ANS Clinical Studies

Autonomic Tone as a Cardiovascular Risk Factor: The Dangers of Chronic Fight or Flight
Brian M. Curtis, Md, and James H. O’Keefe, Jr, Md
Mayo Clin Proc. 2002;77:45-54
Chronic imbalance of the autonomic nervous system is a prevalent and potent risk factor for adverse cardiovascular events, including mortality. Although not widely recognized by clinicians, this risk factor is easily assessed by measures such as resting and peak exercise heart rate, heart rate recovery after exercise, and heart rate variability.
Any factor that leads to inappropriate activation of the sympathetic nervous system can be expected to have an adverse effect on these measures and thus on patient outcomes, while any factor that augments vagal tone tends to improve outcomes. Insulin resistance, sympathomimetic medications, and negative psychosocial factors all have the potential to affect autonomic function adversely and thus cardiovascular prognosis.

Dynamics of Cognitive Aging: Distinguishing Functional Age and Disease from Chronologic Age in a Population
J. E. Graham, A. B. Mitnitski, A. J. Mogilner, and K. Rockwood
American Journal of Epidemiology, 1999
This paper introduces a methodological approach to the dynamics of cognitively normal (i.e., successful) aging compared with aging accompanied by different types of cognitive impairment and dementia. Using secondary analysis of a national representative database (Canadian Study of Health and Aging, 1991-1992), the authors show that the occurrence of an adverse event (symptom, sign, or disease), or the accumulation of a number of events, may be modeled as a logistic function of chronologic age in a population. In the cognitively normal, a linear relation between the logarithm of the odds of events and chronologic age was present for the majority of symptoms and signs. This regression represents the accumulation of each sign in a cognitively successful, aging population. The authors then estimated which ages for this cognitively unimpaired group correspond to the odds of the occurrence of symptoms found for a cognitively impaired population at any given chronologic age. This may be regarded as functional age, based upon the accumulation of a particular functional deficit in the impaired population, analogous to the concept of frailty. The dynamics of aging are a complex process of accumulation of deficits (morbidity), whereby decline from some previously healthy level of synergistically associated symptoms and signs results in distinct patterns of disease and staging. The modeling of these dynamics takes us a step further toward the definition and refinement of disease and normal aging.

Cardiac autonomic balance versus cardiac regulatory capacity
Gary G. Berntson, Greg J. Norman, Louise C. Hawkley, And John T. Cacioppo
Psychophysiology, 45 (2008), 643–652.
The concept of autonomic balance views autonomic states along a bipolar continuum from sympathetic (S) to parasympathetic (P) dominance, whereas regulatory capacity models emphasize overall autonomic flexibility as a marker of the capacity for regulation. These two concepts were evaluated for their utility in characterizing patterns of autonomic control.Measures of P (high frequency heart rate variability, HF) and S (preejection period, PEP) cardiac control were obtained. A measure of cardiac autonomic balance (CAB) was derived as the difference in the normalized P indexminus the S index, and ameasure of cardiac autonomic regulation (CAR) was derived as the normalized P index plus the S index. Results reveal that CAR, but not CAB, was a significant predictor of the prior occurrence of a myocardial infarction, net of demographic and other variables, whereasCAB, but notCAR, was a significant predictor of concurrent diabetes.

Autonomic Nerve Testing Predicts the Development of Complications
Diabetes Care, Volume 30, Number 1, January 2007
Objective: Cardiac autonomic nerve tests have predicted increased mortality in adults with diabetes, predominantly due to nephropathy, cardiac disease, and hypoglycemia. The significance of subclinical autonomic nerve test abnormalities has not been systematically studied in adolescents. We aimed to reassess an adolescent cohort, whose autonomic nervous system had been tested 12 years earlier by both pupillometry and cardiovascular tests.

Autonomic Nervous System and Sudden Cardiac Death
Hal V. Barron, Md, Michael D. Lesh, Md, Facc
JACC Vol. 27, No. 5, April 1996
In the United States, sudden cardiac death is a major public health problem, accounting for - 300,000 deaths annually. Accurate identification of those patients at highest risk for this event has been problematic. The use of signal-averaged electrocardiography, Holter monitoring and assessment of left ventricular function have been shown to be predictive of future arrhythmic events in patients after a myocardial infarction. However, the clinical utility of these tests has been limited by their low sensitivity and positive predictive value.

Diabetic Cardiovascular Autonomic Neuropathy
Aaron I. Vinik and Dan Ziegler
Circulation 2007;115;387-397
One of the most overlooked of all serious complications of diabetes is cardiovascular autonomic neuropathy (CAN), which encompasses damage to the autonomic nerve fibers that innervate the heart and blood vessels, resulting in abnormalities in heart rate control and vascular dynamics.

Gender differences in autonomic cardiovascular regulation: spectral, hormonal, and hemodynamic indexes
Joyce M. Evans, Michael G. Ziegler, Abhijit R. Patwardhan, J. Blaine Ott, Charles S. Kim, Fabio M. Leonelli and Charles F. Knapp
Appl Physiol 91:2611-2618, 2001

Abnormalities of sympathetic and parasympathetic autonomic function in subjects with defaecation syncope
Louise Allan, Emma Johns, Mira Doshi, Rose Anne Kenny, Julia L. Newton
2004 The European Society of Cardiology
Abstract: Defaecation syncope is defined as blacking out at, or around, the time of defaecation. It is associated with increased mortality; however, patients rarely voluntarily report symptoms. We have examined autonomic function in a cohort of patients with defaecation syncope.

Recent Advances in Autonomic Function Tests of the Cardiovascular System in Children
Hidetaka Tanaka, Hiroshi Tamai, Medical College, Osaka, Japan
Med Principles Pract 1998;7:157–171
Recent advances in computer technology have made it possible to noninvasively determine fast and dynamic changes in autonomic nervous activity in humans. Power spectral analysis of heart rate variation, beat-to-beat blood pressure analysis, skin blood flow by the laser Doppler technique, sensitive sudorometry and direct measurement of sympathetic nervous discharge have been successfully applied in adults, but there are still only few studies reported in children and adolescents.
This article reviews the usefulness of these autonomic function tests in the pediatric field including reliability and methodological limits. Power spectral analysis of heart rate variability seems to be a new potential method, but there have been only few studies in children. Orthostatic maneuvers with noninvasive beat-to-beat measurement of finger arterial pressure, especially during active standing, is useful for the evaluation of orthostatic intolerance in children as well as adults with autonomic failure. A new pharmacological method using multiple autonomic agents might indicate a more precise information including alpha- and beta-adrenoceptor sensitivity. It should be realized that a single test cannot identify impaired autonomic functions, and a combination of several autonomic tests should be employed. Moreover, age-related changes and racial differences in autonomic function should be considered when interpreting obtained results.

Autonomic Neuropathy: Patient Care
Raelene E. Maser, PhD, MT(ASCP)
Diabetes Spectrum Volume 11. Number 4. 1998
Diabetic neuropathy, encompassing a wide range of abnormalities within the peripheral nervous system (PNS), is actually a number of different syndromes, each with a vast array of clinical and subclinical manifestations. Given that diabetic neuropathy is a very broad and complex area, this Diabetes Spectrum FROM RESEARCH TO PRACTICE section is devoted to just a few selected issues in the area of autonomic neuropathy.

Autonomic nervous system and lipid metabolism: findings in anxious-depressive spectrum and eating disorders
Elisabetta Pistorio, Maria Luca, Antonina Luca, Vincenzo Messina and Carmela Calandra
Pistorio et al. Lipids in Health and Disease 2011, 10:192

Hyperinsulinemia and Autonomic Nervous System Dysfunction in Obesity: Effects of Weight Loss
Michele Emdin, Amalia Gastaldelli, Elza Muscelli, Alberto Macerata, Andrea Natali, Stefania Camastra and Ele Ferrannini
Circulation 2001;103;513-519

Influence of Autonomic Nervous System Dysfunction on the Development of Type 2 Diabetes
Mercedes R. Carnethon, Phd, David R. Jacobs, Jr., Phd, Stephen Sidney, Md, Mph, Kiang Liu, Phd
Diabetes Care, Volume 26, Number 11, November 2003

The Association Among Autonomic Nervous System Function, Incident Diabetes, and Intervention Arm in the Diabetes Prevention Program
Mercedes R. Carnethon, Phd, Ronald J. Prineas, Md, Phd, Marinella Temprosa, Ms, Zhu-Ming Zhang, Md, Gabriel Uwaifo, Md, Mark E. Molitch, Md
Diabetes Care, Volume 29, Number 4, April 2006
Autonomic nervous system dysfunction, a correlate of obesity and poor cardiorespiratory fitness, is associated with the development of diabetes. We tested whether estimates of autonomic nervous system function improved in the intensive lifestyle versus metformin or placebo arms of the Diabetes Prevention Program (DPP) and whether baseline or a change in autonomic nervous system function was associated with the development of diabetes over 3.2 years.

Cardiac Autonomic Neuropathy Predicts Cardiovascular Morbidity and Mortality in Type 1 Diabetic Patients With Diabetic Nephropathy
Anne Sofie Astrup, Md, Lise Tarnow, Dmsc, Peter Rossing, Dmsc, Birgitte V. Hansen, Jannik Hilsted, Dmsc, Hans-Henrik Parving, Dmsc
Diabetes Care, Volume 29, Number 2, February 2006

Diabetic Autonomic Neuropathy
Aaron I. Vinik, Md, Phd, Raelene E. Maser, Phd, Braxton D. Mitchell, Phd, Roy Freeman, Md
Diabetes Care, Volume 26, Number 5, May 2003
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New insights in diabetic autonomic neuropathy in children and adolescents
A Verrotti, G Loiacono, A Mohn and F Chiarelli
European Journal of Endocrinology (2009) 161 811–818
Diabetic autonomic neuropathy (DAN) represents a major complication of diabetes mellitus but there is considerable uncertainty about its incidence, prevalence, pathogenesis, diagnosis, and prognosis. There are conflicting opinions about the pathogenesis of DAN: the ‘classical hypothesis’ has been supplemented by some new insights. Clinical symptoms of autonomic neuropathy do not generally occur until long after the onset of diabetes. DAN seems to be detectable even in asymptomatic children and adolescents with diabetes and is associated with the most serious consequences, such as cardiovascular dysfunction. Because of its association with a variety of adverse outcomes, including cardiovascular deaths, cardiovascular autonomic neuropathy is the most clinically important and well-studied form of DAN. No form of therapy in DAN has been identified that provides unequivocal, safe, and effective stabilization or reversal of the condition, just a near normal control of blood glucose in the early years after the onset of diabetes that may delay the development of clinically significant nerve impairment. This article reviews recent developments in knowledge of epidemiology, pathogenesis, clinical symptoms, diagnosis, and therapy of DAN.

Heart rate variability: a noninvasive electrocardiographic method to measure the autonomic nervous system.
Juan Sztajzel
Swiss Med Wkly 2004;134:514–522
The autonomic nervous system (ANS) plays an important role not only in physiological situations, but also in various pathological settings such as diabetic neuropathy, myocardial infarction (MI) and congestive heart failure (CHF). Autonomic imbalance associating increased sympathetic activity and reduced vagal tone has been been strongly implicated in the pathophysiology of arrhythmogenesis and sudden cardiac death.
Among the different available noninvasive techniques for assessing the autonomic status heart rate variability (HRV) has emerged as a simple, noninvasive method to evaluate the sympathovagal balance at the sinoatrial level. It has been used in a variety of clinical situations including diabetic neuropathy, MI, sudden death and CHF.

Cardiovascular Autonomic Neuropathy Due to Diabetes Mellitus: Clinical Manifestations, Consequences, and Treatment
Raelene E. Maser and M. James Lenhard
The Journal of Clinical Endocrinology, 2005

Autonomic Nervous System - Fellowship Core Curriculum
American Academy Of Neurology
The program for subspecialty training in Autonomic Neurology is aimed to provide neurologists with basic and advanced knowledge of the anatomy, physiology and pharmacology of the autonomic nervous system (ANS); the nosology and diagnosis of central and peripheral autonomic disorders; the indications, techniques, and pitfalls of noninvasive clinical autonomic function testing; and the basis of nonpharmacological and pharmacological treatment of autonomic dysfunction.

Heart rate variability with deep breathing as a clinical test of cardiovagal function
Robert W. Shields, JR, MD, Cleveland Clinic
Cleveland Clinic Journal Of Medicine, April 2009
Research into heart rate variability (HRV) and respiration over the past 150 years has led to the insight that HRV with deep breathing (HRVdb) is a highly sensitive measure of cardiovagal or parasympathetic cardiac function.
This sensitivity makes HRVdb an important part of the battery of cardiovascular autonomic function tests used in clinical autonomic laboratories. HRVdb is a reliable and sensitive clinical test for early detection of cardiovagal dysfunction in a wide range of autonomic disorders.

Dysautonomias: Clinical Disorders of the Autonomic Nervous System
David S. Goldstein, MD, PhD; Discussants: David Robertson, MD; Murray Esler, MD; Stephen E. Straus, MD; and Graeme Eisenhofer, PhD
Ann Intern Med. 2002;137:753-763.

Osteopathic manipulative treatment and its relationship to autonomic nervous system activity as demonstrated by heart rate variability: a repeated measures study
Charles E Henley, Douglas Ivins, Miriam Mills, Frances K Wen and Bruce A Benjamin
Osteopathic Medicine and Primary Care 2008, 2:7

Testing the Autonomic Nervous System
Paola Sandroni, MD, PhD, Department of Neurology, Mayo Clinic
Technical Corner from IASP Newsletter December 1998
The autonomic nervous system (ANS) is an extensive neural network whose main role is to regulate the milieu intérieur by controlling homeostasis and visceral functions. Although most functions regulated by the ANS are out of conscious control, emotions and somatosensory inputs profoundly influence the ANS. Observing the marked vasomotor and sudomotor changes after traumatic nerve injury, it became apparent long ago that the ANS plays an important role in pain modulation and perception. Despite the debate on whether the role of the sympathetic nervous system in generating and sustaining certain pain syndromes is significant, specialists in pain management have sought tools for investigating the ANS.

Assessment of the Autonomic Control of Heart Rate Variability in Healthy and Spinal-Cord Injured Subjects: Contribution of Different Complexity-Based Estimators
Giampiero Merati, Marco Di Rienzo, Member, IEEE, Gianfranco Parati, Arsenio Veicsteinas, and Paolo Castiglioni
IEEE Transactions On Biomedical Engineering, Vol. 53, No. 1, January 2006
We investigated how complexity-based estimators of heart rate variability can detect changes in cardiovascular autonomic drive with respect to traditional measures of variability. This was done by analyzing healthy subjects and paraplegic patients with different autonomic impairment due to low (vascular impairment only) or high (cardiac and vascular impairment) spinal cord injury, during progressive autonomic activations.
While traditional techniques only quantified the effects of the autonomic activation, not distinguishing the effects of the lesion level, some recently proposed complexity estimators could also reveal the pathologic alterations in the autonomic control of heart rate. These estimators included the detrended fluctuation analysis coefficient (sensitive to both low and high autonomic lesions), sample entropy (sensitive to low-level lesions) and the largest Lyapunov exponent (sensitive to high-level lesions). Thus complexity-based methods provide information on the autonomic function from the heart rate dynamics that cannot be obtained by traditional techniques. This finding supports the combined use of both complexity-based and traditional methods to investigate the autonomic cardiovascular control from a more comprehensive perspective.

The Autonomic Nervous System and it's Relationship to Headache.
Dr. Dietrich Klinghardt, M.D., PhD
Harold Wollf reported in 1930 on the autonomic nervous system (ANS) involvement in migraine headaches: he postulated, that the primary cause of migraine is vasoconstriction of the extracranial arteries in the early phases of the headache followed by vasoconstriction -with associated peripheral vasoconstriction in the limbs(2). Other signs suggesting ANS involvement in headache include nausea, diarrhea(3),constipation (4), coldness in hands and feet, paroxysmal tachycardia (5), chest pain (6), variant angina (7), paraesthesia and numbness of the skin and others. The vascular theory of migraine was the generally accepted working model until the cell receptor theory came along around 1970. In 1908 Nobel prize laureate Paul Ehrlich postulated the existence of cell receptors, whose interaction with specific agents was a mechanism responsible for many illnesses. Receptor biochemistry has become the basis for most pharmacological approaches. A recent example is the development of the drug sumatriptan which attaches to the 5-HT1 receptor. Other receptors involved in headache include the alpha-2 receptors, u-opioid receptors and somatostatin receptors. Until today there are numerous theories on the neurophysiology of headache, none of which are completely proven(8).

Central Nervous System Circuitries Underlying Two Types of Peripheral Autonomic Nervous System Disorders
Fuad Lechin and Bertha van der Dijs
The Open Neuroscience Journal, 2008, 2, 41-50
The assessment of circulating neurotransmitters: noradrenaline, adrenaline, dopamine, platelet serotonin, plasma serotonin and plasma tryptophan before and after many types of stressor agents and neuropharmacological drugs carried out over the last thirty years allowed us to accumulate information dealing with the central nervous system (CNS) versus the peripheral autonomic nervous system (ANS) interactions in healthy as well as diseased mammals. Furthermore, the accurate knowledge about the CNS circuitry disorders which underlie both the CNS and peripheral clinical syndromes, has allowed us to prescribe successful neuropharmacological therapeutical strategies for many types of illnesses. In addition, the demonstration that the clinical improvement was always paralleled by the normalization of the neurochemical, hormonal, immunological and clinical profiles affords strong support to our point of view. According to all the above, the authors postulate the existence of two types of diseases: type A and Type N, which are underlain by two opposite CNS + ANS disorders. Type A diseases should be associated with the "uncoping stress" syndrome and are underlain by hyperactivity of the adrenocortical glands plus the CNS disorder characterized by the predominance of the C1(adrenergic) + DR(serotonergic) axis over the A5(noradrenergic) + MR(serotonergic) binomial, whereas the type N diseases depends on the opposite profile: "endogenous depression" syndrome. Finally, we quoted exhaustive evidence showing that the well known fading of both the A6(noradrenergic) + C1(adrenergic) CNS nuclei activity occurring during aging is responsible for the ANS + CNS disorder which is similar to that underlying psychosis, Alzheimer, post-traumatic stress disorder and deficit-attention hyperactive disorder.

Guidance cues involved in the development of the peripheral autonomic nervous system
H.M. Young, R.B. Anderson, C.R. Anderson, Australia
Autonomic Neuroscience: Basic and Clinical 112 (2004) 1 – 14
All peripheral autonomic neurons arise from neural crest cells that migrate away from the neural tube and navigate to the location where ganglia will form. After differentiating into neurons, their axons then navigate to a variety of targets. During the development of the enteric nervous system, GDNF appears to play a role in inducing vagal neural crest cells to enter the gut, in retaining neural crest cells within the gut and in promoting the migration of neural crest cells along the gut. Sema3A regulates the entry of extrinsic axons into the distal hindgut, netrin-DCC signaling is responsible for the centripetal migration of cells to form the submucosal ganglia within the gut, Slit–Robo signaling prevents trunk level neural crest cells from entering the gut, and neurturin plays a role in the innervation of the circular muscle layer. During the development of the sympathetic nervous system, the migration of trunk neural crest cells through the somites is influenced by ephrin-Bs, Sema3A and F-spondin. The migration of neural crest cells ventrally beyond the somites requires neuregulin signaling and the clumping of cells into columns adjacent to the dorsal aorta is regulated by Sema3A. The rostral migration of cells to form the superior cervical ganglion (SCG) and the extension of axons along blood vessels involves artemin signaling through Ret and GFRa3, and the entry of sympathetic axons into target tissues involves neurotrophins and GDNF. Relatively little is known about the development of parasympathetic ganglia, but GDNF appears to play a role in the migration of some cranial ganglion precursors to their correct location, and both GDNF and neurturin are involved in the growth of parasympathetic axons into particular targets.

Cardiovascular Autonomic Neuropathy Is Associated With Microalbuminuria in Older Patients With Type 2 Diabetes
Andrew Moran, Md, Mph, Walter Palmas, Md, Lesley Field, Rn, Msn, Jyoti Bhattarai, Md, Joseph E. Schwartz, Phd, Ruth S. Weinstock, Md, Phd, Steven Shea, Md, Ms
Diabetes Care, Volume 27, Number 4, April 2004

Thermal Thresholds Predict Painfulness of Diabetic Neuropathies
Heidrun H. Kramer, Md, Roman Rolke, Md, Andreas Bickel, Phd, Frank Birklein, Phd
Diabetes Care, Volume 27, Number 10, October 2004

A statement by the American Diabetes Association: Diabetic Neuropathies
Diabetes Care, Volume 28, Number 4, April 2005

Pharmacology of the Autonomic Nervous System
David Robertson, M.D.
Pharmacology 501, January 10 & 12, 2005

Cardiac autonomic balance versus cardiac regulatory capacity
Gary G. Berntson, Greg J. Norman, Louise C. Hawkley, And John T. Cacioppo
Psychophysiology, 45 (2008), 643–652
The concept of autonomic balance views autonomic states along a bipolar continuum from sympathetic (S) to parasympathetic (P) dominance, whereas regulatory capacity models emphasize overall autonomic flexibility as a marker of the capacity for regulation. These two concepts were evaluated for their utility in characterizing patterns of autonomic control.Measures of P (high frequency heart rate variability, HF) and S (preejection period, PEP) cardiac control were obtained. A measure of cardiac autonomic balance (CAB) was derived as the difference in the normalized P indexminus the S index, and ameasure of cardiac autonomic regulation (CAR) was derived as the normalized P index plus the S index. Results reveal that CAR, but not CAB, was a significant predictor of the prior occurrence of a myocardial infarction, net of demographic and other variables, whereasCAB, but notCAR, was a significant predictor of concurrent diabetes.

The autonomic nervous system and the regulation of body functions
Wilfrid Janig
Cambridge University Press, 2006

The Integrative Action of the Autonomic Nervous System
Wilfrid Janig
Cambridge University Press, 2006

The Relationship between Vascular Function and the Autonomic Nervous System
Eisuke Amiya, MD, PhD, Masafumi Watanabe, MD, PhD, and Issei Komuro, MD, PhD
Ann Vasc Dis Vol. 7, No. 2; 2014
Endothelial dysfunction and autonomic nervous system dysfunction are both risk factors for atherosclerosis. There is evidence demonstrating that there is a close interrelationship between these two systems. In hypertension, endothelial dysfunction affects the pathologic process through autonomic nervous pathways, and the pathophysiological process of autonomic neuropathy in diabetes mellitus is closely related with vascular function. However, detailed mechanisms of this interrelationship have not been clearly explained.
In this review, we summarize fi ndings concerning the interrelationship between vascular function and the autonomic nervous system from both experimental and clinical studies. The clarifi cation of this interrelationship may provide more comprehensive risk stratifi cation and a new effective therapeutic strategy against atherosclerosis.

Assessment: Clinical Autonomic Testing
American Academy of Neurology, 1996

Impact of cancer and chemotherapy on autonomic nervous system function and cardiovascular reactivity in young adults with cancer: a case-controlled feasibility study
Scott C. Adams, Ronald Schondorf, Julie Benoit and Robert D. Kilgour
Adams et al. BMC Cancer (2015) 15:414
Preliminary evidence suggests cancer- and chemotherapy-related autonomic nervous system (ANS) dysfunction may contribute to the increased cardiovascular (CV) morbidity- and mortality-risks in cancer survivors. However, the reliability of these findings may have been jeopardized by inconsistent participant screening and assessment methods. Therefore, good laboratory practices must be established before the presence and nature of cancer-related autonomic dysfunction can be characterized. The purpose of this study was to assess the feasibility of conducting concurrent ANS and cardiovascular evaluations in young adult cancer patients, according to the following criteria: i) identifying methodological pitfalls and proposing good laboratory practice criteria for ANS testing in cancer, and ii) providing initial physiologic evidence of autonomic perturbations in cancer patients using the composite autonomic scoring scale (CASS).

Methods of evaluation of autonomic nervous system function
Agnieszka Zygmunt, Jerzy Stanczyk
Arch Med Sci 2010; 6, 1: 11-18
Disturbances of the autonomic nervous system play a crucial role in the pathogenesis and clinical course of many diseases. Recently, rapid development has occurred in the clinical assessment of autonomic function. Various procedures have been described as diagnostic tools to monitor autonomic dysfunction. Some of them are mostly used for research purposes. Many, however, have found their place in routine clinical evaluation. Our paper presents selected methods of assessment of the autonomic nervous system with particular emphasis on those that are useful in diagnosis and treatment of diseases of the cardiovascular system. We discuss multiple tests based on cardiovascular reflexes, methods of studying heart rate variability as well as direct catecholamine measurements. Moreover, we outline tests of sudomotor function and microneurography.

Association between Cardiac Autonomic Function, Oxidative Stress and Inflammatory Response in Impaired Fasting Glucose Subjects: Cross-Sectional Study
Ramkumar Thiyagarajan, Senthil Kumar Subramanian, Nishanth Sampath, Madanmohan Trakroo, Pravati Pal, Zachariah Bobby, Sankar Paneerselvam, Ashok Kumar Das
PLoS ONE, July 2012, Volume 7
The worldwide burden of diabetes in 2030 is projected around 552 million. Diabetes leads to higher risk for cardiovascular diseases (CVD). Altered cardiac autonomic function (CAF) measured by heart rate variability (HRV) is observed in early stages of diabetes but the relationship between impaired fasting glucose (IFG) and HRV is still debatable. The aim of the study was to evaluate the association between CAF, oxidative stress, insulin resistance (IR), and inflammatory response in IFG subjects.

Pediatric Autonomic Disorders
Felicia B. Axelrod, Gisela G. Chelimsky and Debra E. Weese-Mayer
Pediatrics 2006;118;309-321
The scope of pediatric autonomic disorders is not well recognized. The goal of this review is to increase awareness of the expanding spectrum of pediatric autonomic disorders by providing an overview of the autonomic nervous system, including the roles of its various components and its pervasive influence, as well as its intimate relationship with sensory function. To illustrate further the breadth and complexities of autonomic dysfunction, some pediatric disorders are described, concentrating on those that present at birth or appear in early childhood.

Autonomic nervous system influence on arterial baroreflex control of heart rate during exercise in humans
Shigehiko Ogoh, James P. Fisher, Ellen A. Dawson, Michael J.White, Niels H. Secher, and Peter B. Raven
J Physiol 566.2 (2005) pp 599–611

Heart rate variability and short duration spaceflight: relationship to post-flight orthostatic intolerance
Andrew P Blaber, Roberta L Bondar and Mahmood S Kassam
BMC Physiology 2004, 4:6
Upon return from space many astronauts experience symptoms of orthostatic intolerance. Research has implicated altered autonomic cardiovascular regulation due to spaceflight with further evidence to suggest that there might be pre-flight autonomic indicators of post-flight orthostatic intolerance. We used heart rate variability (HRV) to determine whether autonomic regulation of the heart in astronauts who did or did not experience post-flight orthostatic intolerance was different pre-flight and/or was differentially affected by short duration (8 – 16 days) spaceflight. HRV data from ten-minute stand tests collected from the 29 astronauts 10 days preflight, on landing day and three days post-flight were analysed using coarse graining spectral analysis. From the total power (PTOT), the harmonic component was extracted and divided into high (PHI: >0.15 Hz) and low (PLO: = 0.15 Hz) frequency power regions. Given the distribution of autonomic nervous system activity with frequency at the sinus node, PHI/PTOT was used as an indicator of parasympathetic activity; PLO/PTOT as an indicator of sympathetic activity; and, PLO/PHI as an estimate of sympathovagal balance.

Autonomic diseases: clinical features and laboratory evaluation
Christopher J Mathias
J. Neurol. Neurosurg. Psychiatry 2003;74;31-41
The autonomic nervous system has a craniosacral parasympathetic and a thoracolumbar sympathetic pathway and supplies every organ in the body. It influences localised organ function and also integrated processes that control vital functions such as arterial blood pressure and body temperature. There are specific neurotransmitters in each system that influence ganglionic and post-ganglionic function. The symptoms and signs of autonomic disease cover a wide spectrum that vary depending upon the aetiology. In some they are localised. Autonomic disease can result in underactivity or overactivity. Sympathetic adrenergic failure causes orthostatic (postural) hypotension and in the male ejaculatory failure, while sympathetic cholinergic failure results in anhidrosis; parasympathetic failure causes dilated pupils, a fixed heart rate, a sluggish urinary bladder, an atonic large bowel and, in the male, erectile failure. With autonomic hyperactivity, the reverse occurs. In some disorders, particularly in neurally mediated syncope, there may be a combination of effects, with bradycardia caused by parasympathetic activity and hypotension resulting from withdrawal of sympathetic activity. The history is of particular importance in the consideration and recognition of autonomic disease, and in separating dysfunction that may result from non-autonomic disorders.

Impact of diabetes on heart rate variability and left ventricular function in patients after myocardial infarction.
Viktor Stoickov, Stevan Ilic, Marina Deljanin Ilic, Aleksandar Nikolic, Vojislava Mitic
Medicine and Biology Vol.12, No 3, 2005, pp. 130 - 134

Impact of Reduced Heart Rate Variability on Risk for Cardiac Events
Hisako Tsuji, MD; Martin G. Larson, ScD; Ferdinand J. Venditti, Jr, MD; Emily S. Manders, BS; Jane C. Evans, MPH; Charles L. Feldman, ScD; Daniel Levy, MD
1996 American Heart Association, Inc.

Diabetes, Glucose, Insulin, and Heart Rate Variability
Emily B. Schroeder, Phd, Lloyd E. Chambless, Phd, Duanping Liao, Md, Phd, Ronald J. Prineas, Md, Phd, Gregory W. Evans, Ma, Wayne D. Rosamond, Phd, Gerardo Heiss, Md, Phd
Diabetes Care, Volume 28, Number 3, March 2005

Age and Ethnicity Differences in Short-Term Heart-Rate Variability
Jong-Bae Choi, Md, Suzi Hong, Phd, Richard Nelesen, Phd, Wayne A. Bardwell, Phd, Loki Natarajan, Phd, Christian Schubert, Md, And Joel E. Dimsdale, Md
Psychosomatic Medicine 68:421–426 (2006)

Heart rate variability in an ageing population and its association with lifestyle and cardiovascular risk factors: results of the SAPALDIA study
Denise Felber Dietrich, Christian Schindler1, Joel Schwartz, Jean-Claude Barthelemy, Jean-Marie Tschopp, Frederic Roche, Arnold von Eckardstein, Otto Brandli, Philipppe Leuenberger, Diane R. Gold, Jean-Michel Gaspoz, Ursula Ackermann-Liebrich
Europace (2006) 8, 521–529

Influence of Mental Stress on Heart Rate and Heart Rate Variability
J. Taelman, S. Vandeput, A. Spaepen and S. Van Huffel
ECIFMBE 2008, IFMBE Proceedings 22, pp. 1366–1369
Stress is a huge problem in today’s society. Being able to measure stress, therefore, may help to address this problem. Although stress has a psychological origin, it affects several physiological processes in the human body: increased muscle tension in the neck, change in concentration of several hormones and a change in heart rate (HR) and heart rate variability (HRV). The brain innervates the heart by means of stimuli via the Autonomic Nervous System (ANS), which is divided into sympathetic and parasympathetic branches. The sympathetic activity leads to an increase in HR (e.g. during sports exercise), while parasympathetic activity induces a lower HR (e.g. during sleep). The two circuits are constantly interacting and this interaction is reflected in HRV.
HRV, therefore, provides a measure to express the activity of the ANS, and may consequently provide a measure for stress. We therefore explored measures of HR and HRV with an imposed stressful situation. We recorded changes in HR and HRV in a group of 28 subjects at rest, and with a mental stressor. The results suggest that HR and HRV change with a mental task. HR and HRV recordings may have the potential, therefore, to measure stress levels and guide preventive measures to reduce stress related illnesses.

The Effects of Emotions on Short-Term Power Spectrum Analysis of Heart Rate Variability
Rollin McCraty, Mike Atkinson, William Tiller, Glen Rein, and Alan D. Watkins
The American Journal of Cardiology, Vol. 76, No. 14, November 15, 1995
This study utilizes heart rate variability analysis to examine a new method of intentionally shifting emotional states, and demonstrates that positive emotions lead to alterations in sympathovagal balance that may be beneficial in the treatment of hypertension. Anger, on the other hand, was shown to significantly increase sympathetic activation.

Association Between Major Depressive Disorder and Heart Rate Variability in the Netherlands Study of Depression and Anxiety (NESDA)
Carmilla M. M. Licht, MSc; Eco J. C. de Geus, PhD; Frans G. Zitman, MD, PhD; Witte J. G. Hoogendijk, MD, PhD; Richard van Dyck, MD, PhD; Brenda W. J. H. Penninx, PhD

The relationship between heart rate recovery and heart rate variability in coronary artery disease.
Evrengul H, Tanriverdi H, Kose S, Amasyali B, Kilic A, Celik T, Turhan H.
Ann Noninvasive Electrocardiol. 2006 Apr;11(2):154-62.
PMID:16630090 [PubMed - indexed for MEDLINE]
Reduced heart rate recovery (HRR) in coronary artery disease (CAD) is predictive of increased cardiovascular mortality and is related to reduced parasympathetic tonus.
To investigate HRR and heart rate variability (HRV) measured at steady state condition and the relationship between these two parameters in CAD.
In our study, we enrolled 33 (28 males, mean age 52.4 +/- 9.6 years) patients with CAD who did not have heart failure, atrial fibrillation, pacemaker, and any disease state that could affect the autonomic functions and 38 age-matched healthy subjects (21 males, mean age 48.3 +/- 7.8 years). All the patients underwent submaximal treadmill exercise testing (Bruce protocol). HRR was calculated by subtracting the heart rate values at the 1st, 2nd, and 3rd minutes of the recovery phase from the peak heart rate (HRR(1), HRR(2), HRR(3)). Before exercise testing, short-term steady state HRV analyses of all subjects were obtained with the time- and frequency-domain methods and were correlated to HRR. For frequency-domain analysis, low-frequency HRV (LF, 0.004-0.15 Hz), high-frequency HRV (HF, 0.15-0.5 Hz), and LF/HF ratio were measured for 5 minutes in the morning. For time-domain analysis, standard deviation of the normal-to-normal NN intervals (SDNN), square root of the mean squared differences of successive N-N intervals (RMSSD), and proportion derived by dividing the number of interval differences of successive N-N intervals greater than 50 ms by the total number of N-N intervals (pNN50) were obtained. Only HRR(3) was used for the correlation analysis.
In CAD groups, the HF, an indicator of parasympathetic activation, was significantly reduced, whereas the LF and LF/HF values, which are indicators of sympathetic activity, were increased (P = 0.0001 for each parameter). The time-domain parameters SDNN, RMSSD, and pNN50 were significantly reduced in the patient group (P = 0.0001, P = 0.009, and P = 0.0001, respectively). Similar to the HRV parameters, the HRR(1), HRR(2), and HRR(3) values were significantly reduced in the patient group (P = 0.0001 for each parameter). We observed a significant negative correlation between HRR(3) and LF (r =-0.67, P = 0.0001) and between HRR(3) and LF/HF (r =-0.62, P < 0.0001), while there was a significant positive correlation between HRR(3) and HF, SDNN, RMSSD, and pNN50 (r = 0.69, P = 0.0001; r = 0.41, P = 0.0001; r = 0.31, P = 0.008; and r = 0.44, P = 0.0001).
HRR and HRV are significantly reduced in CAD. The reduction in HRR is parallel to the changes in HRV parameters. HRR, which can be measured easily in the recovery phase of exercise testing, can be used to detect the depression of parasympathetic tonus and to evaluate the basal autonomic balance in this patient group.

Regular overtime and cardiovascular functions.
Park J, Kim Y, Cho Y, Woo KH, Chung HK, Iwasaki K, Oka T, Sasaki T, Hisanaga N.
Ind Health. 2001 Jul;39(3):244-9.
PMID: 11500000 [PubMed - indexed for MEDLINE]
It was concluded that there was sufficient evidence about a possible link between long working hours particularly exceeding 50 a week and the risk of significant health outcomes, including cardiovascular disease from literature review by Spurgeon et al.. This study was conducted to find out the single effect of regular overtime work on the cardiovascular functions through objective biological indices such as blood pressure or heart rate variability. We conducted a field survey of 238 male engineers who were working at the department of research & development of three electronics manufacturing companies in S. Korea. The field survey consisted of (1) self-report questionnaire (working hours and health conditions, and fatigue) and (2) measurements of blood pressure and heart rate variability. By multivariate analyses we could show the relationship between overtime work and some cardiovascular functions after controlling the effects of major confounders such as age and sleeping hours, which were pointed out by Iwasaki et al. (1998) and Sasaki et al. (1999). Especially, low frequency component (power in the low frequency range, 0.04-0.15 Hz) of the heart rate variability during work might be used as early objective biological indices for chronic effect of regular overtime work on cardiovascular functions. However, we should confirm those effect through the well-designed prospective study.

Decreased heart rate variability may predict the progression of carotid atherosclerosis in type 2 diabetes.
Gottsäter A, Ahlgren AR, Taimour S, Sundkvist G.
Clin Auton Res. 2006 Jun;16(3):228-34. Epub 2006 May 12.
PMID:16763752 [PubMed - indexed for MEDLINE]
Heart rate variability (HRV), a measure of autonomic function, can predict survival outcomes. Cardiovascular disease is a known complication of diabetes, and we aimed to determine if autonomic dysfunction was associated with carotid artery atherosclerotic plaques in type 2 diabetic patients. We assessed frequency domain HRV from power spectral analysis of 24 h Holter ECG recordings, expiration/inspiration (E/I) ratio during deep breathing, acceleration index (AI) of R-R interval in response to head-up tilt, and the degree of carotid artery atherosclerosis in 61 type-2 diabetic patients (39 males, 45-69 years). Studies were carried out 5-6 years after diagnosis (baseline) and repeated 8 years after diagnosis (follow-up). At baseline, patients diagnosed with autonomic neuropathy, with abnormal E/I ratio and abnormal AI measurements, had decreased low frequency (LF) HRV. Baseline E/I ratio correlated with day (r = 0.34; P < 0.001) and night-time (r = 0.44; P < 0.001) LF power. Night-time HRV did not differ in patient with and without autonomic neuropathy. Reduced common carotid artery diameter and atherosclerotic intima-media thickness (IMT) both correlated with HRV at baseline. At follow-up, all HRV variables decreased significantly. Furthermore, patients with lower LF power at baseline, had a larger increase in the thickness of the carotid bulb intima-media at follow-up. Our results show that LF HRV power is associated with the extent and progression of carotid atherosclerosis in type 2 diabetes. A low LF HRV may predict the progression of atherosclerosis in these patients.

Decrease heart rate variability but preserve postural blood pressure change in type 2 diabetes with microalbuminuria.
Chen HS, Wu TE, Jap TS, Lee SH, Wang ML, Lu RA, Chen RL, Lin HD.
J Chin Med Assoc. 2006 Jun;69(6):254-8.
PMID:16863010[PubMed - indexed for MEDLINE]
This study compares the cardiovascular autonomic function in type 2 diabetes with and without microalbuminuria, in order to identify the possible links between early nephropathy and diabetic autonomic neuropathy (DAN).
Cardiovascular reflex tests were performed to determine the cardiovascular autonomic function. Thirty cases of type 2 diabetes with microalbuminuria were studied for evidence of DAN to compare with a normoalbuminuric group of 56 diabetic patients.
There was an increased prevalence of autonomic dysfunction in patients with microalbuminuria (63.3% in the microalbuminuria group vs. 40.0% in the normoalbuminuric controls, p = 0.001). These patients had lower heart rate variability during single breathing tests (6.9 +/- 4.3 vs. 9.6 +/- 3.6 beats/minute, p = 0.005), during 6 consecutive breathings (5.8 +/- 3.6 vs. 8.2 +/- 3.3 beats/minute, p = 0.005), after standing up (12.2 +/- 4.6 vs. 15.0 +/- 5.2 beats/ minute, p = 0.012), and during the Valsalva maneuver (11.3 +/- 3.5 vs. 13.2 +/- 3.6 beats/minute, p = 0.022). The heart rate variability with these stresses was revealed to be less favorable in subjects with microalbuminuria. However, blood pressure (BP) changes from the sitting to standing position were not significantly different for systolic BP (11.5 +/- 10.7 vs. 10.7 +/- 7.8 mmHg, p = 0.741) and diastolic BP (5.2 +/- 4.4 vs. 5.9 +/- 4.0 mmHg, p = 0.451) between the 2 groups.
Type 2 diabetic patients with microalbuminuria have diminished heart rate variability in response to deep breathing, change of position and the Valsalva maneuver, but they preserve BP response to postural change. Therefore, microalbuminuria seems to be associated with early DAN, but not with advanced DAN.

Heart rate variability in diabetes patients.
Kudat H, Akkaya V, Sozen AB, Salman S, Demirel S, Ozcan M, Atilgan D, Yilmaz MT, Guven O.
J Int Med Res. 2006 May-Jun;34(3):291-6.
PMID: 16866023 [PubMed - indexed for MEDLINE]
Diabetes mellitus can cause cardiovascular autonomic neuropathy and is associated with increased cardiovascular deaths. We investigated cardiovascular autonomic neuropathy in diabetics and healthy controls by analysis of heart rate variability. Thirty-one diabetics and 30 age- and sex-matched controls were included. In the time domain we measured the mean R - R interval (NN), the standard deviation of the R - R interval index (SDNN), the standard deviation of the 5-min R - R interval mean (SDANN), the root mean square of successive R - R interval differences (RMSSD) and the percentage of beats with a consecutive R - R interval difference > 50 ms (pNN50). In the frequency domain we measured high-frequency power (HF), low-frequency power (LF) and the LF/HF ratio. Diabetes patients had lower values for time-domain and frequency-domain parameters than controls. Most heart rate variability parameters were lower in diabetes patients with chronic complications than in those without chronic complications.

Circadian rhythm of the autonomic nervous system in insulin resistant subjects with normoglycemia, impaired fasting glycemia, impaired glucose tolerance, type 2 diabetes mellitus.
Perciaccante A, Fiorentini A, Paris A, Serra P, Tubani L.
BMC Cardiovasc Disord. 2006 May 2;6:19.
PMID: 16670002 [PubMed - indexed for MEDLINE]
In type 2 diabetes mellitus both insulin resistance and hyperglycemia are considered responsible for autonomic dysfunction. The relation between the autonomic activity, impaired fasting glycemia and impaired glucose tolerance is, however, unclear. The purpose of this study was to evaluate and compare the circadian autonomic activity expressed as heart rate variability (HRV) measured by 24-hours ECG recording in insulin resistant subjects (IR) with characteristics as follow: IR subjects with normal oral glucose tolerance test results, IR subjects with impaired fasting glucose, IR subjects with impaired glucose tolerance and subjects with type 2 diabetes mellitus.
Eighty Caucasian insulin resistant subjects (IR) and twenty five control subjects were recruited for the study. IR subjects were divided into four groups according to the outcoming results of oral glucose tests (OGTTs): IR subjects with normal glucose regulation (NGR), IR subjects with impaired fasting glycemia (IFG), IR subjects with impaired glucose tolerance (IGT) and subjects with type 2 diabetes mellitus (DM). Autonomic nervous activity was studied by 24-hours ECG recording. Heart rate variability analysis was performed in time and frequency domains: SDNN, RMS-SD, low frequency (LF) and high frequency (HF) were calculated.
The total SDNN showed statistically significant reduction in all four groups with insulin resistant subjects (IR) when compared to the control group (p <0,001). During night LF normalized units (n.u.) were found to be higher in all four groups including IR subjects than in the control group (all p < 0,001) and subjects with normal glucose regulation (NGR), with impaired fasting glycemia (IFG) and with impaired glucose tolerance (IGT) were found to have higher LF n.u. than those in the type 2 diabetes mellitus group. The linear regression model demonstrated direct association between LF values and the homeostasis model assessment-index (HOMA-I), in the insulin resistant group (r = 0,715, p <0,0001).
The results of our study suggest that insulin resistance might cause global autonomic dysfunction which increases along with worsening glucose metabolic impairment. The analysis of sympathetic and parasympathetic components and the sympathovagal balance demonstrated an association between insulin resistance and sympathetic over-activity, especially during night. The results indicated that the sympathetic over-activity is directly correlated to the grade of insulin resistance calculated according to the HOMA-I. Since increased sympathetic activity is related to major cardiovascular accidents, early diagnosis of all insulin resistant patients should be contemplated.

Effect of hyperbaric oxygen on cardiac neural regulation in diabetic individuals with foot complications.
Sun TB, Yang CC, Kuo TB.
Diabet Med. 2006 Apr;23(4):360-6.
PMID: 16620263 [PubMed - indexed for MEDLINE]
There are relatively few effective methods to treat autonomic neuropathy in patients with diabetes mellitus. Our aim was to test the hypothesis that hyperbaric oxygen therapy may restore cardiac neural regulation dysfunction in diabetic individuals with foot complications.
We conducted a prospective randomized controlled study in patients with diabetic foot problems. Daily heart-rate variability analysis from 5-min electrocardiography was used to evaluate the temporal change of cardiac neural regulation. The experimental group consisted of 23 subjects exposed to hyperbaric oxygen therapy of 202.65 kPa for 90 min every Monday to Friday for 4 weeks (20 treatments). The control group consisted of 15 age-, sex- and disease-matched subjects who were not exposed to hyperbaric therapy. Patients with medical complications and failure of wound healing were excluded to eliminate possible confounding effects.
There was no significant difference in baseline R-R interval (RR), variance, high-frequency power (HF), low-frequency power (LF), and LF/HF ratio between the two groups. In the hyperbaric oxygen group there were significant increases in changes of RR (82.7 +/- 16.02 ms); variance 0.88 +/- 0.12 ln(ms2); HF 1.06 +/- 0.18 ln(ms2); and LF 0.87 +/- 0.15 ln(ms2) after the treatment. Measurements of tissue oxygen demonstrated significant increases in local tissue oxygenation in the hyperbaric oxygen group (53.0 +/- 2.6 mmHg) compared with the control group (27.5 +/- 3.1 mmHg), P < 0.05.
Hyperbaric oxygen therapy has a significant vagotonic effect, which is beneficial in improving cardiac neural regulation in patients with diabetic autonomic dysfunction.

Differences in heart rate variability in non-hypertensive diabetic patients correlate with the presence of underlying cerebrovascular disease.
Nagata K, Sasaki E, Goda K, Yamamoto N, Sugino M, Yamamoto K, Narabayashi I, Hanafusa T.
Clin Physiol Funct Imaging. 2006 Mar;26(2):92-8.
PMID: 16494599 [PubMed - indexed for MEDLINE]
We previously showed that diabetes contributes to the development of sclerotic lesions in cerebral arteries. In this study, we attempted to clarify whether differences in heart rate variability in non-hypertensive diabetic patients were dependent on the presence or absence of underlying cerebrovascular disease. Thirty diabetic subjects between 40 and 59 years of age and who had no prior history of hypertension were used in this study. Lacunar lesions (LA) were detected with magnetic resonance imaging and atherosclerotic lesions (AS) were detected using intra- and extracranial magnetic resonance angiography, and by ultrasonographic scanning of the carotid artery. Patients underwent a full clinical laboratory screening and a power spectrum analysis of their heart rate variability. Subjects were divided into two groups: those with and without LA. The low frequency/high frequency ratio (LF/HF ratio) was found to be significantly increased (P<0.01) in subjects with LA (2.2 +/- 0.3) compared to those without LA (1.3 +/- 0.1). When subjects were divided into groups based on their presence or absence of AS, high-frequency power was found to be significantly reduced (P<0.05) in the subjects with AS (12.8 +/- 3.4 ms) compared to those without AS (19.4 +/- 1.7 ms). The LF/HF ratio was found to be significantly increased (P<0.05) in the subjects with AS (2.2 +/- 0.3) compared to those without AS (1.4 +/- 0.1). Our data suggested that atherosclerotic lesions in cerebrovascular diseased linked to decrease of vagal nerve activity in non-hypertensive diabetic patients.

Cardiac autonomic neuropathy predicts cardiovascular morbidity and mortality in type 1 diabetic patients with diabetic nephropathy.
Astrup AS, Tarnow L, Rossing P, Hansen BV, Hilsted J, Parving HH.
Diabetes Care. 2006 Feb;29(2):334-9.
PMID: 16443883 [PubMed - indexed for MEDLINE]
Cardiac autonomic neuropathy (CAN) has been associated with a poor prognosis in patients with diabetes. Because CAN is common in patients with diabetic nephropathy, we evaluated the predictive value of CAN in type 1 diabetic patients with and without diabetic nephropathy.
In a prospective observational follow-up study, 197 type 1 diabetic patients with diabetic nephropathy and a matched group of 191 patients with long-standing type 1 diabetes and normoalbuminuria were followed for 10.1 years (range 0.0-10.3 years). At baseline, CAN was assessed by heart rate variation (HRV) during deep breathing. HRV was evaluated as a predictor of the primary end point: cardiovascular morbidity and mortality. As secondary end points, all-cause mortality and the influence of HRV on progression of diabetic nephropathy (decline in glomerular filtration rate [GFR]) was evaluated.
During the follow-up, 79 patients (40%) with nephropathy reached the combined primary end point vs. 19 patients (10%) with normoalbuminuria (log-rank test, P < 0.0001). The unadjusted hazard ratio (HR) for reaching the primary end point when having an abnormal HRV (< or =10 bpm) measured at baseline compared with a normal HRV was 7.7 (range 1.9-31.5; P = 0.004) in patients with nephropathy. Similarly in the normoalbuminuric patients, the unadjusted HR was 4.4 (1.4-13.6; P = 0.009). In patients with nephropathy, abnormal HRV was significantly associated with fatal and nonfatal cardiovascular disease after adjustment for cardiovascular risk factors. The adjusted HR for reaching the primary end point in a patient with nephropathy and an abnormal HRV was 6.4 (1.5-26.3, P = 0.010), as compared with a normal HRV. The unadjusted HR for dying when having an abnormal HRV compared with a normal HRV was 3.3 (95% CI 1.0-10.7; P = 0.043) in patients with diabetic nephropathy. After adjustment for confounding factors, the impact of HRV on all-cause mortality in patients with nephropathy was no longer significant (P = 0.293). There was no relationship between abnormal HRV and rate of decline in GFR.
HRV is an independent risk factor for cardiovascular morbidity and mortality in type 1 diabetic patients with nephropathy.

Heart rate variability and circadian variations in type 1 diabetes mellitus.
Kardelen F, Akçurin G, Ertug H, Akcurin S, Bircan I.
Pediatr Diabetes. 2006 Feb;7(1):45-50.
PMID:16489974 [PubMed - indexed for MEDLINE]
Diabetic autonomic neuropathy (DAN) commonly complicates diabetes and is associated with increased mortality rates over 5 yr. This fact denotes the significance of DAN prevention, mainly with effective glycemic control. However, total prevention of autonomic neuropathy in diabetic patients is not achievable. Thus, the timely detection of DAN and the use of effective means to improve autonomic nervous system function or slow down its progression become of utmost significance. Heart rate variability (HRV) is a technique that measures the beat-to-beat variability in RR intervals, which reflects changes in autonomic activity and their impact on cardiovascular function. Circadian variation in time and frequency domains of heart variability has been shown to correlate with circadian rhythm of ambulatory ischemia and suggests that relative changes in vagal and sympathetic tone at different times during the day may have a direct relationship to the severity of clinical events. Forty-seven (21 boys and 26 girls) type I insulin-dependent diabetics and 46 control subjects (19 boys and 27 girls) were included in the study. Our investigation demonstrated that overall HRV is markedly depressed in diabetes mellitus (DM). All time domain parameters except standard deviation of all 5-min mean RR intervals and all frequency domain indices maintain significant circadian variation. These changes in overall HRV and HRV circadian rhythms reflect significant reductions in cardiac parasympathetic activity and, possibly, increased sympathetic tone.

Relationships between heart rate variability and urinary albumin excretion in patients with type 2 diabetes.
Takebayashi K, Matsutomo R, Matsumoto S, Suetsugu M, Wakabayashi S, Aso Y, Inukai T.
Am J Med Sci. 2006 Feb;331(2):72-8.
PMID: 16479178 [PubMed - indexed for MEDLINE]
Although in type 1 diabetes the close association between heart rate variability and urinary albumin excretion (UAE) is recognized even in patients with normoalbuminuria, this association has not yet been fully established in patients with type 2 diabetes. Therefore, we investigated the association in patients with type 2 diabetes.
All the hospital's 185 inpatients with type 2 diabetes were prospectively enrolled. Heart rate variability was evaluated by coefficients of variance of RR intervals (CVRR).
The mean age, duration of diabetes, and hemoglobin A1C of the patients were 59.7+/-9.9 years, 10.4+/-7.8 years, and 9.7+/-2.3%, respectively. An analysis of the patients showed a significant negative correlation between CVRR and log10-transformed (log) UAE (R=-0.3340, P <0.0001). CVRR showed a significant negative correlation with age, duration of diabetes, hemoglobin AIC, systolic blood pressure, diastolic blood pressure, and triglyceride level. Log UAE showed a significant positive correlation with body mass index, hemoglobin A1C, systolic blood pressure, diastolic blood pressure, total cholesterol, and triglyceride level. In the macroalbuminuric group (UAE above 300 mg/g creatinine; n=57), although CVRR showed a significant negative correlation with log UAE (R=-0.3571, P= 0.0064), but in normoalbuminuric (UAE below 30 mg/g Cr; n=79) and in microalbuminuric groups (30 to 300 mg/g Cr; n = 49), CVRR and log UAE showed no correlation.
Our data suggest that in type 2 diabetes, the association between CVRR and UAE is significant only in patients with macroalbuminuria.

Comparison of fast Fourier transform and autoregressive spectral analysis for the study of heart rate variability in diabetic patients.
Chemla D, Young J, Badilini F, Maison-Blanche P, Affres H, Lecarpentier Y, Chanson P.
Int J Cardiol. 2005 Oct 10;104(3):307-13.
PMID: 16186061 [PubMed - indexed for MEDLINE]
Impaired heart rate variability (HRV) is associated with poor outcome in diabetic patients. The present prospective study compared spectral components of HRV obtained by either fast Fourier transform (FFT) or autoregressive (AR) analyses in diabetic patients.
Thirty patients (49+/-12 years; 11 F/19 M; 60% with insulin-dependent type 1 diabetes) underwent 24-h ambulatory electrocardiographic recordings which comprised a 10-min resting period at the onset (n=30) and end (n=12) of the monitoring. Spectral analysis was applied to 5-min sequences at rest, and the total power and power spectra integrated over the very low (VLF), low (LF), and high (HF) frequency bands were obtained.
Fifteen patients had moderately depressed HRV and two patients had highly depressed HRV (standard deviation of the RR intervals over 24-h<100 ms and <50 ms, respectively). Both raw data and ln-transformed data were significantly different between FFT and AR. All spectra component were obtained in each patient using FFT. Using AR, the LF/HF ratio could not be estimated or was zero in 4 and 11 patients, respectively. The AR results were more sensitive than FFT results to minor changes (+/-5%) in the timing of the onset of analysis. The day-to-day reproducibility of FFT was better than that of AR. Finally, using FFT, the LF/HF ratio, LFnu, and HFnu were essentially redundant (nu=normalized units).
The spectral components of short-term HRV calculated by using the FFT and AR methods were not interchangeable and FFT analysis must be preferred in diabetic patients.

Parasympathetic versus sympathetic control of the cardiovascular system in young patients with type 1 diabetes mellitus.
Javorka M, Javorkova J, Tonhajzerova I, Javorka K.
Clin Physiol Funct Imaging. 2005 Sep;25(5):270-4.
PMID: 16117729 [PubMed - indexed for MEDLINE]
Autonomic neuropathy and cardiovascular dysregulation are common complications of the diabetes mellitus (DM). The aim of the study was to test the hypothesis that cardiovascular regulation is abnormal in young patients with type 1 DM. Patients with type 1 DM (17, 10 females, 7 males) aged 12.9-31.5 years (mean+/-SEM: 22.4+/-1.0 years) were investigated. The mean duration of DM was 12.4+/-1.2 years. The control group consisted of 17 healthy probands matched for sex and age. The length of R-R intervals was measured using telemetric system (VariaCardio TF4; Sima Media) where ECG signal (sampling frequency 1000 Hz) from thoracic belt was transferred into PC for further analysis. Systolic blood pressure (SBP) was monitored beat-to-beat using volume-clamp method by Finapres 2300 (Ohmeda). Spectral power in HF band of HRV (HRV-HF) was taken as an index of parasympathetic control and spectral power in LF band of systolic BPV (BPV-LF) as an index of sympathetic control. In young patients with type 1 DM significant reduction of spectral power in HF band of the heart rate variability was found, whereas no significant difference between DM group and control group was observed in spectral power in LF band of blood pressure variability. In conclusion, we found impaired parasympathetic control of heart rate in young patients with type 1 DM. No differences in blood vessels sympathetic control were detected using spectral analysis of BPV. We suggest that abnormalities in cardiac parasympathetic regulation precede impairment of blood vessels sympathetic control in young diabetics.

Role of heart rate variability in the early diagnosis of diabetic autonomic neuropathy in children.
Chessa M, Butera G, Lanza GA, Bossone E, Delogu A, De Rosa G, Marietti G, Rosti L, Carminati M.
Herz. 2002 Dec;27(8):785-90.
PMID: 12574897 [PubMed - indexed for MEDLINE]
Diabetic autonomic neuropathy (DAN) is a major complication of diabetes. DAN has been shown to be closely related to glycemic control. To contribute significantly to the morbidity and mortality of the disease, and to be indicative of an increased risk of cardiovascular events. Tests assessing the function of the autonomic nervous system, such as the response of heart rate and blood pressure to maneuvers stimulating the autonomic nervous system, including deep breathing. Valsalva maneuver and standing, allowed to detect signs of DAN in adolescents; however, the sensitivity of such tests in revealing an early impairment of the autonomic nervous system proved low. Several studies found heart rate variability (HRV) to be useful in assessing the dysfunction of the autonomic nervous system in diabetic children and adolescents, but only few HRV parameters were evaluated in most of them.
To study cardiac autonomic nervous system in diabetic children, and to investigate whether the duration of diabetes and the degree of metabolic control are determinants for the development of DAN in children.
We analyzed HRV in 50 asymptomatic patients with insulin-dependent diabetes mellitus (IDDM) and 30 healthy children matched for age and sex.
Patients with a history of diabetes > 8 years showed significant alterations of the autonomic nervous system (significant reduction of r-MSSD, pNN50, HF and increase in LF/HF). Conversely, only a reduction in pNN50 was found in patients with a disease duration < 8 years. Furthermore, we also observed significant HRV abnormalities in patients with an impaired metabolic control of diabetes. Compared to controls, patients with glycosylated hemoglobin blood levels (HbA(1C)) > 8% showed a significant reduction of r-MSSD, pHH50 and total power spectrum, whereas no HRV abnormalities were detected in patients with an HbA(1C) < 8%.
HRV analysis can detect early subclinical alterations of the autonomic nervous system in asymptomatic patients with IDDM, which seem to consist mainly in a parasympathetic impairment. Autonomic dysfunction is associated both with the duration and an inadequate metabolic control of the disease.

Heart rate variability analysis: a useful assessment tool for diabetes associated cardiac dysfunction in rural and remote areas.
Flynn AC, Jelinek HF, Smith M.
Aust J Rural Health. 2005 Apr;13(2):77-82.
PMID: 15804330 [PubMed - indexed for MEDLINE]
Cardiovascular complications are the main cause of death in people with diabetes. Early, asymptomatic changes are due to autonomic nervous system dysfunction, which if identified can lead to improved health. This study used detrended fluctuation analysis to identify changes in heart rate variability (HRV) associated with short-time electrocardiograph (ECG) recordings. The aim of the study was to determine whether heart rate variability analysis on short ECG recordings has the potential to be a useful adjunct to clinical practice.
Comparative design with three independent simple random samples.
University-based research project.
Forty-eight people with no diabetes or cardiovascular complications had a 20 min ECG recorded, which was subsequently analysed using mathematical procedures. All participants also had a lying-to-standing autonomic nervous system test. Data was analysed using a Student t-test.
Heart rate variability expressed as a numeric value (alpha(1)), is reduced in disease states. We found a significant difference in alpha(1)(P = 0.03) between the ECG recordings of the diabetes and control groups. In addition lower alpha(1)values were obtained from people identified with autonomic dysfunction within the diabetes group.
The importance of our findings is that abnormal HRV identifies people with cardiovascular disease, irrespective of diabetes status, that may have autonomic neuropathy. HRV analysis is easily implemented by primary health care providers and has the potential to lead to improved health care by reducing inequity in rural areas and specifically addressing cardiovascular complications associated with diabetes.

Cross-spectral analysis of cardiovascular variables in supine diabetic patients.
Gulli G, Fattor B, Marchesi M.
Clin Auton Res. 2005 Apr;15(2):92-8.
PMID:15834765 [PubMed - indexed for MEDLINE]
Cardiovascular autonomic neuropathy in diabetes is associated with a high risk of mortality, which makes its early identification clinically important. An easy method for identification of subjects with autonomic dysfunction would be of clinical benefit. We evaluated the autonomic function in 28 diabetic patients and 21 control subjects recording 12 min time series of heart period (RR) and systolic arterial pressure (SAP, Finapres) during supine rest and 60 degrees head-up tilt. The power of the high (respiratory) and low (LF approximately 0.1 Hz) frequency oscillations was quantified by spectral analysis. The central frequency of the LF oscillations (LF_freq), phase shift, and the transfer function gain between RR interval and SAP fluctuations were provided by cross-spectral analysis, and measured at the point of maximal coherence. In the supine position 15 patients (LF-) displayed atypical LF variability with the LF_freq being shifted towards lower frequencies (about 0.06 Hz). They also showed larger phase angle, lower values or even absence of coherence and smaller transfer function gain between RR and SAP fluctuations. 13 patients (LF+) and the controls showed the LF_freq around 0.1 Hz, higher coherence and transfer function gain values. The orthostatic maneuver induced the expected changes in the spectral parameters (increase in the LF components of both RR and SAP and decrease in the HF variability of RR) into the LF+ patients and all the control subjects and abnormal response in the other 15 LF-patients. These findings indicate that diabetic subjects with uncharacteristic response to the orthostatic test present abnormal LF variability already in the supine position. Crossspectral parameters while supine may be used for the identification of these subjects.

Analysis of the chaotic component of the sinusal R-R intervals as a tool for detecting a silent cardiac dysautonomia in type 2 diabetes mellitus.
Curione M, Cugini P, Cammarota C, Bernardini F, Cipriani D, De Rosa R, Francia P, Colotto M, Napoli A, Fallucca F.
Clin Ter. 2005 Jul-Aug;156(4):151-8.
PMID: 16342516 [PubMed - indexed for MEDLINE]
This study explores the heart rate (HR) variability (V) in order to detect whether the chaotic component of the sinusal R-R intervals (SRRI) can be interpreted as an early indicator of a silent cardiac neurovegetative dysautonomia in apparently uncomplicated Type 2 diabetic patients (DP). The SRRI were provided by the 24-h Holter ECG of 10 Type 2 DP (5 M and 5 F, mean age = 41 +/- 5 years). Control data were obtained by the 24-h Holter ECG of 10 clinically healthy subjects (CHS, 5 M and 5 F, mean age = 38 +/- 6 years). The chaotic component of HRV was investigated via the correlation dimension (CD) analysis (A) of the SRRI, performed per each hour of the ECG recording. The hourly-qualified series of SRRI, HR and CD index (I) were, in turn, analyzed via methods of conventional statistics and chronobiology, the latter ones for assessing the circadian rhythm (CR). The CDI CR was found to peak during the night in CHS, and to be unphysiologically rotated to the diurnal hours of the day in Type 2 DP. The diurnal inversion of the CDI CR in Type 2 DP suggests that the chaotic component of HRV shows an abnormal rhythnic pattern over the day-night period. Considering that the investigated Type 2 DP were lacking of documentable signs of cardiac neuropathy, it is hypothesized that the diurnal phase of shift CDI CR might be a potential indicator of a silent autonomic cardiac dysfunction in Type 2 DP. Such a hypothesis waits for further confirmations.

Heart rate variability and myocardial infarction: systematic literature review and metanalysis.
Buccelletti E, Gilardi E, Scaini E, Galiuto L, Persiani R, Biondi A, Basile F, Silveri NG.
Eur Rev Med Pharmacol Sci. 2009 Jul-Aug;13(4):299-307.
PMID: 19694345 [PubMed - indexed for MEDLINE]
Heart rate, measured as beat-to-beat intervals, is not constant and varies in time. This property is known as heart rate variability (HRV) and it has been investigated in several diseases, including myocardial infarction (MI). The main hypothesis is that HRV embed some physiological processes that are characteristics of regulatory systems acting on cardiovascular system. It is possible to quantify such a complex behaviour starting from RR intervals properties itself with the idea that any event affecting the cardiac regulatory system significantly will disrupt and change HRV. In this article, we first review different methodologies previously published to calculate HRV indexes. We then searched literature for studies published on HRV and MI and we derive a metanalysis where published data allow calculation of composite outcomes.
Articles considered eligible for metanalysis were original retrospective/prospective studies investigating HRV after myocardial infarction, reporting follow up for mortality or significant cardiac complications. Random effect model was used to assessed for homogeneity and calculate composite outcome and its 95% confidence interval (CI).
21 studies were identified as eligible for subsequent analysis. Among these studies 5 large trials were eligible for metanalysis: "they included 3489 total post-MI patient with an overall mortality of 125/577 (21.7%) in patients with standard deviation of RR intervals (SDNN) less than 70 msec compared to 235/2912 (8.1%) in patients with SDNN > 70 msec". Metanalysis demonstrates that, after a MI, patients with SDNN below 70 msec on 24 hours ECG recording have almost 4 times more chance to die in the next 3 years.
Results from metanalysis and other studies considered (but not included in the analysis) are consistent with the final finding, that a disrupted HRV dynamic (low SDNN) is associated with higher adverse outcome. In this perspective, although data are strongly positive for a direct relationship between SDNN and mortality after MI, SDNN value must be considered carefully on a single patient. The primary purpose of the metanalysis was to address whether studies conducted on HRV and MI were consistent rather than established a cut-off for SDNN. HRV is simple, non invasive and relatively not expensive to obtain.

Ultra-short-term heart rate variability for early risk stratification following acute ST-elevation myocardial infarction.
Karp E, Shiyovich A, Zahger D, Gilutz H, Grosbard A, Katz A.
Cardiology. 2009;114(4):275-83. Epub 2009 Aug 18.
PMID: 19690410 [PubMed - indexed for MEDLINE]
To evaluate the prognostic significance of early ultra-short-term heart rate variability (HRV) measurement in patients admitted for ST-elevation myocardial infarction (STEMI).
HRV was calculated retrospectively from the standard admission and discharge 10-second ECG of 196 consecutive patients with STEMI. Reduced HRV was defined as standard deviation of N-N intervals (SDNN) <9.5 (25th percentile). Data regarding all end points were obtained 2 years after discharge for all patients.
Patients' age was 60.9 +/- 13 years and 21% were female. Admission SDNN was lower than discharge SDNN (20.2 +/- 18 vs. 34.2 +/- 31.1, respectively; p = 0.001). Admission and discharge SDNN positively correlated with survival (r = 0.16, p = 0.03 and r = 0.15, p = 0.04, respectively), but were not predictive of other cardiovascular end points. Reduced admission SDNN was associated with increased mortality at 1 and 6 months, and 1 and 2 years after admission, while discharge SDNN was associated only with 1- and 2-year mortality. Using multivariate analysis, adjusted for potential confounders, admission SDNN <9.5 was found to be an independent risk factor for 2-year mortality (odds ratio = 2.9, 95% confidence interval = 1.12-7.56; p = 0.028).
Reduced HRV, recorded from admission and discharge ECG, appears to be a significant and independent predictor of all-cause mortality in patients with STEMI.

Influence of autonomic nervous dysfunction characterizing effect of diabetes mellitus on heart rate response and exercise capacity in patients undergoing cardiac rehabilitation for acute myocardial infarction.
Kasahara Y, Izawa K, Omiya K, Osada N, Watanabe S, Saitoh M, Matsunaga A, Masuda T.
Circ J. 2006 Aug;70(8):1017-25.
PMID:16864935 [PubMed - indexed for MEDLINE]
The aim of this study was to clarify the influence of sympathetic and parasympathetic nerve (SN and PN) dysfunction on the heart rate (HR) response to exercise and the exercise capacity of patients with acute myocardial infarction (AMI) and diabetes mellitus (DM).
Fifty-two male patients who underwent cardiopulmonary exercise testing (CPX) 1 month after onset of AMI were divided into 2 groups: (DM (+) group, n=20; DM (-) group, n=32). HR, peak oxygen uptake (VO2peak), and plasma norepinephrine (NE) levels were measured during CPX. The high-frequency power (HF) was analyzed by HR variability. The DeltaHR/logDeltaNE obtained from changes of HR and NE from rest to peak exercise and HR change from baseline to the minimum HF (DeltaHRHF) were calculated as parameters of HR response derived from SN and PN activities, respectively. DeltaHR, VO2peak, DeltaHR/logDeltaNE, and DeltaHRHF were significantly lower in the DM (+) group than in the DM (-) group, and both of them showed positive correlations with VO2peak.
An inadequate HR response to exercise is a major factor causing a decline of exercise capacity, which is derived from both of SN and PN dysfunction, in AMI patients with DM.

Identifying illness parameters in fatiguing syndromes using classical projection methods.
Broderick G, Craddock RC, Whistler T, Taylor R, Klimas N, Unger ER.
PMID: 16610951 [PubMed - indexed for MEDLINE]
To examine the potential of multivariate projection methods in identifying common patterns of change in clinical and gene expression data that capture the illness state of subjects with unexplained fatigue and nonfatigued control participants.
Data for 111 female subjects was examined. A total of 59 indicators, including multidimensional fatigue inventory (MFI), medical outcome Short Form 36 (SF-36), Centers for Disease Control and Prevention (CDC) symptom inventory and cognitive response described illness. Partial least squares (PLS) was used to construct two feature spaces: one describing the symptom space from gene expression in peripheral blood mononuclear cells (PBMC) and one based on 117 clinical variables. Multiplicative scatter correction followed by quantile normalization was applied for trend removal and range adjustment of microarray data. Microarray quality was assessed using mean Pearson correlation between samples. Benjamini-Hochberg multiple testing criteria served to identify significantly expressed probes.
A single common trend in 59 symptom constructs isolates of nonfatigued subjects from the overall group. This segregation is supported by two co-regulation patterns representing 10% of the overall microarray variation. Of the 39 principal contributors, the 17 probes annotated related to basic cellular processes involved in cell signaling, ion transport and immune system function. The single most influential gene was sestrin 1 (SESN1), supporting recent evidence of oxidative stress involvement in chronic fatigue syndrome (CFS). Dominant variables in the clinical feature space described heart rate variability (HRV) during sleep. Potassium and free thyroxine (T4) also figure prominently.
Combining multiple symptom, gene or clinical variables into composite features provides better discrimination of the illness state than even the most influential variable used alone. Although the exact mechanism is unclear, results suggest a common link between oxidative stress, immune system dysfunction and potassium imbalance in CFS patients leading to impaired sympatho-vagal balance strongly reflected in abnormal HRV.

Reduced heart rate variability and baroreflex sensitivity in primary biliary cirrhosis.
Newton JL, Allen J, Kerr S, Jones DE.
Liver Int. 2006 Mar;26(2):197-202.
PMID: 16448458 [PubMed - indexed for MEDLINE]
Standardized mortality ratio for primary biliary cirrhosis (PBC) is 2.87. Even after accounting for liver and cancer-related deaths there is an unexplained excess mortality associated with PBC. We have assessed heart rate variability (HRV) and baroreflex sensitivity (BRS) risk factors associated with cardiovascular mortality, in 57 PBC patients and age- and sex-matched normal controls.
HRV and BRS were measured non-invasively in subjects and controls. Beat to beat RR interval and 'Portapres' blood pressure data were processed using power spectral analysis. Power was calculated in very low frequency (VLF), low-frequency (LF) and high-frequency (HF) bands according to international guidelines. BRS (alpha) was computed using cross-spectrum analysis. Patients also underwent fatigue severity assessment using a measure validated for use in PBC.
PBC patients had significantly lower total HRV compared with controls (P=0.02), with the reduction occurring predominantly in the LF domain (P=0.03). BRS was also significantly reduced compared with controls (P=0.02). There were no significant differences in HRV or BRS between cirrhotic and non-cirrhotic patients. Within the PBC patient group HRV was significantly lower in fatigued than in non-fatigued patients (P<0.05).
Abnormalities of HRV and BRS in PBC are not specific to advanced disease but are associated with fatigue severity. Abnormalities could be associated with increased risk of sudden cardiac death, potentially contributing to the excess mortality seen in PBC.
Autonomic nervous activity changes in relation to the reporting of subjective symptoms among male workers in an information service company.
Karita K, Nakao M, Nishikitani M, Nomura K, Yano E.
Int Arch Occup Environ Health. 2006 May;79(5):441-4. Epub 2005 Dec 7.
PMID: 16333680 [PubMed - indexed for MEDLINE]
The objective of the study was to clarify the relationship between major subjective symptoms and autonomic nervous system function by power spectral analysis of heart rate variability (HRV).
Short-term HRV was examined for 413 male workers in a Japanese information service company aged 19-45 years, and questionnaire survey on subjective symptoms and biochemical measurements were conducted at annual health checkup.
The most prevalent subjective symptom (> or =10%) was dullness, followed by fatigue, backache, diarrhea, sleep disorder, and irritation. HRV in high frequency (HF 0.15-0.40 Hz) bands and the coefficient of variance in the electrocardiographic R-R interval (CVrr) were lower in the subjects with any of these six symptoms than in those without the symptoms. Both parameters were negatively associated with the reporting of any of the six symptoms by multiple regression analyses, controlling for the significant effects of age (HF and CVrr) and plasma cortisol levels (HF).
It was suggested that the reporting of the subjective symptoms is one of good predictors for reduced parasympathetic tones.

[Synthetic effect analysis of heart rate variability and blood pressure variability on driving mental fatigue].
[Article in Chinese]
Jiao K, Li Z, Chen M, Wang C.
Sheng Wu Yi Xue Gong Cheng Xue Za Zhi. 2005 Apr;22(2):343-6.
PMID: 15884550 [PubMed - indexed for MEDLINE]
Driving mental fatigue is a substantial problem and threatens people's health and life. This investigation was made to evaluate the driving mental fatigue based on power spectral analysis of heart rate variability (HRV) and blood pressure variability (BPV) synthetically. Twenty health male subjects (28.8 +/- 4.3 years) were required to perform the simulated driving for 90 min. The frequency domain indices of HRV such as low frequency (0.04-0.15 Hz, LF), high frequency (0.15-0.4 Hz, HF), LF/HF together with the indices of hemodynamics such as blood pressure (BP) and heart rate (HR) of the subjects were calculated and anlyzed after the simulated driving. The results showed that sympathetic activity of the subjects enhanced after the simulated driving while parasympathetic activities decreased. The sympathovagal balance was also improved. Remarkable linear correlations were observed between all the corresponding indices of HRV and BPV (P<0.05). The findings suggested that the evaluation of autonomic activities by means of multi-variable synthetic effect analysis is scientific and objective.

Depression in patients with acute myocardial infarction: influence on autonomic nervous system and prognostic role. Results of a five-year follow-up study.
Drago S, Bergerone S, Anselmino M, Varalda PG, Cascio B, Palumbo L, Angelini G, Trevi PG.
Int J Cardiol. 2007 Jan 31;115(1):46-51. Epub 2006 Jun 22.
PMID:16797746 [PubMed - indexed for MEDLINE]
Although previous studies demonstrated an association between depressive symptoms and cardiac mortality after acute myocardial infarction (AMI) little is known about the possible mechanisms of this association. The aim of this study was to determine whether depressed patients present a cardiac autonomic dysfunction and whether this could represent the mediator of the influence of depression on their prognosis.
One hundred consecutive patients with AMI were recruited between January and December 1999. Major Depressive Disorder (MDD) was diagnosed by structured clinical interview and the presence of symptoms of depression was evaluated with self-administered Beck Depression Inventory (BDI). The influence of depression on autonomic nervous system was investigated measuring heart rate variability (HRV) and heart rate (HR) during 24-hour electrocardiographic monitoring. The end-points of the study were all-cause mortality, recurrent-AMI, revascularization and a composite end-point of all the previous. Potential confounders for depression status and events were entered into a multivariate regression model.
Fifteen patients met the criteria for MDD and 35 patients showed mild-to-moderate symptoms of depression; women had a higher prevalence of depression than men (35% vs 9%; p<0.01). Depression was not related to the severity of ischaemic disease or to other clinical and demographic variables. Patients with MDD showed lower HRV (76+/-25 SD vs 99+/-33 SD ms; p<0.01) and higher HR (77+/-12 SD vs 68+/-9 SD bpm; p<0.01) than patients without MDD; moreover mild to moderate symptoms of depression (BDI score > or = 10) were associated with lower HRV (84+/-25 SD vs 102+/-35 SD ms; p=0.01) but not with significantly higher HR. After a mean follow-up of 60 months MDD was associated with an increase of all-cause mortality (OR 12; 95% CI 2.6-56; p<0.01) and of composite end-point (OR 2; 95% CI 1.2-3.6; p=0.01) but not with re-AMI and revascularization. In a simple regression model HRV values were predictors of mortality (p<0.01). However when added in the multiple regression model HRV did not have an independent correlation with the end-points considered and did not modify the correlation between depression and mortality.
Patients with post-AMI depression have a cardiac autonomic dysfunction as reflected by decreased HRV and increased HR. This autonomic dysfunction seems not to be an independent mediator of the increased mortality observed in depressed patients during a 5-year follow-up.

Autonomic Dysfunction is a Crucial Clinical Problem with Wide Implications
Ramesh K. Adiraju, MD; Joseph Colombo, PhD
American College of Cardiology Scientific Sessions 2006
Background: Autonomic Nervous System (ANS) balance is vital for most involuntary and essential functions in many organ systems. Evaluation and treatment of ANS dysfunction results in improvement in clinical symptoms and facilitates management in various conditions and disease states. ANS assessment using HRV analysis without respiratory activity has been attempted with inadequate information and clinical sensitivity. Hypothesis: The continuous wavelet transformation (CWT) approach to HRV with respiratory activity analysis, by definition, does not require signal stationarity and is not restricted by time-frequency. Therefore, it is theoretically better suited for wide clinical application. Methods: Serial ANS testing of 3130 consecutive cardiology patients (Diabetics=444; Females=1968; age=49.7±18.6) recruited over a six year period (1998 to 2004) using the ANX-3.0 Autonomic Monitoring System (Ansar, Inc., Philadelphia, PA). Results: We were able to reproducibly assess both ANS branches independently, statically and dynamically. We identified definitive patterns of ANS dysfunction, such as paradoxic parasympathetic syndrome (PPS), that are reproducible and can be followed by serial testing. These dysfunctions have clinical relevance and when corrected, not only treat the clinical syndrome, but also facilitate better management of various chronic clinical conditions, such as cardiomyopathy (CMP) and diabetes. A familial tendency has been observed. These findings suggest a strong etiologic and clinical association between ANS dysfunction and various clinical conditions, including: labile hypertension, SVT/VT, angina, and MVP syndrome. Correcting ANS dysfunction improved outcomes in all patients tested. Conclusions: Definitive etiology bases and a better understanding of pathophysiology and clinical manifestations were identified. Treatment protocols using existing medications with autonomically favorable actions were developed.

Postural Drop of Low Frequency Component of Heart Rate Variability in the Diagnosis of Orthostasis
George Stoupakis, Joe Colombo, Regina Rendas-Baum, Navin Budhwani, Rohit Arora, UMDNJ-New Jersey Medical School, Newark, N.J.
2002 AHA Abstract, Chicago, IL
Background: Orthostasis, defined as sympathetic insufficiency, can result in syncope and falls with serious consequences. Autonomic profiling for patients at risk can be quantitatively measured with real time heart rate variability (RTHRV) that includes an analysis of respiratory rate. Components of RTHRV used to profile the autonomic nervous system (ANS) consist of Low Frequency Area (LFA), a measure of sympathetic tone, Respiratory Frequency Area (RFA), a measure of parasympathetic tone, and LFA/RFA ratio, a measure of sympathovagal balance.
Objective: To compare LFA vs LFA/RFA ratio as an indicator of orthostasis in outpatients.
Methods: Profiling was done using the ANSAR ANX 3.0 ANS monitor on 303 consecutive patients (175 females, mean age 62 years) who presented to their PMD for routine visit. A postural drop in LFA or LFA/RFA ratio on standing indicated orthostasis. Symptoms of orthostasis were present in 104 pts (34%).
Results: LFA identified more pts with orthostasis than LFA/RFA ratio (57% vs 32%, p<0.01). LFA identified more pts than physician diagnosis (57% vs 14%, p<0.01) and combination of diagnosis + symptoms (57% vs 44%, p<0.01). The ratio identified more pts than physician diagnosis (32% vs 14%, p<0.01) but less compared to combination of diagnosis and symptoms (32% vs 44%, p<0.01).
Conclusion: Outpatient profiling of LFA identified orthostasis more readily than LFA/RFA and physician diagnosis. Given the known variability in identifying orthostasis, LFA could become a requisite component of its definition.

Non-invasive, Quantitative, Measurements of Autonomic Nervous System Activity Levels: III. Improved ANS Balance Improves Clinical Outcomes
Ramesh K Adiraju, MD, FACC1; Joseph Colombo, Ph.D.2
Submitted To Clinical Autonomic Research
Introduction: Autonomic Nervous System (ANS) monitoring has come of age. Over the past decade several leading medical associations have called for ANS monitoring as part of the standard of care for their chronic, progressive disease patients.
Methods: Over a three year period, a total of 1552 chronic patients were serially tested in the clinic, samples of which are presented with follow-up data.
Results: One of the most significant findings is that the oppositional relationship that has historically been assumed between the two ANS branches can be misleading. Observations from simultaneous, independent measures of both ANS branches has suggested a more interactive regulatory and responsive relationship between the parasympathetic and sympathetic branches of the ANS, respectively. There is also a physiologic buffer driven by various system responses to ANS challenge and their influence on ANS reaction. Therefore, in the presence of ANS dysfunction (with or without a previous clinical condition) there appears to be paradoxic and/or exaggerated responses of one or both ANS branches which can result in a positive feedback loop created by ANS and organ system reaction leading to symptoms and clinical syndromes. Also, as both branches weaken, the aging effect seems to accelerate, further weakening the ANS. Since quality of life (e.g., GI motility, bladder control and sexual function) and ultimately life itself is dependent on some level of function within the ANS, working to preserve the ANS and prevent further decline is a significant issue. Chronic ANS dysfunction may also lead to disease states such as Diabetes (type-II), Hypertension, Renal disease, Cardiomyopathy, and Multiple System Atrophe. Tighter disease control, anti-oxidants, and healthier life styles (diet and exercise) have all been observed to help protect and in some early cases even improve ANS health.
Discussion: Our team has observed that ANS dysfunction, particularly parasympathetic abnormality, could be a primary abnormality or a secondary physiologic manifestation. This is not surprising considering the interrelationship between the ANS and various body systems such as the GI tract, vascular systems, and the endocrine system. It was also observed that ANS dysfunction could be an early indicator of more serious clinical conditions. The authors have found that modifying and resetting ANS dysfunction can be
achieved using conventional drugs and non-pharmaceutical therapies known to effect the sympathetic and parasympathetic nervous systems (e.g., central adrenergic or cholinergic antagonists, and exercise and diet).
Conclusions: Resetting ANS to normalcy or close to normalcy not only resulted in resolution or avoidance of clinical symptomatology but has lead to, in our experience, improvements in the primary disease manifestations and better responses to treatment. ANS monitoring was found to positively impact treatment and therapy. It helps to individualize or customize treatment by allowing treatment plans to be tailored and titrated based on the details and specific analyses of each ANS test.

Non-invasive, Quantitative, Measurements of Autonomic Nervous System Activity Levels: I. Chronic Patient Care Approaches
Joseph Colombo, Ph.D.1; William C. Shoemaker, MD2; Rohit R Arora, MD, FACC3; Ramesh K Adiraju, MD, FACC4
Submitted To Clinical Autonomic Research
Introduction: Spectral analysis of respiratory activity (RA) concurrent with spectral analysis of heart rate variability (HRV), known as real-time HRV, is now a generally accepted means of non-invasive autonomic nervous system (ANS) monitoring. Spectral analysis of RA is accepted as a measure of Vagal outflow and Vagal influence on HR. It can be regarded as a measure of the strength of the respiratory sinus arrhythmia component of the instantaneous HR signal (the cardiogram). Together, RA and HRV spectral analyses provide for separating the sympathetic nervous system (SNS) from the parasympathetic nervous system (PSNS) resulting in a direct, simultaneous, independent, non-invasive measures of both ANS branches.
Method: A more robust spectral analysis method is presented: a continuous wavelet transform (CWT). The CWT-based approach includes several clinical challenges over a 15:35 minute time period. These are, in order of presentation: 1) a five minute resting baseline to determine the patient’s ANS levels at rest, 2) a one minute relaxed deep breathing period to challenge the PSNS, 3) a one minute baseline to allow the ANS to return to baseline values, 4) a series of five short Valsalvas over a 1:35 minute period to simply challenge the SNS, 5) a two minute baseline to allow the ANS to settle, and 6) a quick postural change (seated to standing) followed by a five minute period of quiet standing.
Results: Expected results are presented with sample adult and child data.
Discussion: The CWT-based ANS monitor is found to be the best mode of analyzing ANS abnormalities in an out patient setting and for longitudinal analyses. Through ANS provocative challenges, the SNS and PSNS responses and interactions were assessed. ANS abnormalities were found to be the etiology in idiopathic clinical syndromes and associated with chronic illnesses like diabetic and metabolic dysfunctions. Early detection of pre-clinical states allows intervention in chronic illnesses preventing long term consequences. We observed that ANS dysfunction, particularly parasympathetic, could be a primary abnormality or a secondary pathophysiologic manifestation in endocrine, autoimmune disorders, and chronic illnesses. Modifying and resetting ANS dysfunction also led to improvement of the primary disease manifestations and response to therapy. The CWT approach seems suited for assessment and the affects of chronic illnesses on the ANS. The authors noted that the CWT based assessment of ANS balance
can provide physicians with the detailed analysis of ANS balance and a basic understanding of the stability of a patient in response to disease state, lifestyle, and therapy plan. Patient and disease instability tends to result from of autonomic imbalances. ANS imbalance has been found to create additional symptoms, and additional symptoms have been shown to be a manifestation of ANS dysfunction. From our observations, typical standard therapies using conventional drugs known to affect the ANS (e.g., central Beta-blockers) have been effective in resetting ANS dysfunction. We have also observed that maintenance therapy may be required in chronic conditions and secondary ANS dysfunction.
Conclusion: Physicians have been manipulating the ANS for decades (e.g., a-blockers, ß-blockers, ACE-Inhibitors, ARBs, Vasopressors, Tricyclics, and SSRIs). The results of these manipulations can now be seen objectively, measured scientifically, and quantified directly. ANS monitoring provides a more precise assessment of disease manifestation and efficacy of treatment, and allows early detection of sub-clinical disease states. Early detection of sub-clinical disease states allows timely intervention in a disease process, preventing long term and often fatal effects of autonomic dysfunction in systemic and metabolic chronic illnesses. Various autonomically active drugs were observed to have a negative effect on the ANS which explains the ineffectiveness and idiopathic adverse reactions seen with some of the drugs (e.g., ACE-Inhibitors). Finally, ANS dysfunction treatment has resulted in better control and treatment responsiveness of disease states such as Diabetes, Cardiomyopathy, and Orthostatic Hypotension.

Autonomic Dysfunction is a Crucial Clinical Problem with Wide Implications
Ramesh K. Adiraju, MD; Joseph Colombo, PhD
American College of Cardiology, Scientific Sessions 2006
Background: Autonomic Nervous System (ANS) balance is vital for most involuntary and essential functions in many organ systems. Evaluation and treatment of ANS dysfunction results in improvement in clinical symptoms and facilitates management in various conditions and disease states. ANS assessment using HRV analysis without respiratory activity has been attempted with inadequate information and clinical sensitivity. Hypothesis: The continuous wavelet transformation (CWT) approach to HRV with respiratory activity analysis, by definition, ...
Danilowicz-Szmanowicz, L., Figura-chmielewska, M., Ratkowski, W., & Raczak, G. (2013). Effect of various forms of physical training on the autonomic nervous system activity in patients with acute myocardial infarction

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Prof. S. Danev MD PhD DSc Publications

1.  Tsaneva N, Danev S, Dobrovolski I. (1966) Recherches sur le travail des operateurs dans l'industrie chimigue. Le Travail Humain, XXIX, 3-4,  161 - 163
2.  Danev S (1966) Processing of information and ergonomical optimisation of "man-machhine" system. In:  Investigation of Working Conditions, 109-121, Prague, (in Czech)
3.  Gantchev G, Danev S, Koitcheva V (1966) La corrrelation entre la frequence  cardiaque et la quantite de l,information. Le Travail Humain, XXIX, 131-133
4.  Gantchev G, Danev S, Koitcheva V (1967) La  frequence cardiaque au cours d'un travail de differente responsabilite et correlation avec la quantite  de l'information  recue et elaboree. Activ Nerv Sup, 9, I, 25-29
5.  Danev S (1968) Heart rate at various types of  information coding  under laboratory conditions. Activ Nerv Sup, 10, I, 15-21
6.  Danev S (1968) A study of some factors influencing pulse frequency in conditions of paced choice-reaction performance. Activ Nerv  Sup, 110, 4, 389-394
7.  Danev S (1968) Heart rate augmentation as a result of increased amount of processed information in connditions of choise reaction performance. Actiiv Nerv Sup, 10, 2, 177-179, (in Czech)
8.  Danev S (1969) Deux mannieres de presenter l'information; leur influence  sur le "time-stress". Le Travail Humain, XXXII, 312-314
9.  Danev S (1969) Comparison of two manner of processing information on the basis of their influence upon "time-stress". Stud Psychol, Bratislava,XI,2,125-130,  (in  Russian)
10.  Danev S, Bink B, Wartna  G  (1970) Assessment of informational load. NIPG-TNO, Leiden, (int. rep.)
11.  Danev S, Wartna G (1970) Relation between making mistakes and the T-P interval in the ECG.  NIPG-TNO,  Leiden, (int. rep.)
12.  Wartna G, Danev S, Bink B (1970) Sinusaritmie als maat voor mentale belasting. Proc. of 11-th Feder Vergadering van Medisch  - Biol Vereningen, Leiden, (in Dutch)
13.  Danev S,  Winter C (1970)  Expectation, attention and heart rate deceleration. NIPG-TNO, Leiden, (int. rep.)
14.  Danev S, Winter C, Wartna G (1970) On the relation between information handling and some cardiovascular parameters in a task with and without "time-stress". NIPG-TNO, Leiden, (int. rep.)
15.  Danev S, Winter C (1970) "Time-stress" and the relation between decision and motion times. NIPG-TNO, Leiden, (int. rep.)
16.  Danev S,  Winter C, Wartna G (1970) "Time-stress" and katachretical behavior. NIPG-TNO, (int. rep.)
17.  Danev S, Wartna G (1970) Information load and "time-stress": some psychophysiological consequences. TNO  - News, 25, II, 389-395
18.  Danev S, Wartna G, Bink B, Radder J (1970) Psychophysiological assessment of information load. Proc.  of 4-th Int.  Congr. Ergonomics, Strassbourg, 26-27
19.  Danev S, Wartna G, Bink B, Radder J, Lutein I (1971) Psychophysiological assessment of information load.  Nederlands Tijdschrift voor de Psychologie, XXVI, I, 23-39
20.  Danev S, Winter  C (1971) On the relation  between  reaction and motion time in a choice reaction task. Acta Psychologica, 35, 188-197
21.  Danev S,  Wartna G, Radder J (1971) Are the R-R intervals normally distributed. Plugers Arch 328,3,261
22.  Danev S. Winter C.R (1971) Heart rate deceleration after erroneous responses-a phenomenon complicating the use of heart rate variability for assessing mental load Psychol. Forsh, 35, 27-34.
23.  Danev S, Winter C,  Wartna G  (1972) Information processing and psychophysiological functions  in a  task with and  without "time-stress". Act Nerv Sup, 14, I, 8-12
24.  Danev S (1973)  Are the R-R  intervals in the ECG normally distributed: an attempt  to  clarify.  Ergonomics 16, I, 311
25.  Danev S, Winter C,  Wartna  G (1973) Improvising in simulated manual tasks as a function of "time-stress". Studia  Psychol, XV, I, 54-64
26.  Danev S, Radneva R, Zlatarov I (1975) Changes  in  heart rate variability due  to informational, physical and emotional load in laboratory and field conditions. Activ Nerv Sup, 17, 3, 187-188
27.  Danev S, Tomov E, Tzaneva L (1976) Upon  the usefulness of  some psychophysiological criteria for assessment of extraaural  noise effect. Ergonomia, 9, 32-38, (in Bulgarian)
28.  Danev S, Zlatarov I, Radneva R (1976)  Changes in heart rate variability due to emotional and mental load. Proc. of 2-nd Int Ind Envir Neur Congr, Prague, 120-123
29.  Ivanovitsh E, Antov G, Danev S,  Goranova L (1976) Ensymic changes in rat myocardium  after brief noise exposure. Proc. of IX-th Congress for Noise Protection, Budapest, 87-89
30.  Ivanovitsh E, Danev S, Antov G,  Goranova L, Nikolova L (1976) Behavioral and biochemical  changes in rat brain due to stady-state  noise. Proc. of IX-th  Congress for Noise  Protection, Budapest, 81-84
31.  Radneva  R, Danev S (1976) Upon the combined noise-vibration influence of some psychophysiological parameters. Proc. of 2-nd Int Ind Envir Neur  Congr, Prague, 423
32.  Danev S (1978) Functional age. Ergonomia, 13, 31-40, (in Bulgarian)
33.  Danev S (1979) Functional music and work performance. Health,  IV, 12-13, (in Bulgarian)
34.  Tzaneva L, Danev S (1981) Upon the influence of  small doses of alcohol upon operator's performance. Work Hygiene and Prof Diseases, Mosque, 5, 36-37 (in Russian)
35.  Danev S (1981) "Man-machine" system. In: Work Psychophysiology, 40-47, Sofia, (first edition), (in Bulgarian)
36.  Danev S, Beraha R (1983) A method estimating the speech intelligibility in noisy industrial conditions. Proc. of 4-th Seminar and Exhibition on Noise Control, Sombathely, Hungary, 234-237
37.  Danev S, Beraha R, Tzaneva L, Datzov E, Dobrovolsky J, Satchanska T, Vangelova K, Shmarov A (1985)  The influence of long-term noise exposure on the  verbal intelligibility  and some psychophysiological parameters.  Proc. of 1-st Int Symp on Human Perf and Envir, Sofia
38.  Danev S (1986) Evaluation methods for self-propelled agricultural machines and tractors.  Paper presented on  Intern Work Shop (WHO) "Occupational  health in agriculture", Sofia
39.  Danev S (1988) Mathematical analysis of heart  rate variability. In: Work Psychophysiology, Sofia, (sec. edition), (in Bulgarian, summary in English)
40.  Danev S, Datzov E (1988) Assessment of work-adaptation by means of heart rate variability. Hygiene and Health Care XXXI,5,33-41, (in Bulgarian)
41.  Nikolova R, Danev S, Datzov E, Beraha R. (1988) Using of the heart rate for assessment of mental work load in video display operators, Proc. of Conf.: The man in conditions of the science technique, Varna
42.  Nikolova R, Danev S, Dazov E. (1988) Changes in the pulse variability in tasks connected with informational processing under conditions of time deficit, paper pres. on V-th National congress of Hygiene, Sofia
43.  Danev S,  Datzov  E, Nikolova R (1988) Analysis of  heart  rate variability: a method estimating the interaction between man and environment. Proc. of 2-nd Sc Sess of Program for Complex investigation of man and  his brain. Sofia, 52-53
44.  Danev S (1988) Une nouvelle methode pour l'evaluation du confort  ergonomigue, fondee sur les changements  du  rhythme cardiaque. Paper pres. on XXIV-th Congress de la SELF, Paris
45.  Danev S, Datzov E (1988) Mathematical indices of heart rhythm for assessment of toxicological  health hazard. Health and Prof Dis, Mosque, 11, 31-33, (in Russian)
46.  Tzaneva  N, Nikolova R, Topalova M,  Danev S (1989) Changes in shift workers operating a day and night 12 hour  schedule in carbon disulfate production. Paper pres. in Shift work: Health, Sleep and Performance, G. Costa ets. et all, P. Lang, Frankfurt am Main, 324-329
47.  Nikolova R, Danev S. (1989) Assessment of working capacity and functional state of operators from electrical power station, working under 12 hour shift, Paper pres. on IX-th Conf. of the Young Specialists, Varna
48.  Nikolova R, Danev S. (1989) Heart rate variability circadian rhythm in work conditions, Paper pres. on Conf. of the Young Specialists, Varna
49.  Danev S  (1989) Heart rate variability in work-physiological aspect. Doctoral Thesis., Medical Academy, Sofia, (summary in English)
50.  Danev S (1990) Assessment of  functional state by means of computer analysis of heart rate variability (HRV). Proc. of I-st Intern Conf: Computers in  Medicine and Health Care, Karlovy vary
51.  Datzov E, Danev S, Beraha R (1990) Computer method for assessing the objective nature of failures during tests involving static muscle effort. Proc. of I-st Intern Conf: Computers in Medicine and Health Care, Karlovy vary
52.  Datzov E, Danev S. (1990) Changes in power density spectrum in tasks comprising static muscule effort. Problems of Hygiene, 16, 71-75, (in Bulgarian, summary in English)
53.  Kazandziev G, Danev S, Brankov B, Todorov E. (1990) Mathematical analysis of heart rate variability as an element increasing security in operative practice (anesthesia with isofuran), Proc. of 4-th National Conference for Anesthesia, Reanimation and Intensive Therapy, Sofia, 32-39, (in Bulgarian)
54.  Datzov E, Danev S (1990) Assessment of toxicological hazard by means of heart rate variability and electroneurography. Proc. of XXI-th Semaine Medicale Balkanique, Varna
55.  Danev S, Datzov  E (1990)  Spectral analysis of heart rate and its correlation with heart rate variability. Proc. XXI-th Semaine Medicale Balkanique,  Varna
56.  Danev S. (1990) Changes in the variability of heart rhythm in diabetes patients, Hygiene and Health Care, XXXIV, 3, 42-46, (in Bulgarian, summary in English)
57.  Danev S, Kazakova M (1990) A new method for cardiovascular examination with informative value for prophylactic and clinical medicine, Contemporary Medicine, XI, I, 16-19, (in Bulgarian)
58.  Danev S, Pavlov E, Koleva E, Nikolova R, Datzov E. (1990) A method augmenting the possibility of system "Sport-tester PE - 3000". Questions of physical education, 7,21-25 (in Bulgarian)
59.  Danev S, Datzov E, Nikolova R., (1990) Corrections of Heart Rate Variability Indices to Minimize the Effect of Postural Change and Circadian Rhythm Acta Medica, vol. XVII, 90, 2, (in Bulgarian, summary in English)
60.  Danev S. (1990) The influence of noise masking effect upon heart rate variability. Paper pres. on Symp: Noise Effects on the Inner Ear, Gera, Germany
61.  Danev S, Bozinova D. (1991) A computer based method for assessment of work-related immobilization. Proc. Of XXII Conf of Hygienic Stations, Varna, 36-41 (in Bulgarian, summary in English)
62.  Danev S. (1991) How to use computer analysis of heart rate variability in sport. Paper pres. At First Transeuropean Meeting "Sport and health", Montpellier, France
63.  Tsaneva L, Danev S, Datzov E. (1991) Ergonomical optimisation of verbal informational exchange in industry, Paper presented on Conf. on Ergonomical Labor Protection, Sofia
64.  Danev S, Zlatarov I. (1991) Labour-physiological evaluation of the load and strain of the labuor of operators from ThEPlant "Varna" with 12-h Work-schedule, Hygiene and Health Care, XXXIV, 4, 52-59, (in Bulgarian, summary in English)
65.  Danev S, Nikolova R, Datzov E. (1991) Changes of pulse arrival time during stress, Hygiene and Health Care, XXXIV, 2, 30-36, (in Bulgarian, summary in English)
66.  Danev S. (1991) Changes in the heart rate variability in diabetic patients, Hygiene and Health Care, XXXIV, 3, 42-46, (in Bulgarian, summary in English)
67.  Danev S, Bozinova D. (1991) The diagnostic of overtraining by computer analysis of heart rate variability. Questions of physical education, 4, 13-18, (in Bulgarian)
68.  Nikolova R, Danev S. (1991) Assessment of the information degree of heart rate variability indexes under situations connected with neuro-emotional treatment, Problems of Hygiene, XVI, 61-69, (in Bulgarian, summary in English)
69.  Danev S, Datzov E, Nikolova R. (1991) Corrections of heart rate variability indicators to minimize thew effect of postural change and circadian rhythm. Acta Medica, 18, 2, 54-59, (in Bulgarian, summary in English)
70.  Nikolova R, Danev S, Amudjev P, Datzov E. (1991) Correlation between some psychological dimensions and heart rate variability, Problems of Hygiene, 18, 34-36, (in Bulgarian, summary in English)
71.  Danev S. Heart Rate Variability indices. Hygiene and Health Care, 4, 1992 (in Bulgarian, summary in English)
72.  Sachanska T, Haralanov H, Savov A, Kamenova A, Danev S, Tsaneva L. (1992) Change in the serotin level of patients with central disequilibrium, Paper presented on XXIII-th Congress of NES, Bad Kissingen, Germany
73.  Danev S, Sachanska T, Dazov E, Nikolova R, Kamenova A, Savov A. (1992) Vestibular disorders, reflected by heart rate variability, Paper presented on IV-th National Neurological Congress, Sofia, (in Bulgarian)
74.  Danev S. (1992) Effect of bearing of antiphons upon verbal communication in noisy industrial conditions, Hygiene and Health Care, XXXV, 3, 24-25
75.  Danev S, Datzov E, Nikolova R, Pavlov E. (1992) Assessment of the functional state in psichosomatic complaints of operators from electrical power station, Problems of Hygiene, XVII, 63-69, (in Bulgarian, summary in English)
76.  Datzov E, Danev S. (1992) Electroneurographic assessment of subjects, exposed on vibration, Hygiene and Health Care, XXXV, 1, 25-28, (in Bulgarian, summary in English)
77.  Danev S. (1992) Beurteilung der Arbeitsadaptation und des toxikologischen Risikos mit Hilfe der rechnergestutzten Analyse der Herzfrequenzvariabilitat. Arbeitsmedizin in Osteuropaischen Staaten 2. Internationales Symposium, 7 - 9, Berlin
78.  Iustinianova B, Danev S, Zlatarov I. (1992) Heart rate variability in children with primary arterial hypertension, Hygiene and Health Care XXXV, 4, 14-16, (in Bulgarian, summary in English)
79.  Danev S. (1992) Informativeness of the pulse frequency power density spectrum, Hygiene and Health Care, XXXV, 4, 13-14, (in Bulgarian, summary in English)
80.  Danev S. (1992) Work hygienic control on bioenergoterapeutic performance, Paper presented on Scientiffic symposium of natural medicine and bioenergoteurapy, Sofia, (in Bulgarian)
81.  Danev S.(1992) Changes in heart rate variability due to 12 hours day and night shift work, Problems of Hygiene, 17, 53-57, (in Bulgarian, summary in English)
82.  Danev S, Datzov E. (1992) Changes in biological synchronisation due to bioenergoterapeutic treatment, Paper presented on scientiffic symposium of natural medicine and bioenergoteurary, Sofia, (in Bulgarian)
83.  Danev S. (1992) Computer based method for assessment of psychosomatic complaints before and after bioenergoterapeuetic treatment, Paper presented on scientific symposium of natural medicine and bioenergoterapy, Sofia, (in Bulgarian)
84.  Danev S. (1993) Une nouvelle methode pour l'evaluation du confort ergonomique, foundee sur les changements du rythme cardiaque, paper presented on XXVIII-eme Congres De La Societe D'Ergonomie De Langue Francaise, Geneve
85.  Tsaneva L, Danev S. (1994) Verbal comunication in hazard industrial conditions, Paper presented on VI-th Nat. Conf. of Hygiene and Health Prophylactic, (in Bulgarian)
86.  Nikolova R, Stanchev V, Danev S. (1994) Assessement of work-related stress in air traffic controllers from Sofia airport. In: A. Grieco, G. Molteni, E. Occhipinti, B. Piccoli (Eds.) Book of short papers: Work With Display Units, Grafica Briantea, S.r.l., Como, 1, F9-F10
87.  Danev S, Datzov E. (1994) Cardiac rhythm disturbonses in operators with 12-h work schedule, Paper presented on 5-th Congress of Hygiene and Health Prophylactic, Sofia, (in Bulgarian)
88.  Nikolova R, Danev S, Amudzhev P, Datzov E. (1995) Correlation dependances between some psychologycal dimensions and heart rate variability. Problems of Hygiene, XX, 74-81, (in Bulgarian, summary in English)
89.  Nikolova R, Danev S, Amudzhev P, Datzov E. (1995) Age transfer coefficients of heart rate variability basic indexes, Problems of Hygiene, XX, 59-68, (in Bulgarian, summary in English)
90.  Danev S, Nikolova R, Svetoslavov S. (1995) Detection of nomotopic and heteretopic heart rhythm disturbances by computer analysis of heart rate variability, Paper pres. on IX-th National Congress of Internal Diseases. Sofia, (in Bulgarian, summary in English)
91.  Nikolova R, Danev S, Datzov E. (1995) Assessment of adaptation profile in operators at TV retranslation station "Botev", Problems of Hygiene, XX, 68-74, (in Bulgarian, summary in English)
92.  Danev S, Dimitrov T, Slavcheva L. (1995) Computer analysis of heart rate variability for assessment of common functional status in pilots, Paper pres. on Nat. Conf. of Aviation Medicine, Sofia, (in Bulgarian, summary in English)
93.  Tsaneva L, Danev S. (1995) Assessment of the effect of masking noise upon the performance of some psychophysiological tasks, Problems of Hygiene, XX, 38-43, (in Bulgarian, summary in English)
94.  Tsaneva L, Danev S, Nikolova R. (1996) Assessment of noise masking effect upon changes in heart rate variability measures. Acta Medica, XXIII, 3, 57-61
95.  Tsaneva L, Danev S, Datzov E. (1996) Hygiene-ergonomical protection of verbal comunication. Problems of Hygiene, XXI, 36-43
96.  Danev S, Datzov E., Svetoslavov S. (1996) Pharmacologically induced sympathetic or parasympathetic influence upon heart rate variability in man. Acta Medica, XXIII, 2, 34-41
97.  Dimitrov T, Danev S. (1996) How to use the analysis of heart rate variability for selection of emploers, exposed to high level work-related stress, Paper presented on Scientific Symposium "The challenge of Stress", Hisar, (in  Bulgarian, summary in English)
98.  Danev S, Nikolova R, Svetoslavov S. (1996) A new approach to health risk assessment by means of heart rate variability. Procidings of First International Conference: Psychophysiology in Ergonomics, 1, 14-16 Wuppertal, Germany
99.  Danev S, Nikolova R, Kerekovska M. (1996) Correlation between chronic distress and serum lipids, Acta Medica, XXIII, 3, 32-37
100.  Danev S, Nikolova R, Kerekovska M, Svetoslavov S. (1997) Relationship between heart rate variability and hypercholesterolemia. Central European Journal of Public Health, 3, 5, 143-147
101.  Danev S, Datzov E, Svetoslavov S. (1997) Assessment of health risk by analysis of heart rate variability in industrial workers. Acta Medica, XXIII, 2, 17-24
102.  Danev S, Datzov E, Svetoslavov S. (1997) Pharmacologically induced sympathetic or parasympathetic influence upon cross spectrum of basic physiological functions. Comptes rendus de l'academie Bulgare des sciences, 12, 83-88
103.  Datzov, E, Danev S, Svetoslavov S. (1997) Stress evaluation: comparative assessment of the spectra of basic physiological functions. Acta Medica, XXIII, 1, 56-62
104.  Nielsen H, Danev S. (1997) The improvement of common functional status by Hugo Nielsen method. Proc. of IIIrd World Congress on Cancer, Darwin, Australia
105.  Danev S, Svetoslavov S, Datzov E., (1997) A chronic decrease of heart rate variability can precede some cases of cancer. Proc. of III-rd World Congress on Cancer, Darwin, Australias
106.  Tzaneva L., Danev S., Nikolova R., (2001), Investigation of noise exposure effect on heart rate variability parameters. Central European Journal of Public Health, Vol. 9 (JHEMI vol. 45), No. 3, 130 - 132.
107.  Tsaneva L., Danev S., Nikolova R., (1996), Assessment of the masking effect of noise on changes in heart rate variability analysis indices. Acta Medica Bulgarica, Vol. XXIII, 1, 57 - 61.
108.  Tsaneva N., Nikolova R., Topalova M., (1993), The effect of psychological factors on the functional state of the organism in chemical industry operators. Acta Medica Bulgarica, Vol. XX, 62 - 68.
109.  Tsacheva N., Datsov E., Simeonov G., (2001), Petrov I., Mladenova R., Nikolova R., Yancheva M. Practical methods for analysis and assessment of employees' health state (part I). Transport Medicine, Vol. XXIII, 10 - 14.
110.  Nikolova R., Slavtcheva L., Zlatev R., (2001), Vukov M. Prognozing of the resistance to hypoxia in military pilots by cardiovascular and respiratory parameters. In: RTO/NATO (Ed.), RTO Meetings Proceedings: MP-062 "Operational Medical Issues in Hypo- and Hyperbaric Conditions", RTO-MP-062, AC/323 (HFM-050) TP/34, St Joseph Ottawa/Hull, pp. 7-1 - 7-15.
111.  Nikolova R., Vukov M., Tzacheva N., (2002), Evaluation of chronic stress effect on operator's functional state. Acta Medica Bulgarica, vol. XXIX, 53 - 64.
112.  Nikolova R., Kurtisheva M., Dimitrova R., (2002), Evaluation of the functional state of cardiovascular system under chronic stress. Acta Medica Bulgarica, vol. XXIX, 65 - 71.
113.  Nikolova R., (2003), Evaluation of the effect of educational load on parameters of heart rate varlability. Scripta Periodica. Medical Review, Vol. VI, No. 1, 11 - 18.
114.  Nikolova R., Tsacheva N., Voukov M., (2003), Investigation of the autonomic cardiovascular regulatory activity under work load effect. Scripta Periodica. Medical Review, Vol. VI, 2, 36 - 48.
115.  Nikolova R., (2003), Determination of autonomic cardiovascular response patterns under emotional stress states. Acta Medica Bulgarica, vol. XXX, 103 - 108.
116.  Nikolova R., Radev V., Vukov M., (2003), Functional determination of the operator state in the interaction of humans with automated systems. In: RTO/NATO (Ed.), RTO Meetings Proceedings: MP-088 "The Role of Humans in Intelligent and Automated Systems", RTO-MP-088, AC/323 (HFM-084) TP/44, St Joseph Ottawa/Hull, pp. 26-1 - 26-12.
117.  Doncheva N., Nikolova R., Danev S., (2003), Overweight, dyslipoproteinemia, and heart rate variability measures. Folia Medica, Tomus XLV, 1, 8 - 12.
118.  Tomova M., Nikolova R., (2004), Job stress assessment method. Social Medicine, year XII, N4, 26 - 28.
119.  Angelova K., Nikolova R., Nikolova N., (2004), Doncheva N., Vukov M. Circadian temporal system, feeding pattern and health risk., Sofia, pages 15-20.
120.  Nikolova R., Alexiev L., Vukov M., (2004), Research potential of a heart rate variability diagnostic system for the study of stress and health risk in peacekeeping operations. In: RTO/NATO (Ed.), RTO Meetings Proceedings: MP-HFM-108 "NATO Medical Surveillance and Response, Research and Technology Opportunities and Options", RTO-HFM-108, AC/323 (HFM-108) TP/55, St Joseph Ottawa/Hull, pp. 18-1 - 18-20.
121.  Nikolova R., Alexiev L., (2005), Psycho-physiological investigation of mental work load and stress in military personnel, Military Medicine, Vol. LVII, No. 1, 69 - 72.
122.  Aleksiev L., Nikolova R., Kanev K., Lessidrenski H., Taskova L., (2005), Psycho-physiological investigation of stress response associated with participation in peacekeeping missions. Military Medicine, Vol. LVI, No. 3, 44 - 46.
123.  Nikolova R., Alexiev L., Taskova L., (2006), Effect of environmental factors on functional state. Scripta Periodica, Vol. IX, No. 1, 9 - 14.
124.  Nikolova R., Angelova K., Vukov M., (2006), Petrova R. Assessment of cardiovascular risk in shift working telephone operators. Ergonomia IJE & HF Vol. 28, No 3, July - September, 199 - 208.
125.  Nikolova R., Tzaneva L., (2007), Investigation of stress response under work load. Social Medicine, year XV, No. 1, 25 - 27.
126.  Nikolova R., (2007), Assessment of the effect of stress generating risk factors on functional state. Social Medicine, year XV, No. 2, 32 - 34.
127.  Nikolova R., Aleksiev L., Vukov M., (2007), Psychophysiological assessment of stress and screening of health risk in peacekeeping operations. Military Medicine, Vol. 172, 1, 44-48.
128.  Nikolova R., Aleksiev L., Vukov M., (2007), Work-load induced autonomic dysfunction - pathophysiological precursor of cardiovascular diseases. Balkan Military Medical Review, Vol. 10, April, No. 2, 78 - 83.
129.  Nikolova R., (2007), Psychophysiological approach to studying the effect of emotional on cardiovascular health state, IV, No. 4, 20 - 25.
130.  Nikolova R., (2007), Assessment of functional state of employees working at the specialized hospital of physiotherapy and rehabilitation. Scripta Periodica, Vol. X, Number 4, 38 - 42.
131.  Nikolova R., Danev S., (2007), Application of the functional diagnostic method for analysis of heart rate variability for stress assessment. Bulgarian Medical Journal, year I, No. 2, 41 - 44.
132.  Nikolova R., (2007), Functional application of methods for analysis of baroreflex sensitivity and blood pressure monitoring in studying individuals exposed to stress, No. 3, 19 - 23.
133.  Datsov E., Tzacheva N., Nikolova R., Vutkova A., (2008), Ethical requirements for the experts in the field of occupational medicine. Health Management, No. 8, N1, 15 - 19.
134.  Nikolova R., (2008), Carbon disulfide - a toxic risk factor for health status. Scripta Periodica, Vol. XI, Number 1, 42 - 52.
135.  Nikolova R., Tzacheva N., (2008), Occupational-physiological screening of risk factors, health risk and recommendations to employees and employer from the bulgarian national radio. Health Management, No. 8, N2, 30 - 39.
136.  Tzacheva N., Datsov E., Nikolova R., Vutkova A., (2008), European dimensions of the occupational medicine. Health Management, No. 8, N2, 66 - 70.
137.  Nikolova R., (2008), Pulse transit time- method for investigation of the cardiovascular system functional status. Bulgarian Medical Journal, year 2, No. 1, 9-13.
138.  Nikolova R., Vodenitcharov E., Tzacheva N., (2010), Physiological mechanisms controlling cardiovascular responses to muscular static load. Acta Medica Bulgariaca, 1.
139.  Nikolova R., Tchacheva N., Vodenitcharov E., (2008), Occupational medicine approach to analysis and assessment of workability and health status of operators from 'Maritza Iztok power plant'. Health Management. 3, 37-43.
140.  Nikolova R., (2008), Effect of physical activity on cardiovascular function in childhood and adolescence. Medical Review, No. 2, 30-35.
141.  Nikolova R., (2008), Mentally-induced stress at the working place-risk factor for genesis of cardiovascular diseases. Modern Medicine, No. 2, 42-47.
142.  Nikolova R, Tzacheva N., 2010, Regulating mechanisms and cardiovascular response pattern in mental and static workload. Comptes Rendus de l'Academie Bulgare Des Sciences. 63, 8, 1219-1224.
143.  Nikolova R, Tzacheva N., (2010), Functional significance of autonomic control for genesis of morbidity with autonomic nervous system origin. Comptes Rendus de l'Academie Bulgare Des Sciences. 63, 8.
144.  Nikolova R., Tzacheva N., Danev S., (2011), Functional significance of job analysis for health and safety at work. Bulgarian Medical Journal. 4.

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