Should heart rate variability be “corrected” for heart rate? Biological, quantitative, and interpretive considerations

Abstract Metrics of heart period variability are widely used in the behavioral and biomedical sciences, although somewhat confusingly labeled as heart rate variability (HRV). Despite their wide use, HRV metrics are usually analyzed and interpreted without reference to prevailing levels of cardiac chronotropic state (i.e., mean heart rate or mean heart period). This isolated treatment of HRV metrics is nontrivial. All HRV metrics routinely used in the literature exhibit a known and positive relationship with the mean duration of the interval between two beats (heart period): as the heart period increases, so does its variability. This raises the question of whether HRV metrics should be “corrected” for the mean heart period (or its inverse, the heart rate). Here, we outline biological, quantitative, and interpretive issues engendered by this question. We provide arguments that HRV is neither uniformly nor simply a surrogate for heart period. We also identify knowledge gaps that remain to be satisfactorily addressed with respect to assumptions underlying existing HRV correction approaches. In doing so, we aim to stimulate further progress toward the rigorous use and disciplined interpretation of HRV. We close with provisional guidance on HRV reporting that acknowledges the complex interplay between the mean and variability of the heart period.

[1]  J. Fleiss,et al.  The ability of several short-term measures of RR variability to predict mortality after myocardial infarction. , 1993, Circulation.

[2]  René van Lien,et al.  Heritability and Temporal Stability of Ambulatory Autonomic Stress Reactivity in Unstructured 24-Hour Recordings , 2015, Psychosomatic medicine.

[3]  D. Mozaffarian,et al.  Physical Activity and Heart Rate Variability in Older Adults: The Cardiovascular Health Study , 2014, Circulation.

[4]  J. Cacioppo,et al.  Autonomic cardiac control. II. Noninvasive indices and basal response as revealed by autonomic blockades. , 1994, Psychophysiology.

[5]  P. Bjerregaard,et al.  Attenuated 24-h heart rate variability in apparently healthy subjects, subsequently suffering sudden cardiac death , 1991, Clinical Autonomic Research.

[6]  P. Grossman,et al.  Toward understanding respiratory sinus arrhythmia: Relations to cardiac vagal tone, evolution and biobehavioral functions , 2007, Biological Psychology.

[7]  D. Randall,et al.  Interactions within the intrinsic cardiac nervous system contribute to chronotropic regulation. , 2003, American journal of physiology. Regulatory, integrative and comparative physiology.

[8]  Bert N. Uchino,et al.  Autonomic cardiac control. III. Psychological stress and cardiac response in autonomic space as revealed by pharmacological blockades. , 1994, Psychophysiology.

[9]  G. Schmidt,et al.  How to strengthen or weaken the HRV dependence on heart rate--description of the method and its perspectives. , 2013, International journal of cardiology.

[10]  H. Stauss Heart rate variability: just a surrogate for mean heart rate? , 2014, Hypertension.

[11]  J. Hayano,et al.  Accuracy of assessment of cardiac vagal tone by heart rate variability in normal subjects. , 1991, The American journal of cardiology.

[12]  A. Camm,et al.  Mortality in Patients After a Recent Myocardial Infarction: A Randomized, Placebo-Controlled Trial of Azimilide Using Heart Rate Variability for Risk Stratification , 2004, Circulation.

[13]  A. Kadish,et al.  Dissociation of heart rate variability from parasympathetic tone. , 1994, The American journal of physiology.

[14]  Jagmeet P. Singh,et al.  Reduced heart rate variability and new-onset hypertension: insights into pathogenesis of hypertension: the Framingham Heart Study. , 1998, Hypertension.

[15]  P. N. Mcwilliam,et al.  The effects of electrical stimulation of myelinated and non‐myelinated vagal fibres on heart rate in the rabbit. , 1986, The Journal of physiology.

[16]  J. Sacha,et al.  Different methods of heart rate variability analysis reveal different correlations of heart rate variability spectrum with average heart rate. , 2005, Journal of electrocardiology.

[17]  F. Carré,et al.  Relationships between heart rate and heart rate variability: study in conscious rats. , 1998, Journal of cardiovascular pharmacology.

[18]  J. Cacioppo,et al.  Autonomic space and psychophysiological response. , 1994, Psychophysiology.

[19]  D L Eckberg,et al.  Human sinus arrhythmia as an index of vagal cardiac outflow. , 1983, Journal of applied physiology: respiratory, environmental and exercise physiology.

[20]  A. Kadish,et al.  Effect of Graded Increases in Parasympathetic Tone on Heart Rate Variability , 1996, Journal of cardiovascular electrophysiology.

[21]  Y Rudy,et al.  Mathematical model of dependence of heart rate on tissue concentration of acetylcholine. , 1989, The American journal of physiology.

[22]  Arie V Nieuw Amerongen,et al.  Innate Secretory Immunity in Response to Laboratory Stressors That Evoke Distinct Patterns of Cardiac Autonomic Activity , 2003, Psychosomatic medicine.

[23]  H Zhang,et al.  Mathematical models of action potentials in the periphery and center of the rabbit sinoatrial node. , 2000, American journal of physiology. Heart and circulatory physiology.

[24]  J. Rottenberg,et al.  RSA fluctuation in major depressive disorder. , 2007, Psychophysiology.

[25]  D H Singer,et al.  Heart rate variability and sudden death secondary to coronary artery disease during ambulatory electrocardiographic monitoring. , 1987, The American journal of cardiology.

[26]  G. Berntson,et al.  Autonomic interactions and chronotropic control of the heart: heart period versus heart rate. , 1996, Psychophysiology.

[27]  K. Quigley,et al.  Autonomic origins of a nonsignal stimulus-elicited bradycardia and its habituation in humans. , 2001, Psychophysiology.

[28]  J. Thayer,et al.  Heart rate variability as a transdiagnostic biomarker of psychopathology. , 2015, International Journal of Psychophysiology.

[29]  Bernhard Dahme,et al.  Implementation and Interpretation of Respiratory Sinus Arrhythmia Measures in Psychosomatic Medicine: Practice Against Better Evidence? , 2006, Psychosomatic medicine.

[30]  C. Saper The central autonomic nervous system: conscious visceral perception and autonomic pattern generation. , 2002, Annual review of neuroscience.

[31]  D. Jewett,et al.  Activity of single efferent fibres in the cervical vagus nerve of the dog, with special reference to possible cardio‐inhibitory fibres , 1964, The Journal of physiology.

[32]  Ying Fu,et al.  Endogenous RGS proteins modulate SA and AV nodal functions in isolated heart: implications for sick sinus syndrome and AV block. , 2007, American journal of physiology. Heart and circulatory physiology.

[33]  J. Jansen,et al.  Functional development of the parasympathetic innervation of the sino-auricular node in newborn rabbits, cats and guinea pigs , 1983, Pflügers Archiv.

[34]  M. Sugimachi,et al.  In vivo direct monitoring of vagal acetylcholine release to the sinoatrial node , 2009, Autonomic Neuroscience.

[35]  T. Kawada,et al.  In vivo monitoring of acetylcholine release from cardiac vagal nerve endings in anesthetized mice , 2013, Autonomic Neuroscience.

[36]  René van Lien,et al.  Underestimation of cardiac vagal control in regular exercisers by 24-hour heart rate variability recordings. , 2011, International journal of psychophysiology : official journal of the International Organization of Psychophysiology.

[37]  J. Cacioppo,et al.  Vagal stimulation and cardiac chronotropy in rats. , 1992, Journal of the autonomic nervous system.

[38]  J. Cacioppo,et al.  Autonomic determinism: the modes of autonomic control, the doctrine of autonomic space, and the laws of autonomic constraint. , 1991, Psychological review.

[39]  T. Opthof,et al.  The normal range and determinants of the intrinsic heart rate in man. , 2000, Cardiovascular research.

[40]  R W Barnes,et al.  Cardiac autonomic function and incident coronary heart disease: a population-based case-cohort study. The ARIC Study. Atherosclerosis Risk in Communities Study. , 1997, American journal of epidemiology.

[41]  J. Fleiss,et al.  Frequency Domain Measures of Heart Period Variability and Mortality After Myocardial Infarction , 1992, Circulation.

[42]  Jan A. Kors,et al.  Normal Values of Corrected Heart-Rate Variability in 10-Second Electrocardiograms for All Ages , 2018, Front. Physiol..

[43]  P. Schwartz,et al.  Autonomic nervous system and sudden cardiac death. Experimental basis and clinical observations for post-myocardial infarction risk stratification. , 1992, Circulation.

[44]  D Kromhout,et al.  Heart rate variability from short electrocardiographic recordings predicts mortality from all causes in middle-aged and elderly men. The Zutphen Study. , 1997, American journal of epidemiology.

[45]  M. Takano,et al.  HCN4 pacemaker channels attenuate the parasympathetic response and stabilize the spontaneous firing of the sinoatrial node , 2018, The Journal of physiology.

[46]  O. Dekkers,et al.  Heart rate variability and first cardiovascular event in populations without known cardiovascular disease: meta-analysis and dose-response meta-regression. , 2013, Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology.

[47]  G R Hageman,et al.  Differential sympathetic-parasympathetic interactions in sinus node and AV junction. , 1986, The American journal of physiology.

[48]  M. N. Levy,et al.  Autonomic control of cardiac pacemaker activity and atrioventricular transmission. , 1969, Journal of applied physiology.

[49]  J. Fleiss,et al.  Components of heart rate variability measured during healing of acute myocardial infarction. , 1988, The American journal of cardiology.

[50]  E. Tobaldini,et al.  Modulation of sympathetic activity and heart rate variability by ivabradine. , 2015, Cardiovascular research.

[51]  D L Eckberg,et al.  Physiological basis for human autonomic rhythms , 2000, Annals of medicine.

[52]  M. Boyett Last Word on Point:Counterpoint. , 2017, Journal of applied physiology.

[53]  J. Cacioppo,et al.  Respiratory sinus arrhythmia: autonomic origins, physiological mechanisms, and psychophysiological implications. , 1993, Psychophysiology.

[54]  P G Katona,et al.  Cardiac vagal efferent activity and heart period in the carotid sinus reflex. , 1970, The American journal of physiology.

[55]  Shin Inada,et al.  Biophysical Characterization of the Underappreciated and Important Relationship Between Heart Rate Variability and Heart Rate , 2014, Hypertension.

[56]  G. Anrep,et al.  Respiratory Variations of the Heart Rate. I.--The Reflex Mechanism of the Respiratory Arrhythmia , 1936 .

[57]  R. Prescott,et al.  Prospective study of heart rate variability and mortality in chronic heart failure: results of the United Kingdom heart failure evaluation and assessment of risk trial (UK-heart). , 1998, Circulation.

[58]  G. Schuler,et al.  Correlation of exercise capacity with high-sensitive C-reactive protein in patients with stable coronary artery disease. , 2005, American heart journal.

[59]  Jørgen K. Kanters,et al.  Heart Rate Versus Heart Rate Variability in Risk Prediction after Myocardial Infarction , 2003, Journal of cardiovascular electrophysiology.

[60]  P. Grossman,et al.  Respiratory sinus arrhythmia, cardiac vagal tone, and respiration: within- and between-individual relations. , 1993, Psychophysiology.

[61]  L. Chambless,et al.  Diabetes, glucose, insulin, and heart rate variability: the Atherosclerosis Risk in Communities (ARIC) study. , 2005, Diabetes care.

[62]  H. Huikuri,et al.  Heart rate variability and recurrence of atrial fibrillation after electrical cardioversion , 2003, Annals of medicine.

[63]  D. McCloskey,et al.  Vagal stimulation and cardiac slowing. , 1984, Journal of the autonomic nervous system.

[64]  Michele A. Parker,et al.  Relationship of Heart Rate Variability to Parasympathetic Effect , 2001, Circulation.

[65]  H. L. Stone,et al.  Autonomic mechanisms in ventricular fibrillation induced by myocardial ischemia during exercise in dogs with healed myocardial infarction. An experimental preparation for sudden cardiac death. , 1984, Circulation.

[66]  Ferdinand J. Venditti,et al.  Reduced Heart Rate Variability and Mortalit Risk in an Elderly Cohort: The Framingham Heart Study , 1994, Circulation.

[67]  John J. B. Allen,et al.  Cardiac vagal control, emotion, psychopathology, and health , 2007, Biological Psychology.

[68]  A. Folsom,et al.  Low Heart Rate Variability in a 2-Minute Rhythm Strip Predicts Risk of Coronary Heart Disease and Mortality From Several Causes: The ARIC Study , 2000, Circulation.

[69]  C. Wientjes,et al.  A comparison of three quantification methods for estimation of respiratory sinus arrhythmia. , 1990, Psychophysiology.

[70]  Hans-Christer Holmberg,et al.  Following a Long-Distance Classical Race the Whole-Body Kinematics of Double Poling by Elite Cross-Country Skiers Are Altered , 2018, Front. Physiol..

[71]  J. Fleiss,et al.  The correlation between heart period variability and mean period length. , 1992, Statistics in medicine.

[72]  Usman Zulfiqar,et al.  Relation of high heart rate variability to healthy longevity. , 2010, The American journal of cardiology.

[73]  Solange Akselrod,et al.  Parametric description of cardiac vagal control , 2003, Autonomic Neuroscience.

[74]  F. Basile,et al.  Heart rate variability and myocardial infarction: systematic literature review and metanalysis. , 2009, European review for medical and pharmacological sciences.

[75]  J. Cacioppo,et al.  Autonomic cardiac control. I. Estimation and validation from pharmacological blockades. , 1994, Psychophysiology.

[76]  P. Graziano,et al.  Cardiac vagal control and children's adaptive functioning: A meta-analysis , 2013, Biological Psychology.

[77]  M. Mark,et al.  G-protein mediated gating of inward-rectifier K+ channels. , 2000, European journal of biochemistry.

[78]  P. Grossman,et al.  Prediction of tonic parasympathetic cardiac control using respiratory sinus arrhythmia: the need for respiratory control. , 1991, Psychophysiology.

[79]  N Lovell,et al.  Ion currents underlying sinoatrial node pacemaker activity: a new single cell mathematical model. , 1996, Journal of theoretical biology.

[80]  D. Eckberg,et al.  The human respiratory gate. , 2003, The Journal of physiology.

[81]  M. N. Levy,et al.  Selective Stimulation of Parasympathetic Nerve Fibers to the Human Sinoatrial Node , 1992, Circulation.

[82]  F Lombardi,et al.  Autonomic indexes based on the analysis of heart rate variability: a view from the sinus node. , 2001, Cardiovascular research.

[83]  D L Eckberg,et al.  Sympathetic restraint of respiratory sinus arrhythmia: implications for vagal-cardiac tone assessment in humans. , 2001, American journal of physiology. Heart and circulatory physiology.

[84]  Sophie van der Sluis,et al.  Comparison of time and frequency domain measures of RSA in ambulatory recordings. , 2007, Psychophysiology.

[85]  J. Hartikainen,et al.  Effect of sympathetic modulation and sympatho-vagal interaction on heart rate variability in anaesthetized dogs. , 1995, Acta physiologica Scandinavica.

[86]  P. Schwartz,et al.  Sympathetic-parasympathetic interaction and accentuated antagonism in conscious dogs. , 1991, The American journal of physiology.

[87]  A. Hofman,et al.  Both decreased and increased heart rate variability on the standard 10-second electrocardiogram predict cardiac mortality in the elderly: the Rotterdam Study. , 1999, American journal of epidemiology.

[88]  J. Borer,et al.  Characterization of the Heart Rate-Lowering Action of Ivabradine, a Selective If Current Inhibitor , 2008, American journal of therapeutics.

[89]  E. D. de Geus,et al.  Parsimonious Correction of Heart Rate Variability for Its Dependency on Heart Rate. , 2016, Hypertension.

[90]  E. D. de Geus,et al.  Differential effects of active versus passive coping on secretory immunity. , 2001, Psychophysiology.

[91]  H. Zhang,et al.  Letter by Monfredi et al regarding article, "Physical activity and heart rate variability in older adults: the cardiovascular health study". , 2015, Circulation.

[92]  Y Rudy,et al.  Mathematical Model of the Changes in Heart Rate Elicited by Vagal Stimulation , 1989, Circulation research.

[93]  Gary G Berntson,et al.  Filter properties of root mean square successive difference (RMSSD) for heart rate. , 2005, Psychophysiology.

[94]  M. Sugimachi,et al.  In vivo direct monitoring of interstitial norepinephrine levels at the sinoatrial node , 2010, Autonomic Neuroscience.

[95]  L. Mulder,et al.  The utility of low frequency heart rate variability as an index of sympathetic cardiac tone: a review with emphasis on a reanalysis of previous studies. , 2013, Psychophysiology.

[96]  R. Tarazi,et al.  Assessment of parasympathetic control of heart rate by a noninvasive method. , 1984, The American journal of physiology.

[97]  P. Schwartz,et al.  Autonomic mechanisms and sudden death. New insights from analysis of baroreceptor reflexes in conscious dogs with and without a myocardial infarction. , 1988, Circulation.

[98]  P. Stein,et al.  Heart rate variability in risk stratification of cardiac patients. , 2013, Progress in cardiovascular diseases.

[99]  Rehan Qayyum,et al.  Heart rate variability predicts ESRD and CKD-related hospitalization. , 2010, Journal of the American Society of Nephrology : JASN.

[100]  Gary G Berntson,et al.  Cardiac autonomic balance versus cardiac regulatory capacity. , 2008, Psychophysiology.

[101]  M. Boyett,et al.  Rebuttal from Boyett et al. , 2017, Journal of applied physiology.

[102]  L. Lind,et al.  A method for heart rate-corrected estimation of baroreflex sensitivity , 2003, Journal of hypertension.

[103]  F Lombardi,et al.  Role of the Input/Output Relation of Sinoatrial Myocytes in Cholinergic Modulation of Heart Rate Variability , 2000, Journal of cardiovascular electrophysiology.

[104]  Ş. Balta,et al.  Ivabradine Improves Heart Rate Variability in Patients with Nonischemic Dilated Cardiomyopathy , 2014, Arquivos brasileiros de cardiologia.

[105]  J. Miller,et al.  Decreased heart rate variability and its association with increased mortality after acute myocardial infarction. , 1987, The American journal of cardiology.

[106]  J. Goldberger,et al.  Sympathovagal balance: how should we measure it? , 1999, The American journal of physiology.

[107]  R. Lane,et al.  A model of neurovisceral integration in emotion regulation and dysregulation. , 2000, Journal of affective disorders.

[108]  N. Craft,et al.  Effects of age on intrinsic heart rate, heart rate variability, and AV conduction in healthy humans. , 1995, The American journal of physiology.

[109]  Daniel C Bartos,et al.  Ion Channels in the Heart. , 2015, Comprehensive Physiology.

[110]  M. N. Levy,et al.  Comparison of the cardiac effects of vagus nerve stimulation and of acetylcholine infusions. , 1969, The American journal of physiology.

[111]  Predictive power of increased heart rate versus depressed left ventricular ejection fraction and heart rate variability for risk stratification after myocardial infarction. Results of a two-year follow-up study. , 1996, Journal of the American College of Cardiology.

[112]  M. Kollai,et al.  Respiratory sinus arrhythmia is a limited measure of cardiac parasympathetic control in man. , 1990, The Journal of physiology.

[113]  K Koizumi,et al.  Effect of cardiac vagal and sympathetic nerve activity on heart rate in rhythmic fluctuations. , 1985, Journal of the autonomic nervous system.

[114]  Maxine Weinstein,et al.  Vagally-Mediated Heart Rate Variability and Indices of Well-Being: Results of a Nationally Representative Study , 2017, Health psychology : official journal of the Division of Health Psychology, American Psychological Association.

[115]  J. Thayer,et al.  Heart Rate Variability, Prefrontal Neural Function, and Cognitive Performance: The Neurovisceral Integration Perspective on Self-regulation, Adaptation, and Health , 2009, Annals of behavioral medicine : a publication of the Society of Behavioral Medicine.

[116]  P. Martin,et al.  Cardiac electrical responses to vagal stimulation of fibers to discrete cardiac regions. , 1990, The American journal of physiology.