Efficacy of Flecainide in the Treatment of Catecholaminergic Polymorphic Ventricular Tachycardia: A Randomized Clinical Trial.

Importance: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially lethal genetic arrhythmia syndrome characterized by polymorphic ventricular tachycardia with physical or emotional stress, for which current therapy with ß-blockers is incompletely effective. Flecainide acetate directly suppresses sarcoplasmic reticulum calcium release-the cellular mechanism responsible for triggering ventricular arrhythmias in CPVT-but has never been assessed prospectively. Objective: To determine whether flecainide dosed to therapeutic levels and added to ß-blocker therapy is superior to ß-blocker therapy alone for the prevention of exercise-induced arrhythmias in CPVT. Design, Setting, and Participants: This investigator-initiated, multicenter, single-blind, placebo-controlled crossover clinical trial was conducted from December 19, 2011, through December 29, 2015, with a midtrial protocol change at 10 US sites. Patients with a clinical diagnosis of CPVT and an implantable cardioverter-defibrillator underwent a baseline exercise test while receiving maximally tolerated ß-blocker therapy that was continued throughout the trial. Patients were then randomized to treatment A (flecainide or placebo) for 3 months, followed by exercise testing. After a 1-week washout period, patients crossed over to treatment B (placebo or flecainide) for 3 months, followed by exercise testing. Interventions: Patients received oral flecainide or placebo twice daily, with the dosage guided by trough serum levels. Main Outcomes and Measures: The primary end point of ventricular arrhythmias during exercise was compared between the flecainide and placebo arms. Exercise tests were scored on an ordinal scale of worst ventricular arrhythmia observed (0 indicates no ectopy; 1, isolated premature ventricular beats; 2, bigeminy; 3, couplets; and 4, nonsustained ventricular tachycardia). Results: Of 14 patients (7 males and 7 females; median age, 16 years [interquartile range, 15.0-22.5 years]) randomized, 13 completed the study. The median baseline exercise test score was 3.0 (range, 0-4), with no difference noted between the baseline and placebo (median, 2.5; range, 0-4) exercise scores. The median ventricular arrhythmia score during exercise was significantly reduced by flecainide (0 [range, 0-2] vs 2.5 [range, 0-4] for placebo; P < .01), with complete suppression observed in 11 of 13 patients (85%). Overall and serious adverse events did not differ between the flecainide and placebo arms. Conclusions and Relevance: In this randomized clinical trial of patients with CPVT, flecainide plus ß-blocker significantly reduced ventricular ectopy during exercise compared with placebo plus ß-blocker and ß-blocker alone. Trial Registration: clinicaltrials.gov Identifier: NCT01117454.

Entrainment to distinguish orthodromic reciprocating tachycardia from atrioventricular nodal reentry tachycardia in children.

BACKGROUND: Studies in adults suggest that after entrainment from the right ventricle, a post-pacing interval (PPI) minus tachycardia cycle length (TCL), when corrected for atrioventricular node delay (cPPI-TCL), is useful to distinguish atrioventricular nodal reentry tachycardia (AVNRT) from orthodromic reciprocating tachycardia (ORT), but this has not been evaluated in children. METHODS: In 100 children undergoing catheter ablation, entrainment of ORT or AVNRT was performed from the right ventricular apex. The atrial-His (AH) interval was measured on the return cycle (post-AH) and during tachycardia just prior to pacing (pre-AH). The cPPI-TCL was calculated as (PPI-TCL) - (post-AH - pre-AH). In the first 50 children, the best cutoff was identified and then validated in the next 50 children. RESULTS: In the first 50 children, cPPI-TCL was longer in AVNRT compared with ORT (122 +/- 19 ms vs 63 +/- 23 ms, P < 0.001). Furthermore, cPPI-TCL exceeded 95 ms in all AVNRT patients, but was less than < 95 ms in 28 of 29 ORT patients. In the next 50 children, a cPPI-TCL < 95 ms was 100% specific for ORT; a cPPI-TCL > 95 ms was 95% specific for AVNRT. There was even greater separation of cPPI-TCL values comparing AVNRT with ORT utilizing a septal accessory pathway. CONCLUSIONS: The cPPI-TCL is a useful technique to distinguish AVNRT from ORT in children. Our data suggest that in children a cPPI-TCL < 95 ms excludes AVNRT, while a value > 95 ms is rarely observed in ORT. This technique is particularly useful to distinguish AVNRT from ORT utilizing a septal accessory pathway. (PACE 2010; 469-474).

Endogenous substance P modulates human cardiovascular regulation at rest and during orthostatic load.

Substance P (SP) is a peptide neurotransmitter identified in many central and peripheral neural pathways. Its precise role in human physiology has been difficult to elucidate. We used the selective neurokinin 1 (NK1) antagonist aprepitant as a pharmacological probe to determine the role of endogenous SP in human cardiovascular regulation. We performed a randomized, double-blind, placebo-controlled, crossover trial in healthy subjects. Blockade of endogenous NK1 receptors reduced resting muscle sympathetic activity 38% (P=0.002), reduced systemic vascular resistance by 25% (P=0.021), and increased cardiac index by 47% (P=0.006). This constellation of changes did not, however, alter either blood pressure or heart rate in the supine position. NK1 antagonism also raised orthostatic heart rate change by 38% (P=0.023), although during the incremental postural adjustment on the tilt table neither heart rate nor blood pressure was altered significantly. Despite a mildly attenuated vagal baroreflex with SP blockade, the depressor and pressor responses to nitroprusside and phenylephrine did not differ compared with placebo, suggesting other compensatory mechanisms. NK1 blockade manifests as a decrease in muscle sympathetic nerve activity and systemic vascular resistance. Our study suggests SP exerts a tonic enhancement of sympathetic outflow to some cardiovascular structures via its modulation of the NK1 receptor. Most likely, this ubiquitous neurotransmitter exerts effects at multiple sites that, in the aggregate, are relatively well compensated under many circumstances but may emerge with perturbations. This study is consistent with a role for SP afferents in supporting peripheral vascular resistance.