PERSPECTIVE
 

Heart Rate Variability following Myocardial Infarction: Prognostic Panacea or Enigma?
 

Gianluca Di Micco°, JP Bourke*, R Saharia*, SS Furniss*, A Iacono°, RWF Campbell*
°Istituto Medico Chirurgico di Cardiologia, Cattedra di Cardiologia, Seconda Universita’
degli Studi di Napoli, Italy and *University Department of Cardiology, Freeman Hospital,
Newcastle upon Tyne, United Kingdom
 

ABSTRACT

   

      In normal individuals, heart rate in sinus rhythm varies widely in the course of a 24-hour period, chiefly under the control of the autonomic nervous system. These fluctuations in heart rate can be quantified and the results are referred to as measures of “heart rate variability” (HRV).

     Time and frequency domain measures of HRV reflect the balance between cardiac sympathetic and para-sympathetic tone during the recording period. This article begins by reviewing the methods and problems of measuring heart rate variability. Impaired HRV is seen in patients following myocardial infarction and is a marker of adverse prognosis, especially of major arrhythmic complications. Acute myocardial infarction affects measurements of HRV. We discuss what can be deduced from abnormally low measures of HRV after infarction. Whether impaired HRV is causally related to arrhythmias or merely an epiphenomenon is then reviewed. The article shows the possible role of heart rate variability as a means of risk stratifying patients after infarction and how the technique could be combined with other tests to optimize risk prediction.

    (Heart Views. 2000;1(8): 291-300) © 2000 Hamad Medical Corporation.

Keywords: ®Heart rate variability ®myocardial infarction ®arrhythmias ®prognosis.


Introduction


      Some 10% of patients die in the year following myocardial infarction (1,2).The majority of deaths occur suddenly and are attributed to ventricular tachy-arrhythmias; the remainder are accounted for by re-infarction and heart failure (3). Prediction of death in the first and second years after the acute infarction by additional testing is desirable, assuming that death can be prevented and that this outcome is not obvious from simple clinical parameters. To be clinically useful, any test identifying a “high risk” cohort of infarct survivors must have high specificity and positive predictive accuracy, otherwise the benefits of testing may be outweighed by the erroneous labeling and treatment as “high risk” of what turn out to be low risk patients. Accurate prediction usually implies some understanding of what the cause of death will be and ideally assumes that therapy, which would not normally be deployed, is available to prevent the adverse outcome.

     Risk stratification of infarct survivors with regard to their risk of sudden death is a complex and controversial area (4). Although a wide variety of tests predicting outcome at the time of hospital discharge have been available for many years, they are rarely used for this purpose routinely. This is probably because: 1) many judge the accuracy of prediction based on population results to be inadequate for intervention in the individual at present.; 2) there are few indicators that “simple” therapies will be effective in preventing arrhythmic deaths and the more aggressive the therapy required, the more potential for harm (5); and 3) many continue to wait for the ideal test to become available for risk assessment – the prognostic panacea.

    Against this background, it is appropriate to examine what the various measures of heart rate variability contribute to risk assessment of patients and to our understanding of the mechanisms of death in the late post-infarction period.
 

  What is Heart Rate Variability?

   
     In normal individuals, heart rate in sinus rhythm varies widely over a 24-hour period, mainly in response to sympathetic and parasympathetic influences. When ectopic beats have been excluded, the resulting fluctuations in RR intervals can be measured over either short periods of two to five minutes or over a whole 24-hour period and reflect the balance between sympathetic and parasympathetic tone during that period (6). Measurement of these fluctuations in sinus rhythm can be performed by either time-domain or frequency-domain analysis and both types of results are measures of heart rate variability (7,8). Time-domain analysis is best from 24-hour ECG recordings, while frequency-domain analysis is probably only meaningful when obtained from two to five minute recordings under steady state conditions.

      There are various different time-domain measures of heart rate variability (Table 1; figure 1). However, four in particular are emerging as superior because of their greater reproducibility and statistical validity:

1. SDNN - a statistical estimate of overall variability

2. SDANN - a statistical estimate of long-term components

3. rMSSD - a statistical estimate of short-term components

4. Triangular Index - a geometric estimate of overall variability
(figure2).


                                           HEART RATE VARIABILITY: TIME DOMAIN ANALYSIS

     Frequency domain (power-spectral density) measures of heart rate variability present greater technical and theoretical problems than those for time-domain analysis (7-10). Frequency domain measures are best obtained from short term ECG recordings of two to five minutes to insure stable conditions throughout. The results are expressed in terms of the very low (VLF), low (LF) and high frequency (HF). At present only low frequency and high frequency components are relevant to clinical cardiology (figure 3). Results from short- versus long-term ECG recordings should be clearly distinguished and are best expressed both in absolute power terms (ms2) and in normalized units (n.s), representing the measure of each component in relation to the total power of the recording.

    Various measures of heart rate variability are now readily available to clinicians from commercially available analyzers to supplement the more traditional types of Holter ECG analyses. The apparent ease of availability belies the concealed complexity of the parameters being measured and the assumptions inherent in the results. It is already clear that a multiplicity of factors affect heart rate fluctuations, many of which remain poorly understood (11,12). Effects of timing of the recording (13,14), its duration, the effects of various therapies (15) taken by the patient during the recording and inconsistent implications in the results from different types of heart rate variability measures may all profoundly affect the clinical value of the results. Furthermore, if heart rate variability only manifests its abnormal pattern for short time periods before arrhythmic events, recordings at times remote from the event might be of negligible prognostic value though the change in the measure might in itself be highly sensitive and specific (16).

     For example: ECG signal noise, missing data and atrial or ventricular ectopy will all affect the results obtained in a more profound way than for more traditional forms of Holter ECG analyses (17,18). While these factors can be identified readily and corrected by meticulous manual editing of short term recordings, analysis of 24 hour recordings is critically dependent on automatic editing computer algorithms if heart rate variability measures are to become part of routine clinical practice. In fact, ECG analysis systems differ in their filtering and RR-interval recognition algorithms, how they handle noise, ectopy and missing data (19).

    Moreover heart rate variability measures may vary from day-to-day, as well as time elapses from the index event, so contributing to variability of the measures obtained (20,21). It is known also that there can be up to 60% change in the measure of the pNN50 from one 24-hour period to the next, although this rarely changes the significance of the result for prognosis (13-20,21). Furthermore, most published series obtained their measures from recordings performed at a mean of 11 days following infarction, while it is now common to perform the analysis at three to five days because of the increasing trend for early hospital discharge of uncomplicated patients following infarction.


                                                        HEART RATE VARIABILITY: POWER SPECTRUM

Heart Rate Variability after acute Myocardial Infarction

  
          
      A variety of different measures of heart rate variability are reduced following acute infarction. For example, when assessed two weeks after acute infarction, frequency domain analysis shows a predominance of sympathetic activity as judged by the spectral components (22). This sympatho-vagal imbalance was found to progressively normalize over the next year, when two-week, six- and twelve-month recordings are compared in this study. Others have shown a temporal decrease in cardiac parasympathetic tone following infarction contributing to the relative sympathetic over activity (23).

      Although heart rate variability has been shown to improve in the twelve months following infarction, it does not do so in all patients, and there is controversy as to whether recovery is partial or complete (22-24,25). It is also suggested that depressed heart rate variability one year after infarction predicts an adverse outcome in the longer term (24) and some show a progressive deterioration in heart rate variability measures with eventual sudden death (25).

    The normal circadian variation in heart rate variability, seen in normal individuals, is frequently lost in patients recovering following acute myocardial infarction (26).

     Another interesting aspect is the attitude of HRV during thrombolysis. In fact, an artery acutely opened by thrombolysis does not seem to result in higher heart rate variability at 24 hours compared to patients whose artery remained occluded (27). This is somewhat surprising if the results do not show any difference during longer term follow-up, since successful thrombolysis is already known to preserve left ventricular function and reduce the incidence both of late potentials on signal averaged ECG, and the inducibility of sustained monomorphic ventricular tachycardia by programmed ventricular stimulation following infarction (28).

     The timing at which the measures are made after the acute infarction could theoretically affect the value of the result. In most early studies the recordings were made 7-11 days after infarction. With the trend for earlier hospital discharge of patients after infarction, recordings are usually made closer to the acute event. The question of whether measures of heart rate variability made 3-5 days after infarction provide the same prognostic information has been addressed by several authors (29,30). Their results suggest that these early recordings provide similar prognostic information to those recorded later.
 
Implications of Reduced Heart Rate Variability Post-Infarctione
 
  

     The first large clinical trial in infarct survivors to show the relationship between abnormally low measures of heart rate variability and mortality was published in 1987 (31). This built on the evidence from earlier observations and studies (32). This prospective study in 800 infarct survivors showed that those whose SDNN measure at 11+3 days after the acute event was less than 50 ms had a 5.3 fold greater incidence of all-cause mortality than those whose SDNN measure was greater than 100 ms. The SDNN measure retained its prognostic significance after adjusting for other variables known to be associated with increased mortality rates (ie: mean heart rate; ejection fraction; segmental wall motion scores; clinical evidence of heart failure; Holter derived measures of ventricular ectopy; age). The authors suggested that low SDNN values were due to increased sympathetic tone, to reduced vagal tone or to a combination of the two.

       Similarly, in a study of 385 survivors of acute infarction, Odemuyiwa et al showed that a heart rate variability index measure of less than 20 U had a sensitivity of 75% and specificity of 52% for all-cause mortality (33). The same measure had a sensitivity of 75% and specificity of 76% for prediction of arrhythmic events and 40% and 83% respectively for sudden deaths. All-cause mortality was equally well predicted by measures of left ventricular ejection fraction, but heart rate variability index was superior in predicting arrhythmic episodes including sudden deaths.
Cripps et al showed in a series of 177 consecutive patients discharged following acute myocardial infarction and followed for a median of 16 months, that those with a mean heart rate variability index of less than 25 had a relative risk of 7 for sudden death and major arrhythmic events compared to those with higher measures (34). Furthermore this index was the best predictor of arrhythmic events when compared to clinical variables, reduced left ventricular ejection fraction, presence of late potentials on signal averaged ECG and non-sustained runs of ventricular tachycardia on Holter ECG.

    In another study from the same group of 416 consecutive survivors of acute infarction, univariate analysis confirmed that arrhythmic events were predicted by a variety of tests including: heart rate variability measure of less than 20 ms, the presence of late potentials on signal averaged ECG, exercise stress testing, ectopic beat frequency and complexity, left ventricular ejection fraction less than 40% and Killip class (35). However, only impaired heart rate variability, followed by late potentials and repetitive ventricular ectopy retained their independent predictive value when submitted to multi-variate analysis. The combination of impaired heart rate variability and late potentials was the best predictor with sensitivity of 58% and positive predictive accuracy of 33% for arrhythmic events (relative risk 18.5) during follow-up ranging from 1-1,112 days.

      Reduced baroreflex sensitivity after myocardial infarction was evaluated in 68 patients and found to be a better predictor of arrhythmic events during follow-up by Farrell et al than ECG derived measures of heart rate variability (36). This has been shown also by the others. However, as baroreflex sensitivity - a measure of reflex cardiac vagal innervation - requires arterial cannulation and phenylephrine infusion, it is less practical for routine use than ECG derived measures. There was a strong correlation between depressed baro-receptor responsiveness and the induction of sustained monomorphic ventricular tachycardia by programmed ventricular stimulation. This association had a relative risk of 36.29 (95% confidence interval) (37-38).

      It is clearly established, therefore, that reduced measures of heart rate variability following infarction indicate an adverse prognosis. Impaired heart rate variability correlates with total mortality and even more closely with sudden death and major arrhythmic events. However, applying these population results to risk stratify the individual still presents problems. Time-domain measures of heart rate variability, for example, are continuous variables and arbitrary selection of a cut-off value which purports to discriminate low from high risk cohorts inevitably tends to juggle sensitivity with specificity to give optimal prediction for the population studied. This results in different values have been recommended from study to study making routine clinical implementation difficult. Furthermore, studies to date have been retrospective in the sense that the definition of what value was deemed abnormal is decided after the population under study had manifest the complication the measure was to predict. While this is understandable, it emphasizes the need for a further phase of prospective studies which might ultimately lead to intervention studies.

      
     Abnormal Heart Rate Variability: Arrhythmogenic Determinant or Bystander Phenomenon?



       The fact that various measures of impaired heart rate variability correlate statistically with all cause mortality and arrhythmic events following myocardial infarction is clearly established. Whether these indicators of cardiac autonomic imbalance are causally related to the occurrence of ventricular tachyarrhythmias or are just bystanders reflecting the degree of cardiac dysfunction remains unresolved (39-43). The answer to this question is fundamental when intervention aimed at improving prognosis is attempted. If it were causally related to sudden death, then therapy to improve prognosis would also be expected to improve measures of heart rate variability.as a sign of effectiveness. If it is merely a marker of risk, it is unlikely to provide any guide as to the effectiveness of therapy and benefit would not necessarily be expected by any change in parameters of heart rate variability.

    One method of testing the hypothesis that impaired heart rate variability is causally related to arrhythmias following infarction, is to examine the effect of therapies already known to improve prognosis in infarct survivors and examine their effects on measures of heart rate variability. Acute thrombolysis during infarct evolution and factors following infarction such as smoking cessation, exercise rehabilitation programmes, beta-adrenergic blockade and introduction of angiotensin converting enzyme inhibitors are all known to improve prognosis. However, the effects of these on measures of heart rate variability are modest or conflicting. There is some evidence that exercise training programmes (44,45) and low dose muscarinic receptor blockers, such as atropine or scopolamine, may improve heart rate variability measures (46,47). However, the effects of beta-blockade on measures of heart rate variability are disputed and probably not clinically significant (48-50). The evidence that ACE-inhibitor therapies improve measures of heart rate variability is conflicting (51-53). Anti-arrhythmic agents either have no effect on heart rate variability measurements or appear to cause further improvement (15-54,55). No effect on mortality was observed in these studies.

    A second method of testing the relationship of impaired heart rate variability to arrhythmias is to examine whether it becomes abnormal in contexts unassociated with arrhythmic risk and whether it is always abnormal in patients who have post-infarct ventricular tachyarrhythmias.

     Marked reductions in heart rate variability measurements can be observed after major surgery, for example, which gradually normalize with a similar time course to those following infarction without any suggestion that these patients are at increased risk of arrhythmias (56). Further evidence against reduced heart rate variability being causatively related to arrhythmias is provided by the fact that infarct survivors who present with sustained monomorphic ventricular tachycardia and who have the same arrhythmia induced by programmed stimulation do not invariably have impaired heart rate variability as judged by published criteria (57).

     Despite theoretical evidence which might support a causative role for impaired heart rate variables in post-infarct arrhythmias, the present evidence would favor the view that it is a bystander phenomenon. The issue is however far from resolved at present and even if only a bystander, it remains a clinically useful screening measure of sudden death risk.
 

What Tests of Risk Stratification can be Recommended for Patients Post-Infarction?

  

    It is well known, that myocardial infarction results in abnormal cardiac autonomic function, which carries an increased risk of cardiac mortality, but it is not well known whether autonomic dysfunction itself predisposes patients to life threatening arrhythmias or whether it merely reflects the severity of underlying ischemic heart disease (58).

     HRV is considered a marker of autonomic nervous activity. Many clinical studies have shown that in patients with previous myocardial infarction, depressed HRV is associated with increased total cardiac mortality and more powerfully, with propensity to malignant ventricular arrhythmias (59-60). Although there is general agreement that the commonest cause of death in the first two years post myocardial infarction is sudden death, there is less agreement, however, that such deaths are due, only, to ventricular tachyarrhythmias and that the initiating arrhythmia is reentrant monomorphic ventricular tachycardia degenerating to ventricular fibrillation. In fact, some contend electromechanical dissociation and bradyarrhythmias underlie a larger proportion of sudden deaths in patients with old infarction (61). It is into this large, complex and controversial area that tests aimed at stratifying infarct survivors are deployed. From many sides, a single and simple test is ideally required; this must be convenient to deploy for doctors and patients and accurately categorize individual patients by means of a result rapidly available.

     But such a test does not exist at present. Perhaps a more realistic strategy is to deploy a simple test initially, chosen because of its ease of deployment and convenience for doctors and patients and its relatively low cost (62). Above all it must have high sensitivity, predictive accuracy for sudden death and arrhythmias after infarction and identify a risk group of manageable size. This group can then be offered additional tests to refine their risk profile and select those in whom intervention is justified. It is evident the accuracy required of the test depends on the risk benefit and cost ratios of the therapy required (63).

     Not enough studies have compared the relative predictive powers of all variables for sudden deaths and ventricualr tachyarrhythmias in the same cohort of infarct survivors. Besides, many other variables must be considered in this analysis: clinical laboratory and x ray parameters, size of infarction, measures of left ventricular ectopy, presence of late potentials and QT dispersion.
Then, is HRV equal to left ventricular function in predicting total mortality and superior to it in predicting sudden death and ventricular tachyarrhythmias? On the basis of the present evidence, therefore, it would appear that HRV should replace ejection fraction as the initial screening test for arrhythmic risk following infarction. Because there is no evidence at present that it provides guidance as to the effectiveness of any intervention and because on its own its predictive powers are limited, it needs to be combined with some additional testing, if the result is abnormal (64).

    Further work is required to clarify what the overlap between abnormal HRV and inducibility of sustained monomorphic ventricular tachycardia. It is conceivable on theoretical grounds that low HRV and inducible ventricular tachycardia identify different cohorts of high-risk patients following infarction, both of whom might die of ventricular arrhythmias. Low HRV might identify those with low ventricular fibrillation threshold whose sudden death is due to ventricular fibrillation from its initiation, while inducible ventricular tachycardia might identify those whose sudden death was due to ventricular tachycardia degenerating to ventricular fibrillation. By this hypothesis, both correlation and lack of correlation between the results of the two tests might still be valid and have similar clinical implications, but differ in the mechanism of their lethal arrhythmia. Considerable overlap of results would, of course, be expected, but the type of intervention to prevent arrhythmias might have to be different
 

CONCLUSION

   
      Our understanding of the mechanisms contributing to changes in heart rate variability is only partly evolved and the apparent ease of obtaining measures of heart rate variability belies its underlying complexity. Much remains to be elucidated but already these measures are providing intriguing insights into many clinical areas including that of risk stratification of patients following infarction. It is premature to answer the question as to whether the technique will prove a prognostic panacea allowing routine initial risk stratification of infarct survivors, but it undeniably remains at least in part an enigma for now.

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