longer-term trends are mediated by changes in parasympathetic activity, the magnitude of either of these measures is taken as a surrogate of parasympathetic modulation of heart rate. https://www.uptodate.com/contents/evaluation-of-heart-rate-variability/print 11/32 7/6/23, 10:42 AM Evaluation of heart rate variability - UpToDate For this reason, these measures should correlate strongly with each other and with HF power, which also measures parasympathetic activity as expressed by changes in the respiratory frequency band. Normal values for HRV One of the complicating factors in using HRV clinically, aside from the technical issues discussed above, is that unlike, for example, a blood pressure measurement, there is a considerable range of normal values even in people of the same age and sex, and considerable ranges of normal change with age. A review of existing studies of normal values for short-term HRV found huge discrepancies in values [72]. More is known about 24-hour HRV measures, which have been collected in a large number of clinical populations and in some nonclinical ones as well. One study compared HRV in healthy middle-aged adults, recent post-MI patients (from the 1980s), and patients who were one-year post-MI [73]. SDNN was highest in the healthy adults, intermediate in the one-year post-MI group, and lowest in the recent MI group, but there were no differences between groups in time domain measures of beat-to-beat HRV (rMSSD and pNN50), potentially because the organization of the heart rate patterns (true RSA versus erratic sinus rhythm) cannot be determined from traditional time domain measures. Importantly, the study reported that at the upper end of the distribution for the three groups, HRV did not separate healthy subjects from patients with either recent MI or one year post-MI. Thus, clinically, it is possible to find normal circadian HRV in a cardiac patient, probably reflecting the ability to sleep well. Conversely, consistent with the notion that very low HRV reflects a significant abnormality, only 2 of 274 normal adults had values for ULF power previously reported to identify CHD patients at high risk of death, and only three had values for LF power below the cut-point for increased risk of mortality in CHD patients, thus supporting the possibility that finding a presumably healthy adult with very low 24-hour HRV would be clinically meaningful but also underscoring the fact the "normal" HRV values may be found in patients with known CVD. A 1998 study of HRV in 260 healthy adults found that HRV was both age and sex- dependent, with 95 percent confidence intervals reported for each decade [74]. Unfortunately, these limits are so broad as to be unusable clinically. For example, among adults in their 60's, normal limits for SDNN were defined as between 68 and 186 ms, and normal limits for 24-hour averaged heart rate were 52 to 99 bpm. The Cardiovascular Health Study examined changes in 24-hour-based frequency domain HRV over five years in 585 adults >65 years old [75]. HRV declined more in the group that was aged 65 to 69 at baseline, less in the group that was 70 to 74, and almost not at all in the group that was 75 years old. Although most HRV was slightly but significantly lower in https://www.uptodate.com/contents/evaluation-of-heart-rate-variability/print 12/32 7/6/23, 10:42 AM Evaluation of heart rate variability - UpToDate the group with prevalent cardiovascular disease, there was no difference in the magnitude of the age-related change in HRV among those with or without CVD. However, heart rate, ratio-based and nonlinear HRV values continued to decline with advancing age [75]. Reproducibility of HRV measures The utility of HRV measures for prediction of outcome or detection of changes in clinical status depends on their stability over time. HRV is influenced significantly by age, race, sex, physical fitness, clinical comorbidities and drug treatment, but most 24-hour HRV appears to be stable when measured on a day-to-day basis and over periods of days to weeks when there are no major intervening events [76-78]. Less is known about serial changes in HRV in the same individuals over longer periods of time, but as previously mentioned, these changes might be age- and measure-dependent [79]. Finally, the limitation of 24-hour recordings is being overcome by advances in technology. Whereas in the early days of clinical HRV data collection, subjects were asked to wear a somewhat cumbersome Holter device that recorded their ECG on reel-to-reel or later cassette tapes (two channels over 24 hours at a sampling rate of 128 Hz), technology permits collection of multichannel, high-resolution ECGs via a small patch attached to the chest, over several days in a row, either using a built-in SSD card or uploaded to a web server. HRV can also be measured from stored signals from inpatient ICU monitoring. This has greatly expanded potential applications of inpatient and outpatient HRV to interventions, eg, dialysis or chemotherapy. Reproducibility in patients with cardiac disease The reproducibility of HR variability measurements in patients with cardiac disease has been found to be comparable to the high stability observed in normal subjects. The stability of measures of HRV makes it possible to distinguish real changes due to progression or regression of cardiac disease or drug effects from apparent changes due to random variation. Unfortunately, criteria for real and significant changes in HRV have not been established. However, if a patient goes from apparently normal HRV (eg, SDNN >120 ms) to markedly decreased HRV (eg SDNN <70 ms) on serial recordings, this would be a matter of concern. As examples: Patients with ventricular arrhythmias In a study that evaluated the day-to-day stability of HRV in two groups of arrhythmia patients (a random sample of 40 patients in the ESVEM study who had sustained ventricular arrhythmias, and a random sample of 40 patients in the placebo group of CAPS who had nonsustained ventricular arrhythmias), there were no significant differences in measures of HRV between the two 24-hour recording sessions in either group [80]. Patients with stable angina In a study of 261 patients with chronic stable angina followed for three years, most HRV measures remained largely unchanged over time, although pNN50 and LF/HF were less stable [81]. Declines in most HRV measures, although not HF https://www.uptodate.com/contents/evaluation-of-heart-rate-variability/print 13/32 7/6/23, 10:42 AM Evaluation of heart rate variability - UpToDate power, were seen in those who suffered a myocardial infarction during that period. However, as previously stated, the magnitude of traditional time and frequency domain HRV measures fails to capture changes in the organization of heart rate patterns, which may be captured by nonlinear measures that were not determined in this study. CLINICAL USES OF HRV IN CARDIOLOGY The traditional clinical applications of HRV are based on a Task Force report published in 1996, in which the Task Force recommended two applications of HRV testing [38]: Prediction of risk of cardiac death or arrhythmic events post-myocardial infarction (MI) Detection and quantification of autonomic neuropathy in patients with diabetes mellitus A 2015 position statement reiterated the potential role for HRV in post-MI patients and also suggested a role in patients with heart failure [43]. While HRV has been investigated and shows potential for risk stratification in a variety of clinical conditions, and HRV can be derived from a Holter recording ordered for other clinical indications, there remains no clear indication for the test in the routine management of most patients. However, the ability of HRV from Holter monitoring to identify patients with sleep-disordered breathing, and the high and increasing prevalence of this disorder in the population (eg, an estimated 17 percent and increasing among males 50 to 70 years of age, the same age group that is likely to be tested for cardiovascular disease) support the possibility that Holter monitoring could be indicated as a screening tool in cardiac patients [82]. In some research labs, where HRV is measured in various clinical studies, significant and unsuspected sleep-disordered breathing is frequently seen and findings reported to the primary investigator, who then notifies the patient and suggests further evaluation by a sleep lab [83]. Prediction of mortality in the early post-MI period The impact of HRV on prognosis post- MI, initially reported in the era prior to treatment with thrombolysis, has also been validated in patients with an MI treated with thrombolytic therapy [84-86]. Patients with reduced indices of HRV measured early following an MI (within 14 days) have a three- to fourfold greater risk of death within three years following an MI. However, the sensitivity of measures like SDNN <50 ms as predictors of mortality, originally estimated to be approximately 30 percent, has declined simply because improvements in post-MI treatment have resulted in markedly fewer patients having SDNN at those levels. In a later study of 412 post-MI patients treated in the era of percutaneous revascularization and followed for 4.3 years, SDNN <50 ms was seen in only 7 percent of patients, and only 31 patients died in the entire cohort [87]. Even though an SDNN measurement of <50 ms was associated https://www.uptodate.com/contents/evaluation-of-heart-rate-variability/print 14/32 7/6/23, 10:42 AM Evaluation of heart rate variability - UpToDate with a doubling of risk of mortality compared with SDNN >50 ms in the earlier landmark study, in the latter study, SDNN <50 ms was only found in 3 of the 31 who died [84,87]. Another open question in this era of lower post-MI mortality is that of the optimal recording time after the event. It is possible that an early recording shortly after MI would identify one set of higher risk patients, and a later one, perhaps six weeks after MI, when patients have or have not recovered well, would provide more useful information. Prediction of mortality in the late post-MI period While reduced HRV in the early post-MI period is clearly associated with a worse prognosis among patients from the pre-PCI era, the substantial recovery of HR variability within the three months after myocardial infarction, particularly following an inferior infarct, raises a question as to whether recovery values for HR variability predict death [73,88]. Among the 68 placebo-treated patients entered into the Cardiac Arrhythmia Pilot Study (CAPS) who had 24-hour ECG recordings at baseline and at 3, 6, and 12 months after MI, there was a substantial increase in all measures of HRV between three weeks and three months [89]. On average, recovery of HRV was completed by three months post-MI; between 3 and 12 months, the values were stable for the group as a whole and for individual patients. Several older studies suggested that reduced HRV months or years post-MI remains a predictor of adverse outcomes [90-93]. As an example, in a study of 292 patients admitted with an acute coronary syndrome between 1991 and 1994, reduced HRV seen on 24-hour Holter recordings three to six months after their event continued to have prognostic value [93]. Patients with stable CHD An association between decreased HRV and the presence of significant coronary heart disease (CHD) has been suggested. Among 470 consecutive patients undergoing elective coronary angiography, patients with obstructive CHD (>50 percent stenosis) had significantly reduced HRV based on five-minute supine measurement, especially in the low 2 frequency (LF) band (180 with versus 267 ms without obstructive CHD) [94]. In a multivariate 2 2 analysis using a cutoff of LF power = 250 ms , persons with LF power below 250 ms were at significantly greater risk of obstructive CHD (adjusted OR 2.4, 95% CI 1.3-4.4) independent of baseline Framingham Risk Scores. Patients with heart failure Several studies have shown that patients with heart failure and/or cardiomyopathy have reduced HRV compared with controls, and that reduced HRV was associated with disease severity measures such as NYHA functional class, left ventricular diastolic dimension, reduced left ventricular ejection fraction, and peak O consumption [62,95- 2 101]. Prognostically, reductions in HRV have been shown to be independent predictors of overall https://www.uptodate.com/contents/evaluation-of-heart-rate-variability/print 15/32 7/6/23, 10:42 AM Evaluation of heart rate variability - UpToDate mortality, mortality from heart failure, sudden cardiac death, ventricular arrhythmias, and the need for transplant [62,100]. Improvements in HRV are seen with effective heart failure therapy (eg cardiac resynchronized therapy [CRT]). Patients with improved HRV after CRT have been shown to have better outcomes than those in whom HRV is not improved [102,103]. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system", section on 'Rationale for CRT'.) A detailed review of studies of HRV applications to heart failure patients is available elsewhere [104]. Patients with atrial fibrillation Though the presence of atrial fibrillation (AF) precludes the use of standard NN variability measures, analysis of the variability and irregularity of the ventricular response interval (VRI) may provide useful information regarding prognosis of patients with chronic AF and likelihood of AF recurrence following cardioversion [105,106]. In a series of 107 patients with chronic atrial fibrillation who underwent 24-hour ambulatory monitoring for VRI variability and irregularity and were followed for 33 months, reductions in all VRI variability and irregularity measures were associated with an increased risk for cardiac death [105]. In a series of 93 patients who underwent cardioversion for AF and had RR variability measured in sinus rhythm, the AF recurrence rate at two weeks was significantly higher (73 versus 9 percent) in patients with reduced RR variability [106]. (See "Paroxysmal atrial fibrillation", section on 'Natural history'.) Furthermore, despite the apparent lack of beat-to-beat autonomic control in AF, a circadian rhythm, measurable by SDANN which averages out the extreme short-term variability in RR intervals, persists and can be assessed, and there is evidence that decreased SDANN is an adverse sign in AF [63]. The clinical applicability of this, like other potential applications of HRV, has not yet been evaluated. Reduced HRV in the general population Reduced HRV has been associated with increased mortality and a greater risk of cardiac events in several population studies [55,107-110]. As examples: In a random sample of 900 patients enrolled in the ARIC (Atherosclerosis Risk in Communities) study who had time-domain measures of RR variability determined from a two-minute ECG rhythm strip, those with low RR variability had a significantly higher risk of cardiovascular death (adjusted relative risk [RR] 1.98, 95% CI 1.06-3.70) and all-cause death https://www.uptodate.com/contents/evaluation-of-heart-rate-variability/print 16/32 7/6/23, 10:42 AM Evaluation of heart rate variability - UpToDate (adjusted RR 1.50, 95% CI ) compared with patients with an intermediate RR variability (SDNN 23.9 to 35.4 ms) [108]. Among 1172 patients aged 65 years or greater from the CHS (Cardiovascular Health Study), even in the lowest stratum of Framingham Risk Score, abnormal values for HRV and HR turbulence identified a group with a significantly increased relative risk of mortality (RR 7.7 compared with those with normal HRV, 95% CI 3.7-16.0) [57]. Among 4652 patients in the MESA (Multi-Ethnic Study of Atherosclerosis) population who had time-domain measures of RR variability determined from a 30-second ECG rhythm strip and who were followed for a median of 7.6 years, patients in the lowest tertile of HRV had a significantly greater risk of developing heart failure (adjusted hazard ratio 2.4, 95% CI 1.4-4.2) [109]. In a 2013 meta-analysis of eight studies involving 21,988 patients, patients with the lowest HRV as measured by SDNN had a significantly higher risk of first cardiovascular events compared with patients with the greatest HRV measurements (RR 1.35, 95% CI 1.1-1.7) [110]. Furthermore, combinations of HRV measures from different domains (time domain, frequency domain, nonlinear, or HRT) may have better predictive value than HRV from a single domain because they capture different aspects of cardiac autonomic activity. HRV in combination with other risk factors By itself, HRV has limited sensitivity and specificity to sufficiently identify high-risk patients, although as previously suggested, normal HRV has been shown to be found in low risk patients. At the same time, correlations between time or frequency domain measures of HRV and previously-identified postinfarction risk factors such as left ventricular ejection fraction (LVEF) and ventricular arrhythmias are remarkably weak [84]. This lack of correlation and the fact that measures of HRV are independent predictors of patients at high risk after myocardial infarction suggest the potential utility of combining abnormal HRV with other risk stratifiers to improve risk prediction, although doing so clearly limits the proportion of patients to whom this applies [73,85,111]. As an example, among 1284 patients with a recent MI (within 28 days) followed for an average of 21 months in the ATRAMI study in whom baroreflex sensitivity and SDNN were used for risk stratification, patients with abnormal values for both had a 17 percent risk of mortality, whereas patients with normal values for both had a 2 percent risk (of note, mortality for the entire cohort was only 3.5 percent) [85]. The small number of patients with reduced HRV and LVEF less than 35 percent had nearly a sevenfold increase in mortality compared with patients with preserved HRV and LVEF of 35 percent or greater. (RR 6.7, 95% CI 3.1-14.6). HRV has also been shown to add to existing risk scores for prediction of HF and of stroke in asymptomatic older adults [112]. https://www.uptodate.com/contents/evaluation-of-heart-rate-variability/print 17/32 7/6/23, 10:42 AM Evaluation of heart rate variability - UpToDate In addition, many other conditions are associated with autonomic abnormalities, including alcoholism, chronic kidney disease, depression, severe hypertension, chemotherapy and other chemotoxins, and sleep apnea. So, if the question is whether the patient has significant autonomic neuropathy, absent or very diminished HRV may provide useful adjunctive information. The ability of serial HRV measures to identify patients with adverse responses to an intervention (eg, cardiotoxic chemotherapy) before they manifest clear deficits in cardiac function as reflected, for example, in reduced LVEF, is being investigated. As a final example, in infants, quantification of relative bradycardia and decreased heart rate variability, likely due to activation of the dorsal branch of the vagus, may provide early warning of infection-related conditions in very low birth weight infants. In preterm babies, the myelinated vagus has not yet become active, and RSA is minimal [113]. OUR APPROACH Guidelines for the routine use of ambulatory monitoring to determine heart rate variability (HRV), based on the original Task Force recommendations from 1996, were also published in 1999 by the American College of Cardiology/American Heart Association [114]. While HRV has been used for risk stratification of all-cause, cardiac, and arrhythmic death post-MI, the role for HRV testing in clinical practice remains undefined [38,115]. Based on the evidence available, we do not recommend the routine use of HRV testing outside of the clinical trial settings. We also believe that to further the field, existing and prospective datasets need to be analyzed with the goal of developing understandable and replicable algorithms that capture the rich and full clinical picture obtainable from these recordings. The diagnostic and prognostic utility of so-called ultra-short ECGs (eg, 10 to 30 seconds) or recordings for reliable estimates of short-term HRV parameters requires further study [116]. Finally, a number of articles have discussed the potential utility of HRV metrics in the diagnosis and prognosis of coronavirus disease 2019 (COVID-19) infections (eg, [117]). However, no specific or sensitive findings have yet emerged from prospective evaluations to guide clinical use of HRV in this syndrome and its associated neuroautonomic effects. (See "COVID-19: Cardiac manifestations in adults" and "COVID-19: Arrhythmias and conduction system disease".) SUMMARY AND RECOMMENDATIONS There are three major noninvasive or minimally invasive assessment approaches to evaluating the autonomic nervous system which provide complementary information https://www.uptodate.com/contents/evaluation-of-heart-rate-variability/print 18/32 7/6/23, 10:42 AM Evaluation of heart rate variability - UpToDate about autonomic as well as nonautonomic regulatory mechanisms in health and disease: heart rate variability (HRV), baroreflex sensitivity, and bedside autonomic function tests. (See 'Introduction' above.) The autonomic nervous system, including the sympathetic and parasympathetic components, has an important role in the triggering or sustaining of malignant ventricular arrhythmias. (See 'Triggering of cardiac arrhythmias and the autonomic nervous system' above.) HRV (derived from intervals between normal sinus beats NN intervals) can be measured by many methods, which can be categorized as time domain measures, frequency domain measures, nonlinear/complexity-based measures, and heart rate turbulence. (See 'HRV methodology, definitions, and normal values' above.) HRV appears to be highly consistent over 24 hours, despite marked differences among the five-minute intervals during a day. The same stability in HRV appears to be true for patients with ventricular arrhythmias, angina, and heart failure. (See 'Reproducibility of HRV measures' above.) HRV has been shown to be significantly decreased, compared with normal values, among post-myocardial infarction patients, although there is considerable inter-individual difference in this. This decreased HRV is a likely marker for autonomic dysregulation and likely reflects both decreased parasympathetic and increased sympathetic activity. Reduced HRV has also been associated with worse outcomes in patients with stable coronary heart disease, heart failure, and atrial fibrillation. Also, however, without accurate ECG analysis and an understanding of what HRV represents, HRV, especially short-term measures, can appear to be higher in the presence of either uneven beat detection or an erratic (fragmented) sinus rhythm. (See 'Clinical uses of HRV in cardiology' above.) We do not recommend the routine use of HRV testing based on clinical Holter scanning. Refinement of the conceptual framework and algorithms by which HRV is interpreted and measured lend support to the anticipation that HRV will have translational value in a variety of clinical settings. (See 'Our approach' above.) 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