Neal Lippman

Mechanism of Repetitive Monomorphic Ventricular Tachycardia

BACKGROUND The most common form of idiopathic ventricular tachycardia (VT) is repetitive monomorphic VT (RMVT), which is characterized by frequent ventricular ectopy and salvos of nonsustained VT with intervening sinus rhythm. Unlike most other forms of idiopathic VT, this tachycardia typically occurs at rest and is nonsustained. The mechanism of RMVT is undefined. Because of a common site of origin, the right ventricular outflow tract (RVOT), we hypothesized that RMVT is mechanistically related to paroxysmal sustained, exercise-induced VT, which has been shown to be consistent with cAMP-mediated triggered activity. Therefore, in this study, we sought to identify (1) the mechanism of RMVT at the cellular level by using electropharmacological probes known to activate either stimulatory or inhibitory G proteins and thereby modify intracellular cAMP levels, (2) potential autonomic triggers of RMVT through analysis of heart rate variability, and (3) whether well-characterized somatic activating mutations in the stimulatory G protein, G alpha s, underlie RMVT. METHODS AND RESULTS Twelve patients with RMVT underwent electrophysiological study. Sustained monomorphic VT was reproducibly initiated and terminated with programmed stimulation and/or isoproterenol infusion in 11 of the 12 patients (the other patient had incessant RMVT). Induction of VT demonstrated cycle length dependence and was facilitated by rapid atrial or ventricular pacing. Termination of VT occurred in response to interventions that either lowered stimulated levels of intracellular cAMP (and thus decreased intracellular Ca2+)--ie, adenosine (12 of 12), vagal maneuvers or edrophonium (8 of 9), and beta-blockade (3 of 5)--or directly decreased the slow-inward calcium current--ie, verapamil (10 of 12). Analysis of heart rate variability during 24-hour ambulatory monitoring in 7 patients showed that the sinus heart rate is increased and accelerates before nonsustained VT (P < .05), whereas high-frequency heart rate variability is unchanged. These findings are consistent with transient increases in sympathetic tone preceding nonsustained VT. Finally, myocardial biopsy samples were obtained from the site of origin of the VT (typically the RVOT) and from the right ventricular apex from 9 patients. Genomic DNA was extracted from each biopsy sample, and three exons of G alpha s in which activating mutations have previously been described were amplified by polymerase chain reaction. All sequences from these regions were found to be identical to that of control. CONCLUSIONS Although the arrhythmia occurs at rest, the constellation of findings in idiopathic VT that is characterized by RMVT is consistent with the mechanism of cAMP-mediated triggered activity. Therefore, the spectrum of VT resulting from this mechanism includes not only paroxysmal exercise-induced VT but also RMVT.

Mechanism-specific effects of adenosine on atrial tachycardia.

BACKGROUND Recent reports suggest that adenosine, in addition to terminating supraventricular tachycardia involving the atrioventricular (AV) node, may have antiarrhythmic effects on atrial tachycardia. The electrophysiological effects of adenosine on supraventricular tissue include shortening of action potential duration in atrial myocytes mediated by the potassium current, IKACh,Ado; shortening of action potential duration and hyperpolarization in sinus node cells; and anti-adrenergic electrophysiological effects resulting from inhibition of adenylyl cyclase. We therefore hypothesized that the response of atrial tachycardia to adenosine would be mechanism specific, with termination of atrial tachycardia due to sinus node reentry or cAMP-mediated triggered activity, transient suppression of automatic atrial tachycardia, and an absence of antiarrhythmic effect on tachycardia due to intraatrial reentry. METHODS AND RESULTS Adenosine (mean +/- SD, 143 +/- 54 micrograms/kg IV) was administered to 27 patients (55 +/- 19 years) in atrial tachycardia whose mechanism was confirmed by electrophysiological study. Adenosine terminated sinus node reentrant tachycardia in 6 of 6 patients and terminated atrial tachycardia due to triggered activity in the 1 patient in whom it was identified. Adenosine transiently suppressed automatic atrial tachycardia in 7 of 7 patients and had no effect in 13 patients with intra-atrial reentrant tachycardia, including 8 patients with atrial flutter. CONCLUSIONS These findings demonstrate that adenosines effects on atrial tachycardia are mechanism specific and can be used to differentiate between reentrant tachycardia confined to the region of the sinus node or atria and between nonreentrant atrial tachycardia due to either triggered activity or automaticity.

Failure to decrease parasympathetic tone during upright tilt predicts a positive tilt-table test

The most frequently proposed mechanism for vasodepressor syncope is based on cardiac mechanoreceptor activation by augmented sympathetic tone. Because of the central role of the autonomic nervous system in this response, we hypothesized that the responses of the sympathetic and parasympathetic nervous systems (as assessed by analysis of heart rate variability) to orthostatic stress would differentiate patients with a positive from those with a negative tilt-table response. We therefore evaluated 28 patients undergoing tilt-table testing for presumed vasodepressor syncope. Based on 5-minute electrocardiographic samples obtained during the supine and upright phases (without isoproterenol infusion), we computed the mean RR interval, reflecting integrated cardiac sympathetic and parasympathetic tone, as well as the root-mean-square of successive differences of the RR intervals (RMSSD), a measure of high-frequency heart rate variability that is correlated with parasympathetic tone. Eleven patients had a negative and 17 a positive tilt response. There were no differences between the groups at baseline. In response to upright tilt, the mean RR decreased by a similar magnitude in both groups. In contrast, RMSSD decreased by 36% (p = 0.05) in response to upright tilt in patients with a negative response, but did not change significantly in patients with a positive tilt response. Absence of a decrease in RMSSD in response to orthostatic stress had 100% specificity and 41% sensitivity for predicting a positive test result. Thus, failure of withdrawal of parasympathetic tone (as assessed by RMSSD) during upright tilt predicts a positive tilt response.(ABSTRACT TRUNCATED AT 250 WORDS)

Differential therapeutic responses of patients with isoproterenol-dependent and isoproterenol-independent vasodepressor syncope☆

Orthostatic stress during tilt table testing (TTT) is used to examine patients who may have vasodepressor syncope. This response is thought to be mediated by activation of left ventricular mechanoreceptors. Isoproterenol, by increasing the rate of discharge of these mechanoreceptors, has been proposed to increase the sensitivity of TTT without decreasing its specificity. This mechanism is not, however, totally consistent with recent observations of vasodepressor responses after cardiac transplantation in patients with denervated hearts. These reports and data showing that not all sympathomimetic agents increase the sensitivity of TTT suggest that more than one mechanism may be responsible for a positive TTT result. Therefore we hypothesized that patients with positive TTT results tests not requiring isoproterenol (iso-independent) would have a different clinical and therapeutic response than patients who required isoproterenol (iso-dependent). One hundred sixty-one consecutive patients who underwent TTT for the evaluation of unexplained syncope were included in the study. TTT was performed without and during isoproterenol infusion. A positive TTT result was defined as syncope or presyncope with a sudden decrease in systolic blood pressure and reproduction of the patients clinical symptoms. Patients with a positive TTT result underwent a second test after 1 to 2 weeks of therapy with an oral beta-blocking agent; if the result remained positive, TTT was performed again with other agents until a satisfactory therapeutic response was obtained. Sixty-six (41%) of 161 patients had a positive result; 18 (27%) were iso-independent, and 48 (73%) were iso-dependent. There were no significant differences in age, gender, or presence of underlying heart disease between these two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

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 β‐adrenergic blockade. We computed the RMS successive difference of the BB intervals (BMSSD: 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. BMSSD did not differ at baseline (supine) between those who did (n = 20) and did not (n = 8) respond to β‐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 β‐blockade failure (odds ratio = 11; P = 0.01). Patients with diminished age adjusted parasympathetic withdrawal during orthostatic stress are less likely to respond to β‐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.

Limitations of adenosine in assessing the efficacy of radiofrequency catheter ablation of accessory pathways

Adenosine has been shown to reliably confirm the success of accessory pathway catheter ablation by producing transient atrioventricular (AV) block during atrial and ventricular pacing. This is due to the insensitivity of accessory pathway conduction to adenosine (with the rare exception of accessory pathways with decremental conduction properties). However, 4 of 204 consecutive patients who underwent successful accessory pathway ablation (as shown by adenosine-induced transient AV block) had recurrent AV reciprocating tachycardia involving a second, previously nonmanifest accessory pathway. In each case, the second accessory pathway was localized to a site disparate from the original pathway. No pathway showed decremental anterograde or retrograde conduction properties. In 2 patients, adenosine initially did not show the presence of the second concealed accessory pathway, because the refractory period of the accessory pathway was longer than the pacing cycle length used to assess ventriculoatrial conduction. Only when the refractory period of this second accessory pathway was shortened by infusion of isoproterenol did adenosine reveal the presence of the pathway during follow-up electrophysiologic study. In another patient, a non-decremental accessory pathway was shown to be sensitive to adenosine. In the remaining patient, the second accessory pathway may have been transiently injured during the initial study, thereby simulating adenosine sensitivity.(ABSTRACT TRUNCATED AT 250 WORDS)

Update on the Non-Pharmacological Management of Stroke Prevention in Patients with Atrial Fibrillation

Non-surgical left atrial appendage occlusion has emerged as an alternative to anticoagulant therapy in the management of stroke risk in patients with atrial fibrillation. This review reports on some of the more common devices that are currently being used to manage patients in this challenging group.