48. Costa MD, Goldberger AL. Heart rate fragmentation: using cardiac pacemaker dynamics to probe the pace of biological aging. Am J Physiol Heart Circ Physiol 2019; 316:H1341. 49. Costa MD, Redline S, Davis RB, et al. Heart Rate Fragmentation as a Novel Biomarker of Adverse Cardiovascular Events: The Multi-Ethnic Study of Atherosclerosis. Front Physiol 2018; 9:1117. 50. Costa MD, Redline S, Soliman EZ, et al. Fragmented sinoatrial dynamics in the prediction of atrial fibrillation: the Multi-Ethnic Study of Atherosclerosis. Am J Physiol Heart Circ Physiol 2021; 320:H256. 51. Costa MD, Redline S, Hughes TM, et al. Prediction of Cognitive Decline Using Heart Rate Fragmentation Analysis: The Multi-Ethnic Study of Atherosclerosis. Front Aging Neurosci 2021; 13:708130. 52. Mietus JE, Peng CK, Henry I, et al. The pNNx files: re-examining a widely used heart rate variability measure. Heart 2002; 88:378. 53. Schmidt G, Malik M, Barthel P, et al. Heart-rate turbulence after ventricular premature beats as a predictor of mortality after acute myocardial infarction. Lancet 1999; 353:1390. 54. Stein PK. Heart rate turbulence: explorations of an emerging risk factor. J Cardiovasc Electrophysiol 2003; 14:453. 55. Stein PK, Barzilay JI. Relationship of abnormal heart rate turbulence and elevated CRP to cardiac mortality in low, intermediate, and high-risk older adults. J Cardiovasc Electrophysiol 2011; 22:122. 56. Bauer, A, Schmidt, G. Heart rate turbulence in ischemic heart disease. In: Dynamic Electroca rdiography. Malik M, Camm AJ (Eds), Futura Publishing Company, Elmsford, NY. p.211. 57. Stein PK, Barzilay JI, Chaves PH, et al. Novel measures of heart rate variability predict cardiovascular mortality in older adults independent of traditional cardiovascular risk factors: the Cardiovascular Health Study (CHS). J Cardiovasc Electrophysiol 2008; 19:1169. 58. Barthel P, Schneider R, Bauer A, et al. Risk stratification after acute myocardial infarction by heart rate turbulence. Circulation 2003; 108:1221. 59. Cygankiewicz I. Heart rate turbulence. Prog Cardiovasc Dis 2013; 56:160. 60. Au-Yeung WT, Reinhall PG, Poole JE, et al. SCD-HeFT: Use of R-R interval statistics for long- term risk stratification for arrhythmic sudden cardiac death. Heart Rhythm 2015; 12:2058. https://www.uptodate.com/contents/evaluation-of-heart-rate-variability/print 23/32 7/6/23, 10:42 AM Evaluation of heart rate variability - UpToDate 61. Takahashi N, Kuriyama A, Kanazawa H, et al. Validity of spectral analysis based on heart rate variability from 1-minute or less ECG recordings. Pacing Clin Electrophysiol 2017; 40:1004. 62. Nolan J, Batin PD, Andrews R, 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). Circulation 1998; 98:1510. 63. Frey B, Heinz G, Binder T, et al. Diurnal variation of ventricular response to atrial fibrillation in patients with advanced heart failure. Am Heart J 1995; 129:58. 64. Taylor JA, Carr DL, Myers CW, Eckberg DL. Mechanisms underlying very-low-frequency RR- interval oscillations in humans. Circulation 1998; 98:547. 65. Tripathi KK. Very low frequency oscillations in the power spectra of heart rate variability during dry supine immersion and exposure to non-hypoxic hypobaria. Physiol Meas 2011; 32:717. 66. Akselrod S, Gordon D, Ubel FA, et al. Power spectrum analysis of heart rate fluctuation: a quantitative probe of beat-to-beat cardiovascular control. Science 1981; 213:220. 67. Peng CK, Mietus JE, Liu Y, et al. Exaggerated heart rate oscillations during two meditation techniques. Int J Cardiol 1999; 70:101. 68. Bernardi L, Sleight P, Bandinelli G, et al. Effect of rosary prayer and yoga mantras on autonomic cardiovascular rhythms: comparative study. BMJ 2001; 323:1446. 69. Peng CK, Henry IC, Mietus JE, et al. Heart rate dynamics during three forms of meditation. Int J Cardiol 2004; 95:19. 70. Badra LJ, Cooke WH, Hoag JB, et al. Respiratory modulation of human autonomic rhythms. Am J Physiol Heart Circ Physiol 2001; 280:H2674. 71. Lombardi F, Stein PK. Origin of heart rate variability and turbulence: an appraisal of autonomic modulation of cardiovascular function. Front Physiol 2011; 2:95. 72. Nunan D, Sandercock GR, Brodie DA. A quantitative systematic review of normal values for short-term heart rate variability in healthy adults. Pacing Clin Electrophysiol 2010; 33:1407. 73. Bigger JT Jr, Fleiss JL, Steinman RC, et al. RR variability in healthy, middle-aged persons compared with patients with chronic coronary heart disease or recent acute myocardial infarction. Circulation 1995; 91:1936. 74. Umetani K, Singer DH, McCraty R, Atkinson M. Twenty-four hour time domain heart rate variability and heart rate: relations to age and gender over nine decades. J Am Coll Cardiol 1998; 31:593. 75. Stein PK, Barzilay JI, Chaves PH, et al. Heart rate variability and its changes over 5 years in older adults. Age Ageing 2009; 38:212. https://www.uptodate.com/contents/evaluation-of-heart-rate-variability/print 24/32 7/6/23, 10:42 AM Evaluation of heart rate variability - UpToDate 76. Bigger, JT. RR variability to evaluate autonomic physiology and pharmacology and to predict cardiovascular outcomes in human. In: Cardiac Arrhythmias: From Cell to Bedside, Zipes DP (Ed), Saunders, Philadelphia 1995. p.1151. 77. Liao D, Barnes RW, Chambless LE, et al. Age, race, and sex differences in autonomic cardiac function measured by spectral analysis of heart rate variability the ARIC study. Atherosclerosis Risk in Communities. Am J Cardiol 1995; 76:906. 78. Kleiger RE, Bigger JT, Bosner MS, et al. Stability over time of variables measuring heart rate variability in normal subjects. Am J Cardiol 1991; 68:626. 79. Stein PK. Heart rate variability and longevity. Am J Cardiol 2010; 106:910. 80. Bigger JT Jr, Fleiss JL, Rolnitzky LM, Steinman RC. Stability over time of heart period variability in patients with previous myocardial infarction and ventricular arrhythmias. The CAPS and ESVEM investigators. Am J Cardiol 1992; 69:718. 81. Bj rkander I, Forslund L, Ericson M, et al. Long-term stability of heart rate variability in chronic stable angina pectoris, and the impact of an acute myocardial infarction. Clin Physiol Funct Imaging 2009; 29:201. 82. Peppard PE, Young T, Barnet JH, et al. Increased prevalence of sleep-disordered breathing in adults. Am J Epidemiol 2013; 177:1006. 83. Stein PK, Duntley SP, Domitrovich PP, et al. A simple method to identify sleep apnea using Holter recordings. J Cardiovasc Electrophysiol 2003; 14:467. 84. Kleiger RE, Miller JP, Bigger JT Jr, Moss AJ. Decreased heart rate variability and its association with increased mortality after acute myocardial infarction. Am J Cardiol 1987; 59:256. 85. La Rovere MT, Bigger JT Jr, Marcus FI, et al. Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction. ATRAMI (Autonomic Tone and Reflexes After Myocardial Infarction) Investigators. Lancet 1998; 351:478. 86. Buccelletti E, Gilardi E, Scaini E, et al. Heart rate variability and myocardial infarction: systematic literature review and metanalysis. Eur Rev Med Pharmacol Sci 2009; 13:299. 87. Erdogan A, Coch M, Bilgin M, et al. Prognostic value of heart rate variability after acute myocardial infarction in the era of immediate reperfusion. Herzschrittmacherther Elektrophysiol 2008; 19:161. 88. Flapan AD, Wright RA, Nolan J, et al. Differing patterns of cardiac parasympathetic activity and their evolution in selected patients with a first myocardial infarction. J Am Coll Cardiol 1993; 21:926. 89. Bigger JT Jr, Fleiss JL, Rolnitzky LM, et al. Time course of recovery of heart period variability after myocardial infarction. J Am Coll Cardiol 1991; 18:1643. https://www.uptodate.com/contents/evaluation-of-heart-rate-variability/print 25/32 7/6/23, 10:42 AM Evaluation of heart rate variability - UpToDate 90. Bigger JT Jr, Fleiss JL, Rolnitzky LM, Steinman RC. Frequency domain measures of heart period variability to assess risk late after myocardial infarction. J Am Coll Cardiol 1993; 21:729. 91. Stein PK, Domitrovich PP, Kleiger RE, CAST Investigators. Including patients with diabetes mellitus or coronary artery bypass grafting decreases the association between heart rate variability and mortality after myocardial infarction. Am Heart J 2004; 147:309. 92. Whang W, Bigger JT Jr. Comparison of the prognostic value of RR-interval variability after acute myocardial infarction in patients with versus those without diabetes mellitus. Am J Cardiol 2003; 92:247. 93. Janszky I, Ericson M, Mittleman MA, et al. Heart rate variability in long-term risk assessment in middle-aged women with coronary heart disease: The Stockholm Female Coronary Risk Study. J Intern Med 2004; 255:13. 94. Kotecha D, New G, Flather MD, et al. Five-minute heart rate variability can predict obstructive angiographic coronary disease. Heart 2012; 98:395. 95. Yi G, Goldman JH, Keeling PJ, et al. Heart rate variability in idiopathic dilated cardiomyopathy: relation to disease severity and prognosis. Heart 1997; 77:108. 96. Szab BM, van Veldhuisen DJ, van der Veer N, et al. Prognostic value of heart rate variability in chronic congestive heart failure secondary to idiopathic or ischemic dilated cardiomyopathy. Am J Cardiol 1997; 79:978. 97. Fauchier L, Babuty D, Cosnay P, et al. Heart rate variability in idiopathic dilated cardiomyopathy: characteristics and prognostic value. J Am Coll Cardiol 1997; 30:1009. 98. Ponikowski P, Anker SD, Chua TP, et al. Depressed heart rate variability as an independent predictor of death in chronic congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 1997; 79:1645. 99. M kikallio TH, Huikuri HV, Hintze U, et al. Fractal analysis and time- and frequency-domain measures of heart rate variability as predictors of mortality in patients with heart failure. Am J Cardiol 2001; 87:178. 100. Fauchier L, Babuty D, Cosnay P, Fauchier JP. Prognostic value of heart rate variability for sudden death and major arrhythmic events in patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol 1999; 33:1203. 101. La Rovere MT, Pinna GD, Maestri R, et al. Short-term heart rate variability strongly predicts sudden cardiac death in chronic heart failure patients. Circulation 2003; 107:565. 102. Fantoni C, Raffa S, Regoli F, et al. Cardiac resynchronization therapy improves heart rate profile and heart rate variability of patients with moderate to severe heart failure. J Am Coll https://www.uptodate.com/contents/evaluation-of-heart-rate-variability/print 26/32 7/6/23, 10:42 AM Evaluation of heart rate variability - UpToDate Cardiol 2005; 46:1875. 103. Landolina M, Gasparini M, Lunati M, et al. Heart rate variability monitored by the implanted device predicts response to CRT and long-term clinical outcome in patients with advanced heart failure. Eur J Heart Fail 2008; 10:1073. 104. Stein PK, Pu Y. Heart rate variability in congestive heart failure. In: Heart rate variability sign al processing: Clinical applications, Kamath M, Watanabe M (Eds), CRC Press (Taylor and Fra ncis LLC), Boca Raton, FL 2012. p.303. 105. Yamada A, Hayano J, Sakata S, et al. Reduced ventricular response irregularity is associated with increased mortality in patients with chronic atrial fibrillation. Circulation 2000; 102:300. 106. Lombardi F, Colombo A, Basilico B, et al. Heart rate variability and early recurrence of atrial fibrillation after electrical cardioversion. J Am Coll Cardiol 2001; 37:157. 107. Tsuji H, Larson MG, Venditti FJ Jr, et al. Impact of reduced heart rate variability on risk for cardiac events. The Framingham Heart Study. Circulation 1996; 94:2850. 108. Dekker JM, Crow RS, Folsom AR, 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. Atherosclerosis Risk In Communities. Circulation 2000; 102:1239. 109. Shah SA, Kambur T, Chan C, et al. Relation of short-term heart rate variability to incident heart failure (from the Multi-Ethnic Study of Atherosclerosis). Am J Cardiol 2013; 112:533. 110. Hillebrand S, Gast KB, de Mutsert R, et al. Heart rate variability and first cardiovascular event in populations without known cardiovascular disease: meta-analysis and dose-response meta-regression. Europace 2013; 15:742. 111. Malik M, Camm AJ, Janse MJ, et al. Depressed heart rate variability identifies postinfarction patients who might benefit from prophylactic treatment with amiodarone: a substudy of EMIAT (The European Myocardial Infarct Amiodarone Trial). J Am Coll Cardiol 2000; 35:1263. 112. Patel VN, Pierce BR, Bodapati RK, et al. Association of Holter-Derived Heart Rate Variability Parameters With the Development of Congestive Heart Failure in the Cardiovascular Health Study. JACC Heart Fail 2017; 5:423. 113. Sullivan BA, Grice SM, Lake DE, et al. Infection and other clinical correlates of abnormal heart rate characteristics in preterm infants. J Pediatr 2014; 164:775. 114. Crawford MH, Bernstein SJ, Deedwania PC, et al. ACC/AHA guidelines for ambulatory electrocardiography: executive summary and recommendations. A report of the American College of Cardiology/American Heart Association task force on practice guidelines (committee to revise the guidelines for ambulatory electrocardiography). Circulation 1999; 100:886. https://www.uptodate.com/contents/evaluation-of-heart-rate-variability/print 27/32 7/6/23, 10:42 AM Evaluation of heart rate variability - UpToDate 115. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction). Circulation 2004; 110:588. 116. Tegegne BS, Man T, van Roon AM, et al. Determinants of heart rate variability in the general population: The Lifelines Cohort Study. Heart Rhythm 2018; 15:1552. 117. Mol MBA, Strous MTA, van Osch FHM, et al. Heart-rate-variability (HRV), predicts outcomes in COVID-19. PLoS One 2021; 16:e0258841. Topic 993 Version 33.0 https://www.uptodate.com/contents/evaluation-of-heart-rate-variability/print 28/32 7/6/23, 10:42 AM Evaluation of heart rate variability - UpToDate GRAPHICS Autonomic innervation of the heart The heart, especially the pacemaker tissue, is innervated by fibers from both the parasympathetic and sympathetic nervous systems. Graphic 69693 Version 1.0 https://www.uptodate.com/contents/evaluation-of-heart-rate-variability/print 29/32 7/6/23, 10:42 AM Evaluation of heart rate variability - UpToDate Definitions for time and frequency domain measures of heart period variability Variable Units Definition Time Domain - Statistical measures Night-day ms Difference between the average of all the normal RR intervals at night difference (24:00 to 05:00) and the average of all the normal RR intervals during the day (07:30 to 21:30). SDNN ms Standard deviation of all normal RR intervals in the entire 24-hour ECG recording. SDANN ms Standard deviation of the average normal RR intervals for all 288 5- minute segments of a 24-hour ECG recording (each average is weighted by the fraction of the 5 minutes that has normal RR intervals). ASDNN ms Average of the standard deviations of normal RR intervals for all 288 5-minute segments of a 24-hour ECG recording. r-MSSD ms Root mean square successive difference, the square root of the mean of the squared differences between adjacent normal RR intervals over the entire 24-hour ECG recording. pNN50 percent Percent of differences between adjacent normal RR intervals that are greater than 50 ms computed over the entire 24-hour ECG recording. NN50 none Number of adjacent normal RR intervals that are greater than 50 ms counted over the entire 24-hour ECG recording. Time Domain - Geometric measures HRV triangular none Total number of NN intervals divided by the number of NN intervals in index the modal bin of a histogram of all NN intervals with a bin width of 7.8125 msec (for a sampling rate of 128/sec). TINN ms Baseline width of the minimum square difference triangular interpolation of the highest peak of the histogram of all NN intervals. Frequency Domain Measures 2 Total power ms The energy in the heart period power spectrum up to 0.40 Hz. 2 Ultra low ms The energy in the heart period power spectrum up to 0.0033 Hz. frequency (ULF) power 2 Very low frequency (VLF) ms The energy in the heart period power spectrum between 0.0033 and 0.04 Hz. power https://www.uptodate.com/contents/evaluation-of-heart-rate-variability/print 30/32 7/6/23, 10:42 AM Evaluation of heart rate variability - UpToDate 2 Low frequency ms The energy in the heart period power spectrum between 0.04 and (LF) power 0.15 Hz. 2 High frequency (HF) power ms The energy in the heart period power spectrum between 0.15 and 0.40 Hz. LF/HF ratio none The ratio of low to high frequency power. beta none Slope of log (power) on log (frequency) between 0.01 and 0.0001 Hz on a log-log plot. Graphic 79145 Version 4.0 https://www.uptodate.com/contents/evaluation-of-heart-rate-variability/print 31/32 7/6/23, 10:42 AM Evaluation of heart rate variability - UpToDate Contributor Disclosures Ary L Goldberger, MD Other Financial Interest: Elsevier book royalties [Clinical electrocardiography]. All of the relevant financial relationships listed have been mitigated. Phyllis K Stein, PhD No relevant financial relationship(s) with ineligible companies to disclose. N A Mark Estes, III, MD Consultant/Advisory Boards: Boston Scientific [Arrhythmias]; Medtronic [Arrhythmias]. All of the relevant financial relationships listed have been mitigated. Susan B Yeon, MD, JD, FACC No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/evaluation-of-heart-rate-variability/print 32/32