Clin. Cardiol. 14, 683-685 (1991)
9
This seiYion edited by A. John Camm, M.D., F.R.C.P.,F. A.C.C.
Heart Rate Variability: An Important New Risk Factor in Patients Following Myocardial Infarction D.J. EWING,M.D., F.R.C.P. Univervity Department of Medicine, Royal Infirmary, Edinburgh, Scotland
Summary: After acute myocardial infarction, cardiac autonomic, and particularly parasympathetic, activity decreases, followed by a gradual return toward normal over the next few weeks and months. The easiest measureable index of autonomic activity is heart rate variability, which can be assessed in a number of different ways. Where heart rate variabikity is low after myocardial infarction, long-term survival is considerably reduced, independent of other known risk factors. This may be caused by patchy autonomic denervation, rendering the heart more susceptible to potentially fatal arrhythmias. Prophylactic drug therapy might reduce mortality in patients with low heart rate variability. Key words: myocardial infarction, heart rate variability, prognosis
Introduction The fact that the autonomic nervous system plays an important role during and after acute myocardial infarction is being increasingly rec0gnized.l Shortly after the acute episode, reduced autonomic activity usually occurs. In the longer term, low heart rate variability, which gives a simple measure of mainly cardiac parasympathetic activity, may provide a good indicator of prognosis
Address for correspondence:
Dr. D. J. Ewing Department of Medicine Royal Infirmary Edinburgh. EH3 9YW, Scotland Received: February 28, 1991 Accepted: March 1, 1991
after a heart attack. This brief review examines the evidence for this, discusses the techniques available for measuring heart rate variability, and speculates on the mechanisms involved.
Autonomic Changes After Myocardial Infarction A number of studies have suggested altered autonomic function in the hours following an acute myocardial infarction. Webb et a1.* postulated increased vagal or sympathetic activity based on heart rate changes and the site of the lesion. Chadda and co-workers3 noted that a bradycardia-hypotension syndrome frequently accompanied an acute episode, and that it was improved with atropine. The arterial responses to the Valsalva manoeuvel-4 and the baroreflex control of vascular resistances have both been found to be impaired in a majority of patients studied. So, too, were conventional noninvasive cardiovascular re flex tests carried out within 3 days of the myocardial infarction63 A recent study on baroreceptor function suggested that a transient impairment of heart rate control occurs with both anterior and inferior myocardial infarction.* In another study, however, it was in patients with anterior infarction particularly that parasympathetic activity, assessed by heart rate variability, was lower.y What happens later on? A clear cut recovery of baroreflex function has been seen after lo* and 4OS days. By contrast, Ryan's group,I0 noted that parasympathetic, but not sympathetic, responses were still impaired 3 months after the acute episode. In a longer follow-up study, Schwartz et a/." found that baroreflex sensitivity had recovered by 3 months and did not change further after 1 year. In another analysis, utilizing heart rate variability, values returned toward normal after 6 months,12 while a spectral analysis study also suggested a return to normal of sympathovagal interaction. l 3 There is, therefore, considerable evidence to support the general pattern of decreased cardiac autonomic, and par-
684
Clin. Cardiol. Vol. 14, August 1991
ticularly parasympathetic activity shortly after acute myocardial infarction, followed by a gradual return toward normal in most patients over the subsequent weeks and months.
Heart Kate Variability Of all the indicators of autonomic activity, probably the easiest to record and measure is heart rate variability. There are a number of different ways of recording it. In the short term, to give a snapshot of cardiac autonomic activity, heart rate variation during deep breathing is an easy and popular bedside method.14 Now emerging, however, are rather more sensitive measures, some of which give a view of longer term variations. In mathematical terms they can be reduced to so-called “time” and “frequency” domain methods. Time domain techniques are those which look at RR interval (or heart rate) changes directly over different periods, either beat by beat or longer. Two methods have proved most popular. The first takes the standard deviation (SD) about the mean RR interval over a specified length of time or number of beats. This reflects both parasympathetic and sympathetic component^.'^. l 6 The second measures beat by beat differences in RR interval, counts all those that exceed a certain threshold (counts method),” and gives an assessment of cardiac parasympathetic activity. There are other time domain methods of varying degrees of complexity, one example of which is mean square successive difference (MSSD), which calculates a variance based on beat by beat changes. Frequency domain techniques utilize a period of recorded heart rate and subject it to spectral analysis to try to determine the frequency of underlying rhythms. The high-frequency component corresponds to cardiac parasympathetic activity, while the low-frequency component reflects both parasympathetic and sympathetic While most of these methods were first popularized in relation to diabetes mellitus, they have increasingly been applied to other disorders, and recently in relation to myocardial infarction. Several papers have compared the techniques in this situation.l9,23-27 The general conclusion has been that the “broader” methods of standard deviation and total power spectrum correlate closely, as do three methods of parasympathetic activity, namely the counts method, MSSD and the power of the high-frequency component of spectral analysis. Comparisons between S D and total power on the one hand, and the parasympathetic measures on the other, reveal weaker correlations. This is to be expected as the first two techniques measure both components of autonomic activity, whereas the latter three are thought to indicate exclusively parasympathetic activity.
rhythmia and prognosis after myocardial infarction. They looked at the number of bursts of sinus arrhythmia over 5 minutes in 62 controls and 59 subjects with myocardial infarction. As has been amply confirmed subsequently, sinus arrhythmia (or heart rate variability) decreased with age and was less in the patients with myocardial infarction. More important, they observed that the 9 patients who died within 18 months were among those with the least evidence of sinus arrhythmia. It took at least 10 years before the next report was published on the subject, this time from Australia. In it Wolf et ~ 1 1 described . ~ ~ 176 patients admitted to a coronary care unit with acute myocardial infarction. The variance of RR intervals over 30 consecutive sinus beats was calculated, and subjects were arbitrarily divided into two groups above and below a particular variance. There was a significantly lower in-hospital mortality in the group with sinus arrhythmia despite similar ages of the two groups and irrespective of the size or site of the infarction. A further decade passed before the next publication on the subject, this time a major study from the Multicenter Post Infarction Group in 1987. Kleiger et d.lh looked at over 800 patients under 7 0 years old who had 24-h ambulatory heart rate recordings just before discharge from hospital following an acute myocardial infarction. The SD of the mean RR interval over the 24-h period was used as a measure of heart rate variability. Of those with an SD of less than 50 ms (125 subjects) 34% had died within the follow-up period which averaged 2.5 years. By contrast, only 9% of the 21 1 subjects with an S D greater than 100 ms had died, making an increased relative risk of 5.3 for those with low heart rate variability. Moreover, decreased heart rate variability increased the risk of subsequent death irrespective of average heart rate, poor left ventricular function, ventricular ectopic beats, clinical or demographic variables and drug treatment. It should be pointed out, of course, that this important large study used standard deviation as the marker of variability, and that this measure encompasses both parasympathetic and sympathetic components of autonomic activity. As yet there have been no published confirmatory studies, and in particular none examining the separate effects of parasympathetic and sympathetic contributions to the increased mortality. A number of groups are currently examining this and if, as is likely, they confirm Kleiger and colleagues’ observations, this will indeed show that heart rate variability is a powerful predictor of subsequent mortality risk.
Possible Mechanisms and Therapeutic Implications Heart Rate Variability and Mortality In a little quoted abstract of 1965, Schneider and Costiloe2xdrew attention to the relation between sinus ar-
How might reduced heart rate variability be associated with a poor prognosis? At this stage, one can only surmise about possible mechanisms. The electrical stability of the heart is dependent on a delicate balance between vari-
D. J. Ewing: Heart rate variability and MI
ous autonomic and humoral inputs. When a myocardial infarction occurs, it may directly damage chemoreceptors and mechanoreceptors in the affected area, release local chemiculs, and impair neural transmission. Each of these factors, in turn, may lead to further reflex effects, resulting in a decrease in parasympathetic and a secondary increase in sympathetic activity. Because, too, the damage is probably no1 uniform, inhomogeneity will add to the imbalance of neural traffic. Indeed, regional sympathetic denervation has been demonstrated using scintiscanning.' It IS well established that, in experimental myocardial infarction, decreased vagal tone and increased sympathetic activity both predispose to ventricular fibrillation; conversely, increase in vagal or decrease in sympathetic activity reduces the vulnerability.' In postmyocardial infarction patients, such a situation could arise with deranged autonomic activity, and this might persist for some time. Here decreased heart rate variability is acting as a marker of decreased vagal activity, and hence of increased vulnerability to potentially fatal ventricular arrhythmias. It is therefore tempting to speculate that if decreased heart rate variability indicates a group at increased risk of dying, then this might be prevented by prophylactic drugs. It could explain why, by reducing sympathetic activity, beta-blocking drugs have a beneficial effect after myocardial infarction. An alternative strategy might be to develop drugh that will increase vagal activity and can be used in the long term.
20.
References
21.
I. 2. 3. 4.
5.
6. 7.
8.
9.
Zipes DP: Influence of myocardial ischemia and infarction on autonomic innervation of heart. Circulation 82, 1095 ( 1990) Webb SW, Adgey AAJ, Pantridge J F Autonomic disturbance at onset of acute myocardial infarction. Br Med J 3,89 (1972) Chadda KD, Lichstein E, Gupta PK, Choy R: Bradycardia-hyporension syndrome in acute myocardial infarction. Reappraisal of the overdrive effects of atropine. Am J Med 59, 158 (1975) Kirby BJ: Circulatory reflexes in myocardial infarction. Br H m r f J 39, 168 (1977) lmaizumi T, Takeshita A, Makino N, Ashihara T, Yamamoto K, Nakamura M: Impaired baroreflex control of vascular retistance and heart rate in acute myocardial infarction. Br Hcrart J 52,4 18 ( 1984) Bhatnagar SK, Al-Yusuf AR, Al-Asfoor AR: Abnormal autonomic function in diabetic and nondiabetic patients after first myocardial infarction. Chest 92, 849 (1987) Niemela MJ, Airaksinen KEJ, Ikaheimo MJ, Groundstroeme K. Linnaluoto MK, Takkunen JT: Impaired parasympathetic control of heart rate after myocardial infarction. I n t J Cardiol24.305 (1989) Owulati G, Grassi G, Giannattasio C, Seravalle G, Valagussa F, Zanchetti A, Mancia G: Early alterations of the baroreceptor control of heart rate in patients with acute myocardial infarction. Circulation 81, 939 (1990) McAreavey D, Neilson JMM, Ewing DJ, Russell DC: Cardiac parasympathetic activity during the early hours of acute myocardial infarction. Br Hear/ J 62, 165 (1989)
10.
11.
15.
16. 17. 18.
19.
22. 23.
24.
25. 26.
27.
28. 29.
685
Ryan C, Hollenberg M, Harvey DB, Gwynn R: Impaired parasympathetic responses in patients after myocardial infarction. Am J Cardiol37, 1013 (1976) Schwartz PJ, Zaza A, Palo M, Locati E, Beria G, Zanchetti A: Baroreflex sensitivity and its evolution during the first year after myocardial infarction. J Am Coll Cardiol 12,629 (1988) Rothschild M, Rothschild A, Heifer M: Temporary decrease in cardiac parasympathetic tone after acute myocardial infarction. Am J Cardiol62, 637 (1988) Lombardi F, Sandrone G, Pempruner S, Sala R, Garimoldi M, Cerutti S, Baselli G, Pagani M, Malliani A: Heart rate variability as an index of sympathovagal interaction after acute myocardial infarction. Am J Cardiol60, 1239 (1987) Ewing DJ: Practical bedside investigation of diabetic autonomic failure. In Autonomic Failure (Ed. Bannister R). Oxford University Press, Oxford (1983) 371 Murray A, Ewing DJ, Campbell IW, Neilson JMM, Clarke B F RR interval variations in young male diabetics. Br Heart J 37,882 ( I 975) Kleiger RE, Miller JP, Bigger JT, Moss AJ: Decreased heart rate variability and its association with increased mortality after acute myocardial infarction. Am J Cardiol59,256 (1987) Ewing DJ, Neilson JMM, Travis P New method for assessing cardiac parasympathetic activity using 24 hour electrocardiograms. Br Heart J 52,396 (1984) Gundersen HJC, Neubauer B: A long term diabetic autonomic nervous abnormality. Reduced variations in resting heart rate measured by a simple and sensitive method. Diuhetologia 13, 137 (1977) Bigger JT, Kleiger RE, Fleiss JL, Rolnitsky LM, Steinman RC, Miller JP:Components of heart rate variability measured during healing of acute myocardial infarction. Am J Cardiol 61,208 (1988) Pomeranz B, Macaulay RJB, Caudill MA, Kutz I, Adam D, Gordon D, Kilbom KM, Barger AC, Shannon DC, Cohen RJ, Benson H: Assessment of autonomic function in humans by heart rate spectral analysis. Am J Physiol248, HI5 1 (1985) Akselrod S, Gordon D, Madwed JB, Snidman NC, Shannon DC, Cohen RJ: Hemodynamic regulation: Investigation by spectral analysis. Am J Physiol249, H867 (1985) Appel ML, Berger RD, Saul JP, Smith JM, Cohen RJ: Beat to beat variability in cardiovascular variables: Noise or music? J Am Coll Cardiol 14, I 139 ( 1 989) Myers GA, Martin GJ, Magid NM, Bamett PS, Schaad JW, Weiss JS, Lesch M, Singer DH: Power spectral analysis of heart rate variability in sudden cardiac death: Comparison to other methods. IEEE Trans Biomed Eng 33, 1 149 (1986) Bigger JT, Albrecht P, Steinman RC, Rolnitzky LM, Fleiss JL, Cohen RJ: Comparison of time- and frequency domain-based measures of cardiac parasympathetic activity in Holter recordings after myocardial infarction. Am J Cardiol64,536 (1989) Malik M, Farrell T, Cripps T, Camm AJ: Heart rate variability in relation to prognosis after myocardial infarction: Selection of optimal processing techniques. Eur Heart J 10, 1060 (1989) Malik M, Cripps T, Farrell T, Camm AJ: Prognostic value of heart rate variability after myocardial infarction. A comparison of different data-processing methods. Med Biol Eng Comput 27,603 (1989) Bigger JT, La Rovere MT, Steinman RC, Fleiss JL, Rottman JN, Rolnitzky LM, Schwartz PJ: Comparison of baroreflex sensitivity and heart period variability after myocardial infarction. J Am Coll Cardiol 14, 15 1 1 (1989) Schneider RA, Costiloe JP: Relationship of sinus arrhythmia to age and its prognostic significance in ischemic heart disease. CIin Res 13,219 (1965) Wolf MM, Varigos GA, Hunt D, Sloman JG: Sinus arrhythmia in acute myocardial infarction. Med J Austral 2,52 (1978)
9
This seiYion edited by A. John Camm, M.D., F.R.C.P.,F. A.C.C.
Heart Rate Variability: An Important New Risk Factor in Patients Following Myocardial Infarction D.J. EWING,M.D., F.R.C.P. Univervity Department of Medicine, Royal Infirmary, Edinburgh, Scotland
Summary: After acute myocardial infarction, cardiac autonomic, and particularly parasympathetic, activity decreases, followed by a gradual return toward normal over the next few weeks and months. The easiest measureable index of autonomic activity is heart rate variability, which can be assessed in a number of different ways. Where heart rate variabikity is low after myocardial infarction, long-term survival is considerably reduced, independent of other known risk factors. This may be caused by patchy autonomic denervation, rendering the heart more susceptible to potentially fatal arrhythmias. Prophylactic drug therapy might reduce mortality in patients with low heart rate variability. Key words: myocardial infarction, heart rate variability, prognosis
Introduction The fact that the autonomic nervous system plays an important role during and after acute myocardial infarction is being increasingly rec0gnized.l Shortly after the acute episode, reduced autonomic activity usually occurs. In the longer term, low heart rate variability, which gives a simple measure of mainly cardiac parasympathetic activity, may provide a good indicator of prognosis
Address for correspondence:
Dr. D. J. Ewing Department of Medicine Royal Infirmary Edinburgh. EH3 9YW, Scotland Received: February 28, 1991 Accepted: March 1, 1991
after a heart attack. This brief review examines the evidence for this, discusses the techniques available for measuring heart rate variability, and speculates on the mechanisms involved.
Autonomic Changes After Myocardial Infarction A number of studies have suggested altered autonomic function in the hours following an acute myocardial infarction. Webb et a1.* postulated increased vagal or sympathetic activity based on heart rate changes and the site of the lesion. Chadda and co-workers3 noted that a bradycardia-hypotension syndrome frequently accompanied an acute episode, and that it was improved with atropine. The arterial responses to the Valsalva manoeuvel-4 and the baroreflex control of vascular resistances have both been found to be impaired in a majority of patients studied. So, too, were conventional noninvasive cardiovascular re flex tests carried out within 3 days of the myocardial infarction63 A recent study on baroreceptor function suggested that a transient impairment of heart rate control occurs with both anterior and inferior myocardial infarction.* In another study, however, it was in patients with anterior infarction particularly that parasympathetic activity, assessed by heart rate variability, was lower.y What happens later on? A clear cut recovery of baroreflex function has been seen after lo* and 4OS days. By contrast, Ryan's group,I0 noted that parasympathetic, but not sympathetic, responses were still impaired 3 months after the acute episode. In a longer follow-up study, Schwartz et a/." found that baroreflex sensitivity had recovered by 3 months and did not change further after 1 year. In another analysis, utilizing heart rate variability, values returned toward normal after 6 months,12 while a spectral analysis study also suggested a return to normal of sympathovagal interaction. l 3 There is, therefore, considerable evidence to support the general pattern of decreased cardiac autonomic, and par-
684
Clin. Cardiol. Vol. 14, August 1991
ticularly parasympathetic activity shortly after acute myocardial infarction, followed by a gradual return toward normal in most patients over the subsequent weeks and months.
Heart Kate Variability Of all the indicators of autonomic activity, probably the easiest to record and measure is heart rate variability. There are a number of different ways of recording it. In the short term, to give a snapshot of cardiac autonomic activity, heart rate variation during deep breathing is an easy and popular bedside method.14 Now emerging, however, are rather more sensitive measures, some of which give a view of longer term variations. In mathematical terms they can be reduced to so-called “time” and “frequency” domain methods. Time domain techniques are those which look at RR interval (or heart rate) changes directly over different periods, either beat by beat or longer. Two methods have proved most popular. The first takes the standard deviation (SD) about the mean RR interval over a specified length of time or number of beats. This reflects both parasympathetic and sympathetic component^.'^. l 6 The second measures beat by beat differences in RR interval, counts all those that exceed a certain threshold (counts method),” and gives an assessment of cardiac parasympathetic activity. There are other time domain methods of varying degrees of complexity, one example of which is mean square successive difference (MSSD), which calculates a variance based on beat by beat changes. Frequency domain techniques utilize a period of recorded heart rate and subject it to spectral analysis to try to determine the frequency of underlying rhythms. The high-frequency component corresponds to cardiac parasympathetic activity, while the low-frequency component reflects both parasympathetic and sympathetic While most of these methods were first popularized in relation to diabetes mellitus, they have increasingly been applied to other disorders, and recently in relation to myocardial infarction. Several papers have compared the techniques in this situation.l9,23-27 The general conclusion has been that the “broader” methods of standard deviation and total power spectrum correlate closely, as do three methods of parasympathetic activity, namely the counts method, MSSD and the power of the high-frequency component of spectral analysis. Comparisons between S D and total power on the one hand, and the parasympathetic measures on the other, reveal weaker correlations. This is to be expected as the first two techniques measure both components of autonomic activity, whereas the latter three are thought to indicate exclusively parasympathetic activity.
rhythmia and prognosis after myocardial infarction. They looked at the number of bursts of sinus arrhythmia over 5 minutes in 62 controls and 59 subjects with myocardial infarction. As has been amply confirmed subsequently, sinus arrhythmia (or heart rate variability) decreased with age and was less in the patients with myocardial infarction. More important, they observed that the 9 patients who died within 18 months were among those with the least evidence of sinus arrhythmia. It took at least 10 years before the next report was published on the subject, this time from Australia. In it Wolf et ~ 1 1 described . ~ ~ 176 patients admitted to a coronary care unit with acute myocardial infarction. The variance of RR intervals over 30 consecutive sinus beats was calculated, and subjects were arbitrarily divided into two groups above and below a particular variance. There was a significantly lower in-hospital mortality in the group with sinus arrhythmia despite similar ages of the two groups and irrespective of the size or site of the infarction. A further decade passed before the next publication on the subject, this time a major study from the Multicenter Post Infarction Group in 1987. Kleiger et d.lh looked at over 800 patients under 7 0 years old who had 24-h ambulatory heart rate recordings just before discharge from hospital following an acute myocardial infarction. The SD of the mean RR interval over the 24-h period was used as a measure of heart rate variability. Of those with an SD of less than 50 ms (125 subjects) 34% had died within the follow-up period which averaged 2.5 years. By contrast, only 9% of the 21 1 subjects with an S D greater than 100 ms had died, making an increased relative risk of 5.3 for those with low heart rate variability. Moreover, decreased heart rate variability increased the risk of subsequent death irrespective of average heart rate, poor left ventricular function, ventricular ectopic beats, clinical or demographic variables and drug treatment. It should be pointed out, of course, that this important large study used standard deviation as the marker of variability, and that this measure encompasses both parasympathetic and sympathetic components of autonomic activity. As yet there have been no published confirmatory studies, and in particular none examining the separate effects of parasympathetic and sympathetic contributions to the increased mortality. A number of groups are currently examining this and if, as is likely, they confirm Kleiger and colleagues’ observations, this will indeed show that heart rate variability is a powerful predictor of subsequent mortality risk.
Possible Mechanisms and Therapeutic Implications Heart Rate Variability and Mortality In a little quoted abstract of 1965, Schneider and Costiloe2xdrew attention to the relation between sinus ar-
How might reduced heart rate variability be associated with a poor prognosis? At this stage, one can only surmise about possible mechanisms. The electrical stability of the heart is dependent on a delicate balance between vari-
D. J. Ewing: Heart rate variability and MI
ous autonomic and humoral inputs. When a myocardial infarction occurs, it may directly damage chemoreceptors and mechanoreceptors in the affected area, release local chemiculs, and impair neural transmission. Each of these factors, in turn, may lead to further reflex effects, resulting in a decrease in parasympathetic and a secondary increase in sympathetic activity. Because, too, the damage is probably no1 uniform, inhomogeneity will add to the imbalance of neural traffic. Indeed, regional sympathetic denervation has been demonstrated using scintiscanning.' It IS well established that, in experimental myocardial infarction, decreased vagal tone and increased sympathetic activity both predispose to ventricular fibrillation; conversely, increase in vagal or decrease in sympathetic activity reduces the vulnerability.' In postmyocardial infarction patients, such a situation could arise with deranged autonomic activity, and this might persist for some time. Here decreased heart rate variability is acting as a marker of decreased vagal activity, and hence of increased vulnerability to potentially fatal ventricular arrhythmias. It is therefore tempting to speculate that if decreased heart rate variability indicates a group at increased risk of dying, then this might be prevented by prophylactic drugs. It could explain why, by reducing sympathetic activity, beta-blocking drugs have a beneficial effect after myocardial infarction. An alternative strategy might be to develop drugh that will increase vagal activity and can be used in the long term.
20.
References
21.
I. 2. 3. 4.
5.
6. 7.
8.
9.
Zipes DP: Influence of myocardial ischemia and infarction on autonomic innervation of heart. Circulation 82, 1095 ( 1990) Webb SW, Adgey AAJ, Pantridge J F Autonomic disturbance at onset of acute myocardial infarction. Br Med J 3,89 (1972) Chadda KD, Lichstein E, Gupta PK, Choy R: Bradycardia-hyporension syndrome in acute myocardial infarction. Reappraisal of the overdrive effects of atropine. Am J Med 59, 158 (1975) Kirby BJ: Circulatory reflexes in myocardial infarction. Br H m r f J 39, 168 (1977) lmaizumi T, Takeshita A, Makino N, Ashihara T, Yamamoto K, Nakamura M: Impaired baroreflex control of vascular retistance and heart rate in acute myocardial infarction. Br Hcrart J 52,4 18 ( 1984) Bhatnagar SK, Al-Yusuf AR, Al-Asfoor AR: Abnormal autonomic function in diabetic and nondiabetic patients after first myocardial infarction. Chest 92, 849 (1987) Niemela MJ, Airaksinen KEJ, Ikaheimo MJ, Groundstroeme K. Linnaluoto MK, Takkunen JT: Impaired parasympathetic control of heart rate after myocardial infarction. I n t J Cardiol24.305 (1989) Owulati G, Grassi G, Giannattasio C, Seravalle G, Valagussa F, Zanchetti A, Mancia G: Early alterations of the baroreceptor control of heart rate in patients with acute myocardial infarction. Circulation 81, 939 (1990) McAreavey D, Neilson JMM, Ewing DJ, Russell DC: Cardiac parasympathetic activity during the early hours of acute myocardial infarction. Br Hear/ J 62, 165 (1989)
10.
11.
15.
16. 17. 18.
19.
22. 23.
24.
25. 26.
27.
28. 29.
685
Ryan C, Hollenberg M, Harvey DB, Gwynn R: Impaired parasympathetic responses in patients after myocardial infarction. Am J Cardiol37, 1013 (1976) Schwartz PJ, Zaza A, Palo M, Locati E, Beria G, Zanchetti A: Baroreflex sensitivity and its evolution during the first year after myocardial infarction. J Am Coll Cardiol 12,629 (1988) Rothschild M, Rothschild A, Heifer M: Temporary decrease in cardiac parasympathetic tone after acute myocardial infarction. Am J Cardiol62, 637 (1988) Lombardi F, Sandrone G, Pempruner S, Sala R, Garimoldi M, Cerutti S, Baselli G, Pagani M, Malliani A: Heart rate variability as an index of sympathovagal interaction after acute myocardial infarction. Am J Cardiol60, 1239 (1987) Ewing DJ: Practical bedside investigation of diabetic autonomic failure. In Autonomic Failure (Ed. Bannister R). Oxford University Press, Oxford (1983) 371 Murray A, Ewing DJ, Campbell IW, Neilson JMM, Clarke B F RR interval variations in young male diabetics. Br Heart J 37,882 ( I 975) Kleiger RE, Miller JP, Bigger JT, Moss AJ: Decreased heart rate variability and its association with increased mortality after acute myocardial infarction. Am J Cardiol59,256 (1987) Ewing DJ, Neilson JMM, Travis P New method for assessing cardiac parasympathetic activity using 24 hour electrocardiograms. Br Heart J 52,396 (1984) Gundersen HJC, Neubauer B: A long term diabetic autonomic nervous abnormality. Reduced variations in resting heart rate measured by a simple and sensitive method. Diuhetologia 13, 137 (1977) Bigger JT, Kleiger RE, Fleiss JL, Rolnitsky LM, Steinman RC, Miller JP:Components of heart rate variability measured during healing of acute myocardial infarction. Am J Cardiol 61,208 (1988) Pomeranz B, Macaulay RJB, Caudill MA, Kutz I, Adam D, Gordon D, Kilbom KM, Barger AC, Shannon DC, Cohen RJ, Benson H: Assessment of autonomic function in humans by heart rate spectral analysis. Am J Physiol248, HI5 1 (1985) Akselrod S, Gordon D, Madwed JB, Snidman NC, Shannon DC, Cohen RJ: Hemodynamic regulation: Investigation by spectral analysis. Am J Physiol249, H867 (1985) Appel ML, Berger RD, Saul JP, Smith JM, Cohen RJ: Beat to beat variability in cardiovascular variables: Noise or music? J Am Coll Cardiol 14, I 139 ( 1 989) Myers GA, Martin GJ, Magid NM, Bamett PS, Schaad JW, Weiss JS, Lesch M, Singer DH: Power spectral analysis of heart rate variability in sudden cardiac death: Comparison to other methods. IEEE Trans Biomed Eng 33, 1 149 (1986) Bigger JT, Albrecht P, Steinman RC, Rolnitzky LM, Fleiss JL, Cohen RJ: Comparison of time- and frequency domain-based measures of cardiac parasympathetic activity in Holter recordings after myocardial infarction. Am J Cardiol64,536 (1989) Malik M, Farrell T, Cripps T, Camm AJ: Heart rate variability in relation to prognosis after myocardial infarction: Selection of optimal processing techniques. Eur Heart J 10, 1060 (1989) Malik M, Cripps T, Farrell T, Camm AJ: Prognostic value of heart rate variability after myocardial infarction. A comparison of different data-processing methods. Med Biol Eng Comput 27,603 (1989) Bigger JT, La Rovere MT, Steinman RC, Fleiss JL, Rottman JN, Rolnitzky LM, Schwartz PJ: Comparison of baroreflex sensitivity and heart period variability after myocardial infarction. J Am Coll Cardiol 14, 15 1 1 (1989) Schneider RA, Costiloe JP: Relationship of sinus arrhythmia to age and its prognostic significance in ischemic heart disease. CIin Res 13,219 (1965) Wolf MM, Varigos GA, Hunt D, Sloman JG: Sinus arrhythmia in acute myocardial infarction. Med J Austral 2,52 (1978)
