Egon Toft

Vernakalant Hydrochloride for Rapid Conversion of Atrial Fibrillation. A Phase 3, Randomized, Placebo-Controlled Trial

Background— The present study assessed the efficacy and safety of vernakalant hydrochloride (RSD1235), a novel compound, for the conversion of atrial fibrillation (AF). Methods and Results— Patients were randomized in a 2:1 ratio to receive vernakalant or placebo and were stratified by AF duration of 3 hours to 7 days (short duration) and 8 to 45 days (long duration). A first infusion of placebo or vernakalant (3 mg/kg) was given for 10 minutes, followed by a second infusion of placebo or vernakalant (2 mg/kg) 15 minutes later if AF was not terminated. The primary end point was conversion of AF to sinus rhythm for at least 1 minute within 90 minutes of the start of drug infusion in the short-duration AF group. A total of 336 patients were randomized and received treatment (short duration, n=220; long duration, n=116). Of the 145 vernakalant patients, 75 (51.7%) in the short-duration AF group converted to sinus rhythm (median time, 11 minutes) compared with 3 of the 75 placebo patients (4.0%; P<0.001). Overall, in the short- and long-duration AF groups, 83 of the 221 vernakalant patients (37.6%) experienced termination of AF compared with 3 of the 115 placebo patients (2.6%; P<0.001). Transient dysgeusia and sneezing were the most common side effects in vernakalant-treated patients. Four vernakalant-related serious adverse events (hypotension [2 events], complete atrioventricular block, and cardiogenic shock) occurred in 3 patients. Conclusion— Vernakalant demonstrated rapid conversion of short-duration AF and was well tolerated.

Effect of fish oil on heart rate variability in survivors of myocardial infarction: a double blind randomised controlled trial

Marine n-3 polyunsaturated fatty acids may protect against ischaemic heart disease.1 In the diet and reinfarction trial patients with an acute myocardial infarction advised to eat fish rich in n-3 polyunsaturated fatty acids had a 29% reduction in two year all cause mortality compared with controls.2 The authors hypothesised that dietary n-3 polyunsaturated fatty acids might reduce malignant ventricular arrhythmias and sudden cardiac death, as reported in animals.3 We investigated a possible antiarrhythmic effect of dietary n-3 polyunsaturated fatty acids in survivors of myocardial infarction. Patients were eligible for study if they had been discharged from the department of cardiology at Aalborg Hospital between November 1991 and August 1993 after a myocardial infarction and had a ventricular ejection fraction below 0.40. We excluded patients aged over 75, patients with pacemakers or permanent tachyarrhythmias, and those with serious non-cardiac disease. Eighty one patients fulfilled the inclusion criteria and 55 gave informed consent to a double blind placebo controlled trial. Patients were randomly …

Fish Consumption, n-3 Fatty Acids in Cell Membranes, and Heart Rate Variability in Survivors of Myocardial Infarction With Left Ventricular Dysfunction

To elucidate a possible antiarrhythmic effect of long-chained n-3 polyunsaturated fatty acids, heart rate variability was assessed in 52 patients with a previous myocardial infarction and left ventricular dysfunction. The content of n-3 polyunsaturated fatty acids in platelets was closely associated with the patients fish-consuming habits, and a significant positive correlation was observed between the n-3 fatty acid docosahexaenoic acid and heart rate variability.

Marine n-3 Fatty Acids, Wine Intake, and Heart Rate Variability in Patients Referred for Coronary Angiography

Background —Dietary n-3 polyunsaturated fatty acids (PUFAs) derived from fish may reduce the incidence of sudden cardiac death (SCD). In addition, wine drinking is suggested to have a protective effect against cardiovascular death. Methods and Results —We included 291 patients referred for coronary angiography in whom ischemic heart disease was suspected and all of whom completed a food questionnaire regarding fish and wine intake. The n-3 PUFA composition of granulocyte membranes and of adipose tissue was measured. In addition, 24-hour heart rate variability (HRV) was analyzed. Fish intake was positively associated with the level of n-3 PUFAs in adipose tissue. Significant positive correlation coefficients were found between HRV indices and the levels of n-3 PUFAs in granulocytes. Wine intake was also significantly positively related to HRV, but the patients with the highest wine intake also had the highest intake of fish, as documented by a high n-3 PUFA content in adipose tissue. Multiple linear regression analysis revealed that traditional factors such as treatment with &bgr;-blockers, smoking, age, and previous myocardial infarction were independently related to HRV, and furthermore that n-3 PUFAs (but not wine intake) were significantly independently associated with HRV. Conclusions —The close positive association between n-3 PUFAs and HRV in patients suspected of having ischemic heart disease may indicate a protective effect of n-3 PUFAs against SCD. This may partly explain the reduction in SCD observed in humans with a modest intake of n-3 PUFA. Wine intake was also positively correlated with HRV, but this correlation was no longer significant after controlling for the cellular level of n-3 PUFA.

C-reactive protein, dietary n-3 fatty acids, and the extent of coronary artery disease

The acute-phase reactant C-reactive protein (CRP) has emerged as an independent risk factor for coronary artery disease. Experimental and clinical studies provide evidence of anti-inflammatory effects of n-3 polyunsaturated fatty acids (PUFA) derived from fish. We have studied the effect of marine n-3 PUFA on CRP levels in 269 patients referred for coronary angiography because of clinical suspicion of coronary artery disease. All patients filled out a food questionnaire regarding fish intake. The n-3 PUFA content of granulocyte membranes was determined and the concentration of CRP in serum was measured using a highly sensitive assay. The results were related to angiographic findings. CRP was significantly higher in patients with significant coronary stenoses than in those with no significant angiographic changes (p <0.001), but the CRP levels were not associated with the number of diseased vessels. Subjects with CRP levels in the lower quartile had a significantly higher content of docosahexaenoic acid (DHA) in granulocytes than subjects with CRP levels in the upper quartile (p = 0.02), and in a multivariate linear regression analysis, DHA was independently correlated to CRP (R(2) = 0.179; p = 0.003). The inverse correlation between CRP and DHA may reflect an anti-inflammatory effect of DHA in patients with stable coronary artery disease and suggest a novel mechanism by which fish consumption may decrease the risk of coronary artery disease.

Vernakalant hydrochloride for the rapid conversion of atrial fibrillation after cardiac surgery a randomized, double-blind, placebo-controlled trial

Background—Postoperative atrial arrhythmias are common and are associated with considerable morbidity. This study was designed to evaluate the efficacy and safety of vernakalant for the conversion of atrial fibrillation (AF) or atrial flutter (AFL) after cardiac surgery. Methods and Results—This was a prospective, randomized, double-blind, placebo-controlled trial of vernakalant for the conversion of AF or AFL after coronary artery bypass graft, valvular surgery, or both. Patients were randomly assigned 2:1 to receive a 10-minute infusion of 3 mg/kg vernakalant or placebo. If AF or AFL was present after a 15-minute observation period, then a second 10-minute infusion of 2 mg/kg vernakalant or placebo was given. The primary end point was the conversion of postcardiac surgery AF or AFL to sinus rhythm within 90 minutes of dosing. In patients with AF, 47 of 100 (47%) who received vernakalant converted to SR compared with 7 of 50 (14%) patients who received placebo (P<0.001). The median time to conversion was 12 minutes. Vernakalant was not effective in converting postoperative AFL to sinus rhythm. Two serious adverse events occurred within 24 hours of vernakalant administration (hypotension and complete atrioventricular block). There were no cases of torsades de pointes, sustained ventricular tachycardia, or ventricular fibrillation. There were no deaths. Conclusions—Vernakalant was safe and effective in the rapid conversion of AF to sinus rhythm in patients who had AF after cardiac surgery. Clinical Trial Registration—clinicaltrials.gov. Identifier: NCT00125320.

Efficacy and safety of vernakalant in patients with atrial flutter: a randomized, double-blind, placebo-controlled trial

AIMS Vernakalant is a novel, relatively atrial-selective antiarrhythmic agent for conversion of atrial fibrillation (AF) to sinus rhythm. This study examined the safety and efficacy of vernakalant in converting atrial flutter (AFL) to sinus rhythm. METHODS AND RESULTS This was a phase 2/3, randomized, double-blind, placebo-controlled trial. Adults with AFL received either a 10 min infusion of 3.0 mg/kg vernakalant (n = 39) or placebo (n = 15). If AFL or AF persisted at the end of a 15 min observation period, a second 10 min infusion of 2.0 mg/kg vernakalant or placebo was administered. The primary efficacy outcome was the proportion of patients who had treatment-induced conversion of AFL to sinus rhythm for a minimum duration of 1 min within 90 min after the start of the first infusion. No patient in the placebo group met the primary outcome. Only one patient receiving vernakalant (1 of 39, 3%) converted to sinus rhythm. A reduced mean absolute ventricular response rate occurred within 50 min in patients receiving vernakalant (mean change from baseline -8.2 b.p.m.) vs. patients receiving placebo (-0.2 b.p.m.) (P = 0.037). A post-hoc analysis revealed that vernakalant increased AFL cycle length by an average of 55 ms, whereas the AFL cycle length was unchanged in the placebo group (P < 0.001). There was no occurrence of 1 : 1 atrio-ventricular conduction. Dysgeusia and sneezing were the most common treatment-related adverse events, consistent with previous reports. CONCLUSION Vernakalant did not restore sinus rhythm in patients with AFL. Vernakalant modestly slowed AFL and ventricular response rates, and was well tolerated.

Effects of trans- and n-3 unsaturated fatty acids on cardiovascular risk markers in healthy males. An 8 weeks dietary intervention study.

Background: Studies of long-term intake of industrially produced trans fatty acids (TFA) and n-3 polyunsaturated fatty acids (PUFA) suggest opposite effects on cardiovascular disease risk. Common mechanisms of action are probable.Objective: To examine the effects on cardiovascular risk markers of dietary enrichment with TFA or n-3 PUFA.Design: Randomized, double-blind, parallel intervention trial.Setting: Department of Human Nutrition, The Royal Veterinary and Agricultural University.Subjects: In all, 87 healthy males included, 79 completed.Intervention: Subjects were randomly assigned to 8 weeks of a daily intake of 33 g of experimental fats from either partially hydrogenated soy oil containing 20 g of TFA, 12 g of fish oil with approximately 4 g of n-3 PUFA and 21 g of control fat, or 33 g of control fat. The experimental fats were incorporated into bakery products. Plasma lipids, blood pressure, heart rate variability (HRV), arterial dilatory capacity, compliance, and distensibility were recorded before and after intervention and at follow-up 12 weeks after the intervention.Results: High-density lipoprotein cholesterol (HDL-C) decreased in the TFA group and triglycerides and mean arterial blood pressure decreased in the n-3 PUFA group compared to the control group. HRV, arterial dilatory capacity, compliance, and distensibility were unchanged.Conclusion: The results indicate that the association between coronary heart disease risk and intake of TFA and n-3 PUFA relates only modestly to changes in traditional risk markers.Sponsorship: Danish Medical Research Council (Grant no. 22-01-0390), Center of Advanced Food Research (Copenhagen, Denmark) (Grant no. KVL-R-2001-107), the Danish Heart Association (Grant no. 99-2-3-45-22748), Novozymes (Bagsvaerd, Denmark), Aarhus Olie (Aarhus, Denmark), and from private sources. The experimental fats were provided by Pronova Biocare (Aalesund, Norway) and Aarhus Olie (Aarhus, Denmark).

Effect of physical exercise on cytokines and lymphocyte subpopulations in human peripheral blood

To examine the effect of intensive physical exercise on interleukin 2 (IL‐2), tumor necrosis factor alpha (TNFα) and lymphocyte subsets, eleven elite and well‐conditioned runners were tested in relation to a five‐kilometer race. IL‐2 was significantly decreased (p < 0.01) immediately after the exercise and significantly increased after 24 hours (p < 0.05), compared to the pre‐exercise values taken at steady state. TNFα was significantly increased after 2 hours (p < 0.05), and returned to habitual values after 24 hours. In the steady state at rest, elevation of HLA‐DR+ cells was observed in all runners compared with control subjects (p < 0.05), indicating a persistent activation of lymphoid cells. In connection with exercise a significant increase in NK cells (CD 16+) was observed (p < 0.01). The T‐helper/T‐suppressor (CD4+/CD8+) ratio was significantly reduced in connection with physical activity (p < 0.01). In seven runners the ratio was reduced to a value of less than one. This decrease was observed immediately after the exercise, followed by increased ratios 2 hours later (p < 0.01), due to oppositely directed quantitative changes of the CD4+ and CD8+ cell populations. After 24 hours the ratios returned to habitual levels. Furthermore, we confirmed an increase in the total number of granulocytes in connection with exercise (p < 0.01), and observed a decrease in absolute numbers of lymphocytes two hours after exercise (p < 0.01). We emphasize the importance of obtaining information about physical activity within the previous 24 hours before measuring white blood cell parameters.

Passive tension of the ankle before and after stretching

The passive tension resulting from dorsiflexion of the ankle was measured in relation to stretching in six handball players and six soccer players. Corresponding values of ankle angle and passive tension were meas ured by a strain gauge and a potentiometer connected to a pedal system. The passive tension versus ankle angle was meas ured before and 90 minutes after a single contract- relax stretching program of the plantar flexors. Stretch ing lowered the passive tension by up to 18%. Contract- relax stretching performed twice a day for 3 weeks lowered the passive tension in the plantar flexors by up to 36%. Before the last measurements, no stretching was performed for 20 hours or more. Stretching thus had both a short-term effect, matching the length of a training session, and a long-term effect, shown in a reduction of passive tension after 3 weeks. The relative decrease in passive tension after stretching exercises was constant from a neutral position of the ankle to maximal dorsiflexion. There was no correlation between 1) flexibility and the short-term effect of stretching, 2) flexibility and the long-term effect of stretching, or 3) the short-term and long-term effects of stretching. This indicates that pas sive tension was decreased in all subjects irrespective of their flexibility, and that subjects who had short-term effects after stretching did not necessarily demonstrate a long-term effect.