Original Paper Nephron Clin Pract 2014;128:361–366 DOI: 10.1159/000368436

Received: April 29, 2014 Accepted: September 18, 2014 Published online: December 6, 2014

Sex-Dependent Association between Heart Rate Variability and Pulse Pressure in Haemodialysis Patients Dimitrios Poulikakos a, b Marek Malik c Debasish Banerjee a, b a Cardiovascular Sciences Research Centre, St. George’s University of London, b Renal and Transplantation Unit, St. George’s Hospital NHS Trust, and c Imperial College of Science Technology and Medicine, London, UK

Abstract Aims: Increased pulse pressure (PP) is associated with increased cardiovascular mortality in haemodialysis (HD) patients. Autonomic imbalance is common in HD patients and predisposes to sudden cardiac death, but its relationship to PP is unknown. We investigated the relationship between cardiac autonomic modulation assessed by heart rate variability (HRV) and PP in HD patients. Methods: Continuous electrocardiograms recorded during HD sessions were repeated 5 times at 2-week intervals in stable HD patients. The high-frequency (HF) and low-frequency (LF) components and the LF/HF ratio of HRV were calculated during the first and last hour of the recordings. These values and the corresponding systolic blood pressure (SBP), diastolic blood pressure (DBP) and PP measurements were averaged in repeated recordings of each patient. Results: Seventy-six patients were included in the final analysis (aged 61 ± 15 years, 32% females, 37% diabetics). In male patients, LF/HF correlated inversely with pre- and post-HD PP (r = –0.369, p = 0.007 and

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r = –0.546, p = 0.000, respectively), positively with pre- and post-HD DBP (r = 0.358, p = 0.009 and r = 0.306, p = 0.028, respectively) and inversely with post-HD SBP (r = –0.350, p = 0.011). In female patients, LF/HF correlated positively with post-HD SBP (r = 0.422, p = 0.040). Conclusion: We observed an association between PP and HRV in male HD patients. Sex differences may be important for cardiac risk assessment. © 2014 S. Karger AG, Basel

Introduction

Cardiovascular mortality in haemodialysis (HD) patients is very high and sudden cardiac death is responsible for approximately two thirds of cardiovascular deaths in these patients [1, 2]. Efforts to reduce cardiovascular mortality in HD patients have concentrated, amongst others, on treating hypertension. However, the relationship between systolic blood pressure (SBP) and cardiovascular mortality is unclear in HD patients [3]. Pulse pressure (PP) is a better

M.M. and D.B. contributed equally to this paper as senior authors.

Dimitrios Poulikakos Cardiovascular Sciences Research Centre St. George’s University of London, Medical School Cranmer Terrace, London SW17 0RE (UK) E-Mail dimitrios.poulikakos @ stgeorges.nhs.uk

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Key Words Heart rate variability · Pulse pressure · Haemodialysis · Autonomic · Sex differences

outcome predictor in HD patients [4] reflecting arterial stiffness which is known to increase in chronic kidney disease [5]. Arterial stiffness has been correlated positively with increased sympathetic activity in healthy males [6]. Autonomic imbalance, a known risk factor for sudden cardiac death, is a hallmark of chronic kidney disease [7]. To our knowledge, the association between cardiac autonomic dysfunction and arterial stiffness has not been investigated in dialysis patients. Furthermore, since sex hormones exhibit unique profiles in dialysis patients [8], potential sex differences in blood pressure (BP) regulation may be important for the selection of HD patients for specific preventive measures. We have recently demonstrated that the intradialytic period provides an investigation opportunity for cardiovascular monitoring as it represents the most standardized period with regard to fluid and electrolyte shifts [9]. This study investigated the association between BP and PP measured before and after HD and cardiac autonomic modulation assessed by short-term spectral components of heart rate variability (HRV) measured during dialysis in male and female HD patients.

recordings were made on the same day of the week in 2-week intervals. Spectral analysis was performed by fast Fourier transformation with Hanning windowing using the software of the analyser [10] and corresponded to previously published standards [11]. In brief, the RR interval tachogram was calculated from the RR interval time series and sampled at 1,024 Hz using linear interpolation within individual 5-min windows. From the resulting spectrum, low-frequency (LF; 0.04–0.15 Hz) and high-frequency (HF; 0.15– 0.40 Hz) components were derived. Heart rate, LF and HF components and the LF/HF ratio were calculated in every 5-min segment of the recording and averaged during the first and the last hour of the recordings to assess the effect of HD. Subsequently, we performed decimal logarithmic transformation of LF, HF and LF/HF to normalize the distributions of the data since all the measurements, including the LF/HF ratio, were not normally distributed. When referring to LF, HF and LF/HF, their logarithmic transformed values are used in this text. Statistical Analysis Two-sided independent or paired sample t tests and χ2 tests were used for comparison of numerical and categorical values. Pearson’s correlation coefficient was used to assess the relationship between variables. Repeated-measures ANOVA was used to test intrasubject reproducibility of measurements in the subgroup of patients who completed all 5 recordings. Proof of reproducibility was based on accepting the null hypothesis that the means were equal. A p value 0.05) was demonstrated for LF, HF and LF/HF during the first and last hour of recordings as well as for pre-HD and post-HD SBP, diastolic BP (DBP) and PP values.

Comparison of mean values between the first and the last hour of HD showed that all BP parameters were lower at the end of dialysis. Heart rate increased and LF and HF decreased. There was no statistically significant change in LF/HF (table 3).

HRV and Pulse Pressure in Haemodialysis

Nephron Clin Pract 2014;128:361–366 DOI: 10.1159/000368436

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Table 1. Baseline characteristics according to sex

Color version available online

80 60 40

40 –0.25

0

0.25 0.50 0.75 1.00

b

90 80 70 60 50 40

–0.25

0

0.25 0.50 0.75 1.00

–0.25

0

0.25 0.50 0.75 1.00

120 post-HD PP (mm Hg)

between LF/HF during the first hour of HD and pre-HD DBP (a), pre-HD PP (b), postHD DBP (c) and post-HD PP (d) in male subjects. Subjects with and without diabetes are marked with open blue and closed red circles, respectively. Linear regressions (straight lines) are plotted with their 95% confidence intervals (curved lines). The LF/HF data are shown after decimal logarithmic transformation. (Colours refer to the online version only.)

post-HD DBP (mm Hg)

100

Fig. 1. Scatter diagrams of the relationship

60

–0.25

0

c

80 60 40 20

0.25 0.50 0.75 1.00 LF/HF

100

d

LF/HF

between LF/HF during the first hour of HD and post-HD SBP in male (a) and female (b) patients. Patients with and without diabetes are marked with open blue and closed red circles, respectively. Linear regressions (straight lines) are plotted with their 95% confidence intervals (curved lines). The LF/HF data are shown after decimal logarithmic transformation. (Colours refer to the online version only.)

160

180

post-HD SBP (mm Hg)

Fig. 2. Scatter diagrams of the relationship

post-HD SBP (mm Hg)

200

160 140 120 100 80

–0.25

a

Nephron Clin Pract 2014;128:361–366 DOI: 10.1159/000368436

120 100

Association between BP Parameters and HRV In male patients, there was an inverse correlation between LF/HF during the first HD hour and pre- and postHD PP, a positive correlation with pre- and post-HD DBP (fig. 1) and a negative correlation with post-HD SBP (fig. 2). In contrast, in female patients, LF/HF did not correlate with DBP or PP before or after HD but correlated positively with post-HD SBP (fig. 2). Table 4 shows correlations between LF/HF and BP parameters. 364

140

0

0.25 0.50 0.75 1.00 LF/HF

0.10 0.20 0.30 0.40 0.50 0.60 0.70

b

LF/HF

Discussion

In male subjects, we observed an inverse relationship between LF/HF ratio and pre- and post-HD PP mediated by a positive LF/HF correlation with DBP and a negative correlation with post-HD SBP. The HRV parameters in HD patients should be considered in the context of severe autonomic imbalance resulting from chronic sympathetic overactivation driven Poulikakos /Malik /Banerjee  

 

 

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20

80

Color version available online

a

100

100

pre-HD PP (mm Hg)

pre-HD DBP (mm Hg)

120

the first hour of HD in males and females Males

Pre-HD SBP, mm Hg Pre-HD DBP, mm Hg Pre-HD PP, mm Hg Post-HD SBP, mm Hg Post-HD DBP, mm Hg Post-HD PP, mm Hg

Females

r

p value

r

p value

–0.062 0.358 –0.369 –0.350 0.306 –0.546

0.664 0.009 0.007 0.011 0.028 0.000

0.208 0.132 0.125 0.422 0.349 0.226

0.330 0.540 0.562 0.040 0.095 0.288

Italics indicate statistically significant correlations. The LF/HF data were used after decimal logarithmic transformation. r = Pearson’s correlation coefficient.

by afferent sensory renal nerves [7], axonal uremic polyneuropathy present in 90% of dialysis patients [12] and impaired arterial baroreflexes [13]. Chronic sympathetic overactivation results in decreased capacity of modulation and LF power, uremic peripheral neuropathy may disturb the autonomic reflex mechanisms and impaired baroreceptors may affect both spectral powers of HRV [14]. In particular, the interpretation of the LF/HF ratio should take into consideration that while the HF power corresponds to parasympathetic modulation, the LF power contains both sympathetic and parasympathetic components [15]. The LF/HF ratio has thus been suggested to represent the relative magnitude of sympathetic saturation of the autonomic tone and decreased capacity of sympathetic modulation in the presence of a global reduction of HRV parameters [16]. The association between HRV and PP in HD patients is a novel finding. Our results are in agreement with two recent studies reporting associations between HRV and PP in elderly healthy subjects [17] and of HRV and aortic stiffness in young diabetics [18]. The relationship between autonomic dysregulation and arterial stiffness is bidirectional. It has been shown that sympathetic activity is linked with measures of aortic stiffness in healthy males [6, 19] and that renal sympathetic denervation improves baroreflex sensitivity [20] and arterial stiffness [21], observations that imply a physiological relationship between sympathetic activation and aortic pulse wave characteristics most likely mediated by changes in vascular smooth muscle cell tone [22]. On the other hand, an opposite primarily anatomical relationship has been suggested, postulating that age-related aortic stiffness and HRV and Pulse Pressure in Haemodialysis

decreased elasticity impairs the capacity for vascular distention and baroreceptor deformation, therefore blunting the baroreflex sensitivity [23] and leading to autonomic dysregulation. The opposite relationship between LF/HF and postHD SBP in males and females warrants further investigation. It is known that substantial sex differences exist in cardiac autonomic regulation [24]. Opposite relations between sympathetic nerve activity and measures of arterial stiffness have been reported in young healthy females and males [6]. These differences are thought to be due to lower α-adrenergic receptor support of BP and enhanced β-receptor-mediated vasodilatation in young women [25]. We also observed sex differences, although our study included almost exclusively post-menopausal women, a finding that may be related to the distinct disturbances of the hormones of the pituitary gonadal axis in both sexes [8] in dialysis patients. These sex differences in cardiovascular autonomic regulation in HD patients, if confirmed in large prospective studies, are important and will warrant focused research on sex-specific risk stratification strategies and modelling that will enable effective and appropriate preventive treatment for predominantly arrhythmic cardiovascular complications. Furthermore, elucidating the physiological mechanisms behind these differences may open up new perspectives for therapeutic interventions. Limitations The number of patients included in the study was not large and the numbers of males and females were not equal. The decreased recruitment rate of females was partially related to the nature of our study and the need for repetitive intimate exposure for the placement of the electrocardiogram electrodes of the Holter devices. We have not performed vascular function tests for assessment of arterial stiffness and we did not directly assess sympathetic activity with microneurography. In addition, some of our patients were on cardiovascular medications, which may affect both the cardiac autonomic modulation and the recorded BP. The statistical testing did not include adjustment of p values for multiple tests since the tested data are not mutually independent.

Conclusion

The study demonstrated an association between PP and spectral HRV parameters in male HD patients that should be further explored for their risk assessment. The Nephron Clin Pract 2014;128:361–366 DOI: 10.1159/000368436

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Table 4. Correlations between BP parameters and LF/HF during

physiological background of sex differences existing in autonomic cardiovascular regulation in HD patients deserves further focused investigations.

Disclosure Statement The authors declare that they have no conflicts of interest.

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Nephron Clin Pract 2014;128:361–366 DOI: 10.1159/000368436

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Sex-dependent association between heart rate variability and pulse pressure in haemodialysis patients.

Increased pulse pressure (PP) is associated with increased cardiovascular mortality in haemodialysis (HD) patients. Autonomic imbalance is common in H...
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