Daniel Flammang

Early Increase of von Willebrand Factor Predicts Adverse Outcome in Unstable Coronary Artery Disease Beneficial Effects of Enoxaparin

BACKGROUND The pathogenesis of unstable angina and non-Q-wave myocardial infarction is still poorly understood, and early evaluation of prognosis remains difficult. We therefore studied the predictive value of 5 biological indicators of inflammation, thrombogenesis, vasoconstriction, and myocardial necrosis, and we examined the effects of enoxaparin and unfractionated heparin on these markers after 48 hours of treatment. METHODS AND RESULTS Sixty-eight patients with unstable angina or non-Q-wave myocardial infarction randomized in the international ESSENCE trial participated in this French substudy. C-reactive protein, fibrinogen, von Willebrand factor antigen, endothelin-1 and troponin I were measured on admission and 48 hours later. The composite end point of death, myocardial infarction, recurrent angina, or revascularization was significantly lower at 14 and 30 days of follow-up in patients allocated to enoxaparin compared with unfractionated heparin. All acute-phase reactant proteins were elevated on admission and increased further at 48 hours. Multivariate analysis demonstrated that the rise of von Willebrand factor over 48 hours was a significant and independent predictor of the composite end point at both 14 days and 30 days. Moreover the early increase of von Willebrand factor was more frequent and more severe with unfractionated heparin than with enoxaparin (mean change was +8.7+/-8.8% with enoxaparin versus +93.9+/-11.7% with unfractionated heparin, P<0.0001). The other clinical and biological variables did not predict outcome. CONCLUSIONS In patients with unstable angina or non-Q-wave myocardial infarction, the acute-phase proteins increase over the first 2 days despite medical treatment. The early rise of von Willebrand factor is an independent predictor of adverse clinical outcome at 14 days and at 30 days. Enoxaparin provides protection as evidenced by the reduced release of von Willebrand factor, which represents a favorable prognostic finding.

Can Adenosine 5′-Triphosphate Be Used to Select Treatment in Severe Vasovagal Syndrome?

BACKGROUND Selection of treatment in vasovagal syndrome should be guided by the mechanism of symptoms. This study determined whether a simple drug test may assess one mechanism. METHODS AND RESULTS To identify patients at risk of severe cardioinhibitory response of vagal origin, we infused 20 mg ATP into 316 patients hospitalized for recurrent syncope (n=195) or presyncope (n=121) of unknown origin and into normal subjects (n=51). We then assessed the ECG and clinical responses to the drug, recommended therapy, and followed up the subjects chronically. A cardiac pause > 10 seconds was seen in only 3 normal subjects (6%). Therefore, a pause < or = 10 seconds yielded the approximately 95th percentile of the normal range. ATP provoked a pause > 10 seconds in 130 symptomatic patients (41%) and a pause < or = 10 seconds in 186 symptomatic patients (59%). Thus, symptomatic patients with pauses > 10 seconds were proposed for pacemaker implantation; all other patients and normal subjects were simply monitored. Among long-pause patients with follow-up, the observed recurrence rate for the 104 with pacemakers was one-third that for the 21 who were only monitored (P<.0001). Among followed-up short-pause patients, the rate in the 153 monitored-only patients did not differ from the 20 implanted patients (P=.432). CONCLUSIONS The vagal effect of ATP may identify the subgroup of patients at high risk of severe cardioinhibitory response of vagal origin who likely will benefit from pacemaker therapy. This fast, uncomplicated test should be considered for further use in screening patients with vasovagal syndrome.

Treatment of unexplained syncope: a multicenter, randomized trial of cardiac pacing guided by adenosine 5'-triphosphate testing

Background— The origin of 40% of syncope cases remains unknown even after a complete diagnostic workup. Previous studies have suggested that ATP testing has value in selecting successful therapy. This patient-blinded, multicenter, randomized superiority trial tested whether, in patients with syncope of unknown origin, selecting cardiac pacing in those with a positive ATP test leads to fewer recurrences than those who do not receive pacing. Methods and Results— From 2000 to 2005, 80 consenting patients (mean age, 75.9±7.7 years; 81% women; 56% without diagnosed structural heart disease) with syncope of unknown origin and atrioventricular or sinoatrial block lasting >10 seconds (average, 17.9±6.8 seconds) under ATP administration (20-mg IV bolus) were recruited from 10 hospitals, implanted with programmable pacemakers, and randomized to either active pacing (dual-chamber pacing at 70 bpm) or backup pacing (atrial pacing at 30 bpm). Patients were followed up regularly for up to 5 years for any syncope recurrence, the primary outcome. Mean follow-up was 16 months. Syncope recurred in 8 of 39 patients (21%) randomized to active pacing and in 27 of 41 (66%) randomized to backup pacing (control), yielding a hazard ratio of 0.25 (95% confidence interval, 0.12–0.56). After recurrence, the 27 recurrent control patients were reprogrammed to active pacing, and only 1 reported subsequent syncope. Conclusion— This study suggests that, in elderly patients with syncope of unknown origin and positive ATP tests, active dual-chamber pacing reduces syncope recurrence risk by 75% (95% confidence interval, 44–88). Clinical Trial Registration— URL: http://www.controlled-trials.com/ISRCTN00029383. Unique identifier: ISRCTN00029383.

Treatment of Unexplained Syncope

Background— The origin of 40% of syncope cases remains unknown even after a complete diagnostic workup. Previous studies have suggested that ATP testing has value in selecting successful therapy. This patient-blinded, multicenter, randomized superiority trial tested whether, in patients with syncope of unknown origin, selecting cardiac pacing in those with a positive ATP test leads to fewer recurrences than those who do not receive pacing. Methods and Results— From 2000 to 2005, 80 consenting patients (mean age, 75.9±7.7 years; 81% women; 56% without diagnosed structural heart disease) with syncope of unknown origin and atrioventricular or sinoatrial block lasting >10 seconds (average, 17.9±6.8 seconds) under ATP administration (20-mg IV bolus) were recruited from 10 hospitals, implanted with programmable pacemakers, and randomized to either active pacing (dual-chamber pacing at 70 bpm) or backup pacing (atrial pacing at 30 bpm). Patients were followed up regularly for up to 5 years for any syncope recurrence, the primary outcome. Mean follow-up was 16 months. Syncope recurred in 8 of 39 patients (21%) randomized to active pacing and in 27 of 41 (66%) randomized to backup pacing (control), yielding a hazard ratio of 0.25 (95% confidence interval, 0.12–0.56). After recurrence, the 27 recurrent control patients were reprogrammed to active pacing, and only 1 reported subsequent syncope. Conclusion— This study suggests that, in elderly patients with syncope of unknown origin and positive ATP tests, active dual-chamber pacing reduces syncope recurrence risk by 75% (95% confidence interval, 44–88). Clinical Trial Registration— URL: http://www.controlled-trials.com/ISRCTN00029383. Unique identifier: ISRCTN00029383.

Contribution of Head-Up Tilt Testing and ATP Testing in Assessing the Mechanisms of Vasovagal Syndrome: Preliminary Results and Potential Therapeutic Implications

BACKGROUND In patients with vasovagal syndrome, head-up tilt testing may reproduce symptoms generally associated with vasodepression. Recent research suggests ATP testing identifies patients with abnormal vagal cardiac inhibition. This preliminary study examined the joint contribution of both tests in identifying underlying mechanisms in the general population with vasovagal syndrome. METHODS AND RESULTS Both tests were performed in random order during 1 session and outside of predominant sympathetic periods in 72 patients hospitalized for syncope (n=56) or presyncope (n=16) for whom no cardiac or extracardiac cause was found. For passive and isoproterenol-provocative tilt testing by standard protocol, reproduction of symptoms defined a positive test. The ATP test consisted of injecting ATP 20 mg IV at bedside, continuously monitoring ECG and blood pressure; a vagal cardiac pause >10 seconds defined a positive test. For most patients (64%), >/=1 test was positive. Of the 41 patients (57%) with a positive tilt test (either passive or provoked by isoproterenol), 32% had cardiac disease; none had significant bradycardia (<50 bpm). Of the 8 patients (11%) with a positive ATP test, 62% had cardiac disease; the probability of a positive result increased with age (P=0.015). Both tests were positive in 3 patients and negative in 26 patients; the tilt and ATP test results were uncorrelated (P=0.28). CONCLUSIONS Results suggest tilt and ATP tests individually and jointly determine the mechanism of vasovagal symptoms in most patients and that vagal cardiac inhibition increases with age.

The Role of the Conduction System in Supraventricular Tachycardias

Unequivocal proof of the reciprocating mechanism of ectopic tachycardias is difficult to obtain if the criteria of initiation and termination by appropriate electrical stimulations are not considered as perfectly reliable. Localizing precisely the pathways of conduction which are involved by the re-entrant impulse, or at least the macroscopic size of the reentry circuit is the best way to rule out both automatic focus and micro-re-entry. The methods used are exemplified in ten cases of supraventricular tachycardia. In two cases the circus movement is intra-atrial, and in one of them it is possible to evidence the macroscopic size of a sinus node re-entry circuit. In A-V junctional tachycardias, localizing precisely the lower junction of the circuit shows that strictly intra-nodal longitudinal dissociation is rarer than usually admitted. Either longitudinal dissociation of the His bundle itself, or the presence of latent accessory pathways (James fibers, Kent bundle and Mahaim fibers) might be more frequent than realized. An exceptional case is reported, where the A-V nodal-His axis does not participate in the re-entry circuit, but two Kent bundles exist, one of them being latent.

Long-term efficacy and safety of oral encainide in the treatment of chronic ventricular ectopic activity: relationship to plasma concentrations--a French multicenter trial.

To establish long-term efficacy and safety of encainide, 48 patients with chronic premature ventricular contractions (PVCs) underwent 6 months of therapy with encainide. Twenty-four-hour ambulatory ECGs were obtained at baseline for each daily dosage of 75 mg, 150 mg, and 225 mg of encainide during the in-hospital titration period and at the end of the first and sixth months during the follow-up period. There was a significant reduction in the median hourly total PVC rates from 480.6 at baseline to 2.0 at the end of the titration period with the highest dosage and to 22.1 at the last visit of the chronic dosing period. Nearly total suppression of PVCs was observed in 56% of patients at the end of the titration period and in 30% at the end of the 6-month follow-up period. The most common side effects were vertigo, vision disturbance, and headache. PR, QRS, and QTc intervals showed consistent significant increases from baseline during the various encainide trial periods. Encainide may have worsened ventricular arrhythmia in four patients who received more than 200 mg of encainide daily. Plasma concentrations of encainide and encainide metabolites showed wide interpatient variation, and no relationship was found between antiarrhythmic efficacy and plasma levels of encainide, O-demethyl-encainide, or 3-methoxy-O-demethyl-encainide.

ATPace™: injectable adenosine 5′-triphosphate

ATPace™, a novel injectable formulation of adenosine 5′-triphosphate (ATP), is developed by Cordex Pharma, Inc. (Cordex) as a diagnostic and therapeutic drug for the management of cardiac bradyarrhythmias. Extracellular ATP exerts multiple effects in various cell types by activating cell-surface receptors known as P2 receptors. In the heart, ATP suppresses the automaticity of cardiac pacemakers and atrioventricular (AV) nodal conduction via adenosine, the product of its degradation by ecto-enzymes, as well as by triggering a cardio-cardiac vagal reflex. ATP, given as a rapid intravenous bolus injection, has been used since the late 1940s as a highly effective and safe therapeutic agent for the acute termination of reentrant paroxysmal supraventricular tachycardia (PSVT) involving the AV node. In addition, preliminary studies have shown that ATP can also be used as a diagnostic agent for the identification of several cardiac disorders including sinus node dysfunction (sick sinus syndrome), dual AV nodal pathways, long QT syndrome, and bradycardic syncope. The US Food and Drug Administration has approved Cordex formulation for ATP as an Investigational New Drug and two pathways for its marketing approval; one therapeutic, i.e., acute termination of paroxysmal PSVT, and the other diagnostic, i.e., the identification of patients with bradycardic syncope who can benefit from pacemaker therapy. The scientific rationale for the development of ATPace™ is discussed.

Adenosine 5'-triphosphate Test in the Management of Patients With Syncope.

The response to adenosine 5′-triphosphate (ATP) identifies patients with syncope who might benefit from pacemaker therapy (ATP test). Two measures have been used to determine the outcome of the ATP test, which have lead to contrasting conclusions regarding its utility: (1) the duration of cardiac pause (CP) mainly due to AV block and (2) the longest RR interval (RRmax). We tested the hypothesis that the discrepancy regarding the utility of the ATP test is mainly because of the different way the 2 measures determine the outcome of the test. Post hoc analysis was applied to data obtained from patients with syncope (n = 33) with a positive and negative ATP test based on the CP duration and RRmax, respectively, subjected to pacemaker therapy. In 19 and 14 patients, the pacemaker was programmed to function as AAI pacing at 30 ppm (control) and as DDD pacing at 70 ppm, respectively. During the follow-up period of 17.0 ± 8.6 months, syncope recurred in only 1 of the 14 patients with DDD pacing; in contrast, 10 of 19 patients with AAI30 pacing experienced syncope within the first 5.3 ± 5.2 months of follow-up (P < 0.009; recurrence rate). The ATP test, the outcome of which is determined by the CP measure, is a useful diagnostic test for the identification of patients with bradycardic syncope who may benefit from pacemaker therapy; the identification of such patients would be missed when the RRmax measure is used to determine the outcome of the test. The efficacy of DDD pacing suggests that atrioventricular nodal conduction block is the primary cause of syncope in patients with a positive ATP test based on the CP measure.