Parasympathetic failure and risk of subsequent coronary events in unstable angina and non-ST-segment elevation myocardial infarction
Olivia Manfrini*,
Carmine Pizzi,
Davide Trerè,
Fiorella Fontana and
Raffaele Bugiardini
Dipartimento di Medicina Interna, Cardioangiologia, Epatologia. Università di Bologna, 40136 Bologna, Italy
* Corresponding author. Dr O. Manfrini, University of Bologna, Via di Gaibola 13/16, 40136 Bologna, Italy. Tel.: +39-051-589116; fax: +39-051-347290
E-mail address: olimanfrini{at}netscape.net
Received 14 January 2003;
revised 20 May 2003;
accepted 12 June 2003
 |
Abstract
|
---|
Aim Previous animal studies suggested that vagal tone contributes to tonic dilatation of coronary arteries. We hypothesized that low parasympathetic activity might be among the causes of coronary instability in the setting of acute coronary syndrome without ST-segment elevation.
Methods and results We studied 172 consecutive patients. Vagal and sympathetic activities were assessed by time domain measures of heart rate variability. PNN50 <3% was used as a marker of low parasympathetic activity. At 6-month follow-up 32 patients developed coronary events. Coronary events were lower during hospitalization (n=9) than during follow-up (n=23). Extremely low values of parasympathetic activity (pNN50 <3%) were strongly related to subsequent events (P<0.001). PNN50 <3% was found in 56% of patients having adverse events versus 5% of patients who had good outcome. Among patients who had pNN50 <3%, 18 patients (72%) had subsequent coronary events vs seven patients (28%) who had a good outcome.
Conclusions These data show that in acute coronary syndrome without ST-segment elevation, a significant number of patients developing subsequent coronary events have a loss of vagal tone. Simple electrocardiographic variables, as pNN50 <3%, may be of great clinical value in identifying patients at high risk of subsequent coronary events even after apparent clinical stabilization.
Key Words: Coronary heart disease Heart rate variability Prognosis
 |
1. Introduction
|
---|
Despite recent therapeutic and diagnostic advances in the management of ischaemic heart disease, patients admitted to coronary care units for acute coronary syndromes still show a high incidence of mortality and morbidity during hospitalization and in the first months following discharge.1Research has been focused to identify patients at high risk. Several studies have suggested a number of unfavourable prognostic factors including: age, gender,2previous history of coronary artery disease,3biochemical markers of myocardial injury and inflammation,4,5low ejection fraction,6and evidence of recurrence of ischaemia.79However, early identification of patients who might benefit from invasive therapeutic strategies remains difficult. Knowledge of the pathophysiology of acute coronary syndromes is far from complete and advances in its understanding may suggest new approaches to therapy.
Sympatho-vagal imbalance, as assessed by heart rate variability, has proved to be an independent predictor of poor prognosis in patients surviving acute myocardial infarction.1012Sudden ischaemic cardiac death is often preceded by changes in autonomic activity.13Furthermore, autonomic changes have been reported to precipitate ischaemia in stable coronary artery disease.14Few data are available in unstable angina and non-ST-segment elevation myocardial infarction (UA and NSTEMI).15,16The aim of this study was to assess whether measures of heart rate variability, as detected upon admission to the coronary care unit, add useful information for the early identification of patients who will develop subsequent coronary events. Animal studies suggested that vagal tone contributes to tonic dilation of coronary artery.17We specifically hypothesized that low parasympathetic activity may contribute to coronary instability in the setting of UA and NSTEMI.
 |
2. Methods
|
---|
2.1. Patients
We studied 172 consecutive patients (Table 1) admitted to the coronary care unit with a diagnosis of UA or NSTEMI. They were eligible for the study if they had an episode of angina at rest or during minimal efforts, or with an accelerating pattern within the preceding 24h. All patients had transient ST-segment depression of at least 0.1mV or T wave inversion, in at least two contiguous leads. Diagnosis of NSTEMI was based on the World Health Organization criteria by the typical enzyme patterns and diagnostic electrocardiographic changes. Patients were excluded if they displayed any of the following criteria: secondary angina, left bundle block, paced rhythm, concomitant diseases or patho-physiological conditions that could alter the analysis of heart rate variability (i.e. diabetes mellitus, atrial fibrillation, and poor ventricular functionejection fraction <40%as detected by echocardiography). Patients were also excluded because of later recognition of inadequate 24-h electrocardiographic recordings.
2.2. Management protocol
At enrolment, all patients underwent 24-h electrocardiographic monitoring for heart rate variability analysis. All patients had conservative treatment, which included: bed rest, oxygen, aspirin, beta-adrenergic blocking agents, intravenous nitrates or oral long-acting nitrates and low weight molecular heparin. None of the patients had opioid administration. If clinically stable, they underwent exercise stress testing (standard Bruce protocol) on drugs prior to discharge. If exercise testing on drugs was positive at stage 3 or higher, elective coronary angiography was performed followed by revascularization when appropriate. Fifty-two patients had elective coronary angiography, but only 36 had revascularization. Decision to intervene was based on an accurate profile of the patient in terms of symptoms, functional disability, quality of life and coronary anatomy.
Patients underwent urgent cardiac catheterization and revascularization only if they had one of the following features: serious arrhythmias, haemodynamic instability, evidence ofongoing ischaemia despite maximal medical therapy, documented ischaemia before the end of stage 2 of exercise testing, and if required, rehospitalization for unstable angina. During the first hospitalization urgent coronary angiography was performed in 12 patients. Urgent coronary angiography was also performed in 22 patients readmitted to coronary care unit with disabling symptoms at rest or during minimal activity despite medical therapy. Follow-up assessment occurred at baseline, hospital discharge, and in out-patient clinic at 30, 90 and 180 days. All patients gave written informed consent to the study.
2.3. End-points
The primary outcome was a composite of cardiac death, myocardial infarction, urgent revascularization, and hospital readmission, due to unstable angina. Patients having more than one end-point were labelled under the hardest end-point. For example, myocardial infarction if followed by sudden death, was reported as sudden death. Re-admission if followed by urgent revascularization was reported as urgent revascularization.
2.4. Heart rate variability
Twenty-four hour electrocardiographic monitoring for heart rate variability analysis was performed during the early phase of the acute coronary syndrome. Recording started within 12h from admission. Time 0 of ECG-recording ranged from 6a.m. to 6p.m., thus excluding nocturnal initiation. An expert technician, blinded to the clinical data analysed electrocardiographic tapes. Analysis was performed using Del Mar Avionics Accuplus 363 in confirm-option, which allows manual labelling of each artefact, premature beat, and pause. We assessed the following time domain measures of heart rate variability:18(1) the standard deviation of all normal RR intervals in the entire 24h electrocardiographic recording (SDNN), (2) standard deviation of the means of all normal RR intervals during each 5-min segment (SDANN); (3) root-mean square of differences of successive RR intervals (rMSSD); (4) the percent of differences of adjacent RR intervals >50msec (pNN50). In addition, pNN50 <3%, rMSSD <25msec and minimum heart rate >65 beats per min were taken as a measure of low parasympathetic activity.19
2.5. Statistical analysis
Associations between continuous and categorical variables were analysed using ANOVA test. Cumulative event-free survival at 180 days was calculated by the KaplanMeier method and compared using the log-rank test. Multivariate analysis was performed by using the Cox proportional hazards regression model.20Statistical evaluation was performed using the SPSS-Win 10.1 (Statistical Package for Social Science, SPSS Inc., Chicago, IL, USA). Values are presented as mean (SD) and as number (percentage) for categorical variables. Values for P less than 0.01 were regarded as significant.
 |
3. Results
|
---|
3.1. In hospital, and post discharge clinical events
The clinical characteristics of patients enrolled in the study are described in Table 1During the six months follow up (Table 2), 32 patients had a major coronary event (five death, eight myocardial infarction, 11 urgent revascularization, eight recurrence of rest angina). Clinical events were lower during hospitalization (n=9) than during post discharge follow-up (n=23). Among the nine patients who had in-hospital events, five had urgent revascularization and four cardiac death (one fatal myocardial infarction and three sudden death). After discharge, one patient had sudden death. The remaining 22 patients were readmitted to the coronary care unit with disabling symptoms at rest or during minimal activity despite medical therapy. All 22 patients had coronary angiography. Eight had myocardial infarction, six underwent urgent coronary revascularization due to severe stenosis and eight were found not to have significant (<50%) stenosis. In these, we favoured proceeding with hospital discharge on further medical treatment. An overall decline in the incidence of complications occurred after 90 days of follow-up.
3.2. Heart rate variability
Time domain measures of heart rate variability are reported in Table 3. Heart rate variability was reduced in all patients. The average of all measures of heart rate variability did not significantly differ between the patients who had favourable and unfavourable outcomes. However, an extremely low value of parasympathetic activity (pNN50 <3%) predicted mortality and total events (Fig. 1). A pNN50 <3% was found in 18/32 (56%) patients having subsequent coronary events and in only 7/140 (5%) patients having a good clinical outcome. pNN50 values are shown in Fig. 2. Among patients who had pNN50 <3%, 18 patients (72%) had subsequent coronary events versus 7 (28%) who had a good clinical outcome. pNN50 <3% showed a significant correlation with a good clinical outcome (log-rank test:
2=78.07; P<0.001, Fig. 1). Similar results were obtained using rMSSD <25msec (log-rank test:
2=59.96; P<0.001) and minimum heart rate >65 beats per min (log-rank test:
2=48.79; P<0.001). rMSSD <25msec was found in 22/32 (69%) patients having subsequent coronary events and in only 16/140 (11%) patients having good clinical outcome. Minimum heart rate >65 beats per min was in 21/32 (66%) patients having subsequent coronary events and 19/140 (14%) patients having good clinical outcome. We also evaluated the association between pNN50, rMSSD and heart rate with possible confounding factors including age, chest pain, history of ischemic heart disease, hypertension, use of ACE inhibitors and amount of beta-blockers. None of these factors was correlated with pNN50, rMSSD, or heart rate. In multivariate analysis pNN50, rMSSD and heart rate showed to be independent of the above mentioned clinical factors.

View larger version (14K):
[in this window]
[in a new window]
|
Fig. 1 KaplanMeier estimates of overall event-free survival (cardiac death, acute myocardial infarction, urgent revascularization and hospital readmission due to recurrence of rest angina) in patients who have pNN50 <3% vs pNN50 3%.
|
|

View larger version (30K):
[in this window]
[in a new window]
|
Fig. 2 Show the distribution of pNN50 value in patients having subsequent coronary events (group 1) versus patients having good clinical outcome (group 2). A pNN50 <3% was found in 18 (56%) group 1 patients vs 7 (5%) group 2 patients. Patients having transient myocardial ischaemia are indicated by the open triangles.
|
|
3.3. Relation between heart rate variability and transient ischaemic episodes
Transient myocardial ischaemia despite medical treatment during 24h electrocardiographic monitoring was found in five of 32 patients with unfavourable outcome and in none of the remaining 140 patients. Four of these patients had in-hospital events (two death, one myocardial infarction and one urgent revascularization). The fifth patient had post-discharge myocardial infarction. Three of these five patients had a pNN50 <3%.
 |
4. Discussion
|
---|
The main finding of the study was that a shift in the autonomic balance with a loss of vagal tone strongly correlated with an adverse outcome of patients with UA and NSTEMI.
Heart rate variability reflects the activity of the autonomic flow to the heart. The percent of differences of adjacent RR intervals >50msec (pNN50) and the root-mean square of differences of successive RR intervals (RMSSD) are a measure of the modulation of parasympathetic tone by respiratory activity. The standard deviation of all normal RR intervals in the entire 24-h electrocardiographic recording (SDNN) and the standard deviation of the means of all normal RR intervals during each 5-min segment (SDANN) indices are measures of both parasympathetic and sympathetic tone as mediated by the baroreflex activity.
In our study population, a pNN50 <3% was found in 5% of patients having a good outcome versus 56% of patients later having an unfavourable outcome. Only a few patients (n=9) had in-hospital coronary events. Silent myocardial ischaemia was strongly related to the occurrence of in-hospital events as previously reported.21,22The present study demonstrates that heart rate variance measured soon after admission to the coronary care unit may identify a larger population of patients having subsequent coronary events, even some months after an apparent clinical stabilization. Specifically a pNN50 <3% might be useful in clinical practice because it shows a strong relation with the later occurrence of coronary events. Thus, this simple electrocardiographic variable may be of great clinical value.
4.1. Heart rate variability in acute coronary syndromes
As early as 1972 Hinkle found that patients with a sustained slow heart rate experienced more sudden cardiac death than expected.23Interest in heart rate variability became greater due to the observations of the Multicenter Post Infarction Research Group. It established that depressed heart rate variability is a powerful and independent risk factor following acute myocardialinfarction.10The prevalence and importance of autonomic dysfunction in the occurrence of sudden ischaemic death have been further recognized by other studies.13,14However, little is known about the potential prognostic role of changes in heart rate variability in UA and NSTEMI.15,16Our observation of vagal withdrawal in a portion of patients presenting with UA and NSTEMI shows for the first time that a change in parasympathetic activity is a marker for poor prognosis. Parasympathetic withdrawal might precipitate vascular instability, which may contribute to further episodes of coronary occlusion, myocardial ischaemia and sudden death. A number of mechanisms have been postulated. Vagal stimulation may potentially improve coronary flow after myocardial ischaemia, which could contribute to its antifibrillatory influence observed in conscious and anaesthetized animals during myocardial ischaemia.24It may also inhibit sympathetic nerve activity via peripheral pre- and post-synaptic interactions.2528Exposure to high levels of noradrenaline results in beta-receptor mediated cytotoxic effects and apoptosis as well as alpha-receptor mediated vasoconstrictor effects.29,30The deleterious effect of vagal withdrawal observed in the present study is in keeping with experimental animal findings. Vagotomy results in coronary vasoconstriction in anaesthetized dogs suggesting vagal modulation of coronary vessel tone.17Interrupting vagal influences might 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. In accordance with these observations, several investigators have recently demonstrated that activation of muscarinic receptors by both acetylcholine and vagal stimulation results in increases in coronary blood flow.31,32These changes are mediated by the endothelium-derived relaxing factor and nitric oxide, and attenuated or abolished by their antagonists.33It seems reasonable that a failure of parasympathetic activity due to chronic stress or other factor34,35may favour coronary instability, which in turn, may precipitate further episodes of coronary ischaemia and contribute to worsen prognosis.
4.2. Limitations of the study
In this study patients affected by diabetes and poor ventricular function are excluded. This is a large portion of the UA/NSTEMI patient population. However many studies proved that heart rate variability is depressed in these pathological conditions and heart rate variability analysis could not be reliable in this setting. The study was designed to help in the process of risk-stratifying patients with UA and NSTEMI. Accordingly, we approached patients with a conservative strategy. The key problem of this investigation was to look for a prognostic factor that could have been useful to precociously identify those patients who were going to have troubles after discharge. Troubles could not be measured only by the incidence of cardiac death and myocardial infarction, but must include the inability to stabilize an unstable condition, which implies further coronary care unit management and, often immediate urgent mechanical support by coronary angioplasty or by-pass surgery. Although the population in this study was not large enough to allow a new approach for early risk stratification, this finding seems to indicate that heart rate variability could be a powerful clinical tool for stratifying patients with UA and NSTEMI. Additional studies of more stringent design are needed to measure the clinical impact of the assessment of heart rate variability in UA and NSTEMI, and to test it in relation to standard or new therapy.
 |
Acknowledgments
|
---|
This study was supported by Grant 9706570507 from the Ministero dellUniversità e della Ricerca Scientifica e Tecnologica, Italy.
 |
References
|
---|
- Braunwald E, Jones RH, Mark DB et al. Diagnosing and managing unstable angina. Agency for Health Care Policy and Research. Circulation. 1994;90:613622.[Abstract]
- Feldman T, Silver R. Gender differences and outcome of interventions for acute coronary syndromes. Cardiol Rev. 2000;8:240247.[Medline]
- Antman EM, Cohen M, Bernink PJ et al. The TIMI risk score for unstable angina/non-ST elevation MI: a method for prognostication and therapeutic decision-making. JAMA. 2000;284:835842.[Abstract/Free Full Text]
- Galvani M, Ottani F, Ferrini D et al. Prognostic influence of elevated values of cardiac troponin I in patients with unstable angina. Circulation. 1997;95:20532059.[Abstract/Free Full Text]
- Biasucci LM, Liuzzo G, Grillo RL et al. Elevated level of C-reactive protein at discharge in patients with unstable angina predict recurrent instability. Circulation. 1999;99:855860.[Abstract/Free Full Text]
- Stein JH, Neumann A, Preston LM et al. Improved risk stratification in unstable angina: identification of patients at low risk for in-hospital cardiac events by admission echocardiography. Clin Cardiol. 1998;21:725730.[Medline]
- Bugiardini R, Borghi A, Pozzati A et al. Relation of severity of symptoms to transient myocardial ischemia and prognosis in unstable angina. J Am Coll Cardiol. 1995;25:597604.[CrossRef][Medline]
- N(rgaard BL, Andersen K, Dellborg M et al. Admission risk assessment by cardiac troponin T in unstable coronary artery disease: additional prognostic information from continuous ST segment monitoring. J Am Coll Cardiol. 1999;33:15191527.[CrossRef][Medline]
- Patel DJ, Knight CJ, Holdright DR et al. Long-term prognosis in unstable angina. The importance of early risk stratification using continuous ST-segment monitoring. Eur Heart J. 1998;19:240249.[Abstract/Free Full Text]
- Kleiger RE, Miller JP, Bigger JT et al. Decreased heart rate variability and its association with increased mortality after acute myocardial infarction. Am J Cardiol. 1987;59:256262.[Medline]
- Bigger JT Jr., Fleiss JL, Rolnitzky LM et al. Time course recovery of heart rate variability after myocardial infarction. J Am Coll Cardiol. 1991;18:16431649.[Medline]
- Bigger JT Jr., Fleiss JL, Steinman RC et al. Frequency domain measures of heart rate variability and mortality after acute myocardial infarction. Circulation. 1992;85:165171.
- Pozzati A, Pancaldi GL, Di Pasquale G et al. Transient sympathovagal imbalance triggers ischemic sudden death in patients undergoing electrocardiographic Holter monitoring. J Am Coll Cardiol. 1996;27:847852.[CrossRef][Medline]
- Kop WJ, Verdino RJ, Gottdiener JS et al. Changes in heart rate and heart rate variability before ambulatory ischemic events. J Am Coll Cardiol. 2001;38:742749.[CrossRef][Medline]
- Huang J, Sopher SM, Leatham E et al. Heart rate variability depression in patients with unstable angina. Am Heart J. 1995;130:772779.[Medline]
- Lanza GA, Pedrotti A, Rebuzzi AG et al. Useful of addition of heart rate variability to Holter monitoring in predicting cardiac events in patients with unstable angina pectoris. Am J Cardiol. 1997;80:263267.[CrossRef][Medline]
- Kovach JA, Gottdiener JS, Verrier RL. Vagal modulation of epicardial coronary artery size in dogs. A two-dimensional intravascular ultrasound study. Circulation. 1995;92:22912298.[Abstract/Free Full Text]
- Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart ratevariability: standards of measurement, physiological interpretation, and clinical use. Circulation. 1996;93:10431065.[Free Full Text]
- Algra A, Tijssen J, Roelandt J et al. Heart rate variability from 24-hour electrocardiography and 2-year risk for sudden death. Circulation. 1993;88:180185.[Abstract]
- Cox DR. Regression models and life-table. J R Stat Soc B. 1972;34:87220.
- Patel DJ, Holdright DR, Knight CJ et al. Early continuous ST segment monitoring in unstable angina: prognostic value additional to the clinical characteristics and the admission electrocardiogram. Heart. 1996;75:222228.[Abstract]
- Rusticali G, Bugiardini R. Unstable angina and non Q-wave myocardial infarction. Early risk stratification: role of silent ischemia and coronary morphology. Int J Cardiol. 1999;68:S43S47.[CrossRef][Medline]
- Hinkle LE Jr., Carver ST, Plakun A. Slow heart rates and increased risk of cardiac death in middle-age men. Arch Internal Med. 1972;129:732748.[CrossRef][Medline]
- Kent KM, Smith ER, Redwood DR et al. Electrical stability of acutely ischemic myocardium. Influences of heart rate and vagal stimulation. Circulation. 1973;47:291298.[Medline]
- Vanhoutte PM. Inhibition by acetylcholine of adrenergic neurotransmission in vascular smooth muscle. Circ Res. 1974;34:317326.[Medline]
- Casado MA, Sevilla MA, Alonso MJ et al. Muscarinic receptors involved in modulation of norepinephrine release and vasodilatation in guinea pig carotid arteries. J Pharmacol Exp Ther. 1994;271:16381646.[Abstract]
- Loffelholz K, Muscholl E. A muscarinic inhibition of the noradrenaline release evoked by postganglionic sympathetic nerve stimulation. Naunyn Schmiedebergs Archiv Pharmakol. 1969;265:115.
- Watanabe AM, McConnaughey MM, Strawbridge RA et al. Muscarinic cholinergic receptor modulation of beta-adrenoreceptor affinity for catecholamines. J Biol Chem. 1978;253:48334836.[Abstract]
- Mann DL, Kent RL, Parsons B et al. Adrenergic effects on the biology of the adult mammalian cardiocyte. Circulation. 1992;85:790804.[Abstract]
- Communal C, Singh K, Sawyer DB et al. Opposing effects of beta (1)- and beta (2)-adrenergic receptors on cardiac myocyte apoptosis. Role of a pertussis-toxin sensitive G protein. Circulation. 1999;100:22102212.[Abstract/Free Full Text]
- Broten TP, Miyashiro JK, Moncada S et al. Role of endothelium-derived relaxing factor in parasympathetic coronary vasodilatation. Am J Physiol. 1992;262:H1579H1584.[Medline]
- Hodgson JMB, Marshall JJ. Direct vasoconstriction and endothelium dependent vasodilation: mechanism of acetylcholine effects on coronary flow and arterial diameter in patients with nonstenotic coronary arteries. Circulation. 1989;79:10431051.[Abstract]
- Quyyumi AA, Dakak N, Mulcahy D et al. Nitric oxide activity in the atherosclerotic human coronary circulation. J Am Coll Cardiol. 1997;29:308317.[CrossRef][Medline]
- Delaney JP, Brodie DA. Effects of short-term psychological stress on the time frequency domains of heart-rate variability. Percept Mot Skills. 2000;91:515524.[Medline]
- Lin LY, Wu CC, Liu YB et al. Derangement of heart rate variability during a catastrophic earthquake: a possible mechanism for increased heart attacks. Pacing Clin Electrophysiol. 2001;24:15961601.[CrossRef][Medline]