The aim of this study was to investigate the usefulness of heart rate variability (HRV) in predicting cardiac mortality in patients with a recent acute myocardial infarction at high risk of events. Time- and frequency-domain HRV was assessed on 24-hour pre-discharge Holter recording of 81 patients (mean age 65 +/- 10 years, 76.5% males) with 1) a recent acute myocardial infarction, and 2) left ventricular ejection fraction < 40% and/or a number of premature ventricular beats > or = 10/hour. There were 15 total cardiac deaths (18.5%) in a follow-up time of 29 +/- 15 months (range 6 to 48 months), with sudden death occurring in 11 patients (13.6%). Median values of low frequency (LF) were lower in patients with, compared to those without, total (p = 0.04) and sudden (p = 0.02) cardiac death. Similarly the low frequency/high frequency (LF/HF) ratio was lower in patients with fatal events (p = 0.03 and p = 0.02, respectively). Furthermore, mean of the standard deviations of all RR intervals for all 5-min segments < 20 ms, among time-domain variables, and very-low frequency (VLF) < 18 ms, among frequency-domain variables, significantly predicted cardiac death (relative risk-RR 2.94, p = 0.03; and RR 3.85, p < 0.005, respectively). Furthermore, VLF < 18 ms and LF/HF ratio < 1.05 significantly predicted the occurrence of sudden death (RR 3.52, p = 0.04; and RR 3.49, p = 0.04, respectively). Thus, our data show that HRV analysis is a useful tool for identifying patients with an actual increased risk of fatal cardiac events among patients who are basically considered at high risk according to the presence of an impaired left ventricular function and/or frequent ventricular arrhythmias.

BACKGROUND:There are limited data about the circadian distribution of ischemic episodes in patients with variant angina. Furthermore, no previous study investigated whether ischemia-related ventricular arrhythmias follow a circadian variation in these patients.METHODS:The circadian variation of transient ischemia and ischemia-induced ventricular arrhythmias was assessed by cosinor methodology on 24-hour Holter recordings of 26 patients with variant angina.RESULTS:On the whole, 301 ischemic episodes were detected in the population, with premature ventricular complexes occurring in 49 of them (16%). Ischemic episodes followed a typical circadian variation (acrophase hr 02:36, p < 0.01) in the total sample. However, a significant circadian variation of ischemic episodes was detectable in the 14 patients without (n = 167, acrophase hr 04:00, p < 0.0001), but not in the 12 patients with (n = 134, p = 0.14) hemodynamically significant coronary stenoses, independently of the location (anterior/inferior) of ischemia. There was no significant circadian variation of ischemia-related ventricular arrhythmias.CONCLUSIONS:Among patients with variant angina, a clearcut circadian variation of ischemia is present in those without, but not in those with, hemodynamically significant coronary artery stenoses, thus suggesting that different pathophysiologic mechanisms may operate, at least in part, in triggering coronary spasm in these two subgroups of patients. There was no significant circadian variation of ischemia-related ventricular arrhythmias in these patients.

Most patients with chronic stable angina show an improvement in ischemic threshold when a second exercise test is performed a few minutes after a first positive test. In this study we evaluated whether this "warm-up" phenomenon also occurs in patients with syndrome X. We performed 2 consecutive exercise tests in 14 patients with chronic stable angina and 11 patients with syndrome X. The second exercise test was performed after 10 minutes from the end of the first one, always after complete recovery to baseline of ST segment. In patients with stable angina, heart rate (108+/-18 vs 99+/-16 beats/min, p = 0.005), rate-pressure product (17,020+/-4,541 vs 15,215+/-3,734 beats/min x mm Hg, p = 0.028), and exercise time (587+/-297 vs 444+/-244 seconds, p = 0.002) at 1-mm ST depression were higher in the second test than in the first one and a significant improvement in these parameters during the second test was also observed at peak exercise. Conversely, in patients with syndrome X, there were no significant differences between the 2 tests in heart rate (128+/-18 vs 131+/-23 beats/min), rate-pressure product (19,922+/-5,153 vs 19,390+/-5,654 beats/min x mm Hg), and exercise time (592+/-243 vs 566+/-228 seconds) at 1-mm ST-segment depression. Similarly, in this group of patients, no significant differences in exercise variables between the 2 tests were observed at peak exercise. Thus, unlike patients with chronic stable angina, patients with syndrome X have no evidence of warm-up in response to repeated exercise testing.

Objectives. This study sought to investigate whether changes in nervous autonomic tone may have a role in the mechanisms triggering spontaneous coronary spasm in variant angina. Background. Previous studies have suggested that both sympathetic and vagal activation may act as a trigger of epicardial artery spasm in patients with variant angina, but the actual role of autonomic changes in spontaneous coronary spasm remains unknown. Methods. We analyzed the changes in heart rate variability associated with episodes of ST segment elevation detected on Holter monitoring in 23 patients,with variant angina (18 men, 5 women; mean [+/-SD] age 59 +/- 12 years). For study purposes, episodes of transmural ischemia lasting greater than or equal to 3 min and without any ST segment changes in the previous 40 min were selected for analysis. Heart rate variability indexes were calculated at 2 min intervals, at 30, 15, 5 and 1 min before ST elevation and at peak ST segment elevation. Ninety-three of 239 total ischemic episodes (39%) fulfilled the inclusion criteria.Results. The results showed that 1) high frequency (HF) (0.04 to 0.15 Hz), a heart rate variability index specific for vagal activity, decreased in the 2 min preceding ST segment elevation (p < 0.001) and, returned to basal levels at peak ST segment elevation; 2) heart I ate and low frequency (0.04 to 0.15 Hz), which are partially correlated with sympathetic activity, showed a significant increase at peak ST segment elevation (p < 0.001 for both); 3) the pattern of the HF reduction before ST segment elevation was consistently confirmed in several subgroups of ischemic episodes, including those of patients with or without coronary stenoses, those of patients with anterior or inferior ST segment elevation, those occurring during daily or nightly hours and silent episodes, There were no significant variations in heart rate variability in control periods selected from Holter tapes of patients and before ST segment elevation induced by balloon inflation in 20 patients undergoing coronary angioplasty. Conclusions. Our data show that changes in autonomic tone are likely to contribute to trigger or predispose to epicardial spasm. In particular, although not excluding an active role for adrenergic mechanisms, our data suggest that a vagal withdrawal may often be a component of the mechanisms leading to spontaneous coronary vasospasm.

To evaluate whether the ischemic threshold has a circadian rhythm in patients with syndrome X, we analyzed 90 episodes of ST depression detected on 24-hour Holter recordings of 12 such patients. Ischemic threshold was considered as heart rate (HR) at 1 mm ST depression. To correct for differences in basal HR among patients, however, the ischemic threshold was also calculated as a normalized index of HR at 1 mm ST depression: [(HR at 1 mm ST-24-hour modal HR)/24-hour modal HR]-100. Mean hourly values of both absolute and normalized HRs at 1 mm ST depression were obtained by grouping and averaging respective values of all episodes detected in every hour of the day in all patients. Chronobiologic analysis was performed by single cosinor method. A significant circadian rhythm was found for HR (mesor 76 beats/min, amplitude 10 beats/min, acrophase at 2:16 P.M., p < 0.001), number of episodes of ST depression (mesor 3.75, amplitude 2.9, acrophase at 2:45 P.M., p < 0.001) and cumulative time of ischemia, with a high correlation of distributions. Episodes of ST depression showed a double peak initially in the morning, and again in the afternoon. Both raw and normalized values of HR at 1 mm ST depression also had a significant circadian variation in ischemic threshold, which was lower in the night and early morning hours, progressively increased until the first afternoon hours, and subsequently decreased in the evening.(ABSTRACT TRUNCATED AT 250 WORDS)

In order to evaluate whether variations in autonomic nervous tone have a significant role in the induction of coronary arterial spasm in variant angina, we analyzed the changes in heart rate variability (HRV) related to spontaneous episodes of ST-segment elevation, recorded during 24-hour ambulatory ECG monitoring, in 13 patients with variant angina (9 men and 4 women, aged 63 +/- 12 years). In order to obtain an accurate analysis of HRV changes, we only included ischemic episodes characterized by silent ST-segment elevation, lasting at least 3 min and without any ST change in the previous 30 min. HRV indexes in the time domain (RR interval, standard deviation of RR intervals [SD], pNN50, r-MSSD) and in the frequency domain (LF = 0.04-0.15 Hz, HF = 0.15-0.40 HZ, LF/HF ratio) were calculated on 2 min intervals, centered at 15 min before (15B), 5 min before ed 1 min before (1B) the appearance of ST elevation, as well as at peak of ST-segment elevation. Of 161 ischemic episodes found on 24-hour Holter recordings, 60 (37%) fulfilled the inclusion criteria for analysis (4.6 +/- 3.5 episodes/patient, range 1-12). The duration of the selected episodes was 6 +/- 2.5 min and ST elevation was 2.2 +/- 1.0 mm. Heart rate (HR) did not have any change before ST elevation, whereas it showed a small, but significant increase at peak ST (73 +/- 12 versus 67 +/- 11 b/min at 15B, p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Two-channel ambulatory electrocardiographic (ECG) monitoring is a useful method for detecting transient myocardial ischemia in patients with coronary artery disease. However, the monitoring of only 2 leads may fail to detect a significant number of ischemic episodes. In this study, the additional diagnostic value of a third bipolar chest lead was evaluated by recording a simultaneous 12-lead electrocardiogram and a 3-channel ambulatory electrocardiogram during exercise testing in 223 patients (aged 63 +/- 10 years) with proved or suspected coronary disease. Leads CM5, CM3, and an inferior lead (Y-modified or CMf) were monitored on the ambulatory electrocardiogram. Diagnostic ST-segment depression on the standard electrocardiogram was detected in 98 patients (44%), 94 (96%) of whom also had diagnostic ST-segment changes on the ambulatory electrocardiogram. Two additional patients had ST-segment depression only on the ambulatory electrocardiogram (both in lead CM5). Maximal ST-segment depression and duration of ischemia detected on standard and ambulatory ECG leads were similar in the 94 patients in whom ST-segment changes were detected on both types of ECG monitoring. CM5 was the single lead with the highest sensitivity (89%) in detecting myocardial ischemia. The addition of CM3 to CM5 increased sensitivity to 91%, and the addition of an inferior lead to CM5 increased sensitivity to 94%, particularly improving the detection of isolated inferior myocardial ischemia. The combination of all 3 ambulatory ECG leads had a sensitivity of 96%, an improvement of only 2% compared with the best combination of 2 leads (i.e., CM5 +/- inferior lead).(ABSTRACT TRUNCATED AT 250 WORDS)

The accuracy of a real-time analysis Holter system (Oxford Medilog 4500) in detecting ventricular and supraventricular arrhythmias was evaluated. Hand-counted data from randomly selected hours of 152 ECG monitorings of 152 patients were used as the control standard. Accuracy of the system was evaluated on 606 hours for premature ventricular complexes (PVC), PVC couplets and supraventricular extrasystoles (SVE), and on 1,789 hours for ventricular tachycardia (VT), accelerated idioventricular rhythm (AIVR), and supraventricular tachycardia (SVT). Sensitivity and positive predictive accuracy for the Oxford system were (1) 92.9% and 94.9% for PVC; (2) 90.1% and 87.8% for PVC couplets; (3) 98.1% and 56% for AIVR; (4) 80% and 82.3% for VT; (5) 88.6% and 56.5% for SVE, and (6) 43.7% and 60.2% for SVT. Furthermore, negative predictive accuracy, the ability to predict the total absence of an arrhythmic event in an hour, was determined. It was 91.7% for PVC, 99.5% for PVC couplets, 99.9% for AIVR, 99.7% for VT, 95% for SVE, and 98% for SVT. Our results show good reliability of the Oxford system in the identification of ventricular arrhythmias, whereas significant inaccuracies appear to exist in the analysis of supraventricular arrhythmias.

To evaluate the existence and reproducibility of a circadian rhythm of ventricular premature complexes (VPCs), 38 patients (mean age 57 ± 17 years) with ≥30 VPCs/hour were studied with 24-hour electrocardiogram Holter monitoring. Nineteen patients had coronary artery disease and 19 had structurally normal hearts. A second Holter electrocardiogram was recorded in all patients from 2 to 47 days (mean 11) after the first. Chronobiologic analysis was made by single and mean cosinor methods. A significant and similar circadian rhythm of VPCs was found in the total sample both on the first (mesor 399, acrophase at 15:08, p < 0.01) and the second day (mesor 306, acrophase at 14:47, p < 0.05), with 2 main peaks, the first in the late morning and the second in the afternoon. However, only 18 patients (47%, group A) had a significant individual circadian rhythm of VPCs on both days, whereas 20 (53%, group B) did not have a significant rhythm in ≥1 day. A high reproducibility of the circadian rhythm of VPCs was found in group A patients, with a difference of 2.1 ± 1.8 hours between the acrophases of the 2 days, whereas this difference was 4.4 ± 3.3 hours in group B patients (p < 0.01). Among group A patients, 14 (78%) had a VPC rhythm with acrophase occurring during waking hours, whereas the acrophase of 4 (22%) occurred during the night. The reproducibility of the circadian rhythm of VPCs was not influenced by gender, presence of coronary disease, medical therapy, basal VPC number, or day-to-day variability of VPCs, although group A patients were older than group B patients (p < 0.05). The evidence, of a reproducible circadian rhythm of VPCs in a significant number of patients, suggests the possibility of a chronopharmacologic approach to their treatment.

A study of the diurnal serum and urine levels of L-carnitine and acetylcarnitine was carried out in eleven healthy volunteers. No significant difference was found between the levels in the morning and in the afternoon, although a higher carnitinaemia was shown in the waking hours when the energy demands were higher.

We report a case of bidirectional tachycardia (BT) found on Holter recording (H-ECG), likely due to antiarrhythmic therapy with lorajmine. The patient, who was not on digitalis therapy and had good myocardial function, was investigated for presyncope. H-ECG revealed frequent premature ventricular complexes (PVC). Disopyramide, lorajmine and amiodarone (in succession) were ineffective in controlling the arrhythmias. During therapy with lorajmine (600 mg/die) H-ECG showed numerous symptomless episodes of BT. Two forms of BT were found. In the first one the PVC had a right bundle branch block (BBB) pattern in lead CM1 and alternating polarity (Rs-rS) in lead CM5, whereas in the second one an alternating right and left BBB pattern in CM1 was found. PVC were subsequently controlled with flecainide. In a 4-year follow-up period the patient underwent several H-ECGs, both with and without antiarrhythmic drugs; however, BT episodes were found only during lorajmine therapy. Thus, this drug was likely responsible for the appearance of BT episodes.

The characteristics of ventricular tachycardia found during Holter ECG monitoring before discharge in patients hospitalized because of acute myocardial infarction were analyzed. One or more ventricular tachycardia episodes were found in 29 of 251 patients (11.5%). On the whole, there were 233 episodes of ventricular tachycardia: 18 patients (62%) had only one episode of ventricular tachycardia, 9 (31%) 2-5 episodes and 2, respectively, 68 and 118 episodes. Episodes of ventricular tachycardia were more numerous in patients with frequent or polymorphic premature ventricular complexes than in patients with sporadic or monomorphic premature ventricular complexes. Fifty-seven ventricular tachycardia episodes were analyzed: 30 of 3 beats, 25 of 4-9 beats and 2 of 15 beats. Forty-seven episodes were monomorphic and 10 (17.5%) were polymorphic. The ventricular tachycardia rate was 136.4 +/- 25 b/m' (range 104-200). The RR'/QT ratio (where RR' = coupling interval of the first beat of ventricular tachycardia) was 1.67 +/- 0.42 and was not correlated either with the rate or the number of beats of ventricular tachycardia. Heart rate at the moment of ventricular tachycardia was 82 +/- 15 b/m' and QT interval 0.36 +/- 0.05 sec; there was no difference when compared to their values of 1 and 5 minutes before ventricular tachycardia. Furthermore, the heart rate showed no difference when compared to the mean value of the hours in which ventricular tachycardia episodes occurred. In addition, heart rate was not correlated with ventricular tachycardia rate, whereas a good correlation was found between the last RR interval preceding ventricular tachycardia and RR' interval (r = 0.61, P less than 0.01).

Circadian rhythms have been described both for acute myocardial infarction (AMI) and sudden death. In this study the diurnal distribution of ventricular tachycardia (VT) in patients with AMI was analyzed. Ninety-four AMI patients with greater than or equal to 1 VT on Holter electrocardiographic monitoring who were not taking antiarrhythmic drugs were studied. Forty-seven patients had a recent AMI (group A) and 47 an old AMI (group B). Chronobiologic analysis was made by single cosinor method. There were 157 VTs (mean 1.67 VTs/patient, range 1 to 10) in the 94 patients: 70 in group A and 87 in group B. A significant circadian rhythm of VT was found in the total population with acrophase at 2:29 P.M. The hourly distribution of VT showed a tendency to bimodality, which seemed due to a different time of peak VT occurrence in group A (significant rhythm with acrophase at 4:40 P.M.) and group B (significant rhythm with acrophase at 12:39 P.M.). Thus, the hourly VT frequency in patients with AMI has a significant circadian variation with the highest occurrence in the awake hours, similar to the rhythms described for AMI and sudden death.