Electrophysiologic effects of a novel selective adenosine A1 agonist (CVT-510) on atrioventricular nodal conduction in humans.

BACKGROUND: CVT-510, N-(3(R)-tetrahydrofuranyl)-6-aminopurine riboside, is a selective A(1)-adenosine receptor agonist with potential potent antiarrhythmic effects in tachycardias involving the atrioventricular (AV) node. This study, the first in humans, was designed to determine the effects of CVT-510 on AV nodal conduction and hemodynamics. METHODS AND RESULTS: Patients in sinus rhythm with normal AV nodal function at electrophysiologic study (n = 32) received a single intravenous bolus of CVT-510. AH and HV intervals were measured during sinus rhythm and during atrial pacing at 1, 5, 10, 15, 20, 30, 45, and 60 minutes after the bolus. Increasing doses of CVT-510 (0.3 to 10 microg/kg) caused a dose-dependent increase in the AH interval. At 1 minute, a dose of 10 microg/kg increased the AH interval during sinus rhythm from 93 +/- 23 msec to 114 +/- 37 msec, p = 0.01 and from 114 +/- 31 msec to 146 +/- 44 msec during atrial pacing at 600 msec, p = 0.003). The AH interval returned to baseline by 20 minutes. CVT-510 at doses of 0.3 to 10 microg/kg had no effect on sinus rate, HV interval, or systemic blood pressure, and was not associated with serious adverse effects. At doses of 15 and 30 microg/kg, CVT-510 produced transient second/third degree AV heart block in all four patients treated. One of these patients also had a prolonged sedative effect that was reversed with aminophylline. CONCLUSIONS: CVT-510 promptly prolongs AV nodal conduction and does not affect sinus rate or blood pressure. Selective stimulation of the A(1)-adenosine receptor by CVT-510 may be useful for immediate control of heart rate in atrial fibrillation/flutter and to convert paroxysmal supraventricular tachycardia to sinus rhythm, while avoiding vasodilatation mediated by the A(2)-adenosine receptor, as well as the vasodepressor and negative inotropic effects associated with beta-adrenergic receptor blockade and/or calcium channel blockers.

Significance of inducible ventricular fibrillation in patients with coronary artery disease and unexplained syncope.

OBJECTIVES: This study was designed to determine the incidence and prognostic significance of inducible ventricular fibrillation (VF) in patients with coronary artery disease (CAD) and unexplained syncope. BACKGROUND: Current American College of Cardiology/American Heart Association practice guidelines recommend implantation of internal cardioverter-defibrillators (ICDs) in patients with unexplained syncope in whom either ventricular tachycardia (VT) or VF is inducible during electrophysiologic (EP) testing. Although the prognostic significance of inducible monomorphic VT is known, the significance of inducible VF remains undefined. METHODS: We evaluated 118 consecutive patients with CAD and unexplained syncope who underwent EP testing. Sustained monomorphic VT was inducible in 53 (45%) patients; in 20 (17%) patients, VF was the only inducible arrhythmia; and no sustained ventricular arrhythmia was inducible in the remaining 45 (38%) patients. The latter two groups of 65 (55%) patients make up the study population. RESULTS: There were 16 deaths among the study population during a follow-up period of 25.3 +/- 19.6 months. The overall one- and two-year survival in these patients was 89% and 81%, respectively. No significant difference in survival was observed between patients with and without inducible VF (80% power to detect a fourfold survival difference). CONCLUSIONS: In 17% of patients with CAD and unexplained syncope, VF is the only inducible ventricular arrhythmia. Within the limits of this pilot study, long-term follow-up of patients with and without inducible VF demonstrates no difference in survival between the two groups. Therefore, the practice of ICD implantation in patients with CAD, unexplained syncope and inducible VF, especially with triple ventricular extrastimuli, may merit reconsideration.

Complex AV nodal dynamics during ventricular-triggered atrial pacing in humans.

In vitro experiments have shown that the complexity of atrioventricular nodal (AVN) conduction dynamics increases with heart rate. Although complex AVN dynamics (e.g., alternans) have been observed clinically, human AVN dynamics during rapid pacing have not been systematically investigated. We studied such dynamics during ventricular-triggered atrial pacing in 37 patients with normal AVN function (18 patients with dual AVN pathway physiology and 19 patients without). Alternans, which always resulted from single pathway conduction, occurred in 18 patients. In 16 patients (3 of whom also had alternans), quasisinusoidal AVN conduction oscillations occurred (mean frequency 0.02 Hz); such oscillations have not been previously reported. There were no significant differences in the dynamics for patients with or without dual AVN pathways. To illuminate the governing dynamic mechanism, a second atrial pacing trial was performed on 12 patients after autonomic blockade. Blockade facilitated alternans but inhibited oscillations. This study suggests that rapid AVN excitation in vivo can lead to autonomically mediated AVN conduction oscillations or single pathway alternans that are a function of inherent nonlinear dynamic AVN tissue properties.

Nonlinear-dynamical arrhythmia control in humans.

Nonlinear-dynamical control techniques, also known as chaos control, have been used with great success to control a wide range of physical systems. Such techniques have been used to control the behavior of in vitro excitable biological tissue, suggesting their potential for clinical utility. However, the feasibility of using such techniques to control physiological processes has not been demonstrated in humans. Here we show that nonlinear-dynamical control can modulate human cardiac electrophysiological dynamics by rapidly stabilizing an unstable target rhythm. Specifically, in 52/54 control attempts in five patients, we successfully terminated pacing-induced period-2 atrioventricular-nodal conduction alternans by stabilizing the underlying unstable steady-state conduction. This proof-of-concept demonstration shows that nonlinear-dynamical control techniques are clinically feasible and provides a foundation for developing such techniques for more complex forms of clinical arrhythmia.

Formal analysis of the optimal duration of tilt testing for the diagnosis of neurally mediated syncope.

BACKGROUND: Although tilt testing has emerged as the test of choice for assessing patients with suspected neurally mediated syncope, the optimum duration of tilt testing is poorly defined. This in part relates to the absence of a gold standard to assess test performance. OBJECTIVE: Our purpose was to formally estimate the effects of varying duration of drug-free tilt testing on test performance in diagnosing neurally mediated syncope. DESIGN: If a test's specificity is known, then in the absence of a gold standard an imputed (estimated) sensitivity may be calculated on the basis of the observed diagnostic yield in a given population as a function of assumed population prevalence. We determined the relationship of specificity to drug-free tilt test duration by use of data from 11 previous studies reporting the results of drug-free tilt testing in a total of 435 control subjects (60 to 80 degrees of tilt, footboard support, 15- to 60-minute duration). Data (weighted for study size) were fit to an exponential function relating specificity to tilt duration. Test yield was evaluated as a function of tilt duration in 213 consecutive patients referred to our laboratory for the evaluation of suspected neurally mediated syncope who underwent passive tilt testing for up to 30 to 60 minutes. RESULTS: The estimated specificity of tilt testing was 94% at 30 minutes, 92% at 40 minutes, and 88% after 60 minutes of passive tilt. The cumulative yield of tilt testing was only 17% at 30 minutes, 22% at 40 minutes, and 28% after 60 minutes. On the basis of an estimated population prevalence of 25% to 50% in this referral population, imputed sensitivity is 27% to 48% at 30 minutes, 36% to 64% at 40 minutes, and 43% to 74% after 60 minutes of passive tilt. The overall diagnostic accuracy was not strongly influenced by tilt duration beyond 30 minutes and ranged from 60% to 84%. CONCLUSIONS: Passive tilt testing (ie, tilt testing without pharmacologic provocation) for durations of up to 60 minutes has limited sensitivity for diagnosing neurally mediated syncope. For populations with a pretest likelihood of 25% to 50%, test results are inaccurate in one to two fifths of patients.

Emerging indications for cardiac pacing.

Substantial data have been accumulated and indications have been well delineated for pacemaker implantation in the treatment of sinus node dysfunction and heart block. However, many other indications have been proposed for pacemaker implantation. In this review, the authors examine available data regarding pacemaker implantation for new indications: neurally mediated syncope, hypertrophic obstructive cardiomyopathy, congestive heart failure, prevention of atrial fibrillation, and the relative merits of single-chamber and dual-chamber pacemakers.

Ventricular arrhythmias in normal hearts.

Idiopathic ventricular tachycardia (VT) is characterized by two predominant forms. The most common form originates from the right ventricular outflow tract and presents as repetitive monomorphic VT or exercise-induced VT. The tachycardia is adenosine sensitive and is thought to be because of cAMP-mediated triggered activity. The other major form of idiopathic VT is owing to verapamil-sensitive intrafascicular re-entrant tachycardia, which most often originates in the region of the left posterior fascicle. Both forms of idiopathic VT can be readily treated with radiofrequency catheter ablation.

Postoperative prophylactic administration of beta-adrenergic blockers in patients at risk for myocardial ischemia.

UNLABELLED: Perioperative myocardial ischemia (MI) is associated with postoperative cardiac morbidity. Postoperative sympatholysis may reduce the incidence of MI. This study evaluated such a reduction postoperatively with the administration of prophylactic beta-blockers in patients undergoing elective total knee arthroplasty with epidural anesthesia and postoperative epidural analgesia. One hundred seven patients were preoperatively randomized into two groups, control and beta-blockers, who received postoperative esmolol infusions on the day of surgery and metoprolol for the next 48 h to maintain a heart rate less than 80 bpm. Patients were followed for ST segment depression by using a Holter monitor and adverse cardiac outcomes. Postoperative electrocardiographic ischemia was significantly more prevalent in the control group compared with the beta-blocker group during esmolol blockade (0 of 52 vs 4 of 55; P = 0.04) and tended to be more common in the control group the next two days (8 of 55 vs 3 of 52; P = 0.135). In addition, the number of ischemic events (control, 50; beta-blockers, 16) and total ischemic time (control, 709 min; beta-blocker, 236 min) were also significantly different from the control group. Myocardial infarctions and cardiac events were more common in the control group, but these differences were not significant. Our results suggest that the use of prophylactic beta-blocker therapy may reduce the incidence of postoperative MI. IMPLICATIONS: Prophylactic beta adrenergic blockade administered after elective total knee arthroplasty was associated with a reduced prevalence and duration of postoperative myocardial ischemia detected with Holter monitoring.

Transthoracic cardioversion of atrial fibrillation: comparison of rectilinear biphasic versus damped sine wave monophasic shocks.

BACKGROUND: Clinical studies have shown that biphasic shocks are more effective than monophasic shocks for ventricular defibrillation. The purpose of this study was to compare the efficacy of a rectilinear biphasic waveform with a standard damped sine wave monophasic waveform for the transthoracic cardioversion of atrial fibrillation. METHODS AND RESULTS: In this prospective, randomized, multicenter trial, patients undergoing transthoracic cardioversion of atrial fibrillation were randomized to receive either damped sine wave monophasic or rectilinear biphasic shocks. Patients randomized to the monophasic protocol (n=77) received sequential shocks of 100, 200, 300, and 360 J. Patients randomized to the biphasic protocol (n=88) received sequential shocks of 70, 120, 150, and 170 J. First-shock efficacy with the 70-J biphasic waveform (60 of 88 patients, 68%) was significantly greater than that with the 100-J monophasic waveform (16 of 77 patients, 21%, P<0.0001), and it was achieved with 50% less delivered current (11+/-1 versus 22+/-4 A, P<0.0001). Similarly, the cumulative efficacy with the biphasic waveform (83 of 88 patients, 94%) was significantly greater than that with the monophasic waveform (61 of 77 patients, 79%; P=0.005). The following 3 variables were independently associated with successful cardioversion: use of a biphasic waveform (relative risk, 4.2; 95% confidence intervals, 1.3 to 13.9; P=0.02), transthoracic impedance (relative risk, 0.64 per 10-Omega increase in impedance; 95% confidence intervals, 0.46 to 0.90; P=0.005), and duration of atrial fibrillation (relative risk, 0.97 per 30 days of atrial fibrillation; 95% confidence intervals, 0.96 to 0.99; P=0.02). CONCLUSIONS: For transthoracic cardioversion of atrial fibrillation, rectilinear biphasic shocks have greater efficacy (and require less energy) than damped sine wave monophasic shocks.

Left ventricular geometry and function preceding neurally mediated syncope.

BACKGROUND: Neurally mediated syncope has been associated with increased left ventricular (LV) fractional shortening (FS) during tilt testing, which is consistent with the hypothesis that the stimulation of LV mechanoreceptors leads to reflex hypotension and/or bradycardia. However, FS does not represent true LV contractility because of its dependence on afterload and preload. METHODS AND RESULTS: To elucidate the role of increased contractility in the mediation of neurally mediated syncope, we compared echocardiographic measures of LV performance corrected for end-systolic stress (ESS) in 21 patients (13 women and 8 men) with unexplained syncope who had either positive (n=10) or negative (n=11) responses to a tilt-table test. Two-dimensional echocardiographic LV imaging was performed at baseline and during the initial 5 minutes of upright tilt. In the supine position, both groups had similar LV end-diastolic volume indexes, stroke volumes, FS, circumferential ESS, and afterload-independent measures of LV performance (stress-corrected midwall and FS). However, after 5 minutes of upright tilt, patients who subsequently had a positive test had a lower stroke volume, lower stress-corrected midwall shortening, and endocardial FS. The tilt-positive group also had a greater fall in ESS and FS early during upright tilt. CONCLUSIONS: Reduced ESS, LV volume, and chamber function during initial upright tilt are associated with a subsequent positive tilt response in patients with unexplained syncope. These data suggest that if paradoxic activation of LV mechanoreceptors has a role in mediating neurally mediated syncope, it is not triggered by LV hypercontractility or increased systolic wall stress during the initial period of upright tilt.

Comparison of a novel rectilinear biphasic waveform with a damped sine wave monophasic waveform for transthoracic ventricular defibrillation. ZOLL Investigators.

OBJECTIVES: We compared the efficacy of a novel rectilinear biphasic waveform, consisting of a constant current first phase, with a damped sine wave monophasic waveform during transthoracic defibrillation. BACKGROUND: Multiple studies have shown that for endocardial defibrillation, biphasic waveforms have a greater efficacy than monophasic waveforms. More recently, a 130-J truncated exponential biphasic waveform was shown to have equivalent efficacy to a 200-J damped sine wave monophasic waveform for transthoracic ventricular defibrillation. However, the optimal type of biphasic waveform is unknown. METHODS: In this prospective, randomized, multicenter trial, 184 patients who underwent ventricular defibrillation were randomized to receive a 200-J damped sine wave monophasic or 120-J rectilinear biphasic shock. RESULTS: First-shock efficacy of the biphasic waveform was significantly greater than that of the monophasic waveform (99% vs. 93%, p = 0.05) and was achieved with nearly 60% less delivered current (14 +/- 1 vs. 33 +/- 7 A, p < 0.0001). Although the efficacy of the biphasic and monophasic waveforms was comparable in patients with an impedance < 70 ohms (100% [biphasic] vs. 95% [monophasic], p = NS), the biphasic waveform was significantly more effective in patients with an impedance > or = 70 ohms (99% [biphasic] vs. 86% [monophasic], p = 0.02). CONCLUSIONS: This study demonstrates a superior efficacy of rectilinear biphasic shocks as compared with monophasic shocks for transthoracic ventricular defibrillation, particularly in patients with a high transthoracic impedance. More important, biphasic shocks defibrillated with nearly 60% less current. The combination of increased efficacy and decreased current requirements suggests that biphasic shocks as compared with monophasic shocks are advantageous for transthoracic ventricular defibrillation.

Long-term outcome of patients with unexplained syncope treated with an electrophysiologic-guided approach in the implantable cardioverter-defibrillator era.

OBJECTIVES: We evaluated the long-term outcome of patients with coronary artery disease and unexplained syncope who were treated with an electrophysiologic (EP)-guided approach. BACKGROUND: Electrophysiologic studies are frequently performed to evaluate unexplained syncope in patients with coronary artery disease. Patients with this profile who have inducible ventricular tachycardia are considered at high risk for sudden death and increased overall mortality, and therefore are often treated with an implantable cardioverter-defibrillator (ICD). The impact of this EP-guided strategy is unknown because there are no data comparing the long-term outcome of ICD recipients with that of noninducible patients. METHODS: We evaluated 67 consecutive patients with coronary artery disease and unexplained syncope. All patients were treated with an EP-guided approach that included ICD implantation in patients with inducible ventricular tachycardia. RESULTS: Electrophysiologic testing suggested a plausible diagnosis in 32 (48%) of these patients. Inducible monomorphic ventricular tachycardia was the most common abnormality. Despite frequent appropriate therapy with ICDs, the total mortality for patients with inducible monomorphic ventricular tachycardia was significantly higher than for noninducible patients. The respective one- and two-year survival rates were 94% and 84% in noninducible patients and 77% and 45% in inducible patients (p = 0.02). CONCLUSIONS: Electrophysiologic testing suggests an etiology for unexplained syncope in approximately 50% of patients and risk stratifies these patients with regard to long-term outcome. Patients who receive an ICD for the management of inducible ventricular tachycardia have a high incidence of spontaneous ventricular arrhythmias requiring ICD therapy. However, despite ICD implantation and frequent appropriate delivery of ICD therapies, patients with inducible ventricular tachycardia have a significantly worse prognosis than do those who are noninducible.

Differential effects of adenosine on focal and macroreentrant atrial tachycardia.

INTRODUCTION: The effects of adenosine on atrial tachycardia (AT) remain controversial, and the mechanistic implications of adenosine termination have not been fully established. The purpose of this study was to elucidate the differential effects of adenosine on focal and macroreentrant AT and describe the characteristics of adenosine-sensitive AT. METHODS AND RESULTS: Thirty patients received adenosine during AT. Tachycardia origins were identified as focal or macroreentrant during invasive electrophysiologic studies. Responses to adenosine were analyzed and characterized as tachycardia termination, transient suppression, or no effect. Electrophysiologic studies demonstrated a focal origin of tachycardia in 17 patients. Adenosine terminated focal tachycardias in 14 patients (dose 7.3 +/- 4.0 mg) and transiently suppressed the arrhythmias in three others (dose 10.0 +/- 6.9 mg). A macroreentrant mechanism was demonstrated in 13 patients; adenosine terminated only one of these tachycardias and had no effect on the remaining 12 patients (dose 10.2 +/- 2.9 mg). Four classes of adenosine-sensitive AT were identified. Class I consisted of nine patients with tachycardia arising from the crista terminalis; these tachycardias also terminated with verapamil (4/4). Class II consisted of four patients with repetitive monomorphic AT arising from diverse sites in the right atrium; these either slowed or terminated in response to verapamil (2/2). Class III consisted of the three patients with transient suppression and demonstrated electropharmacologic characteristics consistent with an automatic mechanism, including insensitivity to verapamil (2/2). In the one patient with macroreentrant AT that was comprised of decremental atrial tissue, adenosine terminated tachycardia in a zone of decremental slow conduction (Class IV); this tachycardia slowed with verapamil. CONCLUSIONS: Adenosine-sensitive AT is usually focal in origin and arises either from the region of the crista terminalis (inclusive of the sinus node) or from diverse atrial sites with an incessant nonsustained repetitive pattern. Although most forms of macroreentrant AT are insensitive to adenosine, rarely macroreentrant AT with zones of decremental slow conduction can demonstrate adenosine sensitivity.

Practical real-time computing system for biomedical experiment interface.

Many biomedical experiments require a precisely timed real-time (RT) computer interface. Because commonly used desktop operating systems are inherently non-real-time, real-time laboratory computer systems are often based on outdated DOS software or expensive proprietary real-time operating systems. Here we discuss a real-time computing system, based on the free RT-LINUX operating system, which we have developed for adaptive pacing control in a clinical cardiac electrophysiology laboratory. This powerful, flexible, and inexpensive system demonstrates that RT-LINUX is well suited for real-time biomedical experiment interface.

Induction of neurally mediated syncope with adenosine.

BACKGROUND: Tilt testing is used to establish the diagnosis of neurally mediated syncope. However, applicability of the tilt test is limited by test sensitivity and length of time required to perform the test. We hypothesized that adenosine could facilitate the induction of neurally mediated syncope through its sympathomimetic effects and therefore could be used as an alternative to routine tilt testing. METHODS AND RESULTS: In protocol 1, the yield of adenosine tilt testing (12 mg while upright, followed by 60 degrees tilt for 5 minutes) and a 15-minute isoproterenol tilt test were compared in 84 patients with a negative 30-minute drug-free tilt test. In protocol 2, 100 patients underwent an initial adenosine tilt test followed by our routine tilt test (30-minute drug-free tilt followed by a 15-minute isoproterenol tilt). Six additional control patients underwent microneurography of the peroneal nerve to compare the sympathomimetic effects during bolus administration of adenosine and continuous infusion of isoproterenol. In protocol 1, the yields of adenosine (8 of 84, 10%) and isoproterenol (7 of 84, 8%) tilt testing were comparable (P=NS). In protocol 2, the yields of adenosine (19 of 100, 19%) and routine (22 of 100, 22%) tilt testing were also comparable (P=NS). Although the yield of adenosine tilt testing was comparable in both protocols, patients with a negative adenosine tilt test but a positive routine tilt test usually required isoproterenol to elicit the positive response. Microneurography confirmed discordant sympathetic activation after adenosine and isoproterenol administration. CONCLUSIONS: Adenosine is effective for the induction of neurally mediated syncope, with a diagnostic yield comparable to routine tilt testing. However, the discordant results obtained with adenosine and the isoproterenol phase of routine tilt testing suggest that adenosine and isoproterenol tilt testing may have complementary roles in eliciting a positive response. Therefore, a tilt protocol that uses an initial adenosine tilt followed, if necessary, by an isoproterenol tilt would be expected to increase the overall yield and reduce the duration of tilt testing.

Catecholamine facilitated reentrant ventricular tachycardia: uncoupling of adenosine's antiadrenergic effects.

INTRODUCTION: Adenosine has no direct electrophysiologic function in ventricular tissue, but in the presence of cyclic adenosine monophosphate (cAMP), stimulation exerts a potent antiadrenergic effect. This effect has been exploited in the recognition and treatment of ventricular tachycardia (VT) due to cAMP-mediated triggered activity and automaticity, which are respectively terminated and suppressed by adenosine. However, the effects of adenosine on catecholamine-facilitated reentrant VT are unknown. A pivotal issue is whether termination of VT with adenosine is mechanism specific, or whether it represents a nonspecific antiadrenergic effect. The purpose of this study, therefore, was to define the effects of adenosine in a well-characterized group of patients with catecholamine-facilitated reentrant VT. METHODS AND RESULTS: Fourteen patients with catecholamine-facilitated reentry were studied. In the 12 patients with structural heart disease (including two with arrhythmogenic right ventricular dysplasia), adenosine (260 to 550 microg/kg) failed to slow or terminate VT. Two patients without structural heart disease had intrafascicular tachycardia confined to the left posterior fascicle, a calcium-dependent, verapamil-sensitive arrhythmia. In the absence of isoproterenol, verapamil terminated VT but adenosine did not. However, when isoproterenol was subsequently required for facilitation of tachycardia, adenosine terminated VT in both patients. CONCLUSION: Adenosine has no antiadrenergic (antiarrhythmic) effect in patients with catecholamine-facilitated VT due to structural heart disease. Patients with verapamil-sensitive, left posterior intrafascicular reentry have an unusual dual response to adenosine. In the unstimulated state, adenosine has no effect on basal inward calcium current and, therefore, no effect on VT. However, when induction of VT requires amplification of the inward calcium current through stimulation of cAMP, adenosine sensitivity of VT becomes manifest. These results indicate that with few exceptions, termination of VT with adenosine is strongly suggestive of a cAMP-mediated triggered mechanism rather than reentry.

The role of nonlinear dynamics in cardiac arrhythmia control.

The field of nonlinear dynamics has made important contributions toward a mechanistic understanding of cardiac arrhythmias. In recent years, many of these advancements have been in the area of arrhythmia control. This paper reviews the literature on analytical, modeling, and experimental nonlinear dynamical arrhythmia control with a focus on stimulation and pharmacologic techniques that have been developed, and in some cases used in experiments, to control reentrant rhythms (including spiral and scroll waves) and fibrillation. Although such approaches currently have practical limitations, they offer hope that nonlinear dynamical control techniques will be clinically useful in the coming years.

Heart rate changes preceding ventricular ectopy in patients with ventricular tachycardia caused by reentry, triggered activity, and automaticity.

OBJECTIVES: Although enhanced sympathetic tone is thought to be proarrhythmic and beta-blockade reduces the risk of sudden cardiac death in survivors of myocardial infarction, the role of the autonomic nervous system in triggering spontaneous ventricular ectopy and ventricular tachycardia (VT) has not been fully elucidated. The purpose of this study was to compare and contrast autonomic tone preceding spontaneous ventricular arrhythmias in patients with reentrant, triggered, and automatic forms of VT. BACKGROUND: The prevailing model of reentrant VT is based on a triggering beat interacting with a fixed substrate. Within this model, cyclic fluctuations in autonomic tone comprise a "third factor" that may initiate the triggering extrasystoles as well as alter the substrate, facilitating perpetuation of tachycardia. Consistent with this model, adrenergic stimulation can facilitate the induction of reentrant arrhythmias as well as arrhythmias resulting from enhanced automaticity and those caused by triggered activity resulting from cyclic adenosine monophosphate-dependent delayed afterdepolarizations. METHODS AND RESULTS: On the basis of the results at electrophysiologic study, 26 patients with coronary artery disease were identified as having reentrant VT, 11 were identified as having idiopathic VT caused by triggered activity, and 4 were identified as having idiopathic VT caused by enhanced automaticity. Each patient underwent 24-hour electrocardiographic monitoring, and the mean sinus R-R intervals immediately preceding each sinus beat as well as the 15 beats preceding sinus beats, premature ventricular contractions (VPCs), and complex ventricular ectopy (couplet/non-sustained VT) were computed. In addition, high-frequency heart rate variability was determined. Heart rate accelerated before spontaneous ventricular ectopy for all three arrhythmia mechanisms. R-R intervals preceding episodes of complex ventricular ectopy were significantly shorter than the corresponding intervals preceding single VPCs in patients with 'riggered VT [p=0.006 and 0.01, R-R(-1) and R-R(-15), respectively] and in those with reentrant VT (p=0.007 and p=0.05). There were no corresponding differences in high-frequency heart rate variability. R-R intervals preceding single VPCs were significantly shorter than the corresponding intervals preceding sinus beats in patients with automatic VT (p=0.0004 and 0.0001, respectively), which was accompanied by a small reduction in high-frequency heart rate variability (p=0.04). CONCLUSIONS: Heart rate accelerates before spontaneous ventricular ectopy in patients with VT. The acceleration is disproportionate to parasympathetic withdrawal, implicating increased endogenous sympathetic tone in the genesis of spontaneous ventricular arrhythmias caused by all three electrophysiologic mechanisms: reentry, triggered activity, and automaticity.

Hospital-wide restriction of clindamycin: effect on the incidence of Clostridium difficile-associated diarrhea and cost.

BACKGROUND: Widespread antibiotic use has been associated with increases in both bacterial resistance and nosocomial infection. OBJECTIVE: To characterize the impact of hospital-wide clindamycin restriction on the incidence of Clostridium difficile-associated diarrhea and on antimicrobial prescribing practices. DESIGN: Prospective, observational cohort study. SETTING: University-affiliated Veterans Affairs Medical Center. PATIENTS: Hospitalized patients with symptomatic diarrhea. MEASUREMENTS: Clinical data on individual patients and data on antibiotic use were obtained from hospital pharmacy records. Hospital-wide use of antimicrobial agents was monitored. Isolates of C. difficile underwent antimicrobial susceptibility testing and molecular typing. RESULTS: An outbreak of C. difficile-associated diarrhea was caused by a clonal isolate of clindamycin-resistant C. difficile and was associated with increased use of clindamycin. Hospital-wide requirement of approval by an infectious disease consultant of clindamycin use led to an overall reduction in clindamycin use, a sustained reduction in the mean number of cases of C. difficile-associated diarrhea (11.5 cases/month compared with 3.33 cases/month; P < 0.001), and an increase in clindamycin susceptibility among C. difficile isolates (9% compared with 61%; P < 0.001). A parallel increase was noted in the use of and costs associated with other antibiotics with antianaerobic activity, including cefotetan, ticarcillin-clavulanate, and imipenem-cilastin. The hospital realized overall cost savings as a result of the decreased incidence of C. difficile-associated diarrhea. CONCLUSIONS: Hospital formulary restriction of clindamycin is an effective way to decrease the number of infections due to C. difficile. It can also lead to a return in clindamycin susceptibility among isolates and can effect cost savings to the hospital.