Changes in autonomic nervous system activity: spontaneous versus balloon-induced myocardial ischaemia
Olivia Manfrinia,*,
Gianluigi Morgagnib,
Carmine Pizzia,
Fiorella Fontanaa and
Raffaele Bugiardinia
a Dipartimento di Medicina Interna, Cardioangiologia e patología, Università degli Studi di Bologna, Via Massarenti 9, 40138 Bologna, Italy
b Servizio di Cardiologia, Ospedale di Macerata, Italy
Received September 25, 2003;
revised March 2, 2004;
accepted March 18, 2004
* Corresponding author. Tel.: +39-51-589116; fax: +39-51-347290
olivia.manfrini{at}unibo.it
See page 1473 for the editorial comment on this article1
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Abstract
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Aims Cardio-cardiac reflexes may be evoked by both myocardial ischaemia and coronary occlusion itself. The aim of the study was to assess the intrapatient behaviour of autonomic nervous system balance during spontaneous and balloon-induced coronary ischaemia.
Methods and results We studied a group of patients admitted to the coronary care unit for acute coronary syndrome without ST-segment elevation who experienced spontaneous episodes of myocardial ischaemia during bed rest and ECG monitoring. The inclusion criterion was 8090% lumen stenosis, amenable to angioplasty. Balloon coronary occlusion was performed at 46 atmospheres for 120 s. Autonomic nervous system activity was assessed by heart rate variability (HRV) analysis in frequency domain. We analysed 14 episodes of spontaneous ischaemia and 14 episodes of balloon coronary occlusion. During spontaneous ischaemia, HRV showed an increase in the low/high frequencies ratio (11.8±5.7), as compared to 5 min before and 5 min after (4.4±2.7 and 3.9±1.8, respectively) (
). The opposite occurred during balloon coronary occlusion (0.8±0.4 vs. 3.9±2.0 and 5.1±2.1, respectively;
).
Conclusions Balloon inflation and occlusion evokes baroreceptor vagal predominance in response to a stretch stimulus of the coronary artery. Conversely, spontaneous occlusion during unstable angina is accompanied by naturally occurring sympathetic activation. Sympathetic activation may have a role in the natural history of the disease.
Key Words: Autonomic nervous system Heart rate variability Ischaemia
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Introduction
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Knowledge of autonomic nervous system activity in the pathophysiology of myocardial ischaemia and acute coronary syndrome is far from complete.
Large, prospective, randomised studies show that autonomic nervous activity has a significant role in the clinical outcome of patients with coronary artery disease.1,2 Sympathetic hyperactivity favours the genesis of life-threatening ventricular tachyarrhythmias,36 as well as vasoconstriction,7 whereas vagal activation exerts an antifibrillatory effect811 and promotes vasodilatation.12
However, it is still unclear whether and how sympatheticparasympathetic balance may be involved in the natural history of coronary heart disease and in the development of coronary occlusion. Cardio-cardiac reflexes may be evoked by both myocardial ischaemia and coronary occlusion itself. In addition, changes in sympathovagal balance could represent the expression of the interaction between pain perceptions, myocardial ischaemia, and neural reflexes.1314
The aim of this study was to assess the varying profile of autonomic nervous system balance during episodes of spontaneous and balloon-induced coronary occlusion and ischaemia in patients with left anterior descending coronary artery disease.
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Methods
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Study population
We studied 14 patients (eight men and six women; age range 4363 years) admitted to the coronary care unit with acute coronary syndrome without ST-segment elevation, referred for percutaneous transluminal coronary angioplasty according to clinical indication. The inclusion criteria were: (1) at least one episode of spontaneous transient myocardial ischaemia documented at ECG monitoring (ST-segment depression >0.1 mV) during bed rest and full medical treatment, (2) single-vessel disease, (3) 8090% lumen stenosis (visual estimation) in the left anterior descending coronary artery, (4) normal antegrade flow (grade 3 according to Thrombolysis in Myocardial Infarction system), and (5) no wall motion abnormalities at echocardiography, as assessed before cardiac catheterisation. Patients were not eligible for the study if they had myocardial infarction or revascularisation (percutaneous coronary intervention and coronary artery bypass surgery). Patients having coexisting conditions that could affect heart rate variability (HRV) analysis, such as atrial fibrillation, paced rhythm, left ventricular bundle-branch block, cancer, renal or hepatic failure, and diabetes mellitus, were excluded as well. Specifically, diabetic patients were excluded because decreased HRV has been shown to be the first sign of autonomic nervous system dysfunction in this subset of patients.15 All patients were treated with standard medical therapy that included ß-blockers, aspirin, nitrate, and heparin throughout the study period. All patients gave informed consent to the study.
Balloon coronary occlusion
Balloon inflation during angioplasty has been used to assess individual variation in the type and severity of autonomic reactions during coronary occlusion.1617 Cardiac catheterisation was performed using the femoral arterial approach. Patients were not sedated during the procedure due to the study protocol. Coronary angiography of the left anterior descending artery was performed in multiple projections. The guide wire was advanced distally to the target lesion. The selection of balloon size was based on visual estimation, using the guide catheter for calibration.
The balloon was placed at the site of the stenosis and inflated under continuous fluoroscopic observation. Balloon coronary occlusion was done according to the coronary diameters with 46 atmosphere balloon inflation for 120 s. Further coronary balloon inflations were done as requested to achieve successful angiographic results.
Arterial pressure was measured from the femoral artery with a Statham P25 transducer.
Heart rate variability
All patients in the coronary care unit underwent ECG monitoring for detection of spontaneous episodes of ischaemia. ECG monitoring was also performed during cardiac catheterisation, starting 26 h before the procedure. ECG recordings were digitised on a Marquette series 8000 Holter scanner. An expert technician who was unaware of the clinical data analysed electrocardiographic digital tapes using the confirm-scanning mode option (Del Mar Avionics AccuPlus 363, Irvine, CA), which allows manual labelling of each artefact, premature beat, and pause. HRV analysis was performed in the frequency domain (Del Mar Avionics HRV Analysis System 1997, Irvine, CA). R-R data from Holter recordings were assessed by power spectral analysis: 5 min before, during episodes of spontaneous and balloon-induced coronary ischaemia, and 5 min after. Low frequencies (LF: 0.040.15 Hz), high frequencies (HF: 0.150.40 Hz), and the LF/HF ratio were used to estimate autonomic nervous system activity. LF reflects both sympathetic and parasympathetic activity, HF primarily reflects vagal activity, and the LF/HF ratio estimates the balance of autonomic nervous system activity.1819 Normalised units, rather than the absolute power of each component, were used to quantify LF and HF. Normalisation tends to minimise the effect of changes in total power due to many stimuli.19
Analysis of HRV during balloon coronary occlusion was limited to the first balloon inflation that lasted 120 s.
Chest pain evaluation
Patients having chest pain during spontaneous episodes of ischaemia or balloon coronary occlusion were asked to grade the severity of symptoms according to Smokler's numeric scale: grade 1 was mild, grade 2 was moderate, grade 3 was moderately severe, and grade 4 was maximally severe.20
Statistical analysis
Data are expressed as means±SD unless otherwise indicated. Because of the limited sample size and skewed distribution of the results, data were analysed with a non-parametric test for paired data (Wilcoxon signed-rank test, two-sided). The correlation between LF/HF ratio and time of ischaemia was obtained by Spearman's analysis. All statistical tests were performed using SPSS-Win 10.1 (Statistical Package for Social Science, SPSS Inc., Chicago, IL). Values for
were considered significant.
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Results
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The clinical characteristics of the patients and additional drug treatment are shown in Table 1
. All patients were haemodynamically stable and none of them had episodes of dyspnoea during the observation period. The mean dose of ß-blockers (metoprolol) was 142.86±63.87 mg/day. Medications were kept constant during the study period. Each patient had both one episode of spontaneous ischaemia and one episode of balloon coronary occlusion. We analysed 14 episodes of spontaneous ischaemia (mean duration 245 s) and 14 episodes of balloon coronary occlusion (mean duration 120 s). All episodes occurred during bed rest and daytime (from 9:00 A.M. to 6:00 P.M. for spontaneous ischaemia and from 10:00 A.M. to 4:00 P.M. for balloon coronary occlusion). None of the episodes analysed was after stent implantation. Mean balloon diameter was 3 mm (range 2.54 mm). Mean balloon length was 13 mm (range 818 mm).
Heart rate and systolic blood pressure during spontaneous episodes of ischaemia were significantly increased as compared to 5 min before (72.8±4.1 vs. 59.8±3.5 beats/min and 143.7±5.6 vs. 135.4±6.7 mmHg, respectively
), and 5 min after (72.8±4.1 vs. 62.3±2.9 beats/min and 143.7±5.6 vs. 133±4.8 mmHg, respectively
). In contrast, during balloon coronary occlusion, heart rate decreased (58.3±2.1 beats/min) compared to 5 min before and 5 min after (59.7±3.1 and 59.8±2.6 beats/min,
). Blood pressure did not significantly change (pre: 133.6±6.1 mmHg; during balloon-evoked ischaemia: 132.4±6.5 mmHg; post: 132.6±6.3 mmHg).
Fig. 1
shows the LF/HF ratio before, during, and after spontaneous episodes of ischaemia and balloon coronary occlusion. The LF/HF ratio 5 min before did not differ between the two modalities of ischaemia, but during balloon inflation it was significantly (
) lower compared to spontaneous episodes. During spontaneous ischaemia we observed a significant increase in the LF/HF ratio (11.8±5.7), compared to 5 min before (4.4±2.7,
) and 5 min after (3.9±1.8,
). The LF/HF ratio had a univocal behaviour. LF components rose in 13/14 patients (93% of episodes). HF components increased in only 3/14 patients (21% of episodes). The opposite occurred during balloon coronary occlusion. The LF/HF ratio during balloon coronary occlusion was dramatically reduced (0.8±0.4) as compared to 5 min before (3.9±2.0,
) and 5 min after (5.1±2.1,
). Balloon inflation provoked a decrease in the LF fluctuation of RR interval variability in 12/14 patients (86% of episodes) and an increase in 2/14 patients (14% of episodes). The HF component increased in 8/14 patients (57% of episodes) and decreased in 6/14 (43% of episodes). The LF/HF ratio decreased in 13/14 (93% of episodes) patients and did not change in 1/14 (7% of episodes).

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Fig. 1 Low-high frequency ratio (LF/HF) before, during, and after spontaneous episodes of ischaemia and balloon coronary occlusion. Results are shown as box plots displaying the 25th and 75th percentile as the box, the whiskers of the box representing the remaining data points, and * marking statistical outliers. The line within the box indicates the median value for the group. Means±SD are reported in the text.
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Tables 2 and 3
show heart rate, arterial blood pressure, LF, and HF before, during, and after ischaemia in each subject. The distribution of the LF and HF components during the two observation periods is represented in Fig. 2
.
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Table 2 Blood pressure, heart rate, LF, and HF measurements: 5 min before, during, and 5 min after spontaneous ischemia
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Table 3 Blood pressure, heart rate, LF, and HF measurements: 5 min before, during, and 5 min after balloon coronary occlusion
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Fig. 2 The balanced behaviour of the two branches of the autonomic nervous system during episodes of spontaneous ischaemia (Fig. 2(a)) and balloon coronary occlusion (Fig. 2(b)) are shown. During spontaneous episodes of ischaemia, LF increased ( ) and HF decreased ( ). The opposite occurred during balloon-induced ischaemia, LF decreased ( ) and HF increased ( ). Box encloses 50% of data points, the whiskers of the box represent remaining data points, and * indicates statistical outlier. Line within box indicates the median value for the group. The following values are mean±SD: for spontaneous ischaemia: LF-pre=0.25±0.05, LF-during=0.32±0.05, LF-post=0.25±0.05, HF-pre=0.07±0.03, HF-during=0.04±0.02, HF-post=0.07±0.03; for balloon coronary occlusion: LF-pre=0.22±0.08, LF-during=0.08±0.04, LF-post=0.23±0.08, HF-pre=0.07±0.04, HF-during=0.10±0.05, HF-post=0.05±0.03.
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ST-segment shift was documented only in precordial (V1V5) leads. The magnitude of the ST-segment deviation (0.18±0.06 vs. 0.15±0.04 mV) and severity of chest pain (1.9±1.2 vs. 1.6±1) during coronary occlusion were comparable during spontaneous and balloon-induced ischaemia (Table 4
). Episodes of spontaneous ischaemia tended to be longer, ranging from 118 to 405 s. The differences with respect to ischaemia induced by balloon occlusion were significant (
). However, there was no correlation between the duration of ischaemia and the LF/HF ratio (
;
).
One patient experienced a spontaneous episode of ischaemia during cardiac catheterisation, before balloon coronary inflation. Angiography showed transient total coronary occlusion at the site of the culprit lesion. This episode of ischaemia (212 s of ST depression, without occurrence of chest pain) was not considered for statistical analysis because it was out of protocol. However, data obtained by HRV analysis are of interest and in agreement with those seen in the 14 episodes of spontaneous ischaemia recorded during the coronary care unit stay. The LF/HF ratio was 12.3, 6.9, and 4.7, respectively, during the ischaemic episode, 5 min before, and 5 min after. Intracoronary nitrates were given to the patient to relieve ischaemia.
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Discussion
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Proof of a causal relation between autonomic dysfunction and the occurrence of ischaemia are required before markers of cardiac autonomic activity can be considered a therapeutic target in clinical practise. This study gives evidence that autonomic dysfunction itself may be part of the natural history of coronary artery disease, being of great significance in this regard. The main finding of this study was the observation of a switch from sympathetic to parasympathetic predominance in the setting of myocardial ischaemia depending upon the induction mechanisms (spontaneous vs. evoked coronary occlusion).
Autonomic imbalance and mechanisms of ischaemia
Other investigators have reported changes in HRV during angioplasty in coronary artery disease.1718 However, the conclusions of these studies are invalidated to some extent by the inclusion of patients with previous acute myocardial infarction, left heart failure, and diabetes. These studies stated that acute myocardial ischaemia may elicit both excitatory and inhibitory reflexes that may be mediated by sympathetic and vagal afferent fibres, respectively, but they did not take into account the overall sympathovagal balance. All of the above-mentioned confounding factors were avoided in the present study, which examined changes in the sympathovagal balance.
Vagal activity is the major contributor to the HF component, as reported in clinical and experimental settings.21 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 influences.22 Analysis of the LF/HF ratio rather than single components is considered by many investigators to better reflect the activity of the sympathovagal balance.18,2325
In the present study, the balance between sympathetic and vagal activity (LF/HF ratio) significantly shifted toward vagal predominance during balloon coronary occlusion. The opposite occurred in the same patients during spontaneous ischaemia. The severity of chest pain, amount of ST-segment change, and location of the coronary occlusion were comparable in spontaneous and balloon-induced coronary occlusion.
The hypothesis that neural reflexes originated by chest pain, the location of coronary occlusion, or ischaemia itself could be the only mechanism that triggers sympathetic activity during acute coronary syndrome appears unlikely. Indeed, we did not observe sympathetic predominance during balloon inflation.
The mechanisms underlying this switch from sympathetic to parasympathetic predominance in spontaneous versus balloon-evoked ischaemia were not examined as a part of this study. Nevertheless, spontaneous ischaemia seems to be accompanied by, or due to, mechanisms that override the vagal reaction associated with mechanical obstruction of the vessel, such as that induced by balloon inflation.
Autonomic response to coronary occlusion
Intrathoracic autonomic neurons receive inputs not only from cardiopulmonary afferent receptors, but also from afferent receptors located in other regions of the body.26 In other words, the activity of efferent sympathetic and parasympathetic neurons is not always reciprocal in nature, because it may be influenced by different cardiac and extracardiac sources.
Coronary occlusion may trigger several neural responses. Some are due to stimulation of coronary mechanoceptors. Others arise from both ventricular mechano- and chemoreceptors that are activated mainly by occlusion and myocardial ischaemia.27 Stimulation of coronary mechanoceptors of the left coronary artery may be elicited by an increase in coronary perfusion pressure as well as mechanical stretch, and may induce a reflex decrease in sympathetic drive.2829 In contrast, reduced myocardial blood flow and ischaemia resulting from experimental occlusion of the left coronary artery may stimulate ventricular mechano- and chemoreceptors and increase activity in sympathetic efferent axons that move toward the heart.30 Vagal fibres seem to play little or no role.29 The net balance between sympathetic reflex interactions appears to be shifted toward sympathetic withdrawal, which could imply vagal predominance.29 In keeping with these findings, we observed vagal predominance during balloon coronary occlusion, which may represent a beneficial adaptive mechanism for increasing coronary flow during myocardial ischaemia.
Spontaneous episodes of myocardial ischaemia show a different neural response. They could be the consequence rather than the cause of an abnormal sympathetic neural balance and may depict an unpredictable interaction between intrathoracic cardiorespiratory reflex responses. Many visceral disorders elicit sympathetic nerve activity.31 Increased sympathetic nerve discharge may also result from a "central command" type mechanism subserving a rapid autonomic response to stress.32 Experiments have demonstrated sympathetic overreactivity and prolonged coronary vasoconstriction in previously stenosed left circumflex coronary arteries during "delayed anger" in dogs.3334 These extracardiac influences may account in part for the complex information that occurs within the intrathoracic nervous system during spontaneous ischaemia and may explain imbalance toward sympathetic predominance. Although mechanisms responsible for changes in the overall vagal-sympathetic balance in humans are still poorly understood, the results of the current study support the hypothesis that reflex activity is altered during spontaneous ischaemia, being reset to regulate sympathetic drive at a fairly elevated level.
Vagal activity and its impairment in coronary disease
Vagotomy results in vasoconstriction in anaesthetised dogs, suggesting a vagal modulation of coronary tone.12 Interrupting vagal influences might produce coronary vasoconstriction as a result of loss of parasympathetic-mediated vasodilatation.
Enhanced sympathetic and/or attenuated vagal activation could represent a neurovegetative adaptation for increasing cardiac performance. Reducing the inhibitory influences of vagal mechanisms or enhancing sympathetic activity might serve to prepare the cardiovascular system for the rapid variations in heart rate, cardiac output, and flow redistribution occurring during ischaemia.35 However, the neural sympathetic reflex seems to aggravate coronary ischaemia.3637 Vagal activation exerts an antifibrillatory effect; sympathetic activation does the opposite.811 Accordingly, life-threatening arrhythmias are easily seen during acute coronary syndrome, but not during percutaneous coronary interventions. Sustained ventricular tachycardia and ventricular fibrillation have been reported in 7.520% of patients with acute coronary syndrome and in 0.52% of patients undergoing coronary angioplasty.3839 Recent studies have demonstrated that increasing vagal activity in postmyocardial infarction by exercise training is not sufficient per se to reduce the risk of subsequent cardiac mortality. It also requires the achievement of a clear shift in autonomic balance toward vagal predominance.10 The availability of quantifiable markers of vagal-sympathetic balance could be of help in addressing the target of many physiologic and pharmacologic interventions.10
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Limitations
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These intrapatient observations have been collected in a relatively small study population. However, patients had fairly homogeneous characteristics that allow comparison of sympatheticparasympathetic balance in the setting of different modalities of ischaemia. All of them were using ß-blocking agents and had a similar grade of chest pain during spontaneous and evoked ischaemia. All of them had single-vessel disease and were investigated during left anterior coronary artery ischaemia.
Changes in the respiratory rate are known to have an effect on HRV. Respiratory rate is inversely correlated with the power of the HF peak.25,40 Therefore, a decrease in the HF peak while breathing rate increases indicates a decrease in vagal activity, which is smaller than estimated if one disregards the change in respiratory rate. We did not measure breathing. However, none of the patients had dyspnoea during episodes of spontaneous and balloon-induced ischaemia. Comparison between the two modalities of ischaemia should not have been substantially affected by respiratory rates.
Many drugs influence the activity of the autonomic nervous system.25,41 We addressed this limitation by considering changes in HRV in a patient relative to the baseline condition of that specific patient (intrapatient evaluation).
Patients were a highly selected group, which enhances data purity. However, they may not be representative of the overall patients with coronary artery disease.
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Acknowledgments
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We thank Dr. Giulia Cavrini for her assistance in the statistical analysis.
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Footnotes
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1 doi:10.1016/j.ehj.2004.07.001. 
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