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 fr equent ventricular ectopy and salves of nonsustained VT with interveni ng sinus rhythm. Unlike most other forms of idiopathic VT, this tachyc ardia typically occurs at rest and is nonsustained. The mechanism of R MVT is undefined. Because of a common site of origin, the right ventri cular outflow tract (RVOT), we hypothesized that RMVT is mechanistical ly related to paroxysmal sustained, exercise-induced VT, which has bee n shown to be consistent with cAMP-mediated triggered activity. Theref ore, in this study, we sought to identify (1) the mechanism of RMVT at the cellular level by using electropharmacological probes known to ac tivate either stimulatory or inhibitory G proteins and thereby modify intracellular cAMP levels, (2) potential autonomic triggers of RMVT th rough analysis of heart rate variability, and (3) whether well-charact erized somatic activating mutations in the stimulatory G protein, 2G a lpha(s), underlie RMVT. Methods and Results Twelve patients with RMVT underwent electrophysiological study. Sustained monomorphic VT was rep roducibly 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. Terminatio n of VT occurred in response to interventions that either lowered stim ulated 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 ca lcium current-ie, verapamil (10 of 12). Analysis of heart rate variabi lity during 24-hour ambulatory monitoring in 7 patients showed that th e 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 wer e obtained from the site of origin of the VT (typically the RVOT) and from the right ventricular apex from 9 patients. Genomic DNA was extra cted from each biopsy sample, and three exons of G alpha(s) in which a ctivating mutations have previously been described were amplified by p olymerase chain reaction. All sequences from these regions were found to be identical to that of control. Conclusions Although the arrhythmi a occurs at rest, the constellation of findings in idiopathic VT that is characterized by RMVT is consistent with the mechanism of cAMP-medi ated triggered activity. Therefore, the spectrum of VT resulting from this mechanism includes not only paroxysmal exercise-induced VT but al so RMVT.