Effect of sertraline on the recovery rate of cardiac autonomic function in depressed patients after acute myocardial infarction.

BACKGROUND: Brain serotonin is known to possess sympathoinhibitory properties. The aim of this clinical physiologic study was to determine whether sertraline, a selective serotonin reuptake inhibitor, facilitates the rate of recovery of cardiac autonomic function after an acute myocardial infarction (MI) in patients with depression. METHODS AND RESULTS: Thirty-eight post-MI depressed patients were randomized to receive either sertraline 50 mg per day or placebo for 6 months. Depression was defined as a score >15 on the standardized Inventory to Diagnose Depression questionnaire taken at prehospital discharge and again within 2 weeks of the acute infarct. Eleven stable post-MI nondepressed patients served as a nonrandomized reference group during follow-up. Twenty-seven patients completed the randomization. All 3 groups were followed up closely in a multidisciplinary post-MI clinic where they underwent serial testing for both time and frequency domain heart rate variability (HRV) indices at baseline (1-2 weeks after MI) and at 6, 10, 14, 18, and 22 weeks. The rate of recovery of HRV was determined by use of a growth curve model based on repeated-measures analysis of variance. There was a linear rate of increase in the SD of 24-hour N-N intervals (SDNN) in the sertraline-treated group that paralleled that of the nondepressed reference group. This contrasted with a modest but significant decline in SDNN in the placebo group from 2 to 22 weeks (t = 2.10, P <.05). However, the short-term power spectral indices, while trending toward a more rapid rate of recovery in the treated group, did not reach statistical significance compared with the placebo group. CONCLUSION: In depressed patients who have survived the acute phase of an MI sertraline facilitates the rate of recovery of SDNN, a recognized predictor of clinical outcome.

Cardiac autonomic function and oesophageal acid sensitivity in patients with non-cardiac chest pain.

BACKGROUND: Acid reflux can elicit non-cardiac chest pain (NCCP), possibly through altered visceral sensory or autonomic function. The interactions between symptoms, autonomic function, and acid exposure are poorly understood. AIM: To examine autonomic function in NCCP patients during exposure to oesophageal acid infusion. SUBJECTS AND METHODS: Autonomic activity was assessed using power spectral analysis of heart rate variability (PSHRV), before and during oesophageal acidification (0.1 N HCl), in 28 NCCP patients (40.5 (10) years; 13 females) and in 10 matched healthy controls. Measured PSHRV indices included high frequency (HF) (0.15-0.5 Hz) and low frequency (LF) (0.06-0.15 Hz) power to assess vagal and sympathetic activity, respectively. RESULTS: A total of 19/28 patients had angina-like symptoms elicited by acid. There were no significant manometric changes observed in either acid sensitive or insensitive patients. Acid sensitive patients had a higher baseline heart rate (82.9 (3.1) v 66.7 (3.5) beats/min; p<0.005) and lower baseline vagal activity (HF normalised area: 31.1 (1.9)% v 38.9 (2.3)%; p< 0.03) than acid insensitive patients. During acid infusion, vagal cardiac outflow increased (p<0.03) in acid sensitive but not in acid insensitive patients. CONCLUSIONS: Patients with angina-like pain during acid infusion have decreased resting vagal activity. The symptoms elicited by perception of acid are further associated with a simultaneous increase in vagal activity in keeping with a vagally mediated pseudoaffective response.

Afferent vagal modulation. Clinical studies of visceral sensory input.

UNLABELLED: The frequency composition of a continuous time series of R-R intervals may be viewed as the phasic output of a central processing system intimately dependent on sensory input from a variety of afferent sources. While different measures of heart rate variability permit a glimpse into the autonomic efferent limb of this complex system, direct access of afferent fibers in humans has remained elusive. Using a specially designed esophageal catheter/manometer probe, we have been able to gain access to vagal afferent fibers in the distal esophagus. Our studies on the effect of vagal afferent electrostimulation on both cerebral evoked potentials (EvP) and the power spectrum of heart rate variability have yielded the following observations: 1. Stimulation of esophageal vagal afferents dramatically and reproducibly increases the high frequency (HF) vagal power and reduces the low frequency (LF) power of the heart rate autospectrum. 2. This effect is constant across stimulation frequencies from 0.1 to 1.0 Hz and across stimulation intensities from 2.5 to 20 mA. 3. Regardless of the stimulation parameters, there are only minimal changes in heart rate (2-6 bpm) and no change in respiratory frequency. 4. There is a linear correlation between electrical stimulation intensity and the amplitude of cerebral evoked potentials, whereas there is a non-linear relationship with all short-term power spectral indices. 5. While cerebral evoked potentials are only elicited at stimulation intensities above perception threshold, there is already a significant shift to increased vagal efferent modulation well below perception threshold. CONCLUSION: These studies support the concept that power spectral indices of heart rate variability represent phasic output responses to tonic afferent viscerosensory signals in humans. These studies also demonstrate the feasibility of accessing vagal afferents in humans.

Abnormal cerebral processing of oesophageal stimuli in patients with noncardiac chest pain (NCCP).

In noncardiac chest pain (NCCP), altered visceral perception may result from abnormal cerebral processing of sensory input rather than abnormalities of afferent pathways. However, the interactions between symptoms, autonomic function and oesophageal stimuli are poorly studied. Oesophageal stimulation elicits reproducible cortical evoked potentials [CEP] and modulates heart rate variability via vagal pathways, as visible on power spectrum analysis of heart rate variability [PS-HRV]. These methods are increasingly used to study the function of visceral afferent neural pathways in human. The aim of this study was to compare EP and PS-HRV during oesophageal stimuli in NCCP and controls. Twelve healthy volunteers (one female, 11 male; aged 24-51 years; mean 32 +/- 8 years), and eight NCCP patients (three female, five male; age range 26-58, mean 40.5 +/- 10 years) were studied. Electrical oesophageal stimulation (EOS; 200 microseconds, 0.2 Hz, 25 stimuli) was applied to the oesophageal wall 5 cm above the lower oesophageal sphincter (LOS), and perception thresholds (measured in mA) determined. EP responses were recorded using 22 standard electroencephalogram scalp electrodes. Autonomic activity was assessed using PS-HRV, before, during, and after oesophageal stimulation. Measured PS-HRV indices included high frequency (HF; 0. 15-0.5 Hz) and low frequency (LF; 0.06-0.15 Hz) power, respectively, assessing vagal and sympathetic activity, and the LF/HF ratio. EOS perception occurred at lower thresholds in NCCP than in controls (3. 6 +/- 1 vs. 7.8 +/- 2 mA, P < 0.05). EP amplitude was greater (13 +/- 2 vs. 6 +/- 1 microV, P < 0.0001), and latency longer in controls vs. NCCP (191 +/- 7 ms vs. 219 +/- 6 ms, P < 0.001). In NCCP, EOS decreased sympathetic outflow (low frequency peak on PS-HRV) and increased cardiovagal activity (high frequency peak, P < 0.02) to a significantly higher degree in comparison with controls. During EOS, heart rate decreased in NCCP from 68 vs. 62 beats min-1 (P < 0.003) but not in controls. In NCCP patients, EOS was perceived at lower intensities and was associated with a greater cardiovagal reflex response. EP responses associated with EOS were smaller in NCCP than in controls, suggesting that an increased perception of oesophageal stimuli results from an enhanced cerebral processing of visceral sensory input in NCCP, rather than from hyperalgesic responses in visceral afferent pathways.

The effects of beta(1)-blockade on oxidative metabolism and the metabolic cost of ventricular work in patients with left ventricular dysfunction: A double-blind, placebo-controlled, positron-emission tomography study.

BACKGROUND: The mechanism for the beneficial effect of beta-blocker therapy in patients with left ventricular (LV) dysfunction is unclear, but it may relate to an energy-sparing effect that results in improved cardiac efficiency. C-11 acetate kinetics, measured using positron-emission tomography (PET), are a proven noninvasive marker of oxidative metabolism and myocardial oxygen consumption (MVO(2)). This approach can be used to measure the work-metabolic index, which is a noninvasive estimate of cardiac efficiency. METHODS AND RESULTS: The aim of this study was to determine the effect of metoprolol on oxidative metabolism and the work-metabolic index in patients with LV dysfunction. Forty patients (29 with ischemic and 11 with nonischemic heart disease; LV ejection fraction <40%) were randomized to receive metoprolol or placebo in a treatment protocol of titration plus 3 months of stable therapy. Seven patients were not included in analysis because of withdrawal from the study, incomplete follow-up, or nonanalyzable PET data. The rate of oxidative metabolism (k) was measured using C-11-acetate PET, and stoke volume index (SVI) was measured using echocardiography. The work-metabolic index was calculated as follows: (systolic blood pressure x SVI x heart rate)/k. No significant change in oxidative metabolism occurred with placebo (k=0.061+/-0.022 to 0.054+/-0.012 per minute). Metoprolol reduced oxidative metabolism (k=0.062+/-0. 024 to 0.045+/-0.015 per minute; P:=0.002). The work-metabolic index did not change with placebo (from 5.29+/-2.46 x 10(6) to 5.14+/-2. 06 x 10(6) mm Hg. mL/m(2)), but it increased with metoprolol (from 5. 31+/-2.15 x 10(6) to 7.08+/-2.36 x 10(6) mm Hg. mL/m(2); P:<0.001). CONCLUSIONS: Selective beta-blocker therapy with metoprolol leads to a reduction in oxidative metabolism and an improvement in cardiac efficiency in patients with LV dysfunction. It is likely that this energy-sparing effect contributes to the clinical benefits observed with beta-blocker therapy in this patient population.

Effects of esophageal stimulation in healthy subjects.

We studied the effects of esophageal electrical stimulation on heart rate variability power spectra (PS/HRV) and cortical evoked potentials (EPs) in healthy subjects. The intensity of stimulation was varied from 2.7 to 20 mA. We found that the amplitude of the cortical evoked potentials (amplitude of the N2/P2 peak) increased from 5.1 +/- 0.7 microV at 5 mA to 16.3 +/- 1.1 microV at 20 mA. The PS/HRV showed an increase in the vagal modulation of the sinus node. When the stimulation frequency was varied from 0.1 to 1 Hz at a constant intensity of 15 mA, the amplitude of cortical EPs (N2/P2 peak) decreased with increase in the frequency of stimulation (p < 0.05). The LF:HF ratio decreased significantly for all frequencies of stimulation (p < 0.005). An experimental paradigm to evoke the cognitive component in the cortical EPs yielded a peak around 354 ms following the stimulus.

Effects of esophageal stimulation in patients with functional disorders of the gastrointestinal tract.

We studied the effects of esophageal electrical stimulation on cortical-evoked potentials (EPs) and power spectrum of heart rate variability (PS/HRV) in patients with diabetes and non-cardiac chest pain (NCCP). We also recorded cognitive-evoked potentials (P300 EPs) in response to an odd-ball stimulation in patients with NCCP. Diabetic patients did not yield reproducible cortical EPs. Their power spectra of heart rate variability (PS/HRV) showed an increased vagal modulation during stimulation. In patients with NCCP the P300 EPs were of greater amplitude (17 +/- 3 microV vs. 12 +/- 1 microV in controls, p < 0.04), while peak latencies were slightly elongated in patients (382 +/- 22 ms vs. 354 +/- 12 ms in controls). The PS/HRV in these patients also showed an increased vagal modulation of the sinus node activity. Our results suggest the following: (1) in patients with diabetes, afferent pathways and processing of sensory signals are likely to be impaired; (2) an increased perception of esophageal stimulation reflects an exaggerated brainstem response and altered cortical processing of visceral sensation in patients with NCCP.

Recovery rates of regional sympathetic reinnervation and myocardial blood flow after acute myocardial infarction.

BACKGROUND: The implication of an arrhythmogenic role for infarction-induced disruption of regional myocardial sympathetic nerve activity has led to a search for noninvasive methods to study regional sympathetic nerve activity in patients after infarction. METHODS AND RESULTS: By using positron emission tomography, we measured the time course of myocardial hypoperfusion with [13N]-ammonia retention and sympathetic innervation with [18F]-6-fluorodopamine within the infarct zone in 10 patients at 2 weeks, 3 months, and 6 months after a first-onset Q-wave myocardial infarction. The time course for reestablishment of global cardiac autonomic function was also determined by measuring the power spectrum of heart rate variability with an autoregressive technique. The average infarct defect size as determined by the fractional uptake of [13N]-ammonia was 17.22% +/- 5.95% of the left ventricular myocardium. The fractional uptake of [18F]-fluorodopamine in the infarct zone was similar, at 15.83% +/- 4.45% (not significant). There was a significant increase (14% to 15%; P <.05) in myocardial blood flow and [18F]-fluorodopamine uptake to the infarct zone between 2 weeks and 3 months, with no further change between 3 months and 6 months. However, the average rate of loss (t1/ 2 hour) of [18F]- fluorodopamine continued to decrease between 2 weeks and 6 months. This paralleled a continuing fall in the low-frequency to high-frequency autospectral power ratio throughout the 6 months after infarction. CONCLUSIONS: This study demonstrates a modest increase in myocardial blood flow and evidence for sympathetic reinnervation to the infarct zone between 2 weeks and 3 months after acute myocardial infarction. Despite a flow-dependent effect on the uptake of [18F]-fluorodopamine by 3 months, there is a suggestion that restoration of sympathetic activity within the infarct zone continues between 3 months and 6 months after acute myocardial infarction.

Assessment of the visceral afferent and autonomic pathways in response to esophageal stimulation in control subjects and in patients with diabetes.

OBJECTIVE: To examine the effects of esophageal stimulation on vagal afferent and efferent pathways in volunteers without diabetes and patients with diabetes. DESIGN: Prospective physiological study. PARTICIPANTS: Fourteen control subjects without diabetes and 6 patients with diabetes. INTERVENTIONS: Electrical and mechanical stimulation of the esophagus. OUTCOME MEASURES: Cortical evoked potentials and the power spectra of heart rate variability. RESULTS: For the control subjects, there was a significant decrease in the ratio of the low frequency to high frequency (LF:HF) power (i.e., increased vagal efferent modulation) during stimulation. Reproducible cortical evoked potentials were obtained from all control subjects. In the 6 patients with diabetes, who had viscerosensory and autonomic neuropathy, the cortical evoked potentials showed an erratic non-reproducible response to electrical esophageal stimulation; however, the LF:HF ratio decreased in these patients during stimulation, suggesting an intact subcortical reflex circuit. CONCLUSIONS: Vago-afferent fibres can be studied using minimally invasive techniques, and the power spectral analysis of heart rate variability permits study of autonomic vago-efferent pathways.

Neurocardiac and cerebral responses evoked by esophageal vago-afferent stimulation in humans: effect of varying intensities.

OBJECTIVE: This study was designed to determine whether esophageal vago-afferent electrostimulation, over a wide range of stimulus intensities, can sustain a cardiac vago-efferent effect by way of central nervous system processing. METHODS: Studies were performed in ten healthy male subjects (23.9 +/- 6.3 years). Esophageal electrostimulation was carried out using a stimulating electrode placed in the distal esophagus. Stimulation of esophageal vago-afferent fibres was employed using electrical impulses (200 microseconds at 0.2 Hz x 128 s) varying from 2.7 to 20 mA. Respiratory frequencies, beat-to-beat heart rate autospectra and cerebral evoked potentials were recorded at baseline and at each stimulus intensity in random order. RESULTS: With esophageal electrical stimulation, we observed a small non-significant decrease in heart rate. There was a dramatic shift of the instantaneous heart rate power spectra towards enhanced cardiac vagal modulation with intensities as low as 5 mA. This effect was sustained throughout all intensities with no further change in either the low frequency or high frequency power. Conversely, there was a linear dose response relationship between cerebral evoked potential amplitude and stimulus intensity mainly occurring above perception threshold (10 mA). Esophageal stimulation had no significant effect on heart rate or respiratory frequency at any stimulus intensity. CONCLUSIONS: These results indicate that electrical stimulation of the distal esophagus across a wide range of current intensities elicits a reproducible shift in the heart rate power spectrum towards enhanced vagal modulation. The data suggest a closed loop afferent/efferent circuitry wherein tonic visceral afferent impulses appear to elicit a phasic or modulatory vago-efferent cardiac response in healthy subjects.

The cerebral response to electrical stimuli in the oesophagus is altered by increasing stimulus frequencies.

Recording of cerebral evoked responses (EP) allows the assessment of visceral afferent pathways and gut-brain communication, but the optimal stimulation parameters remain to be established. The present study determined the optimal stimulation frequency of electrical stimulation of the oesophagus to elicit EP responses. In 13 healthy male volunteers (24.1 +/- 5.9 years), a 5 mm stainless-steel electrode was placed in the distal oesophagus for electrical stimulation (ES). EP were recorded from 21 scalp electrodes placed according to the 10/20 International system. ES (15 mA, 200 microseconds) were delivered in repeated series of 24 stimuli. Stimulus frequency was randomly altered in different series using a pseudologarithmic range (0.1, 0.2, 0.3, 0.5, and 1 Hz). Two series of stimuli were applied using each stimulation frequency. Two-dimensional topographic brain maps were created using interpolation techniques at each stimulation frequency. With increasing stimulus frequency, a significant and progressive decrease of EP amplitudes was observed between frequencies of 0.1 Hz and 1.0 Hz (P1/N2: 7.6 +/- 1.2 vs 1.4 +/- 0.3* microV, N2/P2: 17.2 +/- 1.7 vs 4.6 +/- 0.4* microV, P2/N3: 6.9 +/- 0.7 vs 4.2 +/- 0.5* microV; * = P < 0.05). In addition, there was a significant shortening of the mean peak latency of the intercalated P2 peak (P < 0.0005), with a similar trend for the P3 peak (P < 0.06), with increasing stimulus frequency from 0.1-1.0 Hz. Topographic brain maps localized the maximal early peaks (N1,P1.N2) in the paracentral cortical region (C3, Cz, C4), whereas the later peaks (P2 to P3) were symmetrically spread over the centroparietal and temporal regions (Cz, Pz, T5, T4). There was no difference in the cortical location of maximal EP amplitudes with increasing stimulus frequency. In conclusion, there is a clear relationship between stimulus frequency and amplitude of EP, suggesting rapid attenuation of the cerebral autonomic neural responses with increased electrical stimulation frequency. The effect of increased frequency on peak latencies suggests an alteration of stimulus processing in the thalamocortical region due to an altered perception of stimuli. Early EP peaks originate from basal structures of primarily the dominant hemisphere, while later peaks are localized in centroparietal cortical regions.

Can nitrogen-13 ammonia kinetic modeling define myocardial viability independent of fluorine-18 fluorodeoxyglucose?

OBJECTIVES: The hypothesis of this study was that evaluation of myocardial flow and metabolism using nitrogen-13 (N-13) ammonia kinetic modeling with dynamic positron emission tomographic (PET) imaging could identify regions of myocardial scar and viable myocardium as defined by fluorine-18 fluorodeoxyglucose (F-18 FDG) PET. BACKGROUND: Uptake of most perfusion tracers depends on both perfusion and metabolic retention in tissue. This characteristic has limited their ability to differentiate myocardial scar from viable tissue. The kinetic modeling of N-13 ammonia permits quantification of blood flow and separation of the metabolic component of its uptake, which may permit differentiation of scar from viable tissue. METHODS: Sixteen patients, > 3 months after myocardial infarction, underwent dynamic N-13 ammonia and F-18 FDG PET imaging. Regions of reduced and normal perfusion were defined on static N-13 ammonia images. Patients were classified into two groups (group I [ischemic viable], n = 6; group II [scar], n = 10) on the basis of percent of maximal F-18 FDG uptake in hypoperfused segments. Nitrogen-13 ammonia kinetic modeling was applied to dynamic PET data, and rate constants were determined. Flow was defined by K1; volume of distribution (VD = K1/k2) of N-13 ammonia was used as an indirect indication of metabolic retention. RESULTS: Fluorine-18 FDG uptake was reduced in patients with scar compared with normal patients with ischemic viable zones (ischemic viable 93 +/- 27% [mean +/- SD]; scar 37 +/- 16%, p < or = 0.01). Using N-13 ammonia kinetic modeling, flow and VD were reduced in the hypoperfused regions of patients with scar (ischemic viable flow: 0.65 +/- 0.20 ml/min per g, scar: 0.36 +/- 0.16 ml/min per g, p < or = 0.01; VD: 3.9 +/- 1.3 and 2.0 +/- 1.07 ml/g, respectively, p < or = 0.01). For detection of viable myocardium in these patients, the sensitivity and specificity were 100% and 80% for N-13 ammonia PET flow > 0.45 ml/min per g; 100% and 70% for VD > 2.0 ml/g; and 100% and 90% for both flow > 0.45 ml/min per g and VD > 2.0 ml/g, respectively. The positive and negative predictive values for the latter approach were 86% and 100%, respectively. CONCLUSIONS: In this cohort, patients having regions with flow < or = 0.45 ml/min per g or VD < or = 2.0 ml/g had scar. Viable myocardium had both flow > 0.45 ml/min per g and VD > 2.0 ml/g. Nitrogen-13 ammonia kinetic modeling permits determination of blood flow and metabolic integrity in patients with previous myocardial infarction and can help differentiate between scar and ischemic but viable myocardium.

Neurocardiac response to esophageal electric stimulation in humans: effects of varying stimulation frequencies.

The purpose of this study was to determine if the cardioautonomic responses to esophageal electric stimulation were mediated entirely through modulation of respiratory frequency or a direct vagal effect. We performed electric stimulation of the esophagus in 13 healthy male controls (24 +/- 6 yr) using a manometric catheter to which a stainless steel electrode was attached. Stimulation frequencies ranged from 0.1 to 1 Hz and were applied in random fashion. We computed the power spectra of the heart rate variability and respiratory frequency as measures of autonomic function. Electric stimulation of the esophagus produced significant increases in the high-frequency power of the heart rate autospectrum at all stimulation frequencies (maximal at 0.2 Hz). However, regardless of the frequency of esophageal stimulation, the respiratory rate was not changed from baseline. These studies indicate that enhancement of cardiac vagal modulation observed in response to esophageal electric stimulation is not primarily due to changes in respiratory frequency, but rather occurs through a direct, vagally mediated action through sensory neural pathways involving vagal esophageal afferents.

Modulation of neurocardiac function by oesophageal stimulation in humans.

1. The heart and the oesophagus have similar sensory pathways, and sensations originating from the oesophagus are often difficult to differentiate from those of cardiac origin. We hypothesized that oesophageal sensory stimuli could alter neurocardiac function through autonomic reflexes elicited by these oesophageal stimuli. In the present study, we examined the neurocardiac response to oesophageal stimulation and the effects of electrical and mechanical oesophageal stimulation on the power spectrum of beat-to-beat heart rate variability in male volunteers. 2. In 14 healthy volunteers, beat-to-beat heart rate variability was compared at rest and during oesophageal stimulation, using either electrical (200 microns, 16 mA, 0.2 Hz) or mechanical (0.5 s, 14 ml, 0.2 Hz) stimuli. The power spectrum of beat-to-beat heart rate variability was obtained and its low- and high-frequency components were determined. 3. Distal oesophageal stimulation decreased heart rate slightly (both electrical and mechanical) (P < 0.005), and markedly altered heart rate variability (P < 0.001). Both electrical and mechanical oesophageal stimulation increased the absolute and normalized area of the high-frequency band within the power spectrum (P < 0.001), while simultaneously decreasing the low-frequency power (P < 0.005). 4. In humans, oesophageal stimulation, whether electrical or mechanical, appears to amplify respiratory-driven cardiac vagoafferent modulation while decreasing sympathetic modulation. The technique provides access to vagoafferent fibres and thus may yield useful information on the autonomic effects of visceral or oesophageal sensory stimulation.

Outcome of patients discharged from a coronary care unit with a diagnosis of "chest pain not yet diagnosed".

OBJECTIVE: To determine the outcome and 3-year mortality rate among patients discharged from a coronary care unit (CCU) with a diagnosis of "chest pain not yet diagnosed." DESIGN: Prospective observational cohort study. SETTING: CCU in a university teaching hospital. PATIENTS: All 158 eligible patients discharged from the CCU between August 1986 and December 1988. Of them, 27 refused to participate and 31 did not meet the inclusion criteria because of significant co-morbidity or transportation difficulties. INTERVENTIONS: Evaluation with maximal and thallium exercise stress testing and four major gastrointestinal (GI) investigations: 24-hour intraesophageal pH monitoring, upper GI endoscopy with biopsy, esophageal motility studies and an upper GI barium series. OUTCOME MEASURES: Results of investigations and incidence of recurrent chest pain, CCU readmission, coronary angiography, coronary artery bypass surgery, myocardial infarction and death at 6, 12, 24 and 36 months after the index visit. RESULTS: Of the patients enrolled in the study 79% (79/100) had a normal exercise thallium stress test result, 74% (68/92) had an abnormal result from the 24-hour pH monitoring, 87% (82/94) had abnormal endoscopic results, 90% (84/93) had abnormal manometric results, and 89% (83/93) had signs of reflux with the barium series. At 3 years 50 patients had recurrent chest pain and 3 underwent coronary artery bypass surgery. Three patients died over the 3 years, all of noncardiac causes. CONCLUSION: Many patients discharged from the CCU with a diagnosis of chest pain not yet diagnosed have a high incidence of esophageal disorders and a very low 3-year mortality rate. More research into the early and effective identification and management of patients with such a diagnosis is needed.

Double blind placebo controlled trial of short term transdermal scopolamine on heart rate variability in patients with chronic heart failure.

OBJECTIVE: To test the hypothesis that short term application of transdermal scopolamine increases heart rate variability (HRV) and restores sympathovagal balance in patients with stable congestive heart failure (CHF). DESIGN: A double blind placebo controlled crossover study. SETTING: Tertiary referral centre. PATIENTS: Twelve patients (mean age 66 (10)) with New York Heart Association class II-IV CHF. All patients had coronary artery disease (mean left ventricular ejection fraction 26.7 (8.9) %). INTERVENTION: Patients were randomly assigned to receive either a placebo skin patch or a transdermal scopolamine patch (Transderm, 0.05 mg/h). Patches remained in place for 48 hours with a 24 hour washout period before crossover. OUTCOME MEASURES: HRV was derived from (a) 24 hour time domain indices (mean RR interval, standard deviation of interbeat interval, and the baseline width of the frequency distribution of RR intervals) and (b) short data set (2.2 mm) power spectral measurements using autoregressive modelling. Autospectral measures were performed in both resting supine and standing (orthostatic) states. The 24 hour Holter record was obtained during the second day of patch application. RESULTS: There was a small but significant (P < 0.05) increase in all time domain HRV variables with scopolamine. There was a paradoxical fall in low frequency (LF) spectral power induced by orthostasis during baseline (-30%) and placebo (-34%) states. Conversely, scopolamine was associated with a 14% increase in LF power during orthostatic stress. Scopolamine thus significantly reduced the orthostatic fall in LF (P < 0.01) compared with either baseline or placebo values. No difference in circadian rhythm was seen between the scopolamine and placebo treatment periods. However, the abrupt fall in the high frequency (vagal) power during the early morning sleep-wake hours was reduced by scopolamine. Scopolamine was also associated with a significant rightward shift in the resting LF central frequency consistent with a vagomimetic effect. CONCLUSION: Patients with chronic stable CHF showed a paradoxical fall in the low frequency (sympathetic) power during orthostatic stress. Transdermal scopolamine applied over a 48 hour period partially restored the balance between sympathetic tone and vagal activity in CHF patients and maintained this balance during orthostatic stress.

Prognostic importance of myocardial ischemia detected by ambulatory monitoring early after acute myocardial infarction.

BACKGROUND: After an acute myocardial infarction, it is important to determine the risk of a subsequent coronary event. We studied the prognostic value of myocardial ischemia detected by ambulatory electrocardiographic (ECG) monitoring in patients who had recently had an acute myocardial infarction. METHODS: Five to seven days after acute myocardial infarction, 406 patients underwent 48-hour ambulatory ECG monitoring, with submaximal exercise testing before discharge and measurement of the left ventricular ejection fraction within 28 days after infarction. Death, nonfatal myocardial infarction, and admission to the hospital because of unstable angina were the principal end points recorded during the one-year follow-up period. RESULTS: The overall incidence of myocardial ischemia detected by ambulatory ECG monitoring was 23.4 percent. The mortality rates at one year were 11.6 percent among the patients with ischemia and 3.9 percent among those without ischemia (P = 0.009); 3.9 percent among the patients with a positive exercise test, 3.0 percent among those with a negative exercise test, and 16.4 percent among those in whom an exercise test was not performed (P < 0.001); and 3.6 percent among the patients with an ejection fraction greater than 50 percent, 3.5 percent among those with an ejection fraction between 35 and 50 percent, and 18.2 percent among those with an ejection fraction below 35 percent (P = 0.001). Using multiple logistic regression, we found that no diagnostic test performed after myocardial infarction provided additional prognostic information beyond that provided by the standard clinical variables used to predict the risk of death. When nonfatal myocardial infarction and admission to the hospital because of unstable angina were also included as outcome variables, ambulatory monitoring for ischemia was the only test that contributed significantly to the model. For the patients with ischemia detected by ambulatory monitoring, as compared with those who did not have evidence of ischemia, the odds ratio was 2.3 (95 percent confidence interval, 1.2 to 4.5) for death or nonfatal myocardial infarction (P = 0.009) and 2.8 (95 percent confidence interval, 1.6 to 4.8) for death, nonfatal myocardial infarction, or admission to the hospital because of unstable angina (P < 0.001). CONCLUSIONS: Myocardial ischemia detected by ambulatory ECG monitoring is common early after acute myocardial infarction and provides prognostic information beyond that available from standard clinical information.

Regional distribution and kinetics of [18F]6-flurodopamine as a measure of cardiac sympathetic activity in humans.

OBJECTIVES: To determine whether an increase in cardiac sympathetic activity produced by exercise or sublingual glyceryl trinitrate causes an increased rate of loss of fluorine-18 from the myocardium after intravenous [18F]6-fluorodopamine ([18F]F-DA) in normal volunteers. In addition, to determine the contribution of non-specific uptake of [18F]F-DA in the myocardium in patients with recent heart transplant. PROTOCOL: [18F]F was prepared by direct electrophilic fluorination of dopamine. Nine healthy volunteers each received 1.85 x 10(8) Bq (168-250 micrograms) [18F]F-DA over a period of 3 min and were scanned for 2 h in an ECAT 953/31 tomograph. Three controls were scanned before and after vigorous cycle exercise and two were scanned before and after sublingual glyceryl trinitrate. In addition, two patients (1 and 2 years post-heart transplant) underwent a myocardial perfusion study with ammonia labelled with nitrogen-13 followed by an [18F]F-DA study. RESULTS: There was intense uniform uptake of [18F]F-DA throughout the myocardium in the healthy volunteers. The time course of 18F in the myocardium under resting conditions fitted a biexponential function with mean half-times of 8.0 and 109 min. Vigorous exercise produced a three to fivefold increase in the rate of loss of 18F compared with that when resting. After glyceryl trinitrate, one control had a profound reduction in blood pressure (23%) and twofold increase in the rate of loss of myocardial 18F. The other control had no physiologically significant change in blood pressure, heart rate, or rate of loss of myocardial 18F. Uptake of [18F]F-DA in the two posttransplant patients was confined to a small anterobasal region adjacent to the atrioventricular groove, while blood flow, as measured with [13N] ammonia, was uniformly distributed throughout the myocardium. Partial reinnervation of the myocardium was confirmed by the presence of distinct low frequency spectral peaks of the heart rate power spectrum in both patients. CONCLUSIONS: These results suggest that the uptake of [18F]F-DA reflects the distribution of cardiac sympathetic innervation and that the rate of loss of 18F from the myocardium partially reflects spill over of noradrenaline. The technique may be useful in investigating various cardiac conditions in which the sympathetic system is compromised.