INVITED REVIEW
Heart Rate Variability as a Measure of Cardiac Autonomic Function in Anorexia Nervosa: A Review of the Literature Nazar Mazurak1,2, Paul Enck1*, Eric Muth3, Martin Teufel1 & Stephan Zipfel1 1
Department of Psychosomatic Medicine, University Hospital, Tu¨bingen, Germany
2
Department of Internal Medicine, Ivano-Frankivsk National Medical University, Ukraine
3
Department of Psychology, Clemson University, Clemson, SC, USA
Abstract Objective: Patients with anorexia nervosa (AN) exhibit a wide range of autonomic system disturbances; these patients have also high mortality risk due to cardio-vascular complications. Origin and pathogenesis of such changes are not absolutely clear. Methods: Relevant publications were drawn from PUBMED using the keywords ‘anorexia nervosa’ AND ‘autonomic’. Fifty two abstracts were identified and screened for papers that measured the state of autonomic regulation by means of analysis of heart rate variability either during 24-hour electrocardiography (ECG) monitoring or during a short-term laboratory test. Studies selected were analysed for the number of patients included, the presence and quality of control groups, gender, age and body mass index (BMI) of patients, type of AN as well as methods used to determine heart rate variability (HRV). Results: Twenty papers on HRV in patients with anorexia were identified and analysed, revealing three distinct positions regarding changes of autonomic nervous system (ANS) functions in patients with AN. The majority of papers identified parasympathetic/sympathetic imbalance with parasympathetic dominance and decreased sympathetic modulation; others could not replicate these findings, but instead described sympathetic dominance; finally a group of papers could not identify any autonomic differences in comparison to control samples. We conclude that in its current state of analysis HRV may not be suitable for routine assessment of ANS function in AN patients but rather remains a research tool. Copyright # 2010 John Wiley & Sons, Ltd and Eating Disorders Association.
Keywords autonomic regulation; heart rate variability; anorexia nervosa *Correspondence Professor Paul Enck, Department of Internal Medicine VI: Psychosomatic Medicine and Psychotherapy, University Hospital Tuebingen, Frondsbergstr 23, 72076 Tuebingen, Germany. Tel: þ49 7071 29-89118. Fax: þ49 7071 29-4382. Email: [email protected]
Published online 28 December 2010 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/erv.1081
Introduction Patients with eating disorders exhibit a wide range of autonomic nervous system (ANS) disturbances. For example, patients with anorexia nervosa (AN) are typically bradycardic (resting heart rate (HR) less than
50 per minute) and have relatively low arterial blood pressure (usually lower than 100/50 mm Hg) (Casper, 1986; Kalager, Brubakk, & Bassoe, 1978). Among others, cardiovascular abnormalities reported include QT-interval prolongation (Lesinskiene, Barkus, Ranceva, & Dembinskas, 2008; Takimoto et al., 2004),
Eur. Eat. Disorders Rev. 19 (2011) 87–99 ß 2010 John Wiley & Sons, Ltd and Eating Disorders Association.
87
Heart Rate Variability in Anorexia Nervosa
voltage decrease, T-wave inversion, weight reduction and thinning of the left ventricle, and drop of heart functional parameters (ejection fraction, minute blood volume) (Casiero & Frishman, 2006; Olivares et al., 2005). The origin and pathogenesis of such changes are not absolutely clear, though many authors (Casper, 1986; Fohlin, 1977) regard them as an adaptation to poor nutrition. HR variability (HRV) is an acknowledged tool for estimating autonomic function (Task Force, 1996). Numerous researchers have demonstrated its relevance in assessment of the autonomic status. Clinical significance of HRV was first assessed in 1965, when Lee and Hon (1965) revealed that alternation of the R-R interval preceded fetal distress before any distinguishable HR changes themselves became obvious. Eight years later Sayers (1973) identified physiological rhythms of HR. In the 1970s Ewing et al. (1974, 1978) suggested some simple bedside tests to diagnose vegetative neuropathy in patients with diabetes mellitus by means of recording transient RR-intervals changes. Correlations between increased mortality risk in patients with myocardial infarction and low HRV were for the first time demonstrated by Wolf et al. (1978). Akselrod et al. (1981) applied spectral analysis to quantitatively evaluate cardiovascular parameters from beat to beat. The true clinical significance of HRV was established in the late 1980s (Kleiger, Miller, Bigger, & Moss, 1987; Lombardi et al., 1987; Singer et al., 1988), when it was found that HRV is a steady and independent predictor of mortality in patients with myocardial infarction. Mortality is also important for patients with AN, because different studies, including long-term follow-ups, have described high mortality risk in this cohort of patients often connected with different cardio-vascular complications, e.g. fatal arrhythmias (Casiero & Frishman, 2006; Lo¨we et al., 2001; Zipfel, Lo¨we, Reas, Deter, & Herzog, 2000). We would recommend our readers that are interested in detailed history of the method to apply to other sources, e.g. Task Force (1996).
Methods of this review In the paper, we summarize the results of studies in anorectic patients that assessed HRV as a main method to estimate autonomic regulation, alone or in combination with other parameters. Relevant publications were drawn from PUBMED using the keywords 88
N. Mazurak et al.
‘anorexia nervosa’ AND ‘autonomic’. Fifty-two abstracts were identified and screened for papers that measured the state of autonomic regulation by mean of analysis of HRV. The searched pool was enlarged by references found in these articles. Among the many methodological approaches for assessment of autonomic function like skin conductivity, impedance cardiography and others, we choose HRV analysis because of its frequent use for research in AN in recent years. We included only papers where diagnosis of AN was confirmed based on DSM-III/IV or ICD-10 criteria. Only the papers where HRV was measured by mean of ‘traditional’ HRV parameters such as standard deviation of the normal-to-normal (NN) interval (SDNN), standard deviation of sequential 5-minute R-R interval means (SDANN), root mean square successive difference (RMSSD), the mean number of times per hour in which the change in consecutive normal sinus (NN) intervals exceeds 50 milliseconds (pNN50) (time domain), very low frequency (VLF), low frequency (LF), high frequency (HF) and total power (TP) (frequency domain) were reviewed; we also made the analysis of data received with non-parametric models. Twenty studies published between 1994 and 2009 were selected and analysed in detail for the number of patients included, the presence and quality of control groups, gender, age, BMI of patients, type of AN pathology (restricted or binge/purging type), method used to determine HRV (24-hours ambulatory monitoring, short term laboratory assessment), method of HRV analysis (time domain, frequency domain or nonlinear methods) and major outcome measures. Table 1 lists the frequently used abbreviations of ANS parameters. For further analysis, these studies were divided into subgroups: HRV calculated by means of 24-hour Holter monitoring, and HRV analysis based on short-term ECG recorded under laboratory conditions, often in combination with functional tests. In case of 24-hour monitoring, subjects usually maintained their normal lifestyle, but were requested to avoid abnormal activities and the consumption of ANS-interfering substances (caffeine, alcohol, etc.). These conditions are usually poorly controlled and not standardized, and they usually provide an approximation of ANS function over the entire circadian period. Frequently, daytime and nocturnal data are separated, although the border between both is often unclear.
Eur. Eat. Disorders Rev. 19 (2011) 87–99 ß 2010 John Wiley & Sons, Ltd and Eating Disorders Association.
N. Mazurak et al.
Heart Rate Variability in Anorexia Nervosa
Table 1 Abbreviations used for describing ANS functions SDNN SDANN RMSSD
pNN50 HF LF MF VLF TP ApEn Scaling exponent a
Standard deviation of the normal-to-normal (NN) interval; reflects general variability of heart rate influenced by both sympathetic and parasympathetic branches, also endocrine and thermoregulatory mechanisms Standard deviation of sequential five-minute R-R interval means; mostly is used as a parameter in 24 hours recordings. It is suggested that it reflects mostly humoral influence and the activity of central autonomic structures on heart rate Root mean square successive difference (the square root of the mean squared differences of successive NN interval); the RMSSD statistic is shown to represent a high-pass filter that effectively captures respiratory sinus arrhythmia but also passes lower frequency fluctuations that can include sympathetic influences The mean number of times per hour in which the change in consecutive normal sinus (NN) intervals exceeds 50 milliseconds; it is suggested that it reflects, similar to RMSSD, mostly the influence of parasympathetic activity High frequency power of spectral analysis of heart rate, 0.15–0.4 Hz; reflects short term fluctuation of HR induced by parasympathetic part of ANS Low frequency power of spectral analysis of heart rate, 0,03(0,04)-0,15 Hz; clinical meaning is widely discussed; most authors suggest that it reflects both sympathetic and parasympathetic (baroreflex) influences of HR Mid frequency power of spectral analysis of heart rate, 0.05–0.15 Hz; was proposed as a part of spectrum that likely reflects a baroreceptor activity; at present is rarely used Very low frequency power of spectral analysis of heart rate,
Heart Rate Variability as a Measure of Cardiac Autonomic Function in Anorexia Nervosa: A Review of the Literature Nazar Mazurak1,2, Paul Enck1*, Eric Muth3, Martin Teufel1 & Stephan Zipfel1 1
Department of Psychosomatic Medicine, University Hospital, Tu¨bingen, Germany
2
Department of Internal Medicine, Ivano-Frankivsk National Medical University, Ukraine
3
Department of Psychology, Clemson University, Clemson, SC, USA
Abstract Objective: Patients with anorexia nervosa (AN) exhibit a wide range of autonomic system disturbances; these patients have also high mortality risk due to cardio-vascular complications. Origin and pathogenesis of such changes are not absolutely clear. Methods: Relevant publications were drawn from PUBMED using the keywords ‘anorexia nervosa’ AND ‘autonomic’. Fifty two abstracts were identified and screened for papers that measured the state of autonomic regulation by means of analysis of heart rate variability either during 24-hour electrocardiography (ECG) monitoring or during a short-term laboratory test. Studies selected were analysed for the number of patients included, the presence and quality of control groups, gender, age and body mass index (BMI) of patients, type of AN as well as methods used to determine heart rate variability (HRV). Results: Twenty papers on HRV in patients with anorexia were identified and analysed, revealing three distinct positions regarding changes of autonomic nervous system (ANS) functions in patients with AN. The majority of papers identified parasympathetic/sympathetic imbalance with parasympathetic dominance and decreased sympathetic modulation; others could not replicate these findings, but instead described sympathetic dominance; finally a group of papers could not identify any autonomic differences in comparison to control samples. We conclude that in its current state of analysis HRV may not be suitable for routine assessment of ANS function in AN patients but rather remains a research tool. Copyright # 2010 John Wiley & Sons, Ltd and Eating Disorders Association.
Keywords autonomic regulation; heart rate variability; anorexia nervosa *Correspondence Professor Paul Enck, Department of Internal Medicine VI: Psychosomatic Medicine and Psychotherapy, University Hospital Tuebingen, Frondsbergstr 23, 72076 Tuebingen, Germany. Tel: þ49 7071 29-89118. Fax: þ49 7071 29-4382. Email: [email protected]
Published online 28 December 2010 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/erv.1081
Introduction Patients with eating disorders exhibit a wide range of autonomic nervous system (ANS) disturbances. For example, patients with anorexia nervosa (AN) are typically bradycardic (resting heart rate (HR) less than
50 per minute) and have relatively low arterial blood pressure (usually lower than 100/50 mm Hg) (Casper, 1986; Kalager, Brubakk, & Bassoe, 1978). Among others, cardiovascular abnormalities reported include QT-interval prolongation (Lesinskiene, Barkus, Ranceva, & Dembinskas, 2008; Takimoto et al., 2004),
Eur. Eat. Disorders Rev. 19 (2011) 87–99 ß 2010 John Wiley & Sons, Ltd and Eating Disorders Association.
87
Heart Rate Variability in Anorexia Nervosa
voltage decrease, T-wave inversion, weight reduction and thinning of the left ventricle, and drop of heart functional parameters (ejection fraction, minute blood volume) (Casiero & Frishman, 2006; Olivares et al., 2005). The origin and pathogenesis of such changes are not absolutely clear, though many authors (Casper, 1986; Fohlin, 1977) regard them as an adaptation to poor nutrition. HR variability (HRV) is an acknowledged tool for estimating autonomic function (Task Force, 1996). Numerous researchers have demonstrated its relevance in assessment of the autonomic status. Clinical significance of HRV was first assessed in 1965, when Lee and Hon (1965) revealed that alternation of the R-R interval preceded fetal distress before any distinguishable HR changes themselves became obvious. Eight years later Sayers (1973) identified physiological rhythms of HR. In the 1970s Ewing et al. (1974, 1978) suggested some simple bedside tests to diagnose vegetative neuropathy in patients with diabetes mellitus by means of recording transient RR-intervals changes. Correlations between increased mortality risk in patients with myocardial infarction and low HRV were for the first time demonstrated by Wolf et al. (1978). Akselrod et al. (1981) applied spectral analysis to quantitatively evaluate cardiovascular parameters from beat to beat. The true clinical significance of HRV was established in the late 1980s (Kleiger, Miller, Bigger, & Moss, 1987; Lombardi et al., 1987; Singer et al., 1988), when it was found that HRV is a steady and independent predictor of mortality in patients with myocardial infarction. Mortality is also important for patients with AN, because different studies, including long-term follow-ups, have described high mortality risk in this cohort of patients often connected with different cardio-vascular complications, e.g. fatal arrhythmias (Casiero & Frishman, 2006; Lo¨we et al., 2001; Zipfel, Lo¨we, Reas, Deter, & Herzog, 2000). We would recommend our readers that are interested in detailed history of the method to apply to other sources, e.g. Task Force (1996).
Methods of this review In the paper, we summarize the results of studies in anorectic patients that assessed HRV as a main method to estimate autonomic regulation, alone or in combination with other parameters. Relevant publications were drawn from PUBMED using the keywords 88
N. Mazurak et al.
‘anorexia nervosa’ AND ‘autonomic’. Fifty-two abstracts were identified and screened for papers that measured the state of autonomic regulation by mean of analysis of HRV. The searched pool was enlarged by references found in these articles. Among the many methodological approaches for assessment of autonomic function like skin conductivity, impedance cardiography and others, we choose HRV analysis because of its frequent use for research in AN in recent years. We included only papers where diagnosis of AN was confirmed based on DSM-III/IV or ICD-10 criteria. Only the papers where HRV was measured by mean of ‘traditional’ HRV parameters such as standard deviation of the normal-to-normal (NN) interval (SDNN), standard deviation of sequential 5-minute R-R interval means (SDANN), root mean square successive difference (RMSSD), the mean number of times per hour in which the change in consecutive normal sinus (NN) intervals exceeds 50 milliseconds (pNN50) (time domain), very low frequency (VLF), low frequency (LF), high frequency (HF) and total power (TP) (frequency domain) were reviewed; we also made the analysis of data received with non-parametric models. Twenty studies published between 1994 and 2009 were selected and analysed in detail for the number of patients included, the presence and quality of control groups, gender, age, BMI of patients, type of AN pathology (restricted or binge/purging type), method used to determine HRV (24-hours ambulatory monitoring, short term laboratory assessment), method of HRV analysis (time domain, frequency domain or nonlinear methods) and major outcome measures. Table 1 lists the frequently used abbreviations of ANS parameters. For further analysis, these studies were divided into subgroups: HRV calculated by means of 24-hour Holter monitoring, and HRV analysis based on short-term ECG recorded under laboratory conditions, often in combination with functional tests. In case of 24-hour monitoring, subjects usually maintained their normal lifestyle, but were requested to avoid abnormal activities and the consumption of ANS-interfering substances (caffeine, alcohol, etc.). These conditions are usually poorly controlled and not standardized, and they usually provide an approximation of ANS function over the entire circadian period. Frequently, daytime and nocturnal data are separated, although the border between both is often unclear.
Eur. Eat. Disorders Rev. 19 (2011) 87–99 ß 2010 John Wiley & Sons, Ltd and Eating Disorders Association.
N. Mazurak et al.
Heart Rate Variability in Anorexia Nervosa
Table 1 Abbreviations used for describing ANS functions SDNN SDANN RMSSD
pNN50 HF LF MF VLF TP ApEn Scaling exponent a
Standard deviation of the normal-to-normal (NN) interval; reflects general variability of heart rate influenced by both sympathetic and parasympathetic branches, also endocrine and thermoregulatory mechanisms Standard deviation of sequential five-minute R-R interval means; mostly is used as a parameter in 24 hours recordings. It is suggested that it reflects mostly humoral influence and the activity of central autonomic structures on heart rate Root mean square successive difference (the square root of the mean squared differences of successive NN interval); the RMSSD statistic is shown to represent a high-pass filter that effectively captures respiratory sinus arrhythmia but also passes lower frequency fluctuations that can include sympathetic influences The mean number of times per hour in which the change in consecutive normal sinus (NN) intervals exceeds 50 milliseconds; it is suggested that it reflects, similar to RMSSD, mostly the influence of parasympathetic activity High frequency power of spectral analysis of heart rate, 0.15–0.4 Hz; reflects short term fluctuation of HR induced by parasympathetic part of ANS Low frequency power of spectral analysis of heart rate, 0,03(0,04)-0,15 Hz; clinical meaning is widely discussed; most authors suggest that it reflects both sympathetic and parasympathetic (baroreflex) influences of HR Mid frequency power of spectral analysis of heart rate, 0.05–0.15 Hz; was proposed as a part of spectrum that likely reflects a baroreceptor activity; at present is rarely used Very low frequency power of spectral analysis of heart rate,
