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.

Relation of age to left ventricular function and systemic hemodynamics in uncomplicated mild hypertension.

Previous studies in normotensive subjects have shown a slight decline in resting left ventricular pump function and midwall contractility with aging. We examined the relations of age to these variables and to peripheral resistance and vascular stiffness in 272 asymptomatic, unmedicated adults (25 to 80 years old) who had uncomplicated essential hypertension. Cardiac and carotid ultrasound and carotid pressure waveforms were obtained to measure left ventricular dimensions, endocardial and midwall left ventricular shortening, stroke index and cardiac index, end-systolic stress, and pulse pressure/stroke index and beta, pressure-dependent and independent measures of vascular stiffness, respectively. Endocardial and midwall stress-corrected left ventricular shortening assessed ventricular performance. Cardiac index and TPRI did not change with age in either gender, with age-related increases in systolic pressure offset by increasingly concentric ventricular geometry in women and enhanced ventricular systolic function in men. In contrast to the lack of age-related change in traditional hemodynamic indexes, pulse pressure/stroke volume and beta strongly increased with age (P<0.001). Thus, in uncomplicated, relatively mild essential hypertension, neither cardiac index nor peripheral resistance is associated with age. This hemodynamic stability is associated with age-related increased concentricity of ventricular geometry in women and increased ventricular performance indexes in hypertensive men. Vascular stiffness progressively increases with age, independent of change in mean pressure or resistance, possibly contributing to increased rates of cardiovascular events in older individuals.

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.

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.

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.

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.

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.

Relation of age to left ventricular function in clinically normal adults.

The extent to which age, independent of cardiovascular diseases, influences left ventricular (LV) function in adults is uncertain. Echocardiograms and simultaneous arterial pressure in 464 clinically normal adults aged 16 to 88 years were used to measure LV dimensions, endocardial and midwall LV fractional shortening, stroke volume, cardiac output, and circumferential end-systolic stress. The ratios of observed endocardial and midwall shortening to values predicted for observed end-systolic stress were used as measures of chamber and myocardial function. LV endocardial shortening increased slightly with age, as did an index of LV chamber performance, the end-systolic stress/volume index ratio (r = 0.11, p = 0.019, and r = 0.20, p <0.001). However, when age-related increases in LV wall thickness and blood pressure were controlled for by examining afterload-corrected endocardial shortening, no age relation was detected. Weak age-related declines were observed in midwall shortening (r = -0.09, p = 0.043) and afterload-corrected midwall shortening (r = -0.12, p <0.01). Cardiac index decreased slightly with advancing age (r = -0.14, mean -6.7 ml/min/m2/ year, p = 0.003). Total peripheral resistance and the pulse pressure/stroke volume ratio, a measure of arterial stiffness, increased more strongly with age (r = 0.27 and 0.38, both p <0.001). Thus, LV pump performance at rest measured by cardiac index is slightly lower in older than in younger clinically normal adults. Endocardial fractional shortening was slightly higher in older subjects, but the physiologically more appropriate midwall measures of myocardial function decreased slightly. The observed change in LV pump performance was related to smaller LV chamber size and higher total peripheral resistance in older subjects.

Response of neurocardiac syncope to beta-blocker therapy: interaction between age and parasympathetic tone.

Beta-blockers are a first line therapy for neurocardiac syncope, but are not always effective. The purpose of this study was to determine whether differential autonomic responses to orthostasis predict the response of patients with neurocardiac syncope to beta-adrenergic blockade. We computed the RMS successive difference of the RR intervals (RMSSD: a measure of cardiac parasympathetic tone) during supine and upright phases of the initial tilt test in 28 patients with syncope and positive tilt tests who were treated with atenolol. Follow-up tilt testing was performed to assess the efficacy of the drug in preventing tilt induced neurocardiac syncope. RMSSD did not differ at baseline (supine) between those who did (n = 20) and did not (n = 8) respond to beta-blockade. However, withdrawal of parasympathetic tone in response to tilt varied inversely with age (r = -0.69; P < 0.01). Reduced age adjusted parasympathetic withdrawal during orthostasis was associated with a 47% versus 8% risk of beta-blockade failure (odds ratio = 11; P = 0.01). Patients with diminished age adjusted parasympathetic withdrawal during orthostatic stress are less likely to respond to beta-blocker therapy of neurocardiac syncope than their counterparts. This may reflect a correspondingly greater sympathetic response to orthostasis in these patients, but the mechanism for this interaction is undetermined.