Progress in Cardiovascular Diseases 55 (2012) 321 331 www.onlinepcd.

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Heart Rate Variability Today

Borejda Xhyheri, Olivia Manfrini, Massimiliano Mazzolini, Carmine Pizzi, Raffaele Bugiardini
Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale. University of Bologna, Bologna, Italy

Abstract

Heart rate variability (HRV) non-invasively assesses the activity of the autonomic nervous system. During the past 30 years, an increasing number of studies have related the imbalance of the autonomic nervous system (as assessed by HRV) to several pathophysiogical conditions, particularly in the setting of cardiovascular disease. Sudden death, coronary artery disease, heart failure, or merely cardiovascular risk factors (smoking, diabetes, hyperlipidemia, and hypertension) are the best-known clinical circumstances that can affect and/or be affected by the autonomic nervous system. Analyses of HRV variables have been proposed as a component of the clinical evaluation for patient risk stratification due to its independent prognostic information. Yet the potential for HRV to be used widely in clinical practice remains to be established. (Prog Cardiovasc Dis 2012;55:321-331) 2012 Elsevier Inc. All rights reserved.
Heart rate variability; Autonomic nervous system; Coronary circulation; Parasympathetic activity

Keywords:

A balance that does not tremble cannot weigh, A man who does not oscillate is a dead one Erwin Chargaff

The autonomic nervous system regulates visceral functions through the sympathetic and parasympathetic branches which act antagonistically to preserve a dynamic equilibrium of vital functions. In the cardiovascular system this nonstationary balance results in the uctuation between intervals of consecutive heart beats, so called heart rate variability (HRV). Impaired autonomic activity has been shown to be an independent predictor of mortality after myocardial infarction. 16 A wide spectrum of other pathophysiological conditions are inuenced by an imbalance in autonomic activity, including atherosclerothic plaque progression, congestive heart failure, diabetic neuropathy,

susceptibility to sudden death in infancy and psychiatric disorders such as depression. HRV has emerged as the most valuable non invasive test to assess autonomic nervous system function. The aim of our work is to give readers a rst approach in understanding how HRV observation may be helpful in explaining autonomic variations in common physiological and pathologic conditions, with greater focus on cardiovascular manifestations. Analysis of HRV In 1996, a task force composed of members of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology created the necessary guidelines for comparing different assessment models of HRV. HRV measures were divided into two broad categories: time domain and frequency domain measures. 7 The rule of thumb is that data obtained from short-term (5 minutes) recordings should be processed with frequency-domain methods, whereas time-domain analyses should be performed to analyze

Statement of Conict of Interest: see page 327. Address reprint requests to Raffaele Bugiardini, Via Massarenti 9 padiglione 11, Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale. University of Bologna, 40138 Bologna, Bologna, Italy. E-mail address: raffaele.bugiardini@unibo.it (R. Bugiardini).

0033-0620/$ see front matter 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pcad.2012.09.001

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24 hour, long-term, recordings. Both time CRT = cardiac window recordings resynchronization therapy have some limitations. HF = high frequency Short-term recordings may fail to detect very HRV = heart rate variability low frequency oscillaLF = low frequency tions, while data from PNN50 = ratio between NN50 long-term recordings are and the total number of NN more prone to be inuintervals enced by external alternating environmental RMSSD = root mean square conditions. It is thereof successive R-R interval fore important to nordifferences malize environmental SDANN = standard deviation situations when examinof the average normal R-R ing HRV data. Furtherintervals more, as the HRV SDNN = standard deviation of reects the activity of normal R-R intervals the autonomic nervous system on the sinus ULF = ultra low frequency node, abnormal heart VLF = very low frequency beats and artefacts should be excluded from electrocardiographic (ECG) recordings to achieve more reliable results. Time-domain methods Time domain methods in a continuous ECG recording permit determination of either instant heart rate or intervals between successive normal QRS complexes (normal-tonormal R-R interval, NN) and other variables derived from NN intervals, for instance, mean NN interval, the mean heart rate, the difference between the longest and shortest NN interval, and the difference between night and day heart rate (Table 1). More clinically useful parameters of HRV, assessed with statistical operations on R-R intervals, are a measure of the dispersion of individual cardiac cycle length around their mean, including standard deviation of normal R-R intervals (SDNN), the standard deviation of the average normal R-R intervals (SDANN), the root mean square of successive R-R interval differences (RMSSD) and the percentage of normal R-R intervals that differ by 50 ms (pNN50). All the HRV indices with the exception of pNN50 are reported in units of time (ms). SDNN is a marker of the total power (variance) of HRV and reects all long-term components responsible for variability in the recording period, including circadian rhythm and physical activity. It is typically measured over 24 hours by Holter monitor. Since the total variance of HRV is directly related to the length of analyzed recording 8 it is misleading to compare SDNN measures obtained from ECG strips of different durations. The role of SDNN in predicting mortality after acute

Abbreviations and Acronyms

myocardial infarction was rst demonstrated by Kleiger et al. 2 in 1987 and later corroborated by several studies including Autonomic Tone and Reexes After Myocardial Infarction (ATRAMI) and Gruppo Italiano per lo Studio della Sopravvivenza nell' Infarto Miocardico 2 (GISSI-2). 9,10 HRV analysis in ECG recordings shorter or longer than 24 hours may be estimated by dividing the long-term ECG Holter monitor into 5-minute segments and may be performed in order to calculate either the mean of all the 5-minute standard deviations of NN intervals or the standard deviation of the average NN intervals. The former index measures the variability due to cycles shorter than 5 minutes and the latter estimate the variability due to cycles of 5 minutes or longer providing highly sensitive information on the low frequencies such as physical activity, changes in position, or circadian rhythm 1115. The number of successive NN length differences larger than 50 ms, either expressed in percentage as the ratio between NN length differences larger than 50 ms and the total number of NN intervals, or the square root of the mean squared differences of consecutive NN intervals are all measurements of short-term variation in the NN cycles and detect high frequency oscillations caused by parasympathetic activity. Geometrical time-domain methods are obtained through the conversion of the NN interval data into geometrical forms like histograms or the HRV triangular

Table 1 Selected time domain measures of HRV (adapted from ESC/NASPE guidelines). 7 Variable Units SDNN ms Description Consensus for abnormal value

Standard deviation of all NN intervals SDANN ms Standard deviation of the averages of NN intervals in all 5-minute segments of the entire recording RMSSD ms The square root of the mean of the sum of the squares of differences between adjacent NN intervals SDNN ms Mean of the standard deviations of index all NN intervals for all 5-minute segments of the entire recording SDSD ms Standard deviation of differences between adjacent NN intervals NN50 count Number of pairs of adjacent NN intervals differing by more than 50 ms in the entire recording; three variants are possible counting all such NN intervals pairs or only pairs in which the rst or the second interval is longer pNN50 % NN50 count divided by the total number of all NN intervals

= increased sympathetic activity; = decreased vagal activity.

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index that is a valuable estimate of overall HRV. These methods differ from the statistical methods described previously because they are less inuenced by the quality of the NN intervals data, although are inappropriate to assess short-term changes. 7 Frequency domain methods Short-term recordings of HRV distinguish two main spectral components: a high-frequency (HF) component (ranging between 0.15-0.40 Hz), and a low-frequency (LF) component (ranging between 0.04-0.15 Hz), respectively considered markers of parasympathetic and sympathetic control (Table 2). Frequency domain methods are used to study heart rate variations by breaking the heart rate signal into its constituents (frequencies) and quantifying their relative intensity (power). Calculation of power spectral density can be obtained either by parametric and non-parametric methods. Suitability of parametric methods (autoregressive model estimation) needs to be veried for the chosen model, reducing their applications, although they can be used even with shorter intervals (1-5 minutes) without missing relevant information on HRV 7 and have the best sensitivity to fast HR changes. Conversely, non-parametric methods are easier to use because they are based on the fast Fourier transformation that converts RR interval data into a spectrum of frequencies, 7 but they have less sensitivity to rapid and transitory HRV variations. The fast Fourier transformation results are converted to Hertz (Hz) by dividing them by the mean RR length. In a short-term recording (usually 5 minutes) the main components are: High frequency (HF), from 0.15 to 0.4 Hz: a marker of the parasympathetic tone

Low frequency (LF), from 0.04 to 0.15 Hz: possibly correlated to sympathetic tone or to autonomic balance Very low frequency (VLF), from 0.0033 to 0.04 Hz: role remains uncertain LF/HF ratio: index of the interaction between sympathetic and vagal activity A ratio between LF and HF is used to assess the fractional distribution between the two systems and is an important marker of sympathovagal balance. Ultra Low Frequency (ULF) is derived if long term data are under evaluation. HF, LF, ULF are all measured in standard units called absolute values of power (ms 2); HF and LF can also be measured in normal units, although the normalization tends to underestimate their values in total power changes. 7 ULF power correlates with SDNN and SDANN index; VLF power and LF power with SDNN index; and HF power with RMSSD and pNN50. 16 Implications of abnormal HRV parameters HRV analysis is based on the concept that rapid uctuations may specically reect changes of sympathetic and vagal activity. Previous work has shown that PNN50 and RMSSD are measures of parasympathetic activity whereas SDNN and SDANN reect both sympathetic and parasympathetic modulation of heart rate. 7 Among time domain measures of HRV, PNN50 b 3% and RMSSD b 25 ms are used to assess impairment of vagal activity; SDANN b 50 ms and SDNN b 100 ms are considered as a rough index of abnormal sympathetic outow. The frequency domain measures of HRV require more technical sophistication and are subject to greater error than the time domain measures. However, there is consensus that vagal activity is the major contributor to the

Table 2 Frequency domain measures of HRV (adapted from ESC/NASPE guidelines). 7 Variable Units Description The variance of NN intervals over the temporal segment Power in VLF range Power in LF range LF power in normalized units LF/(total power-VLF)100 Power in HF range HF power in normalized units HF/(total power-VLF)100 Ratio LF [ms 2]/HF[ms 2] Frequency Range 0.4 Hz 0.04 Hz 0.040.15 Hz 0.150.4 Hz

Analysis of short-term recordings (5 min) 5-min total power ms 2 VLF ms 2 LF ms 2 LF norm nu HF ms 2 HF norm nu LF/HF Analysis of entire 24 hours Total power ULF VLF LF HF

ms 2 ms 2 ms 2 ms 2 ms 2

Variance of all NN intervals Power in the ULF range Power in the VLF range Power in the LF range Power in the HF range

0.4 Hz 0.003 Hz 0.0030.04 Hz 0.040.15 Hz 0.150.4 Hz

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HF component. More controversial is the interpretation of the LF component, which is considered by some as a marker of sympathetic activity and by others as the resultant of both sympathetic and vagal inuences. 18 An analysis of LF/HF ratios rather than single components is considered by many investigators to better reect the activity of the sympathovagal balance. Reduction of LF/ HF ratio appears to be a clear sign of unbalance between sympathetic reex interactions with shift toward sympathetic withdrawal, and consequent vagal predominance. Overall, low HRV values usually indicate a relative sympathetic dominance, which may be due to high sympathetic activity and/or low parasympathetic activity. On the other hand, high HRV values indicate a shift of the sympathetic/parasympathetic balance toward increased vagal activity.

Circadian pattern of HRV In middle-age subjects, HRV follows a periodic circadian pattern (cosine function). Higher values of HF and RMSSD are indicative of more parasympathetic modulation. These variables decrease during the AM hours and reach the lowest levels in the afternoon (03:0006:00 PM), then turn upwards in the evening and reach the acrophase (timing of the highest oscillation) in the early morning (3:005:00 AM). LF/HF and heart rate can be used as markers of more sympathetic modulation and show an opposite behaviour, reaching the peak in the afternoon (02:00-04:00 PM), then decreasing until the rst hours after midnight. 15

The preservation of this function and the level reached after the eighth decade increase have been related to a longer survival and identied as predictive markers for longevity. 21 HRV is signicantly lower in healthy women compared with healthy men. 19,22 This nding may be explained by a lower sympathetic activity, which can be ascribed in the well documented pathophysiological gender related differences among women and men. 2331 A low HRV may provide protection against arrhythmias and against the early development of coronary heart disease. Ethnicity related differences have also been found. Lower HF, LF power, and LF/HF are signicantly related to older age in Caucasian Americans but not in African Americans. Young African Americans already have a lower parasympathetic activity than do comparable-aged Caucasian Americans, which, in turn, suggests that young African American individuals might show signs of premature aging in their autonomic nervous system. 32

HRV and diabetes Autonomic dysfunction has been related to a wide range of diabetic complications and to progression of the disease (Table 4). Early detection of subclinical autonomic impairment through HRV measurements in diabetic individuals may be important for risk stratication and subsequent therapeutic management, including pharmacologic and lifestyle interventions 3338 (Table 5). Previous work documents signicant differences in both frequency and time domain measures of HRV between healthy populations and diabetic patients. Diabetic subjects show parasympathetic impairment as assessed by frequency domain measures shifted towards the low frequency side and decline of the time domain measures namely SDNN, RMSDD, NN50 count, pNN50. Of note, autonomic dysfunction is associated with both an inadequate metabolic control of the disease and occurrence of diabetic neuropathy. 39 Diabetic patients presenting with autonomic dysfunction have a poor cardiovascular prognosis with 8year mortality up to 23%. 40,41 Early identication of cardiovascular autonomic neuropathy permits timely initiation of therapy.

HRV, aging, gender and ethnicity In a population between 20 and 70 years old, 24hour Holter recordings revealed a age-related decrease of all parameters, especially of parasympathetic cardiac activity due to aging. 19 The circadian pattern itself is altered, with a more pronounced parasympathetic depression during night-time. More detailed studies have investigated the pattern of loss of autonomic function during aging and have demonstrated that HRVparasympathetic activity decreases faster until the age of 80 and then it starts to increase again 20,21 (Table 3).

Table 3 Comparison of HRV values in young, middle age and older subjects. 21 Age 20-29 y.o. /n = 47 40-49 y.o./n = 96 60-69y.o./n = 38 80-99 y.o./n = 20 RMSSD (ms) 41 16 27 10 20 10 30 21 SDNN (ms) 151 37 125 33 114 33 109 30 SDANN (ms) 134 36 112 35 106 34 99 29

Table 4 Diabetic and impaired fasting glucose subjects have lower LF and HF power values compared with normal fasting glucose subjects. 38 LF DM IFG NFG 6.03 0.08 6.26 0.10 6.77 0.02 HF 4.95 0.09 5.06 0.11 5.55 0.02

DM: diabetes mellitus; IFG: impaired fasting glucose; NFG: normal fasting glucose.

B. Xhyheri et al. / Progress in Cardiovascular Diseases 55 (2012) 321331 Table 5 ARIC (Atherosclerosis Risk factors In Communities) data. Baseline SDNN DM NFG 32.75 (31.7133.7) 37.57 (37.0538.09) Baseline RMSSD 24.27 (22.7524.98) 29.39 (28.5229.45) SDNN reduction/year 0.95 ms/year 0.66 ms/year

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RMSSD reduction/year 0.66 ms/year 0.36 ms/year

(SDNN and RMSSD in diabetic patients than in non diabetics and in a 9 years follow up a greater SDNN and RMSSD reduction has been observed compared to NFG subjects 37). DM: diabetes mellitus; NFG: normal fasting glucose.

The results from the Diabetes Control and Complications Trial in patients with type 1 diabetes show that intensive glycaemic control can prevent HRV imbalance, slowing the deterioration of autonomic dysfunction over time. 42 As in patients with microalbuminuria, the stepwise implementation of intensied multifactorial treatment slows the progression to autonomic neuropathy. 4345 Preliminary ndings indicate that -blocker treatment could restore HRV in type I diabetic patients as soon as after 6 weeks treatment. 46 Angiotensin-converting enzyme inhibitors improve HRV after 3 months of treatment. 47,48 On the other hand, spironolactone impairs HRV and endothelial function, 49 also a predictor of outcome. 5052 HRV and cardiovascular risk factors An inverse relation between cholesterol serum levels and HRV values has been observed both in patients with and without a history of ischemic heart disease. 53,54 This alteration has been conrmed in obese subjects, supporting an independent role of autonomic deregulations in hyperlipidemia. 55 Obese patients show attenuated SDANN and HF power, markers for sympathetic and parasympathetic activity respectively, when compared to lean subjects. Loss of weight contributes to restoration of autonomic function. 55 Likewise, in patients with metabolic syndrome, all HRV parameters measured are reduced. 54 Metabolic impairment causes demyelination and axonal degeneration, which may cause an autonomic impairment, increasing the risk for cardiovascular events. Hypertension is related to overall lower HRV values. 56,57 Signicant trends of association for LF/HF and SDNN and the incidence of hypertension were also found by Liao et al. 54 Early changes in these parameters could, therefore, predict greater risk of incipient hypertension. The results regarding the effect of cigarette smoking on HRV are conicting. 5861 Some studies failed to nd any effect. 59,60 Conversely, other studies found that parasympathetic modulation among smokers tend to be lower than that among nonsmokers. For example, HRV values (SDNN and RMSSD) are decreased in long-term smokers when compared with nonsmokers. 58 Moreover, smoking reduces SDNN, RMSSD and LF/HF ratio particularly

within the rst 5 to 10 minutes after smoking. 61 Constriction of proximal and distal epicardial coronary arteries, and increase in coronary resistance vessel tone is mediated the autonomic nervous system. 62 Parasympathetic-sympathetic unbalance may contribute to the adverse cardiovascular consequences attributed to cigarette smoking. 63 HRV and atherosclerosis The involvement of the autonomic nervous system in the development of atherosclerosis is matter of investigation. Vagal bres are distributed both in the perivascular connective tissue and in the adventitia surrounding arteries and contribute to arterial dilation. A reduction of HRV parameters seems to be closely associated to a more rapid subintimal lipid accumulation, which leads, in turn, to a coronary narrowing. 64 Regression in vessel damage correlates with restoration of higher HRV values. 64 Depressed HRV has been also described in patients with stroke and the subsequent risk of mortality. 65 Low HRV, namely, SDNN values were able to predicted intima media thickness 66 and progression of coronary atherosclerosis, 64 in patients with recent cardiovascular disorders. The mechanisms of these associations are still unclear. Manfrini et al. examined whether morphologic changes in the vessel wall due to the atherosclerotic process correlated with imbalance of HRV in the frequency domain. 67 Patients with expansive remodeling showed lower HF values and higher LH/HF ratio compared with those with negative remodeling. Hence, outward stretch of the vessel wall behind the plaque, as a consequence of increasing plaque size and expansive arterial remodeling is associated to autonomic dysfunction due to impairment of the vagal tone. It is, however, unknown if remodeling is a cause of vagal impairment or if vagal impairment may contribute to arterial remodeling. HRV and coronary artery disease In 1987, the Multicenter Post Infarction Research Group published a work demonstrating that reduced HRV was able of identifying a group of patients with increased

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cardiac mortality after myocardial infarction. 2 The predictive value of HRV was independent from traditional risk factors. This initial observation was followed by several other studies. Ischemic cardiac death has been found to be often preceded by changes in autonomic activity. 68,69 Autonomic changes have been reported to be associated with ischemia in stable coronary artery disease. 70 Low parasympathetic activity was found to be a marker for poor prognosis in patients presenting with unstable angina and non ST-elevation myocardial infarction. 69

ischemia) and functional (autonomic dysfunction) abnormalities may trigger fatal tachyarrhythmia in the setting of a chronic substrate (coronary artery disease). Other potential mechanisms, less likely germame to the DINAMIT population, include myocardial ischemia induced by plaque rupture and thrombosis, which may lead directly to acute myocardial electric instability. 77 Patients with ventricular hypertrophy appear to be at a higher risk of sudden cardiac death. 78 Furthermore, sudden death occurs more frequently in patients with impaired left ventricular function, in whom acute ischemia is usually less important than is the presence of a myocardial scar.

Relation between HRV and ischemic sudden death Patients at risk of sudden cardiac death have decreased HRV. Investigators have shown low HRV values in apparently healthy people who had ECG-Holter recordings prior to their sudden death, 71 anginal patients who died suddenly while wearing a Holter monitor, 68 and patients surviving from cardiac arrest. 72,73 The AzimiLide post-Infarct surVival Evaluation (ALIVE) trial identied a high risk subgroup based on low HRV. 74 The highest rate of death was reported among this population, independent of randomization either to drug or to placebo. 74 Despite these consistent results, identication of patients at high risk for sudden death, who may benet from an implantable cardioverter debrillator, remains elusive. 75 HRV was used as a risk stratifying entry criterion in the recent Debrillator in Acute Myocardial Infarction Trial (DINAMIT), which randomized patients with ejection fraction of 0.35 or less and SDNN of 70 msec or less to an implantable cardioverter debrillator or standard care 640 days post myocardial infarction. 76 The study failed to show a benet for implantable cardioverter debrillator. That failure could have been due to a lack of benet of the cardioverter debrillator so shortly after infarction or to inability of HRV to identify those patients who can benet from such therapy. We believe that there are alternative explanations. There are other pathways through which coronary artery disease may trigger sudden cardiac death.. Pozzati et al. 68 have shown a dramatic decrease in HRV (SDNN b 35 ms) 5 minutes before the episode of transient myocardial ischemia leading to sudden death, compared with ndings (SDNN 35 ms) in those patients who have transient myocardial ischemia as well, but without triggering of death or malignant arrhythmias. Data were obtained in a cohort of patients with anginal symptoms, but without prior myocardial infarction or other cardiovascular disorder known to reduce HRV, such as heart failure or diabetes. Therefore, the observed decrease in SDNN intervals occurring in the 5 min before fatal ST segment changes suggests that complex interactions between structural (arrhythmia-threshold lowered by Relation between HRV and coronary instability Vagal stimulation may improve coronary blood ow. It may also inhibit sympathetic nerve activity via peripheral pre- and post-synaptic interactions. 7982 Exposure to high levels of noradrenaline results in betareceptor mediated cytotoxic effects and apoptosis as well as alpha-receptor mediated vasoconstrictor effects 83,84 The deleterious effect of vagal withdrawal has been largely documented by previous work. Data have shown that extremely low values of parasympathetic activity (pNN50 b 3%) in acute coronary syndrome without STsegment elevation were strongly related to subsequent events. 67 Of note, PNN50 b 3% was found in 56% of patients having adverse events (cardiac death, myocardial infarction, urgent revascularization, and hospital readmission) versus 5% of patients who had good outcomes. These clinical data are in keeping with ndings of experimental studies. Vagotomy results in coronary vasoconstriction in anaesthetized dogs suggesting vagal modulation of coronary vessel tone. 85 Interrupting vagal inuences might, therefore, produce coronary vasoconstriction, as a result of loss of parasympathetically mediated vasodilatation. Abnormalities of coronary vasomotor tone, if superimposed on atherosclerosis, may lead to severe coronary narrowing and clinical instability even in the presence of minor vessel wall irregularities. 8693 It seems reasonable that a failure of parasympathetic activity due to chronic stress or other factors 9498 may favor coronary instability, which in turn, may precipitate further episodes of coronary ischemia and contribute to worsen prognosis.

HRV and heart failure Several studies of HRV have led to signicant prognostic information in chronic heart failure of both ischemic and nonischemic etiology. 99104 The majority of studies have shown that low SDNN predicts mortality. Kearney et al found that low serum

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sodium, low SDNN and high serum creatinine identify patients at increased risk of death due to progressive heart failure in ambulant outpatients. 100 The United Kingdom Heart Failure Evaluation and Assessment of Risk Trial 105 (in 433 outpatients) found that reduced SDNN was able to predict death from progressive heart failure, but not sudden death. Reduced short-term LF power during controlled breathing has been shown to be a powerful predictor of sudden death in patients with chronic heart failure independently of many other variables. 106 A recent study has shown that the HRV triangular index provides independent information on clinical status and prognosis in patients with chronic congestive heart failure. 107 These data, however, were discordant with some other observations. Takase et al. observed that mean SD of 24-h R-R intervals was signicantly lower in nonsurvivors as compared to survivors from chronic heart failure. 108 Much more importantly, as previously mentioned, the DINAMIT study failed to show a benet for implantable cardioverter debrillator in patients with ejection fraction of 35% or less and SDNN of 70 msec or less. 76 A plausible explanation for such discrepancies may be found in the complex nature of the disease and of the different mechanisms of death. 109113 Determining the cause of death in heart failure can be difcult.

activity (PNN50) are markedly higher in trained versus untrained individuals. 14 Moderate alcohol use may signicantly shift HRV (SDNN and SDANN) toward sympathetic predominance during nighttime hours. 120 Measures of HRV can be inuenced by changes in the breathing pattern. 11 Also, HRV measures decrease with age. 20,21 Females had a higher heart rate but more pronounced vagally modulated activity than males. 121 Outpatients had better HRV than in-patients. 121 Denition of a clear border between normal and abnormal values is, therefore, too subjective, limiting the use of HRV in clinical practice. There is a need to establish some cutoff levels between normal and abnormal HRV values in clearly identiable patient subsets and these must be data driven and not arbitrary . A consensus is also lacking on the best HRV measures for clinical purposes. Time and frequency domain measures of HRV have been most commonly used.

Conclusions Although several studies have reported on the clinical and prognostic value of HRV analysis in the assessment of patients with cardiovascular diseases, this technique has not been incorporated into clinical practice. This might be due to the fact that researchers have used many methods for analyzing nonspectral and spectral HRV indexes and reproducibility among these methods is limited. Furthermore, despite a number of commercial analytical systems, evaluation of HRV for each individual patient requires timeconsuming manual editing of artifacts. To welcome HRV analysis onto the clinical stage, further research is needed, including prospective, randomized studies focusing on the clinical utility of HRV as a means of assessing cardiovascular risk in primary prevention or adequacy of therapy in secondary prevention, specifically in patients with recent myocardial infarction or chronic heart failure.

Heart failure and cardiac resynchronization therapy Cardiac resynchronization therapy (CRT) is emerging as a long-term therapy that favorably impacts functional capacity in heart failure patients. 114117 An improvement in cardiac performance from CRT positively alters the autonomic control of heart rate and beta blocker therapy seems to potentiate the autonomic improvement with CRT. 118 Moreover, CRT appears to increase baroreex sensitivity by 35% (from 2.96 to 3.79 ms/mmHg). 119 The CRT-induced relative change in baroreex sensitivity correlates with the change in left ventricular function. A recent study has shown that the 2year event-free survival rate was signicantly lower (62% versus 94%) in patients without any SDANN change compared with patients who showed an increase in SDANN 4 weeks after CRT initiation. 114 Indices of HRV might be useful parameters for identifying patients who may respond to CRT and who may require additional interventions. Randomized studies are warranted to verify these ndings.

Statement of Conflict of Interest The authors declare that there are no conicts of interest.

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