rate Variability in Adults with Growth Hormone Deficiency1

King S. Leong, Paul Mann, Maureen Wallymahmed, Ian A. MacFarlane and John P. H. Wilding

Address all correspondence and requests for reprints to: Dr. John P. H. Wilding, University Clinical Departments, University Hospital Aintree, Longmoor Lane, Liverpool, United Kingdom L9 7AL. E-mail: j.p.h.wilding{at}liv.ac.uk


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
GH-deficient (GHD) patients have increased risk of cardiovascular death and may have cardiac structural abnormalities. In non-GHD patients these are associated with cardiac autonomic dysfunction, and it is possible that autonomic dysfunction is also present in GHD patients. Power spectral analysis (PSA) of heart rate variability (HRV) indirectly measures cardiac autonomic tone and generates peaks at 3 frequency bands, very low frequency (VLF), low frequency (LF) and high frequency (HF). The area under the LF curve is considered to reflect predominantly cardiac sympathetic activity, whereas HF indicates parasympathetic activity. PSA of HRV was performed in 14 normotensive GHD patients (5 men and 9 women; mean age, 35.2 yr) and 19 healthy controls (9 men and 10 women; mean age, 38.3 yr). GHD patients had 26% lower normalized LF power (P < 0.004), 39% higher normalized HF power (P < 0.001), 28% lower normalized VLF power (P < 0.046), and 51% lower LF/HF ratio (an index of sympathovagal balance; P < 0.001) compared to controls. These data indicate that heart rate variability is abnormal in patients with GHD. The decreased sympathetic tone could be a consequence of reduced central sympathetic tone or altered cardiac responsiveness to autonomic control and may contribute to the increased cardiovascular risk in GHD patients.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
GH DEFICIENCY is associated with increased premature mortality, especially from cardiovascular (1) and cerebrovascular (2) diseases, which have been attributed to dyslipidemia (3, 4, 5) and increased fat mass (6, 7, 8). Abnormalities of cardiac structure and function have also been demonstrated in GH-deficient (GHD) patients (9, 10, 11), which may also predispose to their increased cardiac mortality.

Cardiac autonomic tone can be assessed from heart rate variability (HRV), i.e. the variation in consecutive R-R intervals from one heart beat to another (12, 13, 14). Patients with known abnormalities in cardiac structure, such as after myocardial infarction (15, 16) and congestive cardiac failure (17), have changes in cardiac autonomic tone that can be measured using power spectral analysis (PSA) of HRV. PSA of HRV using Fast Fourier Transformation (FFT) has shown that there are three main frequency peaks, very low frequency (VLF; 0–0.04 Hz), low frequency (LF; 0.04–0.15 Hz), and high frequency (HF; 0.15–0.4 Hz) (13). Using this technique, a spectral graph is obtained, and the area under the curve for each frequency band is defined as the power for that frequency range.

HF power is generally considered a marker of vagal activity, and LF power is considered to be due to sympathetic activity (12, 13, 16). It is generally thought that the LF/HF ratio is a measure of sympathovagal tone (13). The origin of VLF remains controversial and may be related to thermogenesis (18), the renin-angiotensin system (12, 19), or peripheral chemoreceptors (20). As cardiac abnormalities have been shown to be present in GHD patients, it is possible that cardiac autonomic dysfunction may coexist in these patients, and we, therefore, compared HRV measurements between GHD patients and a matched group of healthy controls.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Fourteen GHD patients (nine women and five men; aged 19–56 yr; average, 35.2 yr) were recruited from the endocrine clinic at University Hospital Aintree. Five patients (four women and one man) had developed GHD in childhood, and nine (five women and four men) had adult-onset GHD. The diagnoses and treatments for these patients are listed in Table 1Go. The estimated duration of GHD was 6.4 ±1.2 yr (mean ± SEM; minimum, 6 months). Symptoms such as tiredness, fatigue, and lack of concentration were present in these GHD patients, all of whom were being considered for GH treatment. All patients had GHD, defined as a peak GH less than 10 mU/L after administration of 1 mg glucagon, sc (21, 22, 23). In fact, the GH response in all patients was less than 2.5 mU/L (Table 2Go). These GHD patients had no significant medical illness and, apart from pituitary hormone replacement, were not taking any other medication.


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  		Table 1. Causes of GH deficiency and previous treatments in the GHD patients

 

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  		Table 2. Characteristics of the GH-deficient patients and controls studied

 
The GHD patients were compared with a group of normal healthy volunteers, who were matched for age, sex, and body mass index (Table 2Go). The healthy controls did not have any significant medical problems and were not taking any medication. All patients and controls had normal renal function and fasting blood glucose. The GHD patients all had free T4 levels within the normal range (mean, 16.2 ± 0.9 pmol/L), which was 9.5–23.5 pmol/L. For the control population, normal thyroid function tests were defined as a normal TSH level (mean, 2.02 ± 0.2 mU/L; normal range, 0.3–5.5 mU/L). This study had the approval of the local ethics committee, and all subjects gave their informed consent.

We excluded subjects with diabetes or cardiac problems including hypertension (blood pressure >140/90 mm Hg), those taking drugs known to influence the cardiovascular system, and subjects with any psychiatric illness (including anxiety attacks) or taking any psychiatric drugs.

All tests were performed in the morning between 0900–1200 h with the subjects fasted overnight. No cigarettes, alcohol, or caffeine-containing drinks were taken for 24 h before the tests.

Autonomic function tests

All subjects were tested for cardiac autonomic dysfunction with an automated device (24). This measures R-R interval data during a standard set of heart rate variability tests as described by Ewing and Clarke (25). Three heart rate variability tests were used, the Vasalva maneuver, inspiration/expiration, and lying/standing. In addition, the blood pressure response to standing from a supine position was measured. Normal results with the four tests were as defined by Ewing and Clarke (25) and Sundkvist (26).

Heart rate data acquisition

The tests were performed in a quiet temperature-controlled (18–22 C) room. Three electrocardiogram (ECG) limb leads were attached to the subject, and after resting supine for 10 min (with the headrest at 30° tilt), ECG data were collected using the BIOPAC (Biopac Systems, Inc., Santa Barbara, CA) data acquisition system for 15 min. This system consists of an electrocardiogram amplifier module (ECG100B), a signal conditioning module (UIM100), and an analog to digital signal converter (MP100). The ECG signals were sampled at 200 Hz and were transmitted to MP100 using 2-mm shielded cables. From the MP100 module the signals were transferred into a desktop computer and stored on AcqKnowledge (Biopac Systems, Inc.). At the end of 15 min, three blood pressure readings were obtained using the Omron Corp. (Tokyo, Japan) automatic oscillometric digital blood pressure monitor (model HEM-705CP), and the results were averaged. The average heart rate over the duration of ECG recordings (15 min) was also calculated in all subjects.

Signal processing

The ECG signals were analyzed off-line. Data stored in AcqKnowledge were converted to ASCII files and then analyzed using a commercial HRV analysis software package (PowerMedic, OkiiMura, Taiwan, Republic of China). After manually excluding all ectopic beats, the data were resampled at 2 Hz, and the Hamming spectral window was employed to reduce spectral leakage (13).

The FFT method was used for the calculation of the power spectral density. The advantages of this method are the simplicity of the algorithm used (FFT) and the high processing speed (13). Three different frequency bands (VLF, 0–0.04 Hz; LF, 0.04–0.15 Hz; HF, 0.15–0.4 Hz) were identified using power spectral analysis, and power spectral density plots for the frequencies were obtained. The area under the power spectral density curve is the power of each frequency band. The total spectral power (0–0.4 Hz) was also calculated, and all spectral components were expressed in square milliseconds. In addition, VLF, HF, and HF powers were expressed as normalized units (nVLF, nLF, and nHF), which is the expression of the power as a proportion of the total power. For nLF and nHF, the total power is defined as the power between 0.04–0.4Hz (13), and for nVLF it is between 0–0.4 Hz (27). The normalization process was used because it provides a reliable quantitative estimate of autonomic balance (28).

Statistical analysis

All results are expressed as the mean ± SEM. The heart rate variability data between groups were analyzed using the Mann-Whitney U test, and the rest of the data were analyzed using unpaired t tests. Significance was defined as a two-tailed test result of P < 0.05.

Ethics

This study had the approval of the local ethics committee, and all subjects and patients gave their informed consent.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The demographic details of GHD patients and controls are shown in Table 2Go. Systolic blood pressure was significantly lower in the GHD patients compared to controls (P < 0.05). There was no difference in diastolic pressures or resting heart rate between the two groups. No abnormalities in cardiac autonomic function were detected in either group of subjects using standard autonomic tests (25) (Table 3Go). PSA of HRV revealed differences in autonomic tone between the GHD patients and the control group. Typical power spectral graphs obtained from a GHD patient and a healthy control are shown in Fig. 1Go.


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  		Table 3. Results of the autonomic function tests performed on GHD patients and the control group

 


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  		Figure 1. Typical spectral graphs obtained from a GHD patient and a control subject. The area under the curve is the power of that particular frequency band. The proportions of VLF and LF compared to TP are clearly lower in the GHD patient.

 
Absolute total power (0–0.4 Hz) and absolute power within each frequency band (VLF, LF, and HF) were similar between the groups. However, when the power within each frequency band was normalized, significant differences in all three main frequency bands (VLF, LF, and HF) were demonstrated between the two groups (Table 4Go and Fig. 2Go). The GHD patients had significantly lower nLF and nVLF, whereas nHF was significantly higher compared to the control value. This corresponded to a halving of the LF/HF ratio in the GHD patients compared to controls (P < 0.001).


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  		Table 4. Power of the different frequency bands in GHD patients and controls

 


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  		Figure 2. a, Difference in LF/HF ratio between GHD patients (open bars; n = 14) and controls (closed bars; n = 19). *, P < 0.001. b, Differences in normalized VLF, LF, and HF power between GHD patients (open bars; n = 14) and controls (closed bars; n = 19). *, P < 0.05; **, P < 0.005.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Interestingly, the standard autonomic function tests (25) detected no evidence of cardiac autonomic neuropathy in the GHD patients. Despite this, we have shown for the first time that differences in cardiac autonomic tone exist between GHD patients and healthy controls using PSA of HRV.

A potential variable accounting for the differences we observed is the effect of other hormonal replacement therapy, such as T4 and corticosteroid. However, subgroup analysis of the GHD patients showed that the differences in HRV compared to controls still existed regardless of whether the GHD patients were taking T4 or corticosteroid.

A previous study examining the peripheral sympathetic nervous system in GHD patients reported increased muscle sympathetic nerve activity (MSNA) in GHD patients compared with controls, as measured by microneurography (29). However, we have shown that cardiac sympathetic activity is low in this group of patients. Two different components of the sympathetic nervous system are being assessed by the two techniques; MSNA is a measure of peripheral sympathetic activity, and HRV is a measure of cardiac autonomic tone. In healthy volunteers, there is good concordance between MSNA and HRV (30), but in subjects with structural cardiac damage, such as those with heart failure (31, 32), there is high peripheral sympathetic activity (raised MSNA) but low cardiac sympathetic tone (low LF). However, a recent study has shown that there is no correlation between MSNA and HRV in normal subjects and heart failure patients (33), but they also showed that LF was inversely related to MSNA in patients with heart failure. It is possible that activation of the sympathetic nervous system is nonuniform and may be reduced in certain regions in GHD patients. The hypothalamus is part of the central autonomic network (34), and animal studies have demonstrated that sympathetic activity can be increased by insulin (35), but this is regional (35, 36). Similarly, GH may also increase sympathetic nervous activity via the hypothalamus in a regional distribution.

Secondly, the GHD patients in the two studies differed in several respects. The average age of GHD patients in the MSNA study was much higher (56 yr) than that of our GHD population (35.2 yr), and the average blood pressure in that study was also higher (146/75 mm Hg) compared with that in our group (134/88 mm Hg). In addition, there was no difference in the blood pressure of the GHD patients in that study and that of the controls; in the present study the GHD patients had significantly lower systolic blood pressure compared to controls.

It is also possible that the abnormalities in HRV detected in our subjects are a consequence of abnormal cardiac structure due to GH deficiency. Previous studies have shown that cardiac structural abnormalities, such as decreased left ventricular mass and reduced left ventricular ejection fraction, can be present in GHD patients (9, 10, 11, 37, 38, 39). These cardiac abnormalities may reduce the ability of the heart to respond to the sympathetic nervous system. Similar to our findings, Merola et al. showed that a young group of GHD patients (mean age, 27.3 yr) with childhood-onset GHD also had significant reductions in systolic blood pressure compared to controls (37). Furthermore, this group of patients had reductions in interventricular septum and left ventricular posterior wall thickness. The low systolic blood pressure and sympathovagal balance (a low LF/HF ratio) seen in our study may indicate underlying cardiac structural abnormalities.

Abnormalities of the cardiac structure in GHD patients are not surprising, as the heart is a major target organ for GH (9). Rodent studies have shown that higher numbers of insulin-like growth factor receptors are present in the heart than in any other organ (40). GH treatment improved cardiac function in experimental myocardial infarction and heart failure in rodents (41, 42). In humans, GH treatment has also been used as a treatment for dilated cardiomyopathy with some success (43, 44). Furthermore, improvements in cardiac function and left ventricular mass thickness have been seen 4–12 months after GH treatment in patients with GHD (45, 46). Another study also showed that the physical performance of GHD patients improved with improvements in cardiac function (improved stroke volume and reversal of diastolic abnormalities) after 6 months of GH treatment (47). It remains to be seen whether the observed abnormalities in HRV can be reversed by adequate GH replacement.

It is of interest that patients with severe congestive cardiac failure also have reduced LF and LF/HF ratio (32, 48) as seen in our GHD patients. These abnormalities may be of prognostic importance, as survival is worse in patients who have a low LF/HF ratio postmyocardial infarction (15) and in intensive care patients (49). However, the main differences between these patients studied and our GHD patients is that all of these patients also have global reductions in TP, HF, LF, and VLF. In our patients, the absolute values were not significantly different from those in the healthy controls.

In addition to changes in nLF, nHF power, and LF/HF ratio, a significant reduction in nVLF power was demonstrated in our GHD patients. The origin of VLF is uncertain, but reductions in VLF power are present in subjects after myocardial infarction, and such changes have been shown to be predictive of cardiac mortality in these patients (50, 51). It is possible that the low normalized VLF seen in these GHD patients may also represent a nonspecific marker for poor cardiovascular outcome.

In summary, we have shown that several indexes of cardiac autonomic dysfunction, in particular a reduction in sympathetic activity, is present in symptomatic GHD patients. We propose that these changes may be related to abnormalities in cardiac structure or central autonomic tone and could contribute to the lower blood pressure seen in these patients. Furthermore, VLF is lower in GHD patients, and this may represent a marker for poor prognosis. It remains to be seen whether normalization of these autonomic indexes will occur with GH replacement.


   Footnotes
 
1 This work was supported by Eli Lilly & Co. Back

Received July 13, 1999.

Revised October 25, 1999.

Accepted November 8, 1999.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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