Heart Rate Variability, Left Ventricular Functions, and Cardiac Autonomic Neuropathy in Patients Undergoing Chronic Hemodialysis

Abstract

Objective. Autonomic neuropathy and impairment of left ventricular functions (LVF) have been frequently encountered in chronic renal failure (CRF). The aim of the present study was to evaluate the relationship of cardiac autonomic modulation impairments, as assessed by means of heart rate variability (HRV), with clinical characteristics, and left ventricular function in the patients with CRF undergoing hemodialysis (HD). Methods. Twenty control subjects (Group I) and 22 comparable by age and gender patients with CRF undergoing hemodialysis (Group II) were enrolled in the study. After routine clinical and biochemical evaluations, electrocardiography, and 2 Dimensional, M Mode echocardiography were performed in all participants. Frequency domain HRV analysis was studied by using Kardiosis System. The powers (P₁ and P₂) and the central frequencies (F₁ and F₂) of low and of high frequency spectral bands were recorded. Results. End systolic (ESV) and end diastolic volumes (EDV) were significantly higher in Group II (59.3 ± 21.1 mL vs. 34.0 ± 14.3 mL and 131.5 ± 37.3 mL vs. 96.9 ± 18.9 mL, p<0.01, p<0.05, respectively) when compared to those of Group I. Ejection fraction (EF) and fractional shortening (FS) were significantly lower in Group II than in control subjects (52.3 ± 2.4% vs. 63.7 ± 10.1% and 0.29 ± 0.01 vs. 0.34 ± 0.07, p<0.001, p<0.05, respectively). P1 and P2 were decreased in Group II than in Group I (136.2 ± 173.9 m s² vs. 911.0 ± 685.5 and 96.5 ± 149.6 vs. 499.7 ± 679.5, p<0.001, p<0.01, respectively). Significant correlations were found between high frequency spectral power and dialysis duration (DD), ESV, EDV, EF, FS (r = 0.52 p<0.01, r = 0.68 p<0.001, r = 0.65 p<0.002, r = 0.66 p<0.02, and r = 0.69 p<0.01). Conclusion. As a result, the dependence of cardiac autonomic neuropathy on the disease duration and degree of left ventricular function impairment was shown in the patients undergoing chronic hemodialysis.

• Autonomic neuropathy
• Heart rate variability
• Cardiac functions
• Hemodialysis

Introduction

Autonomic nervous system dysfunction (ANSD) and cardiac involvement have been known to be encountered in patients undergoing hemodialysis. Several factors such as hypertension, anemia, AV fistula, may cause left ventricular hypertrophy, dilated cardiomyopathy, and ischemic heart disease. In addition, life-threatening arrhythmias are frequently observed in patients undergoing dialysis therapy. Also, one of the most common complications in these patients is nervous system dysfunction; moreover variety of neurologic disorders can even occur after adequate dialysis. Autonomic nervous system dysfunction (ANSD) is frequently encountered in patients undergoing hemodialysis. The latter may affect the functions of end organs, including heart. Thus, orthostatic hypotension, persistent hypotension, abnormal circadian pattern of blood pressure, reduced baroreceptor sensitivity have been described, and some observations indicate that ANSD may increase the risk for arrhythmias and sudden deaths.[[1]], [[2]], [[3]], [[4]], [[5]]

Plenty of tests for autonomic functions have been used to document the localization of dysfunction for autonomic nervous system. Abnormalities of both low and high-pressure baroreceptors have been observed in uremic patients.[[6]] Furthermore, efferent pathway of autonomic nervous system may be affected in uremic patients. HRV is a useful marker of cardiac response to parasympathetic and sympathetic modulation. It is generally accepted that at least two spectral components extracted from short-term electrocardiographic recordings represent the cardiac response to autonomic modulation; a low frequency component (LF) (0.04–0.15 Hz), which reflects both parasympathetic and sympathetic modulations of heart rate; and high frequency component (HF) (>0.15 Hz) which shows parasympathetic modulation alone.[[4]]

Atropine and propranolol can inhibit low frequency component during supine and tilting positions and atropine high frequency component can be inhibited by atropine as well.[[7]], [[8]]

Previous studies using heart rate variability analysis have demonstrated the disturbances of cardiac autonomic modulation in patients with chronic renal failure.[[6]], [[9]], [[10]] However, data on factors contributing for cardiac autonomic regulation of heart rate in this category of patients is lacking.

The aim of the present study was to evaluate the relationship of the degree of cardiac autonomic modulation impairments, as assessed by means of heart rate variability (HRV), with clinical characteristics, and left ventricular function in the patients with CRF undergoing hemodialysis (HD). We used frequency domain analysis of HRV for quantitative assessment of cardiac autonomic function.

Material and Methods

Twenty-two patients followed-up at Hemodialysis (HD) Center (Group II) in the mean ages of 30.7 ± 21.9 years (range 20–60 years) and comparable by age and gender 20 healthy control subjects (Group I) in the mean ages of 31.6 ± 13.0 years (range 18–45 years) participated in the study. The patients were undergoing dialysis for 4 h each time, two or three times weekly. By using polysulphone hollow-fiber dialyzers, with a blood flow 250–300 mL/min and the patients were treated with HD for a period between two months to 72 months.

There were 12 men and 10 women in Group II. Besides that there were 10 men and 10 women in Group I. In Group II, the average duration of HD was 21.1 ± 8.2 months (range 2–72 months).

The causes of chronic renal failure were chronic glomerulonephritis in eight, chronic pyelonephritis in seven, primary hypertension with nephrosclerosis in five, and unknown etiology in two patients.

Two-dimensional and M Mode echocardiography simultaneously with electrocardiographic recordings with assessment of LV systolic performance were performed by using Toshiba SSH160A system with pulse wave transducer 3.75 MHz on the same day of investigation.

All echocardiographic measurements including LV end-diastolic and end-systolic dimensions were made according to the recommendations of American Society of Echocardiography.[[1]] Left ventricular volumes were calculated by Teicholtz formulation and calculations of LV fractional shortening (FS) and ejection fraction were done further by automatic autoanalisator. Left ventricular mass was calculated using Penn-cube method and LV hypertrophy was defined as LVM index >134 g/m².

Cardiac autonomic functions were assessed by means of frequency-domain analysis of heart rate variability.

Short-term electrocardiogram recordings were accomplished using Kardiosis Ard-LP, PC-based high-resolution system. Bipolar X deviation (0.5–340 Hz) was recorded and sampled at a rate of 1000 samples/second and digitized using a 12-bit A/D converter. Each recording lasted 7 min and raw data were stored in the disk for post processing heart rate variability analysis. RR tachograms were extracted from the data. The detection of R waves was visually confirmed and any undetected regular R wave was marked either manually or by interpolation. Similarly, any point which is not R wave but found as so, was unmarked manually. The final RR tachogram obtained was then interpolated at 1 s intervals by linear interpolation. From the interpolated RR tachogram, power spectral densities were calculated by autoregressive model.[[2]]

For Frequency-Domain Analysis

In power spectrums of RR intervals, three major peaks, one around <0.03 Hz (very low frequency, VLF peak) following around 0.04–0.15 Hz (LF peak), and the third around >0.15 Hz (HF peak) have been observed. When RR spectrums were investigated, it was seen that considerable amount of energy lied in the very low frequency components. VLF range was filtered out of the tachograms before modeling. The power under each spectral peak was calculated by residual integration method.[[2]] This method is roughly equal to calculating the area under each peak. For spectral analysis, the following variables were calculated:

Central frequencies of LF and HF peaks (F₁ and F₂) were expressed in Hz, powers of low and high frequency bands (P₁ and P₂) were expressed as m s².

Study protocol had been explained to the participants at the time of their examinations they were included into the study and after their consent was taken. All subjects were instructed to avoid taking alcohol and caffeine containing beverages, refrain from smoking for the day before investigation. The investigation was started after 15 min of rest at supine position. Respiration rate, heart rate, and blood pressure measurements were recorded in all the participants during the investigation.

Statistics

Comparisons between two groups were performed using student's t test for unpaired data, and p<0.05 was considered statistically significant. All results are presented as mean ± standard of the mean deviation. Simple regression analysis was applied for the estimation of relationship between HRV indices and clinical (age, duration of the dialysis, blood pressure) and LV functional parameters.

Results

Table 1 shows basic characteristics of subjects in Group I and Group II. There were no significant differences in age and gender between Groups. Blood pressure and echocardiographic findings showed significant differences between two Groups. The patients on HD had impaired LV performances. The higher end-systolic and end-diastolic volumes were found in patients Group II than in control group (p<0.01, p<0.05, respectively). Also, significant reductions were observed in EF and FS in patients with CRF (p<0.001, p<0.05 respectively).

Table 1. Baseline values, heart rate variability, and echocardiographic parameters of subjects in Group I and Group II

Parameters	Group I	Group II	P value
Age, years	31.6±13.0	30.7±21.9	NS
Gender, male/female	10/10	12/10	NS
HD duration, months	—	21.11±8.2
SBP supine, mmHg	113.1±15.3	150.1±39.3	P<0.01
DBP supine, mmHg	72.1±9.7	100.3±17.2	P<0.01
ESV, mL	34.0±14.3	59.3±21.1	P<0.05
EDV, mL	96.9±18.9	131.5±37.3	P<0.01
EF, %	63.7±10.1	52.3±2.4	P<0.001
FS, %	34.0±7.0	29.0±1.0	P<0.05
F1, Hz	0.08±0.01	0.09±0.01	NS
P1, msec^2	911.0±685.5	136.2±173.9	P<0.001
F2, Hz	0.29±0.08	0.32±0.06	NS
P2 msec^2	499.7±679.5	96.5±149.6	P<0.01
P1/P2	1.82±1.00	1.41±1.12	NS

HD: Hemodialysis; FS: Fractional shortening; SBP: Systolic blood pressure; F₁: Central frequencies of LF peak; DBP: Diastolic blood pressure; F₂: Central frequencies of HF peak; ESV: End systolic volume; P₁: Power of low frequency band; EDV: End diastolic volume; P₂: Power of high frequency band; EF: Ejection fraction.

Significant positive correlations were found between dialysis duration, EF, FS, and parasympathetic component of HRV in patients on HD. Furthermore significant negative correlations existed between EDV, ESV, and P₂ of patients of Group II.

Figures 1a–c shows the RR interval tachograms and spectrums of HRV in the representative subjects in Group I and in Group II (after 2 and 64 months in HD). Figure 1a, high frequency component was observed clearly in the power spectrum in controls, whereas in Fig. 1b low frequency component is shown to predominate in the power spectrum after two months in HD. High frequency component is nearly absent. Figure 1c shows that both P₁ and P₂ significantly reduced in a patient with duration of dialysis of 64 months, but no predomination of low frequency power is seen.

Figure 1. Time series of RR intervals and the power spectra in control subject (a), in patients undergoing hemodialysis for two months (b), and 64 months (c).

Discussion

In this study, we assessed the relationship between the degree of cardiac autonomic imbalance and left ventricular (LV) performance and clinical characteristics in the patients with CRF being observed in our HD center.

Our results indicated the fact that the powers of low and high frequency bands (P₁ and P₂) of HRV were significantly lower in Group II than in Group I. These observations allow considering the reduction of parasympathetic modulation of heart rate in patients undergoing hemodialysis as compared with apparently healthy persons.

The patients undergoing HD may have autonomic nervous system dysfunction. Using many classic autonomic nervous system tests, autonomic dysfunctions can be measured in HD patients. Valsalva maneuver, sustained handgrip exercise, sweating activity, baroreflex sensitivity, cold pressor test, and postural changes have been performed on HD patients to assess autonomic functions. Heart rate response to standing and inhalation of amyl nitrate tests assess low-pressure baroreceptor integrity and afferent limb. Conversely, the injection of phenylephrine hydrochloride test allows evaluation high-pressure baroreceptor integrity and afferent limb. Hyperventilation has been used to test central function. Efferent autonomic limb have been tested by using cold pressor test, arithmetic computations with harassment, sweat test, and atropine sulfate therapy. Infusion of tyramine and norepinephrine as invasive tests has been used to document efferent autonomic function.[[2]], [[13]]

Heart rate variability is accepted as a marker of cardiac response to parasympathetic and sympathetic modulations. Several methods for quantitative measurement of HRV are available such as simple methods, spectral methods, time domain, or frequency domain method. Although alterations in normal cardiac rhythm have been known for long time, utility of HRV in clinical cardiology has being used since 1978.[[7]], [[9]], [[13]], [[14]], [[15]], [[16]], [[17]], [[18]]

Axelrod et al. analyzed autonomic function in HD patients by using spectral analysis of HRV first in 1987. Their observations indicated that the spectral powers of HRV were reduced in the patients with renal failure.[[8]] Cloarec-Blanchard et al. reported that uremic patients exhibited a reduction in Mayer waves of SBP and DBP spectrum.[[6]] Vita et al. demonstrated that hemodialysis patients had definite parasympathetic damage or, both parasympathetic and sympathetic damage.[[10]]

Takahashi et al. that observed LF and HF amplitudes in supine position were significantly lower in both normotensive and persistent hypotensive hemodialysis patients than in control subjects.[[19]] Our findings are similar to above-mentioned earlier observations in the literature. There were strong reductions in the powers of low and high frequency bands in the hemodialysis patients than in control subjects. These observations suggest that autonomic function impairment exists in both parasympathetic and sympathetic cardiac modulations in HD patients.

Our findings extends previous studies by demonstration of the existence of positive correlations among parasympathetically mediated components and dialysis duration, ejection fraction, fractional shortening as well. Negative correlations were found both between parasympathetic and sympathetic components and left ventricular volumes. Such relationships have not exactly been known and established before.

Autonomic dysfunction is observed in both acute and chronic renal failure. The mechanisms of cardiac autonomic neuropathy are not clearly defined yet. It might be supposed, that autonomic dysfunction may result from “Uremic State” and uremic state may be toxic for central and peripheral nervous systems. Increased level of parathyroid hormone as a toxic marker may play an important role on the genesis of autonomic nervous dysfunction. Duration of exposure to uremic toxins may increase the degree of derangement of autonomic nervous system.[[4]], [[5]]

At the same time left ventricular dysfunction is often observed in hemodialysis patients. The negative relationship of increased LV volumes with parasympathetically mediated component of HRV may reflect the greater extent of autonomic withdrawal in those patients with higher LV volumes. The similar associations have been found previously in patients with congestive heart failure.[[20]] Furthermore, it has been revealed that HRV is depressed in patients with heart failure and may predict adverse outcomes.[[21]]

Also, the reduced left ventricular ejection fraction reflects impaired left ventricular function and such patients who have reduced left ventricular ejection fractions have high risk of developing heart failure.[[18]] Whether the reduced LV ejection fraction in HD patients may contribute to autonomic dysfunction has not been clearly defined before. Our observation on the positive correlation of FS and EF with parasympathetically modulated component of HRV in HD patients may be partly explained by compensatory adaptations of autonomic regulations to the LV dysfunction from one side and possibly might reflect the favorable effects of hemodialysis on LV global systolic function and further autonomic modulation. The latter assumption is supported by presence of positive association of HRV with the duration of the dialysis in our patients.

Though the primary causes of cardiac autonomic neuropathy are related to the effects of uremia, we can assume that duration of dialysis, and left ventricular dysfunction are also contributing factors of cardiac autonomic imbalance in patients with chronic renal failure undergoing hemodialysis.

In conclusion, the frequency domain spectral analysis of heart rate variability is a useful marker for the assessment of autonomic nervous system in HD patients. The powers of low and high frequency component were significantly lower in HD patients that in control subjects. These results suggest that both parasympathetic and sympathetic dysfunctions exist in HD patients, being dependent on the degree of LV systolic dysfunction and dialysis duration.