Heart rate variability: a noninvasive electrocardiographic method to measure the autonomic nervous system Juan Sztajzel Cardiology Center and Medical Policlinics, University Hospital, Geneva, Switzerland The autonomic nervous system (ANS) plays an important role not only in physiological situa- tions, but also in various pathological settings such as diabetic neuropathy, myocardial infarction (MI) and congestive heart failure (CHF). Autonomic imbalance associating increased sympathetic activ- ity and reduced vagal tone has been been strongly implicated in the pathophysiology of arrhythmo- genesis and sudden cardiac death. Among the different available noninvasive techniques for assessing the autonomic status heart rate variability (HRV) has emerged as a simple, noninvasive method to evaluate the sympatho- vagal balance at the sinoatrial level. It has been used in a variety of clinical situations including diabetic neuropathy, MI, sudden death and CHF. The standard measurements intervening in the analysis of HRV comprise time domain indices, geometric methods and components of the fre- quency domain. Measurements of HRV are gen- erally performed on the basis of 24 hour Holter recordings (long-term recordings) or on shorter periods ranging from 0.5 to 5 minutes (short-term recordings). The use of long or short-term record- ings depends on the type of study that has to be realised. Established clinical data based on numerous studies published during the last decade consider decreased global HRV as a strong predictor of in- creased all-cause cardiac and/or arrhythmic mor- tality, particularly in patients at risk after MI or with CHF. This article reviews the mechanism, the pa- rameters and the use of HRV as a marker reflect- ing the activity of the sympathetic and vagal com- ponents of the ANS on the sinus node, and as a clinical tool for screening and identifying patients particularly at risk for cardiac mortality. Key words: autonomic nervous system arrhythmo- genesis sudden cardiac death heart rate variability risk stratification myocardial infarction congestive heart failure In the course of the last two decades numerous studies in both animals and human beings have shown a significant relationship between the ANS and cardiovascular mortality, particularly in pa- tients with MI and CHF. Perturbations of the ANS and its imbalance consisting of either increased sympathetic or reduced vagal activity may result in ventricular tachyarrhythmias and sudden cardiac death, which is nowadays one of the leading causes of cardiovascular mortality [1].There are presently various methods available for assessing the status of the ANS, which include cardiovascular reflex tests [2���4], and biochemical [5] and scintigraphic tests [6]. Techniques giving direct access to recep- tors at the cellular level or to neural traffic, are not routinely available. In recent years noninvasive techniques based on the electrocardiogram (ECG) have been used as markers of autonomic modula- tion of the heart, these include HRV [7, 8], baro- reflex sensitivity (BRS) [9], QT interval [10], and heart rate turbulence (HRT), a new method based on fluctuations of sinus rhythm cycle length after a single premature ventricular contraction [11]. Among these techniques analysis of HRV has emerged as a simple, noninvasive method to eval- uate the sympatho-vagal balance at the sinoatrial level. Summary No financial support declared. Introduction 514 Review article S W I S S M E D W K LY 2 0 0 4 1 3 4 : 5 1 4 ��� 5 2 2 �� w w w. s m w. c h Peer reviewed article

S W I S S M E D W K LY 2 0 0 4 1 3 4 : 5 1 4 ��� 5 2 2 �� w w w. s m w. c h 515 Although automaticity is intrinsic to different cardiac tissues with pacemaker properties, the electrical and contractile activity of the myo- cardium is largely modulated by the ANS. This neural regulation is effected through the interplay of the sympathetic and vagal outflows. In most physiological conditions the efferent sympathetic and parasympathetic branches have opposing ac- tions: the sympathetic system enhances automatic- ity, whereas the parasympathetic system inhibits it. While the effect of vagal stimulation on the car- diac pacemaker cells is to cause hyperpolarisation and to reduce the rate of depolarisation, sympa- thetic stimulation causes chronotropic effects by increasing the rate of pacemaler depolarisation. As seen in figure 1 both branches of the ANS influence ion channel activity implicated in the regulation of depolarisation of the cardiac pacemaker cells [12]. Abnormalities of the ANS have been demon- strated in diverse conditions such as diabetic neu- ropathy [13] and coronary heart disease, particu- larly in the context of MI [14]. A dysregulation in the autonomic nervous control of the cardiovascu- lar system associating increased sympathetic and reduced parasympathetic tone plays an important role in coronary artery disease and in the genesis of life-threatening ventricular arrhythmias [15, 16]. The occurrence of ischemia and/or myocar- dial necrosis may induce a mechanical distortion of the afferent and efferent fibers of the ANS due to changes in the geometry related to necrotic and noncontracting segments of the heart. Newly recognised is the phenomenon of electrical remod- eling due to local nerve growth and degeneration at the level of the myocardial cell in the setting of ischemia and/or myocardial necrosis [17]. Taken as a whole, in patients with coronary artery disease and a history of MI, cardiac autonomic function associating increased sympathetic and decreased vagal tone are conditions favourable to the com- plex phenomenon of life threatening arrhythmias because they modulate cardiac automaticity, con- duction and importantly haemodynamic variables. The autonomic nervous system and the heart Parasympathetic activity (Ach) Sinus automaticity If Ca Sympathetic activity (E, Ne) + - + - - - IKAch I + + + Figure 1 Effects of the auto- nomic nervous regu- lation on the ionic currents and the resulting changes of sinus automaticity. E = epinephrine NE = norepinephrine Ach = acetylcholine Ica = calcium current If = hyperpolarisa- tion-activated ���pace- maker��� current IKAch = potassium current. (Adapted from reference [12].) Definition and mechanisms of heart rate variability Heart rate variability is a noninvasive electro- cardiographic marker reflecting the activity of the sympathetic and vagal components of the ANS on the sinus node of the heart. It expresses the total amount of variations of both instantaneous HR and RR intervals (intervals between QRS com- plexes of normal sinus depolarisations) [7, 8]. Thus, HRV analyses the tonic baseline autonomic function. In a normal heart with an integer ANS, there will be continuous physiological variations of the sinus cycles reflecting a balanced symptho- vagal state and normal HRV [8]. In a damaged heart which suffered from myocardial necrosis, the changes in activity in the afferent and efferent fibers of the ANS and in the local neural regula- tion will contribute to the resulting sympatho- vagal imbalance reflected by a dimished HRV. Analysis of HRV consists of a series of mea- surements of successive RR interval variations of sinus origin which provide information about au- tonomic tone [18]. Different physiological factors may influence HRV such as gender, age, circadian rhythm, respiration and body position [19]. Mea- surements of HRV are noninvasive and highly reproducible. They may generally be performed on the basis of 24 hour Holter recordings or on shorter periods ranging from 0.5 to 5 minutes par- ticularly in the field of dynamic electrocardiogra- phy [8]. Most Holter apparatus manufacturers nowadays propose HRV analysis programs which are incorporated into their instrument systems [20]. Although computer analysis of tape record- ings has improved, human intervention is required in most measurements of HRV parameters in order to detect erroneous beats, artifacts, and alter- ations in tape speed that may alter timing intervals. In 1996 a Task Force of the European Society of Cardiology (ESC) and the North American So- ciety of Pacing and Electrophysiology (NASPE) defined and established standards of measurement, physiological interpretation and clinical use of HRV [21]. Time domain indices [22, 23], geomet- ric measures [24, 25]and frequency domain indices [26���28] constitute nowadays the standard clini- cally used parameters. Measurements of heart rate variability