Do Increases in Markers of Vagal Activity Imply Protection From Sudden Death?
The Case of Scopolamine
Background Low-dose scopolamine increases heart rate variability (HRV) in patients with a prior myocardial infarction (MI). This observation, combined with the evidence that elevated cardiac vagal activity during acute myocardial ischemia is antifibrillatory, has generated the hypothesis that scopolamine might be protective after MI. We tested low-dose scopolamine in a clinically relevant experimental preparation for sudden death in which other vagomimetic interventions are effective.
Methods and Results Nineteen mongrel dogs that survived an anterior MI were used in the study. Occurrence or lack of ventricular fibrillation (VF) due to acute myocardial ischemia during submaximal exercise identified dogs at high and low risk for sudden death. Dose-response curves performed in 12 dogs at high (n=6) and low (n=6) risk showed that scopolamine at 3 μg/kg exerts the greatest effect on HRV. A second group of 7 high-risk dogs were exposed to an exercise-and-ischemia test after treatment with scopolamine (3 μg/kg IV). Scopolamine increased the standard deviation of RR intervals by 41%, increased the high-frequency band of spectral analysis by 48%, and decreased resting heart rate by 14%. Despite the increase in markers of vagal activity, VF recurred during the exercise-and-ischemia test in 6 dogs (86%).
Conclusions The significant increase in HRV induced by acute scopolamine did not result in a decreased risk for VF due to acute myocardial ischemia in association with sympathetic activation. Caution must be applied when extrapolating the potential antifibrillatory activity of an intervention from its influence on autonomic markers.
Experimental1 2 and clinical3 4 5 studies have provided strong evidence for an association between signs of depressed cardiac vagal activity and increased risk for subsequent mortality, particularly sudden cardiac death. This has stimulated research toward assessing the potential antifibrillatory efficacy of increasing vagal activity in clinically relevant preparations and appeared to provide a rationale for modifying markers of vagal activity.
The concept that interventions augmenting vagal activity might be protective against lethal arrhythmias has been recently reviewed in detail6 and is supported by numerous experimental data.7 There is evidence that ventricular fibrillation (VF) during acute myocardial ischemia may be in large part prevented by electrical stimulation of the right cervical vagus,8 pharmacological stimulation of cholinergic receptors with oxotremorine,9 10 and exercise training.11 12 In addition to their relevance to novel therapeutic approaches, these findings have generated growing attention toward heart rate variability (HRV) and baroreflex sensitivity (BRS) for the early identification of post–myocardial infarction (MI) patients at high risk for lethal ventricular arrhythmias.
This background fostered the idea that the rationale for modifying HRV or BRS, as a marker of vagal activity, is sound. There has been proliferation of articles reporting the “positive” effect of a variety of interventions on the most commonly used marker of vagal activity, ie, HRV.13 This concept, however, contains the inherent danger of leading many investigators to the unwarranted assumption that modification of HRV translates directly into cardiac protection. This may or may not be true. It should be noted that the correct target is improvement in cardiac electrical stability and that HRV is just a marker of autonomic activity.
The present study was designed with the specific goal of verifying whether an intervention known for its ability to increase markers of vagal activity would, at the same time, effectively reduce the incidence of ischemia-induced VF in a clinically relevant animal model.14 In 1993, four independent studies showed that among post-MI patients, low-dose scopolamine was capable of producing significant increases in HRV15 16 17 18 ; the studies all suggested, with varying degrees of enthusiasm, that scopolamine might have been useful in decreasing the risk of sudden death among post-MI patients. Accordingly, we examined the effect of scopolamine on HRV and on the incidence of VF in high-risk post-MI conscious dogs.
Forty healthy mongrel dogs (weight, 18 to 25 kg) were selected for the study, and all procedures were conducted following federal, state, and institutional guidelines pertaining to the appropriate use of laboratory animals. During general anesthesia, an anterior MI was created as previously described.14 The dogs were instrumented with epicardial leads on the right atrium and ventricle, a pneumatic vascular occluder, and a proximal blood flow probe on the left circumflex coronary artery. The instrumentation was exteriorized at the neck dorsum.
At 3 to 4 weeks after surgery, HRV was measured according to a previously described method.2 HRV was derived from 25 minutes of continuous digitized ECG recordings while the animals were at rest. Time domain measures of HRV were expressed as the standard deviation (SD) of the mean RR interval and the coefficient of variance, which normalizes the SD to heart rate. Spectral analysis of HRV was performed by fast Fourier transformation of the RR time interval series into the frequency domain. Data in the low-frequency ([LF] 0.04 to 0.15 Hz) and high-frequency ([HF] 0.15 to 0.50 Hz) bands were expressed as percentage of total spectral power. Data were collected after intravenous injection of saline and after IV injection of cumulative doses of scopolamine at 0.1, 0.3, 1.0, 3.0, and 10 μg/kg.
After 3 to 4 weeks of recovery and daily acclimation to the laboratory and treadmill, each dog was evaluated with a submaximal exercise-and–myocardial ischemia test.14 Dogs ran on a motorized treadmill for 12 to 15 minutes, at increasing speed and elevation from 4.8 km/h at 0% incline to 6.4 km/h at 8% incline, until heart rate reached approximately 210 to 220 beats per minute. Two minutes of acute myocardial ischemia followed; after 1 minute of coronary occlusion, the treadmill was stopped. The outcome of this test unambiguously establishes risk for lethal arrhythmias on the basis of the occurrence of VF. Dogs developing VF during myocardial ischemia were designated susceptible, immediately defibrillated, and used to test the hypothesis of an antifibrillatory effect of scopolamine. Dogs that survived the test were labeled resistant.
The study protocol consisted of two parts. In the first part, HRV was determined in six resistant and six susceptible dogs during a dose-response curve to scopolamine. In the second part, seven susceptible dogs were evaluated by an additional exercise-and-ischemia test after administration of 3.0 μg/kg scopolamine IV, ie, the dose that produced the greatest effect on HRV. In these seven susceptible dogs, HRV was assessed before and after administration of scopolamine.
Data were statistically analyzed using two-way ANOVA for repeated measures and Student’s t test for paired and unpaired data. Fisher’s exact test was used to calculate the probability of binomial events (presence or absence of VF). An α level of P<.05 was considered significant. Data are presented as mean±SEM.
In 40 mongrel dogs, an anterior MI was created. Of the first 20 dogs, 7 died early after MI, 1 had occluder failure, 6 were identified at high risk for VF, and 6 were identified at low risk for VF. High- and low-risk dogs were used for the dose-response curves. Of the 20 dogs in the second group, 15 survived. Of these 15 dogs, 7 were identified as susceptible and were used to test the antifibrillatory effect of scopolamine.
Effect of Scopolamine on Autonomic Markers
Before administration of scopolamine, the average SD of the mean RR interval was higher in the resistant dogs than in the susceptible dogs (224±33 versus 136±30 milliseconds, +65%, P<.05), whereas the mean RR interval was not significantly different (739±42 versus 645±37 milliseconds). ANOVA showed a significant drug effect on SD in both groups. Furthermore, increasing doses of scopolamine progressively reduced the difference between high- and low-risk dogs from 65% to 20% (Table). At the highest dose, 10 μg/kg, SD decreased in both groups. At the maximal vagomimetic effect of scopolamine, the mean RR interval was 967±67 and 817±42 milliseconds in the resistant and susceptible dogs, respectively. The coefficient of variance showed the same pattern observed for the SD; before scopolamine, it was higher in the resistant than in the susceptible dogs (294±33 versus 203±40, +45%, P<.05). This difference was reduced to 2% after administration of 3 μg/kg scopolamine (311±19 versus 304±43; P=NS).
HRV After Scopolamine and Risk for VF
In the second group of seven susceptible dogs, 3.0 μg/kg scopolamine increased HRV as predicted by the dose-response curves assessed in the first part of the study (Fig 1⇓). The coefficient of variance increased by 29% (P<.01) from 198±31 to 256±9. In this group, spectral analysis of HRV was also performed. HF power increased by 48%, whereas ratio of LF to HF decreased after scopolamine by 63% (P<.01) from 1.55±0.3 to 0.58±0.1. Scopolamine reduced heart rate at rest and during the lower levels of the exercise-and-ischemia test (Fig 2⇓). However, the chronotropic effect of scopolamine disappeared at the higher levels of exercise. Just before coronary artery occlusion, heart rate was 227±8 beats per minute in the control group and 226±7 beats per minute (P=NS) in the test with scopolamine. The reflex response to acute myocardial ischemia was unaffected by scopolamine. Heart rate at 30 seconds of ischemia was 245±15 beats per minute in the control group and 244±15 beats per minute in the group that received scopolamine.
Scopolamine had minimal antifibrillatory effect. VF was prevented in only one of the seven dogs (14%) tested. In this dog, protection was associated with the occurrence of second-degree atrioventricular block, possibly facilitated by scopolamine, which caused a sudden drop in heart rate from 266 to 135 beats per minute at 45 seconds of myocardial ischemia.
The present internal control study indicates that even significant increases in markers of vagal activity at rest cannot be automatically equated to increases in cardiac electrical stability and protection from sudden death, particularly during activities that increase heart rate.
The effect of scopolamine on autonomic markers observed in the present study is the same as observed in clinical studies,15 16 17 18 confirming the clinical relevance of the experimental preparation. On the other hand, the lack of efficacy on ischemia-dependent VF is a novel and major finding that has important implications for the use of autonomic markers in predicting therapeutic efficacy.
The experimental basis for the clinical observations is constituted by the evidence that low-dose atropine increases neural activity directly recorded in the vagus.19 Acetylcholine mediates inhibitory effects that depend on inhibitory fibers projecting from the ventrolateral respiratory reticular formation and making synaptic connections with vagal motoneurons.20 Specifically, during inspiration, acetylcholine released from these fibers causes hyperpolarization of vagal motoneurons and, consequently, a reduction in their firing rate. Atropine, by blocking these inhibitory mechanisms, may increase the activity of vagal motoneurons. This hypothesis is supported by the fact that iontophoretic administration of atropine in the area of the nucleus ambiguous increases the activity of cardiac vagal motoneurons.20 In addition to central actions, peripheral mechanisms, notably blockade of the presynaptic muscarinic modulation of acetylcholine release,21 may contribute to the effect of low-dose scopolamine on HRV. This is suggested by the evidence that pirenzepine, an analogue of scopolamine that does not appear to have central actions, increases HRV.22
Effects of Scopolamine on HRV and VF
Low doses of scopolamine caused a dose-dependent marked increase in all measures of HRV up to 3 μg/kg. Beyond this dose, the postsynaptic peripheral effect of scopolamine became prevalent; both mean RR interval and HRV decreased. The animals susceptible to VF had, as expected,2 the lowest values of HRV, but the difference compared with the resistant dogs was progressively diminished by scopolamine at doses up to 3 μg/kg.
The chronotropic effects of scopolamine decreased during exercise and were lost at the highest workload of the submaximal test. Among the limitations of HRV23 24 is that it is greatly reduced at elevated heart rates, such as during exercise or behavioral stress; nevertheless, its prognostic value is largely derived by measures at rest or during moderate activity. The reflex response to acute myocardial ischemia also was unaffected by scopolamine. Overall, the vagal antagonism of the detrimental electrophysiological effects of adrenergic activation25 was absent when most needed. Based on these new findings, the failure of scopolamine in preventing VF is no longer surprising, particularly in a preparation in which sympathetic reflexes are major contributors to the occurrence of lethal arrhythmias and agrees with a recent preliminary report.26
The dose of scopolamine may represent a possible mechanism involved in the apparent discrepancy between effects on autonomic markers and effects on lethal arrhythmias. At doses of more than 3 μg/kg, scopolamine produces opposite effects: it markedly increases efferent vagal activity while simultaneously blocking the vagal effects on heart rate.19 Thus, the prevalence of the cardiac postsynaptic vagolytic effect of scopolamine at higher doses limits its use to doses probably inadequate to counteract the elevated adrenergic activation due to exercise and ischemia-dependent reflexes.
The present data suggest that scopolamine, despite its effect on autonomic markers, may be ineffective in preventing lethal arrhythmias in high-risk post-MI patients, particularly under conditions of elevated sympathetic activity. This is distinctly at variance with another intervention, such as exercise training, that alters several aspects of the cardiovascular system and neural regulation, significantly increasing autonomic markers and providing striking protection from VF.11 12 The potential importance of a long-term (eg, exercise training) versus a short-term (eg, scopolamine) modulation of the autonomic activity should not be underestimated.
The rationale for attempts to increase HRV in post-MI patients rests on the multiple evidence that the risk for cardiac mortality and sudden death is higher among individuals with signs of decreased vagal activity. A major limitation is represented by the fact that the degree of increase in vagal activity needed to produce antifibrillatory effects is still unknown. The uncertain value of changes in autonomic markers is compounded by the fact that in clinical practice they are usually determined at rest even though they are expected to predict outcome under conditions of elevated sympathetic activity. Based on the present data, it appears to be appropriate to call for caution before attributing excessive importance to changes in “markers” of vagal activity in the absence of clear-cut evidence of a causal relation with an antifibrillatory effect.
This work was supported by grants from the National Institutes of Heath (HL-42321-03; Bethesda, Md) and Presbyterian Health Foundation (Oklahoma City, Okla). We are especially grateful for the time commitment and energy of Christina R. Leviston, Ian D. Smit, and John T. Clarke.
- Received February 9, 1995.
- Revision received March 3, 1995.
- Accepted March 10, 1995.
- Copyright © 1995 by American Heart Association
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