Differences in heart rate variability parameters during the post-dialytic period in type II diabetic and non-diabetic ESRD patients
Mauro Giordano1,,
Daniela Manzella2,
Giuseppe Paolisso2,
Alberto Caliendo3,
Michele Varricchio2 and
Carmelo Giordano3
1 The Institute of Clinical Medicine L. Condorelli, University of Catania,
2 The Department of Geriatric Medicine and Metabolic Disease, II University of Naples,
3 The Institute of Internal Medicine and Nephrology, II University of Naples, Italy
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Abstract
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Background. Heart rate variability parameters were evaluated in 10 healthy subjects, 10 type II diabetic patients and 20 end-stage renal disease (ESRD) patients (11 non-diabetic and nine type II diabetic) undergoing chronic haemodialysis. The study was divided in two phases.
Methods. In the first phase all subjects underwent electrocardiograph (ECG) recording under baseline conditions. In the second phase only ESRD patients underwent haemodialysis and ECG recording. On the day of dialysis and ECG recording the ECG recording was started 1 h before the haemodialysis session (pre-dialytic period), and continued throughout the dialysis (dialytic period), until the morning after (post-dialytic period).
Results. Compared with ESRD patients, non-ESRD patients showed the lowest cardiac sympathetic activity. Diabetic patients compared to non-diabetic patients showed a prevalence of cardiac sympathetic activity in the pre-dialytic period (P<0.01). During the dialytic period in comparison with the pre-dialytic one, a further increase in cardiac sympathetic activity was observed in both diabetic and non-diabetic ESRD patients (P<0.001). However, in the post-dialysis period the cardiac autonomic nervous system activity remained at the pre-dialytic condition in the diabetic group. In contrast, in the non-diabetic group the cardiac autonomic balance shifted towards a parasympathetic prevalence in the post-dialytic period (P<0.01). In addition, a significant correlation was found between changes in heart rate variability and changes in plasma urea concentration in the non-diabetic group only (r=0.65; P<0.03).
Conclusions. Non-insulin-dependent diabetic uraemic patients undergoing a chronic haemodialysis programme have a severe impairment of heart rate variability. This is probably due to autonomic neuropathy related to the effects of both diabetes and chronic uraemic conditions. In non-diabetic haemodialysis patients uraemia causes similar but reversible changes in heart rate variability compared with the changes caused by diabetes.
Keywords: diabetes mellitus; end-stage renal disease; heart rate variability; sympathetic activity
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Introduction
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Cardiovascular events represent the leading cause of mortality in patients with end-stage renal disease (ESRD) [13]. In particular, an association between compromised autonomic function and sudden cardiac death in patients awaiting kidney transplantation has been reported recently [4]. In addition, previous data suggest that a prevalence in sympathetic activity results in ventricular arrhytmias that are potentially life-threatening [5].
Power spectral analysis of heart rate variability (HRV) is a useful and safe tool to evaluate cardiac autonomic nervous system activity [69]. Among HRV parameters, the low-frequency (LF) to high-frequency (HF) ratio is considered to be an index of cardiac sympatho-vagal balance [69]. In fact, specific interventions for increasing or lowering the LF/HF ratio may indicate a shift of the cardiac autonomic nervous system balance towards the sympathetic or parasympathetic predominance [69].
Previous evidence showed prevalent cardiac sympathetic nervous system activity, evaluated by HRV technique, in ESRD patients compared to healthy subjects [10]. This unbalanced sympathetic/parasympathetic activity seems due mainly to the effect of uraemia or its consequences, rather than to the state of chronic illness per se [11]. Surprisingly, there is little data in the literature regarding the effects of haemodialysis therapy on HRV parameters in ESRD diabetic patients. In particular, there is a lack of information on HRV parameters during the 24 h that includes the immediate pre- and post-dialytic periods. In addition, it has been shown that ESRD diabetic patients undergoing chronic haemodialysis have a greater cardiovascular mortality than non-diabetic ESRD patients [12]. The exact reasons for the difference have not been completely elucidated. However, it has been demonstrated that autonomic neuropathy represents a major complication of diabetes and is associated with a marked increase in mortality and cardiac arrhythmias [13]. One could hypothesize that cardiac autonomic nervous system activity may be impaired further in diabetic ESRD patients due to the co-occurrence of uraemic and diabetic neuropathy.
In the light of such evidence we investigated whether there is any difference in baseline conditions in HRV parameters among healthy subjects, diabetic ESRD patients, non-diabetic ESRD patients, and type II diabetic patients without ESRD. If differences were detected we asked if HRV parameters were different between diabetic and non-diabetic ESRD patients in the immediate pre-dialysis period, during the dialysis session and in the 24 h after dialysis. Thus, we evaluated HRV parameters in baseline conditions in healthy subjects, non-diabetic ESRD patients, type II diabetic patients without ESRD, and diabetic ESRD patients. Furthermore, we evaluated HRV parameters in both non-diabetic and diabetic ESRD patients on a chronic haemodialysis programme immediately before dialysis (with the strongest uraemic toxicity) throughout haemodialysis and immediately after the dialysis period (when beneficial effects of haemodialysis are maximal).
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Subjects and methods
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Subjects
Fifty patients volunteered for the study. They were divided into the following groups: 20 patients with ESRD (11 non-diabetic and nine diabetic), 10 with type II diabetic patients, and 10 healthy subjects. Haemodialysis treatment for patients with ESRD (Drake Willock, System 1000, Althin Medical, Inc. Miami, FL, USA) was performed three times per week; each session lasted 34 h. Polysulphone capillary dialysers, Fresenius model 68 (Fresenius Medical Care, Bad Homburg, Germany) were used. During haemodialysis, blood flow was maintained at a value of 250300 ml/min; dialysate flow was 500 ml/min.
Inclusion criteria for haemodialysis-treated patients were: age <75 years; serum albumin concentration >3.5 g/dl; mean arterial pressure (MAP)<110 mmHg; differential MAP during dialysis <25 mmHg; and fractional urea clearance during dialysis (Kt/V)>1.0. Patients with chronic cardiac failure, cardiac rhythm disturbances, or taking drugs known to affect the autonomic nervous system, were excluded. Unstable patients suffering from severe haemodialysis hypotension, whose last 13 treatments were complicated by at least two episodes of cardiovascular collapses, were also excluded from the study. Except for diabetes, both study groups were fully matched. All non-diabetic ESRD patients had normal glucose tolerance [14]. Aetiology of ESRD in non-diabetic patients included: chronic glomerulonephritis (n=3); nephrosclerosis (n=2); polycystic kidney disease (n=2); interstitial nephritis (n=1); pyelonephritis (n=1) and unknown (n=1). ESRD in all diabetic patients was secondary to diabetic nephropathy; all diabetics had sufficient glucose control achieved by multiple daily dosages of insulin. The purpose and potential risks of the study were explained to all patients and their voluntary written consent was obtained before their participation.
Experimental design
The study was divided in two phases. In the first phase all subjects were studied at 8:00 am, in a quiet, comfortable room with a temperature between 22° and 24°C; each subject rested in the supine position for at least 30 min before starting a baseline Holter monitor recording, which lasted 120 min. In the second phase, only patients with ESRD were admitted to our Institute for 2 days for haemodialysis and were on bedrest throughout Holter monitor recording. Blood pressure was measured while patients were supine in haemodialysis chairs. Measurements were taken every 10 min during a 1-h baseline pre-dialysis period and every 30 min during haemodialysis using a standard mercury sphygmomanometer. Holter monitor recording was started 1 h before the haemodialysis session (pre-dialytic period), continued throughout haemodialysis (dialytic period) until the morning after haemodialysis (post-dialytic period).
Cardiovascular determination
All cardiovascular measurements were carried out under quiet conditions. Before recording, we asked subjects to breathe at a normal frequency and respiratory rate was determined. Respiratory frequency was calculated over a period of 2 min before the test. Subjects with a respiratory rate less than 10 breaths/min (i.e. <0.15 Hz) were excluded from the study, in order to avoid the overlap of oscillations of low and high frequency at spectral analysis. Electrocardiograph (ECG) recordings with ambulatory ECG monitoring were performed with two-channel frequency modulating tape recorders (Remco Italy Cardioline AD 35, recorder model number LP103, Milan, Italy). To ensure that variations did not introduce frequency components to the data, an expert technician checked the speed of the tape recorder.
After accurate skin preparation, the electrodes were placed on the chest in order to obtain the bipolar chest leads CM1 (modified V1) on the first channel and CM4 (modified V4) on the second channel. Two independent, blinded experienced investigators analysed the ambulatory electrocardiographic recording tapes by Holter AD35 TOP (Remco Italy Cardioline, Milan, Italy). Ectopic beats were corrected for linear interpolation with the adjacent complexes. Electrocardiographic tracings with >1% premature beats were eliminated from the analysis.
Power spectral analysis was calculated from a consecutive series of 512 intervals. An autoregressive algorithm computed the power spectral densities. Autoregressive spectral analysis was undertaken after estimation of model coefficients by the LevinsonDurbin algorithm. The model order selection was performed according to the Akaike [15] information criterion. Spectral components were identified and estimated using the spectral-decomposition algorithm proposed by Jonsen and Andersen [16] and were then assigned, on the basis of their central frequency, to one of the three bands: very-low-frequency (VLF) band (00.03 Hz), LF band (0.040.15 Hz), and HF band (0.160.45 Hz).
Because the physiological explanation of the VLF component is not as well defined as the LF and HF bands and the existence of a specific physiological process attributable to these heart period changes has been seriously questioned [6], only the LF and HF components are normally considered. LF and HF components are always reported in normalized units, which represent the relative value of the power of each component in proportion to the total power minus the VLF component [6]. Normalized units tend to minimize the effect of the changes in total power on the values of LF and HF components [6]. The respiratory rate for data analysis was obtained from the central frequency of the HF component [17]. Among the HRV parameters we also calculated the interval between two or more beats (RR interval) and total power, which is variance of all RR intervals.
Calculation and statistics
All results are mean±SD. MAP was calculated as diastolic plus 1/3 of pulse pressure. During haemodialysis, urea clearances (Kt/V) were calculated from the Daugirdas formula [18]. The model generates the following equation in which: Kt/V=-ln(R-0.33)+[(4-3.5R)x(UF/W)], where R is the post-dialysis blood urea nitrogen (BUN) divided by the pre-dialysis BUN, UF is the ultrafiltration volume in litres, and W is the post-dialysis weight in kilograms. Delta LF/HF ratio was calculated as difference between pre-dialytic period and those found throughout and after haemodialysis. Analysis of variance (ANOVA) allowed calculating difference among the different experimental conditions. Time-dependent changes in each group were evaluated by ANOVA for repeated measures. When a P value <0.05 was found, a Scheffe test was performed to determine which intervention most influenced the overall difference between groups. Pearson productmoment correlations were calculated to test the association among variables. A P value of 0.05 was chosen as the level of significance. All calculations were made on IBM PC computer by Sigma Stat (Jandel Scientific-Chicago-USA).
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Results
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Basal data in healthy, diabetic, and uraemic subjects
Clinical and laboratory characteristics of study patients are reported in Table 1
. All subjects were adult, non-obese, and normotensive. Analysis of data showed that patients with ESRD (whether diabetic or non-diabetic) had more elevated fasting plasma creatinine, BUN and potassium levels than controls and patients without ESRD. In contrast, control patients (healthy subjects and diabetic non-ESRD patients) had the highest plasma albumin levels and haematocrit values. As far as the cardiovascular parameters are concerned, healthy subjects had the lowest LF value and LF/HF ratio and the highest value for RR mean, total power and HF components (Table 2
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Time course differences in patients undergoing to haemodialysis
Arterial blood pressure before haemodialysis (132±8 vs 131±6 mmHg; P=NS), at the end of haemodialysis (114±7 vs 110±8 mmHg; P=NS) and at the end of the study (128±8 vs 123±7 mmHg; P=NS) was not different between diabetic and non-diabetic ESRD patients. During the haemodialysis session, mean ultrafiltration volume was not different between diabetic (3.2±0.3 l) and non-diabetic (3.3±10.5 l) patients. There was no statistical difference in interdialytic weight gain, expressed as per cent change of body weight, average 4.4±0.5 and 4.7±0.4% in diabetic and non-diabetic haemodialysis patients respectively. Time course changes in HRV parameters in both study groups are shown in Figure 1
. Pre-dialytic values of RR mean, total power and HF component were significantly higher in the pre-dialytic than during the dialytic period (P<0.007 for all dialytic study times) in both diabetic and non-diabetic ESRD patients. In contrast, LF component (P<0.01 for all dialysis study times) and LF/HF (P<0.001 for all haemodialysis study times) had opposite trends in both study groups. During the post-dialytic state, all HRV parameters returned gradually (P<0.01 for the trend) to the pre-dialytic state in diabetic patients. In fact, no significant differences (P<0.10) between the last measurements and the pre-dialytic values were found in diabetic patients. In contrast, non-diabetic ESRD patients had RR mean, total power and HF component significantly higher and LF component and LF/HF ratio significantly lower during the post-dialytic period than in pre-dialytic conditions (P<0.01 for trend). In particular, the last LF component and LF/HF ratio value were significantly lower (P<0.01 for both) compared with pre-dialytic periods. Typical patterns of pre-, during, and post-dialysis spectral analysis in one ESRD diabetic patient and one ESRD non-diabetic patient are reported in Figure 2
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Fig. 1. Time changes in heart rate variability parameters. RR mean (ms), total power (ms2), low frequency (LF) (nu), high frequency (HF) (nu), LF/HF ratio, and delta of LF/HF ratio during pre-dialytic, dialytic and post-dialytic periods. Heart rate variability parameters are reported as evaluated: during 1 h (pred 1) prior to haemodialysis session (pre-dialytic period); during 3 h (d1, d2 and d3) of haemodialysis session (dialytic period); and 1, 6, 12, and 24 h (pd1, pd6, pd12, and pd24) following dialysis session (post-dialytic period) in non-diabetic group () and in diabetic group ( ). nu, normalized units. *P<0.05 and **P<0.01 in non-diabetic vs diabetic groups.
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Fig. 2. Spectral pattern from typical registration for one non-diabetic (A) and one diabetic (B) end-stage renal disease patient in pre-dialytic, dialytic, and post-dialytic periods.
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Group differences
Differences in HRV parameters between diabetic and non-diabetic ESRD patients are shown in Figure 1
. In pre-dialytic conditions, RR mean, total power and HF component were significantly higher in non-diabetic ESRD than in diabetic ESRD patients. In contrast, LF component and LF/HF had an opposite trend. During haemodialysis, no significant differences between the two study groups were found. During the post-dialytic period RR mean, total power and HF component were significantly higher, and LF component and LF/HF significantly lower in non-diabetic than in diabetic ESRD patients. Due to the occurrence of statistically significant differences in baseline LF/HF ratio between the two study groups, we calculated the delta change in LF/HF for comparing non-diabetic and diabetic ESRD patients more appropriately. Delta changes in LF/HF ratio were not significantly different during haemodialysis, while non-diabetic ESRD patients had significantly greater reduction in LF/HF ratio than diabetic ESRD patients during the post-dialytic period. Furthermore, because LF/HF ratio and plasma urea concentration were significantly different at the end of the post-dialytic period, we also reported individual changes in LF/HF and plasma urea concentration between baseline and 24-h periods in diabetic and non-diabetic ESRD patients. Interestingly, delta LF/HF and delta plasma urea in the post-dialytic period were correlated only in non-diabetic patients (Figure 3
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Fig. 3. Correlation between delta LF/HF ratio and the delta of plasma urea concentration, before and 24 h after haemodialysis, in non-diabetic patients () (r=0.65, P<0.03) and diabetic patients ( ) (P=NS).
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Discussion
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The main findings of our study include (i) evidence for a prevalence of cardiac sympathetic activity in ESRD patients compared with non-ESRD patients; (ii) evidence for a prevalence of cardiac sympathetic activity, in the pre-dialytic period, in diabetic compared with non-diabetic ESRD patients; (iii) evidence for a further increase in cardiac sympathetic activity during the dialytic period compared with the pre-dialytic period in both diabetic and non-diabetic ESRD patients; (iv) demonstration that only diabetic patients with ESRD do not present changes in cardiac autonomic nervous system activity in the post-dialysis vs pre-dialytic period.
Our results are in agreement with previous reports demonstrating a dysfunction in the autonomic nervous system in both diabetic [19,20] and non-diabetic uraemic patients [21,23] compared with non-uraemic diabetic patients and controls. Such dysfunction, characterized by a prevalence of sympathetic activity, is an important prognostic factor, since this prevalence is significantly associated with sudden death [24], increased mortality after myocardial infarction [25], and the occurrence of ventricular arrhythmia [26]. Dysfunction in the autonomic nervous system in patients undergoing chronic haemodialysis appears to be mainly due to the negative effects of uraemia [11]. In particular, in diabetic ESRD patients autonomic disorders are even more severe. This may be due to the superimposed negative impact of the duration of both diabetes and uraemia [27,28].
Several epidemiological studies have reported that the mortality rate of dialysis patients is more than three times higher than that observed in the age-matched general population and that this is mainly due to cardiovascular events [13]. In particular, a recent report indicated that type II diabetic subjects have a much poorer prognosis than non-diabetics upon their entry into a dialysis programme [29]. The prevalence of cardiac sympathetic activity, constantly present in our study, may contribute to the genesis of cardiovascular events. Reports in the literature on the effect of haemodialysis on the autonomic nervous system are controversial. Some investigators have not observed any change in autonomic function by haemodialysis treatment [22,30], while others found significant improvement [11,31]. In particular, Agarwal et al. [30] reported data from patients receiving renal replacement therapy with haemodialysis sessions twice per week. Unfortunately, investigators did not report the Kt/V urea of their patients. Thus, it may be that these patients received low haemodialysis adequacy, which could explain the lack of beneficial effect from haemodialysis treatment on the impaired autonomic function.
Cloarec-Blanchard et al. [22] reported data regarding the analysis of HRV that was evaluated before and only 1 h after the dialysis session. This was not in contrast with our findings, as in our study we observed a significant improvement in HRV only 6 h after the haemodialysis session. However, our results are in agreement with those of other investigators who found that the autonomic nervous system dysfunction is more extensive in pre-dialysis patients than in dialysis patients [11,31]. While uraemic neuropathy has been shown to improve after haemodialysis, probably because the toxic effect of uraemia is removed [11], diabetic neuropathy is unaffected by haemodialysis treatment [31]. Such a difference in response to haemodialysis might also justify our finding that non-diabetic ESRD patients have a different cardiac autonomic nervous system response to haemodialysis. In other words, haemodialysis might affect cardiac activity only in non-diabetic ESRD patients, improving the cardiac autonomic tone as suggested by a lower LF/HF ratio in diabetic than non-diabetic patients, and by the occurrence of a significant correlation between changes in HRV and changes in plasma urea concentration only in the non-diabetic group. Thus our findings suggest that the beneficial effects of haemodialysis are most pronounced during the first day of the interdialytic period.
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Conclusions
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Diabetic and non-diabetic uraemic patients, undergoing chronic haemodialysis have a severely impaired autonomic nervous system. In particular, in diabetic patients this is probably due to autonomic neuropathy related to the effects of both diabetes and chronic uraemic conditions. However, the most important difference between the two study groups is represented by a persistent shift of the cardiac autonomic balance toward sympathetic activity after haemodialysis sessions in diabetics. In contrast, non-diabetic ESRD patients show a prevalence of parasympathetic activity at some study times. The constant and irreversible alteration of the sympatho-vagal balance observed in ESRD diabetic patients, despite haemodialysis treatment, might be a further risk factor for cardiovascular events. Nevertheless, only future epidemiological studies devoted to this specific issue will be able to confirm such a hypothesis.
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Notes
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Correspondence and offprint requests to: Mauro Giordano MD PhD, Assistant Professor of Nephrology, Universita di Catania, Istituto di Clinica Medica L. Condorelli, Ospedale Vittorio Emanuele, Via Plebiscito, 628, I-95124, Catania, Italy. 
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Received for publication: 24. 1.00
Accepted in revised form: 10. 7.00