Leon Lurje

Anti-Ischemic and Anti-Anginal Effects of Thoracic Epidural Anesthesia Versus Those of Conventional Medical Therapy in the Treatment of Severe Refractory Unstable Angina Pectoris

BACKGROUND Cardiac sympathetic blockade by thoracic epidural anesthesia (TEA) dilates stenotic coronary arteries and has been used to control pain in patients with unstable angina. The aim of the present study was to evaluate the potential anti-ischemic effects of cardiac sympathetic blockade by TEA in severe, refractory, unstable angina. METHODS AND RESULTS Forty patients with unstable angina refractory to standard anti-anginal therapy were randomized to receive either continuous epidural infusion of bupivacaine (TEA, Th1 to Th5) or to standard anti-anginal therapy including beta-blockers, calcium antagonists, aspirin, heparin, and nitroglycerin infusion (control group). The primary end points were number of anginal attacks and severity of myocardial ischemia assessed by 48-hour ambulatory Holter monitoring. The incidence of myocardial ischemia was lower in the TEA group (22% versus 61%; P<.05). The number of ischemic episodes per patient was 1.0+/-0.6 in the TEA group and 3.6+/-0.9 in the control group (P<.05). The episode duration per patient was 4.1+/-2.5 minutes and 19.7+/-6.2 minutes in the TEA and the control groups, respectively (P<.05). The mean area-under-the-ST-time-curve was 6.8+/-4.3 and 32.2+/-14.3 (mm-min) in the TEA and the control groups, respectively (P<.05). Fifteen anginal attacks were recorded in the control group and one attack in the TEA group (0.83+/-0.21 versus 0.06+/-0.06/patient, respectively, P<.01). CONCLUSIONS The anti-ischemic and anti-anginal effects of continuous TEA are superior to those of conventional therapy in the treatment of refractory unstable angina.

Patients with uncomplicated coronary artery disease have reduced heart rate variability mainly affecting vagal tone

AIM To investigate whether uncomplicated chronic coronary artery disease causes changes in heart rate variability and if so, whether the heart rate variability pattern is different from that described in patients with acute myocardial infarction. METHODS Heart rate variability was studied in 65 patients with angina who had no previous myocardial infarcts, no other diseases, and were on no drug that could influence the sinus node. Results were compared with 33 age matched healthy subjects. The diagnosis of coronary artery disease in angina patients was established by coronary angiography in 58, by thallium scintigraphy in six, and by exercise test only in one. Patients and controls were Holter monitored 24 hours outside hospital, and heart rate variability was calculated in the frequency domain as global power (GP: 0.01–1.00 Hz), low frequency peak (LF: 0.04–0.15 Hz), high frequency peak (HF: 0.15–0.40 Hz), LF/HF in ms2, and in the time domain as SDNN (SD of normal RR intervals), SDANN (SD of all five minute mean normal RR intervals), SD (mean of all five minute SDs of mean RR intervals), rMSSD (root mean square of differences of successive normal RR intervals) (all in ms), and pNN50 (proportion of adjacent normal RR intervals differing more than 50 ms from the preceding RR interval) as per cent. RESULTS The mean age in patients and controls was 60.4 (range 32–81) and 59.1 (32–77) years, respectively (NS), the male/female ratio, 57/65 and 24/33 (NS), and the mean time of Holter monitoring, 23.0 (18–24) and 22.8 (18–24) hours (NS). Mortality in angina patients was 0% (0/65) at one year, 0% (0/56) at two years, and 3% (1/33) at three years. Compared with healthy subjects angina patients showed a reduction in GP (p = 0.007), HF (p = 0.02), LF (p = 0.02), SD (p = 0.02), rMSSD (p = 0.01), and pNN50 (p = 0.01). No significant difference was found in RR, LF/HF, SDNN, or SDANN. CONCLUSIONS Uncomplicated coronary artery disease without previous acute myocardial infarction was associated with reduced high and low frequency heart rate variability, including vagal tone. SDANN and SDNN, expressing ultra low and very low frequencies which are known to reflect prognosis after acute myocardial infarction, were less affected. This is in agreement with the good prognosis in uncomplicated angina in this study.

Incidence of Sudden Death After Radiofrequency Ablation of the Atrioventricular Junction for Atrial Fibrillation

This study assesses the incidence of sudden death and classifies the causes of death following radiofrequency ablation of the atrioventricular (AV) junction. We studied 220 patients with paroxysmal (n = 105) or chronic (n = 115) atrial fibrillation (AF) and a mean age of 64 +/- 12 years. These patients were followed 31 +/- 15 months after radiofrequency ablation of the AV junction and pacemaker implantation. In 86 patients, structural heart disease was identified before the procedure. All patients were traced via the Swedish National Civic Registry and Cause of Death Registry. The cause-of-death was classified according to data from death certificates, autopsy protocols, and medical records. Thirty-one patients (mean age 69 +/- 11 years, 16 men) died 15 +/- 15 months (range 0.2 to 60) after the procedure. There were 6 sudden unexplained deaths, 14 cardiovascular deaths, and 11 deaths from noncardiovascular causes. Eleven patients, all with structural heart disease, died suddenly out of hospital 16 +/- 16 months (range 0.2 to 42) after the procedure. In 6 of these there was no obvious cause of death. Three of these 6 patients underwent autopsy, which showed extensive coronary artery disease (n = 1), severe heart failure (n = 1) and cardiac hypertrophy and dilation (n = 1). The remaining 3 all had depressed left ventricular systolic function and a history of congestive heart failure. Five of the patients who died suddenly from cardiovascular causes had autopsies that revealed acute myocardial infarction (n = 4) and massive pulmonary embolism (n = 1).

Circadian variation of heart rate variability and the rate of autonomic change in the morning hours in healthy subjects and angina patients

BACKGROUND Incidence of sudden cardiac death peaks during the early morning hours when there is a rapid withdrawal of vagal and an increase of sympathetic tone. The rate of autonomic change could be of prognostic importance. PATIENTS AND METHODS A total of 65 patients with angina pectoris, free from other diseases and drug free, were Holter monitored for 24 h. A total of 30 patients were also monitored on isosorbide-5-mononitrate (IS-5-MN) and on metoprolol respectively. A total of 33 age-matched healthy subjects served as controls. Spectral components of heart rate variability (HRV) were analysed hourly, with special reference to the rapid changes of autonomic tone during the night and early morning hours. Circadian variation was assessed in two ways: (1) Mean HRV day (8 a.m.-8 p.m.) and night (0-5 a.m.) were compared. (2) For the morning/night hours (0-10 a.m.), individual hourly values for max. and min. HRV, the difference max.-min. (gradient), the rate of change per hour between max. and min. (velocity) and the largest difference between two consecutive hours (max. velocity) were recorded and the mean value for the group calculated. RESULTS During the night/morning hours, healthy controls demonstrated faster HF max. velocity (P=0.002) and higher HF gradient (P=0.011) than angina patients. Metoprolol and IS-5-MN increased the HF gradient (P=0.008 and P=0.003, respectively), and metoprolol tended to increase the max. velocity (P=0.02). Metoprolol substantially decreased the LF/HF gradient (P=0.001), velocity (P=0.008) and max. velocity (P=0.0001). CONCLUSION Rapid vagal withdrawal seemed to be a sign of a healthy autonomic nervous system in the control group but was significantly slower in angina patients. IS-5-MN and metoprolol tended to normalise vagal withdrawal and metoprolol slowed down the rapid increase in sympathetic predominance in the morning in patients.

Metoprolol treatment for two years after coronary bypass grafting: effects on exercise capacity and signs of myocardial ischaemia.

OBJECTIVE--To evaluate whether prophylactic treatment with metoprolol for two years after coronary artery bypass grafting improves working capacity and reduces the occurrence of myocardial ischaemia in patients with coronary artery disease. METHODS--After coronary artery bypass grafting, patients were randomised to treatment with metoprolol or placebo for two years. Two years after randomisation, a computerised 12-lead electrocardiogram was obtained during a standardised bicycle exercise test in 618 patients (64% of all those randomised). RESULTS--The median exercise capacity was 140 W in the metoprolol group (n = 307) and 130 W in the placebo group (n = 311) (P > 0.20). An ST depression of > or = 1 mm at maximum exercise was present in 34% of the patients in the metoprolol group and 38% in the placebo group (P > 0.20) and an ST depression of > or = 2 mm at maximum exercise was present in 11% in the metoprolol group and 16% in the placebo group (P = 0.09). The median values for maximum systolic blood pressure were 200 mm Hg in the metoprolol group and 210 mm Hg in the placebo group (P < 0.0001), while the median values for maximum heart rate were 126 beats/min in the metoprolol group and 143 beats/min in the placebo group (P < 0.0001). The occurrence of cardiac and neurological clinical events two years postoperatively among exercised patients was comparable in the treatment groups. CONCLUSIONS--Treatment with metoprolol for two years after coronary artery bypass grafting did not significantly change exercise capacity or electrocardiographic signs of myocardial ischaemia.

Reduced Heart Rate Variability in Ischemic Heart Disease Is Only Partially Caused by Ischemia

Background: Reduced heart rate variability (HRV) after acute myocardial infarction (AMI) indicates poor prognosis. HRV in patients with uncomplicated coronary artery disease is reduced, and an association with poor prognosis has been suggested. The mechanism of the HRV reduction is not known, but ischemia is a possibility. Aim: To evaluate, in angina patients with no prior AMI, no other disease and drug-free, if complete revascularization and thus important reduction of ischemia by means of PTCA influences HRV. Patients and Methods: Twenty-four-hour Holter recordings were performed at baseline prior to PTCA in 48 patients with angina and in 41 age-matched healthy control subjects. The recording was repeated 1 and 6 months after complete revascularization. In addition, HRV was registered during controlled respiration in the supine and standing positions and during cold pressure test at baseline in all angina patients and controls and in 17 consecutive angina patients 6 months after PTCA. Results: Compared to controls, angina patients had a significantly reduced mean RR interval (p = 0.02), SD (p = 0.003), rMSSD (p = 0.03), pNN50 (p = 0.03), total power (p = 0.003), low- (p = 0.004) and high-frequency peak (p = 0.04), but normal SDNN, SDANN and LF/HF. One and 6 months after PTCA, 42/46 and 32/40 follow-up patients, respectively, were free of angina. Six months after PTCA, there was a significant recovery of vagal modulation seen in the frequency domain during controlled respiration, but only nonsignificant trends in HRV parameters analyzed over 24 h. Conclusion: Patients with uncomplicated angina had reduced HRV, mainly affecting vagal activity, but normal low frequency variability associated with mortality. Complete revascularization caused a partial normalization of vagal modulation indicating that ischemia may be one of but not the only mechanism of the HRV reduction in uncomplicated chronic coronary artery disease.

Effect of Endoscopic Transthoracic Sympathicotomy on Heart Rate Variability in Severe Angina Pectoris

Endoscopic transthoracic sympathicotomy (ETS) is a recently developed technique to divide sympathetic nerves. ETS has been shown to improve symptoms and reduce ischemia in patients with severe angina pectoris. Low heart rate variability (HRV) in patients with ischemic heart disease carries an adverse prognosis. HRV reflects autonomic response of the heart and a shift in the sympathovagal balance towards parasympathetic dominance could be a marker of improved prognosis. HRV might also be used as an indicator of surgical success in sympathetic heart denervation. Heart rate was recorded in 57 patients before and after ETS. Registration was recorded during controlled respiration in the supine position and at tilt test over 10 minutes and spectral analysis was performed. Twenty-four hour Holter recordings were analyzed in the time domain. During the controlled setting, the high-frequency (HF) component (0.15 to 0.40 Hz) increased significantly whereas the low-frequency (LF) component (0.04 to 0.15 Hz) did not change significantly. The LF/HF ratio at tilt test was reduced from 1.3 to 0.8 (p <0.01). The time-domain analysis showed a significant increase of the mean RR interval (923 to 1,006 ms, p <0.001) and indexes reflecting parasympathetic tone also increased significantly (the root-mean square of difference measured from 24.3 to 29.5 ms, p <0.001 and the proportion of adjacent RR intervals >50% measured from 5.5% to 8.2%, p <0.01), whereas measurements reflecting global HRV did not change. In addition to relief of symptoms and reduced ischemia in severe angina pectoris, ETS caused a shift of sympathovagal balance toward parasympathetic tone. This might explain the anti-ischemic effect and have prognostic implications.

Short- and long-term prognosis after coronary artery bypass grafting in relation to smoking habits.

We describe the 2- and 5-year prognoses following coronary artery bypass grafting (CABG) in relation to smoking habits among consecutive patients being operated on in western Sweden during a 3-year period. Among the 2,121 patients, 10.2% admitted smoking at coronary angiography as compared with 7.5% 2 years after CABG (NS). Among smokers, the mortality during the subsequent 2 years was 8.9% as compared with 6.5% for exsmokers and 7.3% for never smokers (NS). During the 5-year follow-up, smokers had a mortality of 18.8% as compared with 13.6% for exsmokers and 12.5% for never smokers (p = 0.03). When correcting for dissimilarities in previous history, smoking was a strongly significant independent (p < 0.0001) predictor of 5-year mortality.

Death, mode of death, morbidity and requirement for rehospitalization during 2 years after coronary artery bypass grafting in relation to preoperative ejection fraction

Objective To describe the impact of ejection fraction on the prognosis during 2 years after coronary artery bypass grafting (CABG).Patients All patients in western Sweden who underwent CABG without concomitant valve surgery between June 1988 and June 1991.Results In all, 2121 patients were operated upon and information on ejection fraction was available for 1961 patients (92%). Of these patients, 178 (9%) had an ejection fraction < 40%, 517 (26%) an ejection fraction of 40–59% and 1266 (65%) an ejection fraction ≥ 60%. In these groups the mortalities during the first 30 days after CABG were 5.1, 4.3 and 2.2%, respectively (P<0.01). The corresponding values for mortalities between 30 days and 2 years were 7.7, 4.3 and 3.3%, respectively (P<0.01). Patients with a lower ejection fraction were more frequently men and more frequently had a history of cardiovascular disease. In multivariate analysis the preoperative ejection fraction was an independent predictor for total 2-year mortality. Patients with a low ejection fraction died more frequently in association with ventricular fibrillation. Morbidity was, with the exception of that for rehospitalization due to heart failure and infection, not associated significantly with the preoperative ejection fraction.Conclusion During the 2 years after CABG a low preoperative ejection fraction was associated with a higher mortality, but the association with morbidity was more complex.

Effects on Heart Rate Variability of Isosorbide-5-Mononitrate and Metoprolol in Patients with Recent Onset of Angina pectoris

Background: β-Blockers reduce sympathetic tone, increase vagal tone and improve prognosis in ischaemic heart disease. Nitroglycerin, being a vasodilator, may theoretically have an opposite effect and worsen the prognosis. The purpose of the present study was to analyse heart rate variability (HRV), which reflects autonomic tone, in angina patients on isosorbide-5-mononitrate (IS-5-MN) and/or metoprolol. Methods and Results: Thirty-two patients (32–81 years old), with recently developed angina (median duration: 3 months), showing no other disease and on no drugs, were Holter-monitored 24–48 h at baseline and after 4–5 days on IS-5-MN (mean daily dose: 33 mg), on metoprolol (mean daily dose: 184 mg) and on the combined treatment. Recordings were analysed on the Marquette Series 8000 Holter scanner. Both IS-5-MN and metoprolol significantly reduced myocardial ischaemia (ST integral) and ventricular tachycardias. Metoprolol induced significant changes in the following parameters (baseline versus metoprolol): high-frequency peak 9 ± 4 versus 11 ± 4 ms (p < 0.001), low-to-high frequency ratio 2.5 ± 0.6 versus 1.9 ± 0.6 (p < 0.0001), root mean square of RR interval difference 23 ± 7 versus 31 ± 9 ms (p < 0.0001), RR intervals differing more than 50 ms from the preceding one 4.8 ± 3.9 versus 10.0 ± 7.0% (p < 0.0001), mean of all 5-min standard deviations 50 ± 12 versus 56 ± 11 ms (p < 0.001) and mean RR interval 819 ± 90 versus 1,019 ± 120 ms (p < 0.00001). The combined treatment caused approximately the same HRV changes as metoprolol alone. IS-5-MN had no significant effect on any HRV parameter, neither alone nor in combination with metoprolol. Conclusion: A clinically effective dose of metoprolol had potentially positive effects on HRV with increase in vagal and decrease in sympathetic tone while IS-5-MN had no effect on HRV, neither positive nor negative, neither alone nor in combination with metoprolol.