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Notes: Adenosine is an endogenous nucleoside that has potent antiarrhythmic effects on paroxysmal supraventricular tachycardia (PSVT) due to its negative dromotropic effects on the atrioventricular node. In addition to its electrophysiologic effects, adenosine has important effects on vascular smooth muscle cells, inflammatory cells, the central nervous system, and the kidney. Four known adenosine receptor subtypes (A1, A2A, A2B, and A3) mediate the pleiotropic effects of adenosine in humans. These receptors are coupled to a wide range of second messenger cascades. Activation of the A1 adenosine receptor accounts for the negative chronotropic and dromotropic effects of adenosine, whereas A2A, A2B and A3 adenosine receptor activation are responsible for such effects as coronary vasodilation, bronchospasm, inhibition of platelet aggregation, and neuronal stimulation. Elucidation of the specific properties of each of the adenosine receptor subtypes has led to the development of selective ligands as potential therapeutic agents. CVT-510, N-(3(R)-tetrahydrofuranyl)-6-aminopurine riboside, was developed as a selective A1 adenosine receptor agonist that specifically targets the atrioventricular node for termination of PSVT. Preliminary clinical trials have shown that CVT-510 is effective in terminating PSVT and eliminating many of the undesirable adverse effects of adenosine. CVT-510 is also being explored as a potential agent for controlling the ventricular rate of atrial fibrillation and flutter.

Notes: Introduction: We previously have shown that a 3-minute single-stage adenosine tilt test has a diagnostic yield comparable to a two-stage protocol consisting of a 30-minute drug-free tilt followed by a 15-minute isoproterenol tilt. In this study, we sought to further define the clinical utility of adenosine tilt testing in patients with unexplained syncope by prospectively evaluating test specificity and determining predictors of a positive test response. Methods and Results: The specificity of single-stage adenosine tilt testing was determined using 30 control subjects. To determine the diagnostic yield of this protocol, adenosine tilts were performed in 129 patients with unexplained syncope. The adenosine tilt test protocol had high specificity (100%) but a low overall diagnostic yield (18%). However, the yield was affected significantly by age. In patients ≤40 years of age, the tilt test was positive in 15 (41%) of 37 patients, which was significantly greater than the yield in patients between the ages of 41 and 64 years (6/41 patients [15%], P = 0.012) and those ≥65 years of age (2/41 patients [5%], P 〈 0.0001). Conclusion: These data support single-stage adenosine tilt testing in patients ≤40 years of age because the diagnostic yield of the test is maximal in this group and the test can be completed in ≤3 minutes. Conversely, the diagnostic yield of adenosine tilt testing in patients 〉40 years of age is low, suggesting that the clinical utility of this protocol is limited in these patients. (J Cardiovasc Electrophysiol, Vol. 15, pp. 1-4, June 2004)

Notes: Ventricular Tachycardia After Revascularization. Introduction: Two randomized trials (Multicenter Automatic Defibrillator Implantation Trial [MADIT] and Multicenter Unsustained Tachycardia Trial [MUSTT]) suggest that implantable cardioverter defibrillator (ICD) placement is associated with improved survival in patients with coronary artery disease, depressed left ventricular function, and nonsustained ventricular tachycardia (VT) who also have inducible sustained VT. However, neither study directly addresses the management of such patients who develop nonsustained VT early after revascularization. Methods and Results: We evaluated 109 consecutive patients who underwent electrophysiologic testing to evaluate nonsustained VT, which occurred 5 ± 4 days following revascularization. Sustained monomorphic VT was inducible in 46 (42%) patients; these patients received an ICD. The remaining 63 (58%) noninducible patients received neither antiarrhythmic drug therapy nor an ICD. During 27 ± 12 months of follow-up, 15 (33%) of 45 patients with an implanted ICD received at least one appropriate therapy from the device and 26 (24%) of the 109 study patients died. The 1- and 2-year freedom from ventricular tachycardia/fibrillation or sudden death in noninducible patients (97% and 93%) was significantly greater than that of inducible patients (84% and 71%; P = 0.001). However, no difference was observed in total mortality. Conclusion: Patients with nonsustained VT during the early postrevascularization period who have inducible VT have a high incidence of arrhythmic events. Although this study was not designed to assess the impact of ICD placement on the total mortality of inducible patients, the finding that one third of these patients received appropriate ICD therapy suggests that the device may have a protective effect in these patients.

Notes: Catecholamine Facilitated Reentry. 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 μ/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.

Notes: Introduction: Mutations in the PRKAG2 gene that encodes the gamma2 regulatory subunit of AMP-activated protein kinase have been shown to cause autosomal dominant Wolff-Parkinson-White (WPW) syndrome associated with hypertrophic cardiomyopathy. Prior studies focused on familial WPW syndrome associated with other heart disease such as hypertrophic cardiomyopathy. However, such disease accounts for only a small fraction of WPW cases, and the contribution of PRKAG2 mutations to sporadic isolated WPW syndrome is unknown. Methods and Results: Subjects presented for clinical electrophysiologic evaluation of suspected WPW syndrome. WPW syndrome was diagnosed by ECG findings and/or by clinically indicated electrophysiologic study prior to enrollment. Echocardiography excluded hypertrophic cardiomyopathy. Denaturing high-performance liquid chromatography and automated sequencing were used to search for PRKAG2 mutations. Twenty-six patients without a family history of WPW syndrome were studied. No subject had cardiac hypertrophy, and only one patient had associated congenital heart disease. Accessory pathways were detected at diverse locations within the heart. Two polymorphisms in PRKAG2 were detected. [inv6+36insA] occurred in intron 6 in 4 WPW patients and [inv10+10delT] in intron 10 in 1 WPW patient. Both occurred in normal unrelated chromosomes. No PRKAG2 mutations were detected. Conclusion: This study shows that, unlike familial WPW syndrome, constitutional mutation of PRKAG2 is not commonly associated with sporadic WPW syndrome. Although polymorphisms within the PRKAG2 introns were identified, there is no evidence that these polymorphisms predispose to accessory pathway formation because their frequency is similarly high in both WPW patients and normal individuals. Further studies are warranted to identify the molecular basis of common sporadic WPW syndrome. (J Cardiovasc Electrophysiol, Vol. 14, pp. 263-268, March 2003)

Notes: 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 local 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 cither 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.