• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of ajpgiPublished ArticleArchivesSubscriptionsSubmissionsContact UsAJP - Gastrointestinal and Liver PhysiologyAmerican Physiological Society
Am J Physiol Gastrointest Liver Physiol. Feb 2009; 296(2): G330–G338.
Published online Nov 20, 2008. doi:  10.1152/ajpgi.90488.2008
PMCID: PMC2643913

Decreased heart rate variability in patients with cirrhosis relates to the presence and degree of hepatic encephalopathy

Abstract

Heart rate variability (HRV) is reduced in several clinical settings associated with either systemic inflammation or neuropsychiatric impairment. The possibility that the changes in HRV observed in patients with neuropsychiatric impairment might relate to the overproduction of inflammatory cytokines does not seem to have been considered in the studies undertaken to date. HRV is decreased in patients with liver cirrhosis but its relationship to the impairment of neuropsychiatric performance, commonly observed in these patients, is unknown. The aim of this study was to investigate the relationship between HRV, hepatic encephalopathy, and production of inflammatory cytokines in patients with cirrhosis. Eighty patients with cirrhosis [53 men, 27 women; mean (±1SD) age 54 ± 10 yr], classified as neuropsychiatrically unimpaired or as having minimal or overt hepatic encephalopathy, and 11 healthy subjects were studied. HRV was assessed by applying Poincaré plot analysis to the R-R interval series on a 5-min ECG. Inflammatory cytokines (TNF-α, IL-6, IL-10, and IL-12) were measured in a subgroup of patients. Long-term R-R variability was significantly decreased in the patients with cirrhosis, in parallel with the degree of neuropsychiatric impairment (P < 0.01) and independently of the degree of hepatic dysfunction (P = 0.011). The relative risk of death increased by 7.7% for every 1-ms drop in this variable. Plasma levels of IL-6 significantly correlated with indexes of both HRV and neuropsychiatric performance. The changes observed in HRV and in neuropsychiatric status in patients with cirrhosis are significantly correlated, most likely reflecting a common pathogenic mechanism mediated by inflammatory cytokines.

Keywords: inflammatory cytokines, electroencephalogram, linear/nonlinear dynamics, Psychometric tests, systemic inflammatory responses

heart rate variability (HRV) is a measure of the physiological fluctuation of the cardiac cycle over time, which reflects the output of the complex control of the heart mediated by the autonomic nervous system (1, 21). Contrary to the predictions of the classical concept of homeostasis, the output of a wide variety of physiological systems, such as the normal heart beat, fluctuates in a complex manner, even under resting conditions (1, 21). Deceased variability or increased regularity of the cardiac rhythm has been reported in different clinical settings associated with systemic inflammation and increased production of inflammatory cytokines, such as sepsis, diabetes mellitus, ischemic heart disease, congestive heart failure, and hepatic failure; in these contexts, it is a negative predictor of outcome (5, 6, 2224, 31).

The underlying mechanism of decreased HRV during systemic inflammation is unknown. However, it appears that the inflammatory cytokine IL-6 might play a role, since circulating levels of IL-6 correlate significantly with indexes of depressed HRV in various clinical conditions (5, 22, 54).

HRV is also decreased in patients with chronic liver disease (6, 12, 17, 25, 32, 37, 39). Plasma concentrations of inflammatory cytokines are increased in these patients, even in the absence of active infection (19, 50, 55), and this activation of inflammatory mediators might explain the decrease in HRV observed in these patients.

Decreased HRV has also been reported in several neuropsychiatric conditions, such as dementia (29, 62), mood disorders in postmenopausal women (28), and depression in patients with ischemic heart disease (58). Several mechanisms have been proposed to explain reduced heart rate fluctuations in these patients (28, 29, 58, 62). However, the possibility that the changes in HRV observed in patients with neuropsychiatric impairment might relate to the overproduction of inflammatory cytokines does not seem to have been considered in the studies undertaken to date. This is surprising given that increased production of inflammatory cytokines is known to occur in a number of neuropsychiatric disorders (4, 11, 20, 26, 57).

Hepatic encephalopathy is a neuropsychiatric syndrome that develops in patients with liver disease. It has recently been suggested that inflammatory mediators might play a crucial role in the pathogenesis of this syndrome (27, 42, 51). Serum levels of inflammatory cytokines have been shown to correlate with the severity of encephalopathy in patients with cirrhosis (43, 44). Both the presence of hepatic encephalopathy and the reduction in HRV have negative prognostic value in this patient population (7, 17). However, it is unknown whether any relationship exists between HRV parameters, neuropsychiatric impairment, and inflammatory cytokines in this clinical context.

The present study was undertaken to explore the relationship between HRV and neuropsychiatric performance in patients with cirrhosis in order to test the hypothesis that the decrease in HRV correlates with the presence and degree of hepatic encephalopathy via circulating inflammatory cytokines was explored in a subset of the same patient population.

METHODS

Study Population

The patient population comprised 80 individuals [53 men, 27 women; mean (±1SD) age 54 ± 10 yr], with biopsy-proven cirrhosis referred for assessment of their neuropsychiatric status. The etiology of the liver disease was determined by use of clinical, laboratory, radiological and histological variables. The functional severity of the liver injury was assessed by using Pugh's modification of the Child's grading system (48). Patients were excluded from the study if they were under 16 or over 80 yr of age; had misused alcohol or suffered a significant upper gastrointestinal hemorrhage within the preceding 3 mo; had a history of diabetes mellitus, pancreatitis, anemia, cardiovascular/cerebrovascular disease, or systemic hypertension, significant head injury, or recent infection; or were taking neuroactive drugs or drugs known to affect the cardiac rhythm such as propranolol. The reference population comprised 11 healthy volunteers (5 men, 6 women) of mean age 49 ± 10 yr. None had a history, clinical, or laboratory evidence of alcohol misuse, chronic liver disease, or heart disease; none drank alcohol in excess of 20 g/day or took prescription medication.

Neuropsychiatric Assessment

Neuropsychiatric status was assessed in a single 90- to 120-min sitting. Patients' mental state was evaluated by the West Haven criteria (15). Psychometric performance was assessed, under standardized conditions, by Number Connection Tests A and B (14), and the Digit Symbol subtest of the Wechsler Adult Intelligence Scale (59). Psychometric test results were scored in relation to age- and education-adjusted reference values (3, 60). Performance was defined as impaired if at least two of the three test scores were below two standard deviations of the normative reference range.

Electroencephalograms (EEGs) were recorded, under standardized conditions, by using silver-silver chloride electrodes placed according to the International 10–20 system (Walter-Graphtec system equipment). The traces underwent spectral analysis and were classified according to Amodio et al. (2), with a modified slow theta activity threshold of 30% (38).

Neuropsychiatric status was classified as 1) unimpaired: no clinical evidence of hepatic encephalopathy and no defining EEG or psychometric abnormalities; 2) minimal hepatic encephalopathy: no clinical evidence of hepatic encephalopathy but abnormal EEG and/or impaired psychometric performance; and 3) overt hepatic encephalopathy: clinically evident neuropsychiatric disturbances.

Assessment of HRV

Data acquisition.

A 10-min, single channel electrocardiogram (ECG) was recorded simultaneously with the EEG by placing a silver-silver chloride electrode on each wrist (WG PLEEG system). The ECG data were exported at a sampling rate of 256 Hz. The R peaks were detected and the R-R interval series was generated by using an ad hoc computer program. The R-R interval series was visually inspected and 5-min, artifact-free continuous R-R interval sections were selected for analysis (53).

Linear analysis of HRV.

Linear measures of HRV provide information on the degree of variability in the R-R time series. The standard deviation of the R-R intervals (SDNN) was calculated on the selected artifact-free trace and used as a measure of total HRV. Spectral analysis of the R-R interval time series was carried out by fast Fourier transformation on 1,024 sample points, by applying Welch's window, with software developed by Niskanen et al. (41). Two bands were identified: 1) a low-frequency component (LF: 0.04–0.15 Hz), which reflects the oscillatory pattern of the baroreflex loop and is jointly mediated by sympathetic and parasympathetic activities (1), and 2) a high-frequency component (HF: 0.15–0.4 Hz), which reflects the inhibition of vagal tone during inspiration (1). The LF/HF ratio was used as a measure of sympathovagal balance (1).

Nonlinear analysis of HRV.

Nonlinear measures of HRV provide information on the structure or complexity of the R-R time series. In the present study nonlinear measures of HRV was assessed using Poincaré plot as well as sample entropy analysis.

POINCARÉ PLOT.

The Poincaré plot is a graphical representation of the correlation between consecutive R-R intervals [x-axis: R-R (n): y-axis: R-R (n+1); Fig. 1]. If the cardiac rhythm is regular, the points on the Poincaré plot will be located close to the line of identity. The standard deviation of the points perpendicular to the line of identity (SD1) describes short-term variability, which is mainly related to the effects of respiration on vagal drive (56); the standard deviation along the line of identity (SD2) describes the long-term R-R interval variations and accounts for all other heart rate changes, including those associated with sympathetic oscillations, baroreflex loop, thermoregulation, and fluctuations in humoral factors (56). The parameters SD1 and SD2 were calculated by using software developed by Niskanen et al. (41).

Fig. 1.
Poincaré plot is a graphical presentation of the correlation between the consecutive R-R intervals of the ECG [x-axis: R-R (n): y-axis: R-R (n+1)]. An ellipse is fitted on to the line of identity at 45° to the normal ...

SAMPLE ENTROPY.

The sample entropy (SampEn) quantifies the degree of regularity vs. the degree of unpredictability of a time series (49). SampEn is the logarithmic likelihood of the repetition of patterns in the time series; it calculates the probability that an epoch of window length m, with a degree of tolerance r, will be repeated at later time points. Regular time series are characterized by low SampEn, whereas random time series are characterized by high SampEn. In the present study, m was fixed at 2 and r at 0.2 ms (49).

Measurement of Plasma Cytokine Concentration

Plasma samples were collected from the last 18 patients with cirrhosis enrolled in the study and were stored at −80°C until analyzed for TNF-α, IL-6, IL-10, and IL-12 by using eBioscience ELISA kits (San Diego, CA) on Nunc Maxisorb 96-well ELISA plates (Nunc, Roskilde, Denmark), according to the manufacturers' instructions. The lower detection limit for the assays was 3 pg/ml. The intra-assay coefficients of variation for TNF-α, IL-6, IL-10, and IL-12 were 2.9, 3.9, 1.2, and 1.3%, respectively.

Statistical Analysis

Differences between normally distributed variables were examined by the Student's t-test or by one-way ANOVA; post hoc analyses were performed by Tukey's test. Differences between nonnormally distributed variables were examined by the Mann-Whitney U-test or by Kruskal-Wallis ANOVA; post hoc analyses were performed by using Dunn's test. The relationship between HRV and neuropsychiatric impairment was examined by analysis of covariance, adjusted for the degree of liver failure and vagal modulation. Correlations between variables were tested by using the Spearman R coefficient of correlation. Patients were followed prospectively for a mean (range) of 20.3 (1.0–44.9) mo from the date of initial assessment. The relationship between HRV indexes and survival was examined by Cox's proportional hazards model. Analyses were undertaken using Statistica 6.0 (StatSoft, Tulsa, OK), GraphPad Prism (version 3.03, GraphPad Software, 1994–2002, San Diego, CA), and Stata (release 9.1, StataCorp, 1984–2005, College Station, TX) statistical packages.

Ethics

This study was conducted according to the Declaration of Helsinki (Hong Kong Amendment) and Good Clinical Practice (European guidelines). The protocol was approved the Royal Free Hampstead National Health Service Trust Ethics Committee. All participating subjects provided written, informed consent.

RESULTS

All 80 patients were clinically stable at the time of assessment; 66 (83%) were assessed as outpatients. The etiology of the cirrhosis was alcohol in 65 (81%), chronic viral hepatitis (hepatitis B or C virus) in seven (9%), and “various” in the remaining eight (10%). Functionally, 51 (64%) of the 80 patients were classified as Child's grade A, 13 (16%) as Child's grade B, and 16 (20%) as Child's grade C. Four of the patients with overt hepatic encephalopathy were incapable of performing the psychometric tests. One clinically unimpaired patient was noncompliant; he was classified as having minimal hepatic encephalopathy on the basis of an abnormal EEG. Thus, on the day of study, 44 (55%) of the 80 patients were classified as neuropsychiatrically unimpaired, seven (9%) as having minimal, and 29 (36%) as having overt hepatic encephalopathy (Table 1). The patients with alcohol-related cirrhosis had been abstinent from alcohol for a mean (range) of 34 (3–360) mo. None of the patients had historical, clinical, or ECG evidence of intrinsic or ischemic heart disease.

Table 1.
Demographic and assessment variables in the reference population and in the patients with cirrhosis, by degree of hepatic encephalopathy

HRV Assessments

The patients with cirrhosis had a significantly higher mean heart rate than the healthy controls, although this increase in rate was confined to the patients with the most compromised liver disease (Table 2). The mean HRV was significantly decreased, in the patient population, reflecting reductions in both the variability of the R-R time series (linear measures: SDNN, P < 0.001; LF, P < 0.001; HF, P < 0.01) and its complexity (nonlinear measures: SD1, P < 0.01; SD2, P < 0.001; SampEn, P < 0.01) (Table 2). No significant differences in HRV were observed between patients with alcohol-related cirrhosis and patients with cirrhosis of other etiologies.

Table 2.
Indexes of HRV in healthy volunteers and in patients with cirrhosis, by degree of hepatic dysfunction and neuropsychiatric status

In the patients with cirrhosis, mean HRV indexes decreased in parallel with the degree of hepatic dysfunction (Table 2). Thus, significant correlations were observed between the Child's grade and indexes of both R-R variability [SDNN (P < 0.01), LF (P < 0.01)] and complexity [SD1 (P < 0.05), SD2 (P < 0.01) and SampEn (P < 0.05)]; significant differences in HRV variables were observed between patients with Child's grade A and Child's grade C disease (Table 2). Mean HRV indexes also decreased in parallel with the degree of neuropsychiatric impairment. Thus significant correlations were again observed between the grade of hepatic encephalopathy and indexes of both R-R variability [SDNN (P < 0.01), LF (P < 0.01), HF (P < 0.01)] and complexity [SD1 (P < 0.01), SD2 (P < 0.01) and SampEn (P < 0.05)]; significant differences in HRV variables were observed between neuropsychiatrically unimpaired patients and patients with overt hepatic encephalopathy (Table 2).

Thus HRV, which is best represented by the nonlinear variable SD2, decreased significantly in parallel with both deterioration in hepatic function and deterioration in neuropsychiatric status. However, whereas the relationship between SD2 and the degree of neuropsychiatric impairment was independent of the degree of hepatic dysfunction [F(2,76) = 4.8; P = 0.011; Figs. 2 and and3A],3A], the relationship between SD2 and the degree of hepatic dysfunction was lost when adjusted for the degree of neuropsychiatric impairment [F(2,76) = 0.3; P = 0.73; Fig. 3B].

Fig. 2.
Poincaré plots depicting the correlation between consecutive R-R intervals, in 4 representative patients with cirrhosis, by degree of hepatic dysfunction and neuropsychiatric status. SD1 and SD2 represent the length and width of the Poincaré ...
Fig. 3.
Analysis of long-term HRV (mean SD2) in patients with cirrhosis, adjusted for neuropsychiatric status [hepatic encephalopathy (HE)] and the degree of hepatic dysfunction (Child's grade). A: relationship between decreasing SD2 and deteriorating ...

The association between SD2 and neuropsychiatric impairment held firm even when controls were exercised for indicators of vagal modulation, viz., the linear spectral high-frequency component, HF, which reflects the inhibition of vagal tone during inspiration [F(2,76) = 6.7; P = 0.002; covariate mean: 56.6] and the nonlinear variable SD1, which mainly reflects the effects of respiration on vagal drive [F(2,76) = 5.7; P = 0.005; covariate mean: 12.3] (Table 3).

Table 3.
Relationship between long-term HRV (SD2) and the degree of neuropsychiatric impairment in patients with cirrhosis, adjusted for HF and SD1 as indicators of vagal modulation of HRV

Significant correlations were observed between HRV indexes and individual psychometric and spectral EEG variables (Table 4).

Table 4.
Correlation matrix for indexes of HRV and selected psychometric/EEG variables in patients with cirrhosis

Plasma Cytokines

Plasma cytokine concentrations were below the assays' levels of detection in the healthy volunteers. In the patients with cirrhosis, significant concentrations of all the measured cytokines were detected, viz., TNF-α: 12.1 ± 21.6 pg/ml; IL-12: 6.8 ± 1.73 pg/ml; IL-10: 9.0 ± 13.3 pg/ml, and IL-6: 5.1 ± 3.35 pg/ml.

Significant correlations were observed between plasma IL-6 concentrations and both linear and nonlinear HRV indexes (Table 5). Similarly, significant correlations were observed between cytokine plasma concentrations and psychometric test variables (Table 5).

Table 5.
Correlations between plasma cytokine concentrations and psychometric test performance and indexes of HRV in patients with cirrhosis

Survival

Patients were followed prospectively for a mean (range) of 20.3 (1.0–44.9) mo from the date of initial assessment. Nine patients died during the follow-up period and two underwent orthotopic liver transplantation. There was a significant relationship between SD2 and survival (P = 0.01); the relative risk of death increased by 7.7% (95% confidence interval, 1.8–13.6) for every 1-ms drop in this variable.

DISCUSSION

HRV decreased significantly in the patients with cirrhosis, in the present study, in parallel with their degree of neuropsychiatric impairment, independently of their degree of hepatic dysfunction. In addition, significant correlations were observed between HRV indexes and individual EEG spectral parameters and psychometric variables. Decreased HRV has been documented in patients with cirrhosis in a small number of studies (6, 12, 17, 25, 32, 37, 39). However, in the majority of these HRV was used as a measure of autonomic dysfunction and was analyzed by linear measures only (6, 12, 25, 32, 37, 39). In consequence, although there is a clear consensus that HRV is decreased in patients with cirrhosis, there is little agreement about its relationship to the degree of the hepatic dysfunction (6, 12, 17, 25, 32, 37, 39). In the present study, HRV indexes decreased in parallel with the degree of hepatic dysfunction but this relationship was lost when adjusted for the degree of neuropsychiatric impairment.

The spontaneous variations that occur in heart rate result from a series of complex interactions between multiple regulatory processes that operate over different time scales (1, 21). In previous studies the changes in HRV observed in patients with cirrhosis have been variously attributed to parasympathetic hypofunction (17, 25, 37), sympathetic hyperfunction (37), or, more frequently, sympathovagal imbalance (6, 12, 32, 37, 39). However, in the present study a much more detailed investigation of the disturbed process was undertaken that identified a complex, multifaceted disturbance, involving nonlinear interactions within the system.

The possibility that the changes in HRV observed in patients with cirrhosis might relate to the changes in neuropsychiatric status commonly observed in this patient population does not appear to have been considered previously. This is surprising given that 1) reductions in HRV are known to occur in a number of neuropsychiatric disorders (28, 29, 58, 62) and 2) Miyajima and colleagues (37) reported a highly significant relationship between decreased HRV and gastric dysmotility in patients with cirrhosis and a positive correlation between gastric motility and the degree of hepatic encephalopathy.

There are several possible explanations for the relationship between HRV and neuropsychiatric status observed in these patients. The two most likely are 1) the presence of an autonomic neuropathy or 2) the presence of a mechanism involving circulating inflammatory cytokines.

Vagal neuropathy is common in patients with cirrhosis and is an independent predictor of mortality (17, 25). Its presence may lead to prolongation of gastrointestinal transit time, small bowel bacterial overgrowth, bacterial translocation and endotoxemia, all of which may predispose to hepatic encephalopathy. Indeed, Maheshwari and colleagues (33) reported that patients with cirrhosis and evidence of an autonomic neuropathy are more likely to develop hepatic encephalopathy than those without. They did not, however, objectively quantify their patients' neuropsychiatric status.

Many of the measures of HRV obtained by using nonlinear dynamics, such as SD2 and SampEn, are conceptually complete but can be optimized to provide useful information to clinicians. In the present study, Poincaré plots were used to distinguish the effects of vagal modulation from other causes of heart rate variation (56). In these plots, the variable SD1 reflects short-term R-R interval variations, which mainly relate to vagal drive (56), whereas the variable SD2 reflects long-term R-R interval variations and reflects all the other causes of heart rate change, e.g., those associated with sympathetic oscillations, the baroreflex loop, thermoregulation, and fluctuations in humoral factors (56). The heart rate variable that showed the strongest correlation with neuropsychiatric status was SD2, and this relationship held firm even when control was exercised for vagal drive. This indicates that the relationship between HRV and hepatic encephalopathy cannot be attributed simply to vagal dysfunction.

Decreased HRV has been reported in a variety of clinical settings associated with increased production of inflammatory cytokines (6, 2224, 31). Circulating levels of inflammatory cytokines are increased in patient with cirrhosis (19, 55) and positively correlate with the severity of hepatic encephalopathy in this patient population (19, 43, 44). In the present study, plasma IL-6 concentrations correlated significantly with both indexes of HRV and neuropsychiatric performance, suggesting that these changes share a common etiology. These data also provide support for the potential role of inflammatory mediators in the pathogenesis of hepatic encephalopathy (27, 42, 51).

The physiological mechanism underlying the loss of HRV during the systemic inflammatory response is unknown but cytokine-induced autonomic dysfunction or disruption of intracellular signal transduction processes undoubtedly play a role (30, 45). Among the cytokines, IL-6 exhibited the strongest correlation with the indexes of depressed HRV (5, 22, 54). Cytokines can potentially blunt β-adrenergic signaling (47), and thus it has been suggested that overexpression of cytokines and subsequent loss of β-adrenergic responsiveness might contribute to the decrease in HRV during inflammation (34). Although this hypothesis is attractive within the context of “cirrhotic cardiomyopathy” (18, 61), recent studies have shown that decreased HRV following endotoxin challenge is not related to alterations in cardiac β-adrenergic signaling in endotoxemic mice (36). In addition, loss of HRV in a rat model of cirrhosis occurs independently of any impairment in cardiac β-adrenergic responsiveness (35).

Although the brain used to be considered an “immune-privileged” organ, it is now thought to monitor peripheral innate immune responses by several mechanisms involving parallel pathways (16). These include 1) primary afferent neurons, such as the vagus nerve, which carries information from the viscera; 2) Toll-like receptors on macrophage-like cells residing in the periventricular regions; 3) cytokine receptors located on the endothelial cells of brain venules; and 4) cytokine transporters at the blood brain barrier level (16). Within this frame, a reciprocal relationship between hepatic and central nervous system (CNS) inflammatory responses has been postulated (810). Pioneering studies by Campbell and colleagues (810) have shown that the liver plays a putative role in the CNS inflammatory response. Thus selective depletion of hepatic Kupffer cells or hepatic nuclear factor-κB, a proinflammatory transcription factor, attenuate the inflammatory response in experimental models of cytokine-induced brain injury (9, 10). On the basis of these observations, it is possible to postulate that hepatic inflammation may potentiate the effect of cytokines on the brain. Such an interaction between neural and hepatic inflammatory responses might also play a mechanistic role in the development of hepatic encephalopathy.

Cytokine-induced neural modulation can affect the brain cortex as well as subcortical regions such as the medullary centers (16). There is convincing evidence that the central cardiovascular medullary center is disordered in experimental cirrhosis (52), which may result in uncoupling of the cardiac pacemaker cells from their brain stem regulators. Following from Pincus's reasoning that uncoupling and increased “system isolation” are associated with greater regularity (46), medullary center dysfunction may be implicated in the regularization of the cardiac cycle during systemic inflammation.

The present study shows a relationship between inflammatory markers, neuropsychiatric impairment, and decreased HRV in patients with hepatic encephalopathy. These findings are in agreement with a recent report by Newton et al. (40), who showed that cognitive symptoms in patients with primary biliary cirrhosis are independent of liver disease severity and are associated with autonomic dysfunction. The correlation between neuropsychiatric status and HRV observed in the present study suggests a common pathogenic mechanism mediated by cytokine-induced changes in the cortical and medullary brain regions involved in cardiovascular control.

There is also some evidence, from previous studies, that decreased HRV is an independent risk factor for death and thus has a negative prognostic value in this patient population (6, 25). This finding was confirmed in the present study; the relative risk of death increased by 7.7% for every 1-ms drop in SD2. Thus, whatever the causal link between changes in HRV and neuropsychiatric status in patients with hepatic encephalopathy, a reduction in HRV identifies individuals who at risk of death and this variable could be used to monitor patients over time and perhaps facilitate selection for transplantation.

Limitations of the Study

A potential limitation of the present study is that a significant proportion of the patients had alcohol-related cirrhosis. However, since they had been abstinent from alcohol for a minimum of 3 mo and, in most cases, for years, the observed relationship between HRV and hepatic encephalopathy is unlikely to be related to the acute effects of ethanol on the cardiovascular and/or the nervous system. In addition, frozen plasma samples were not available for all patients enrolled in the study. Although the presented correlation between plasma IL-6 levels and HRV indexes observed in the 18 patients with available data is promising, an IL-6 threshold value to predict hepatic encephalopathy or decreased HRV could not be identified, most likely because of insufficient study power.

Larger studies in patients with cirrhosis of varying etiology and more complete cytokine data analysis should be carried out in the future to confirm our findings and further clarify the relationship between cardiovascular variability, neuropsychiatric impairment, and systemic inflammation.

GRANTS

A. R. Mani and K. P. Moore are supported by a grant from the British Heart Foundation.

Acknowledgments

Present address of A. R. Mani: Department of Physiology, School of Medical Sciences, Tarbiat Modares University, Tehran, Iran.

Notes

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

REFERENCES

1. Altimiras J Understanding autonomic sympathovagal balance from short-term heart rate variations. Are we analyzing noise? Comp Biochem Physiol A Mol Integr Physiol 124: 447–460, 1999. [PubMed]
2. Amodio P, Marchetti P, Del Piccolo F, de Tourtchaninoff M, Varghese P, Zuliani C, Campo G, Gatta A, Guérit JM. Spectral versus visual EEG analysis in mild hepatic encephalopathy. Clin Neurophysiol 110: 1334–1344, 1999. [PubMed]
3. Amodio P, Wenin H, Del Piccolo F, Mapelli D, Montagnese S, Pellegrini A, Musto C, Gatta A, Umiltà C. Variability of trail making test, symbol digit test and line trait test in normal people. A normative study taking into account age-dependent decline and sociobiological variables. Aging Clin Exp Res 14: 117–131, 2001. [PubMed]
4. Anisman H, Merali Z. Cytokines, stress, and depressive illness. Brain Behav Immun 16: 513–524, 2002. [PubMed]
5. Aronson D, Mittleman MA, Burger AJ. Interleukin-6 levels are inversely correlated with heart rate variability in patients with decompensated heart failure. J Cardiovasc Electrophysiol 12: 294–300, 2001. [PubMed]
6. Ates F, Topal E, Kosar F, Karincaoglu M, Yildirim B, Aksoy Y, Aladag M, Harputluoglu MM, Demirel U, Alan H, Hilmioglu F. The relationship of heart rate variability with severity and prognosis of cirrhosis. Dig Dis Sci 51: 1614–1618, 2006. [PubMed]
7. Bustamante J, Rimola A, Ventura PJ, Navasa M, Cirera I, Reggiardo V, Rodes J. Prognostic significance of hepatic encephalopathy in patients with cirrhosis. J Hepatol 30: 890–895, 1999. [PubMed]
8. Campbell SJ, Perry VH, Pitossi FJ, Butchart AG, Chertoff M, Waters S, Dempster R, Anthony DC. Central nervous system injury triggers hepatic CC and CXC chemokine expression that is associated with leukocyte mobilization and recruitment to both the central nervous system and the liver. Am J Pathol 166: 1487–1497, 2006. [PMC free article] [PubMed]
9. Campbell SJ, Zahid I, Losey P, Law S, Jiang Y, Bilgen M, van Rooijen N, Morsali D, Davis AE, Anthony DC. Liver Kupffer cells control the magnitude of the inflammatory response in the injured brain and spinal cord. Neuropharmacology 55: 780–787, 2008. [PubMed]
10. Campbell SJ, Anthony DC, Oakley F, Carlsen H, Elsharkawy AM, Blomhoff R, Mann DA. Hepatic nuclear factor kappa B regulates neutrophil recruitment to the injured brain. J Neuropathol Exp Neurol 67: 223–230, 2008. [PubMed]
11. Capuron L, Su S, Miller AH, Bremner JD, Goldberg J, Vogt GJ, Maisano C, Jones L, Murrah NV, Vaccarino V. Depressive symptoms and metabolic syndrome: is inflammation the underlying link? Biol Psychiatry 64: 896–900, 2008. [PMC free article] [PubMed]
12. Coelho L, Saraiva S, Guimaraes H, Feitas D, Providencia LA. Autonomic function in chronic liver disease assessed by heart rate variability study. Rev Port Cardiol 20: 25–36, 2001. [PubMed]
14. Conn HO Trail making and number-connection tests in the assessment of mental state in portal systemic encephalopathy. Am J Dig Dis 22: 541–550, 1977. [PubMed]
15. Conn HO, Leevy CM, Vlahcevic ZR, Rodgers JB, Maddrey WC, Seeff L, Levy LL. Comparison of lactulose and neomycin in the treatment of chronic portal-systemic encephalopathy: a double blind controlled trial. Gastroenterology 72: 573–583, 1977. [PubMed]
16. Dantzer R, O'Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 9: 46–56, 2008. [PMC free article] [PubMed]
17. Fleisher LA, Fleckenstein JF, Frank SM, Thuluvath PJ. Heart rate variability as a predictor of autonomic dysfunction in patients awaiting liver transplantation. Dig Dis Sci 45: 340–344, 2000. [PubMed]
18. Gaskari SA, Honar H, Lee SS. Therapy insight: cirrhotic cardiomyopathy. Nat Clin Pract Gastroenterol Hepatol 3: 329–337, 2006. [PubMed]
19. Genesca J, Gonzalez A, Segura R, Catalan R, Marti R, Varela E, Cadelina G, Martinez M, Lopez-Talavera JC, Esteban R, Groszmann RJ, Guardia J. Interleukin-6, nitric oxide, and the clinical and hemodynamic alterations of patients with liver cirrhosis. Am J Gastroenterol 94: 169–177, 1999. [PubMed]
20. Gimeno D, Kivimäki M, Brunner EJ, Elovainio M, De Vogli R, Steptoe A, Kumari M, Lowe GD, Rumley A, Marmot MG, Ferrie JE. Associations of C-reactive protein and interleukin-6 with cognitive symptoms of depression: 12-year follow-up of the Whitehall II study. Psychol Med 4: 1–11, 2008. [PMC free article] [PubMed]
21. Goldberger AL, Amaral LA, Hausdorff JM, Ivanov PCh, Peng CK, Stanley HE. Fractal dynamics in physiology: alterations with disease and aging. Proc Natl Acad Sci USA 99: 2466–2472, 2002. [PMC free article] [PubMed]
22. González-Clemente JM, Vilardell C, Broch M, Megia A, Caixàs A, Giménez-Palop O, Richart C, Simón I, Martínez-Riquelme A, Arroyo J, Mauricio D, Vendrell J. Lower heart rate variability is associated with higher plasma concentrations of IL-6 in type 1 diabetes. Eur J Endocrinol 157: 31–38, 2007. [PubMed]
23. Griffin MP, Lake DE, Bissonette EA, Harrell FE Jr, O'Shea TM, Moorman JR. Heart rate characteristics: novel physiomarkers to predict neonatal infection and death. Pediatrics 116: 1070–1074, 2005. [PubMed]
24. Hamaad A, Sosin M, Blann AD, Patel J, Lip GY, MacFadyen RJ. Markers of inflammation in acute coronary syndromes: association with increased heart rate and reductions in heart rate variability. Clin Cardiol 28: 570–576, 2005. [PubMed]
25. Hendrickse MT, Thuluvath PJ, Triger DR. Natural history of autonomic neuropathy in chronic liver disease. Lancet 339: 1462–1464, 1992. [PubMed]
26. Henry CJ, Huang Y, Wynne A, Hanke M, Himler J, Bailey MT, Sheridan JF, Godbout JP. Minocycline attenuates lipopolysaccharide (LPS)-induced neuroinflammation, sickness behavior, and anhedonia. J Neuroinflammation 5: 15, 2008. [PMC free article] [PubMed]
27. Jover R, Rodrigo R, Felipo V, Insausti R, Saez-Valero J, Garcia-Ayllon MS, Suarez I, Candela A, Compañ A, Esteban A, Cauli O, Ausó E, Rodríguez E, Gutiérrez A, Girona E, Erceg S, Berbel P, Pérez-Mateo M. Brain edema and inflammatory activation in bile duct ligated rats with diet-induced hyperammonemia: a model of hepatic encephalopathy in cirrhosis. Hepatology 43: 1257–1266, 2006. [PubMed]
28. Kim CK, McGorray SP, Bartholomew BA, Marsh M, Dicken T, Wassertheil-Smoller S, Curb JD, Oberman A, Hsia J, Gardin J, Wong ND, Barton B, McMahon RP, Sheps DS. Depressive symptoms and heart rate variability in postmenopausal women. Arch Intern Med 165: 1239–1244, 2005. [PubMed]
29. Kim DH, Lipsitz LA, Ferrucci L, Varadhan R, Guralnik JM, Carlson MC, Fleisher LA, Fried LP, Chaves PH. Association between reduced heart rate variability and cognitive impairment in older disabled women in the community: Women's Health and Aging Study I. J Am Geriatr Soc 54: 1751–1757, 2006. [PMC free article] [PubMed]
30. Kuster H, Weiss M, Willeitner AE, Detlefsen S, Jeremias I, Zbojan J, Geiger R, Lipowsky G, Simbruner G. Interleukin-1 receptor antagonist and interleukin-6 for early diagnosis of neonatal sepsis 2 days before clinical manifestation. Lancet 352: 1271–1277, 1998. [PubMed]
31. Lanza GA, Sgueglia GA, Cianflone D, Rebuzzi AG, Angeloni G, Sestito A, Infusino F, Crea F, Maseri A; SPAI (Stratificazione Prognostica dell'Angina Instabile) Investigators. Relation of heart rate variability to serum levels of C-reactive protein in patients with unstable angina pectoris. Am J Cardiol 97: 1702–1706, 2006. [PubMed]
32. Lazzeri C, La Vila G, Laffi G, Vecchiarino S, Gambilonghi F, Gentilini P, Franchi F. Autonomic regulation of the heart and QT interval in non-alcoholic cirrhosis with ascites. Digestion 58: 580–586, 1997. [PubMed]
33. Maheshwari A, Thomas A, Thuluvath PJ. Patients with autonomic neuropathy are more likely to develop hepatic encephalopathy. Dig Dis Sci 49: 1584–1588, 2004. [PubMed]
34. Malave HA, Taylor AA, Nattama J, Deswal A, Mann DL. Circulating levels of tumor necrosis factor correlate with indexes of depressed heart rate variability: a study in patients with mild-to-moderate heart failure. Chest 123: 716–724, 2003. [PubMed]
35. Mani AR, Ippolito S, Ollosson R, Moore KP. Nitration of cardiac proteins is associated with abnormal cardiac chronotropic responses in rats with biliary cirrhosis. Hepatology 43: 847–856, 2006. [PubMed]
36. Mani AR, Ollosson R, Mani Y, Ippolito S, Moore KP. Heart rate dynamics in iNOS knockout mice. Life Sci 79: 1593–1599, 2006. [PubMed]
37. Miyajima H, Nomura M, Muguruma N, Okahisa T, Shibata H, Okamura S, Honda H, Shimizu I, Harada M, Saito K, Nakaya Y, Ito S. Relationship between gastric motility, autonomic activity, and portal hemodynamics in patients with liver cirrhosis. J Gastroenterol Hepatol 16: 647–659, 2001. [PubMed]
38. Montagnese S, Jackson C, Morgan MY. Spatio-temporal decomposition of the electroencephalogram in patients with cirrhosis. J Hepatol 46: 447–458, 2007. [PubMed]
39. Newton JL, Allen J, Kerr S, Jones DEJ. Reduced heart rate variability and baroreflex sensitivity in primary biliary cirrhosis. Liver Int 26: 197–202, 2006. [PubMed]
40. Newton JL, Hollingsworth KG, Taylor R, El-Sharkawy AM, Khan ZU, Pearce R, Sutcliffe K, Okonkwo O, Davidson A, Burt J, Blamire AM, Jones D. Cognitive impairment in primary biliary cirrhosis: symptom impact and potential etiology. Hepatology 48: 541–549, 2008. [PubMed]
41. Niskanen JP, Tarvainen MP, Ranta-Aho PO, Karjalainen PA. Software for advanced HRV analysis. Comput Methods Programs Biomed 76: 73–81, 2004. [PubMed]
42. O'Beirne JP, Chouhan M, Hughes RD. The role of infection and inflammation in the pathogenesis of hepatic encephalopathy and cerebral edema in acute liver failure. Nat Clin Pract Gastroenterol Hepatol 3: 118–119, 2006. [PubMed]
43. Odeh M, Sabo E, Srugo I, Oliven A. Serum levels of tumor necrosis factor-alpha correlate with severity of hepatic encephalopathy due to chronic liver failure. Liver Int 24: 110–116, 2004. [PubMed]
44. Odeh M, Sabo E, Srugo I, Oliven A. Relationship between tumor necrosis factor-alpha and ammonia in patients with hepatic encephalopathy due to chronic liver failure. Ann Med 37: 603–612, 2005. [PubMed]
45. Pavlov VA, Ochani M, Gallowitsch-Puerta M, Ochani K, Huston JM, Czura CJ, Al-Abed Y, Tracey KJ. Central muscarinic cholinergic regulation of the systemic inflammatory response during endotoxemia. Proc Natl Acad Sci USA 103: 5219–5223, 2006. [PMC free article] [PubMed]
46. Pincus SM Greater signal regularity may indicate increased system isolation. Math Biosci 122: 161–181, 1994. [PubMed]
47. Prabhu SD Cytokine-induced modulation of cardiac function. Circ Res 95: 1140–1153, 2004. [PubMed]
48. Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 60: 646–649, 1973. [PubMed]
49. Richman JS, Moorman JR. Physiological time-series analysis using approximate entropy and sample entropy. Am J Physiol Heart Circ Physiol 278: H2039–H2049, 2000. [PubMed]
50. Riordan SM, Skinner N, Nagree A, McCallum H, McIver CJ, Kurtovic J, Hamilton JA, Bengmark S, Williams R, Visvanathan K. Peripheral blood mononuclear cell expression of toll-like receptors and relation to cytokine levels in cirrhosis. Hepatology 37: 1154–1164, 2003. [PubMed]
51. Shawcross DL, Davies NA, Williams R, Jalan R. Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonaemia in cirrhosis. J Hepatol 40: 247–254, 2004. [PubMed]
52. Song D, Sharkey KA, Breitman DR, Zhang Y, Lee SS. Disordered central cardiovascular regulation in portal hypertensive and cirrhotic rats. Am J Physiol Gastrointest Liver Physiol 280: G420–G430, 2001. [PubMed]
53. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart rate variability. Standards of measurement, physiological interpretation, and clinical use. Eur Heart J 17: 354–381, 1996. [PubMed]
54. Tateishi Y, Oda S, Nakamura M, Watanabe K, Kuwaki T, Moriguchi T, Hirasawa H. Depressed heart rate variability is associated with high IL-6 blood level and decline in the blood pressure in septic patients. Shock 28: 549–553, 2007. [PubMed]
55. Tilg H, Wilmer A, Vogel W, Herold M, Nolchen B, Judmaier G, Huber C. Serum levels of cytokines in chronic liver diseases. Gastroenterology 103: 264–274, 1992. [PubMed]
56. Tulppo MP, Makikallio TH, Takala TE, Seppanen T, Huikuri HV. Quantitative beat-to-beat analysis of heart rate dynamics during exercise. Am J Physiol Heart Circ Physiol 271: H244–H252, 1996. [PubMed]
57. Vaccarino V, Brennan ML, Miller AH, Bremner JD, Ritchie JC, Lindau F, Veledar E, Su S, Murrah NV, Jones L, Jawed F, Dai J, Goldberg J, Hazen SL. Association of major depressive disorder with serum myeloperoxidase and other markers of inflammation: a twin study. Biol Psychiatry 64: 476–483. [PMC free article] [PubMed]
58. Vigo DE, Nicola Siri L, Ladrón De Guevara MS, Martínez-Martínez JA, Fahrer RD, Cardinali DP, Masoli O, Guinjoan SM. Relation of depression to heart rate nonlinear dynamics in patients > or =60 yr of age with recent unstable angina pectoris or acute myocardial infarction. Am J Cardiol 93: 756–760, 2004. [PubMed]
59. Wechsler D Wechsler Adult Intelligence Scale. New York: Psychological Corporation, 1955.
60. Weissenborn K, Ennen JC, Schomerus H, Rückert N, Hecker H. Neuropsychological characterization of hepatic encephalopathy. J Hepatol 34: 768–773, 2001. [PubMed]
61. Zambruni A, Trevisani F, Caraceni P, Bernardi M. Cardiac electrophysiological abnormalities in patients with cirrhosis. J Hepatol 44: 994–1002, 2006. [PubMed]
62. Zulli R, Nicosia F, Borroni B, Agosti C, Prometti P, Donati P, De Vecchi M, Romanelli G, Grassi V, Padovani A. QT dispersion and heart rate variability abnormalities in Alzheimer's disease and in mild cognitive impairment. J Am Geriatr Soc 53: 2135–2139, 2005. [PubMed]

Articles from American Journal of Physiology - Gastrointestinal and Liver Physiology are provided here courtesy of American Physiological Society
PubReader format: click here to try

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • MedGen
    MedGen
    Related information in MedGen
  • PubMed
    PubMed
    PubMed citations for these articles
  • Substance
    Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...