Recent Advances in Right Ventricular Out_ow Tract Tachycardia Bruce B. Lerman, Kenneth M. Stein, Steven M. Markowitz, Suneet Mittal and David J. Slotwiner Department of Medicine, Division of Cardiology, The New York Hospital–Cornell University Medical Center, New York, NY Since our last review on right ventricular out_ow tract (RVOT) tachycardia appeared in this journal [1], there have been a number of new contributions regarding the pathogenesis, diagnosis, and natural history of this entity. The intent of this brief review will be to high- light these recent advances. Pathogenesis In general, conventional diagnostic studies (e.g., echo- cardiography, coronary arteriography, ventriculogra- phy, and myocardial biopsy) in patients with RVOT tachycardia reveal no evidence of structural heart dis- ease. The cellular mechanism of the tachycardia is thought to be due to cAMP-mediated triggered activ- ity that is dependent on delayed afterdepolarizations (DADs). Clinically, this mechanism is con~rmed by demonstrating sensitivity of the tachycardia to adeno- sine [2–4]. The underlying etiology of this form of ventricular tachycardia (VT) has not been identi~ed. Possibilities include subtle structural abnormalities in the right ventricle (RV) not readily detected on standard stud- ies, abnormalities of myocardial innervation or a defect at the molecular or cellular level of the b-adrenergic signal transduction cascade. Several studies have now shown that magnetic resonance imaging (MRI) detects mild RV structural abnormalities in up to 70% of pa- tients with RVOT tachycardia [5–7]. For example, Markowitz et al. studied 14 patients with adenosine- sensitive idiopathic VT, the majority of whom had RVOT tachycardia [5]. Ten of 14 patients had abnormal scans, which included focal RV wall thinning, fatty in~ltration and wall motion abnormalities of the RV (Figs. 1 and 2). The only abnormality in a control group of 18 patients without VT or clinical heart disease, was RV thinning in one patient. The clinical signi~cance of these ~ndings is uncertain since the anatomic abnor- malities were usually remote from the site of origin of VT and nearly one-third of patients had no identi~able defect. To test the hypothesis that there may be a defect in presynaptic reuptake of norepinephrine, Schafers et al. had patients with RVOT tachycardia undergo positron emission tomography (PET) with the norepinephrine analogue [ 11 C] hydroxyephedrine and the b-adrenergic antagonist [ 11 C] CGP 12177 [8]. This study showed that presynaptic reuptake of norepinephrine and postsy- naptic b-receptor density are reduced in comparison with controls. It was therefore suggested that in- creased norepinephrine concentration in the myocar- dial synaptic cleft is a potential mechanism by which RVOT tachycardia may be initiated. Signi~cant prob- lems with the interpretation of these data include the limited spatial resolution of the RV with PET. As a result, the pre-and postsynaptic ~ndings could only be con~rmed in the left ventricle and the abnormal ~ndings were global rather than focal. The speci~city of these ~ndings is also unknown since reduced uptake of norepinephrine is also found in patients with ar- rhythmogenic right ventricular dysplasia and in those with VT due to coronary artery disease. Recent ~ndings have demonstrated a potential mo- lecular etiology for a variant form of RVOT tachy- cardia (catecholamine-facilitated but adenosine-insen- sitive). A somatic point mutation was identi~ed from the arrhythmogenic myocardial focus in the GTP bind- ing domain of the inhibitory G protein G ai2 [9]. This mutation increased intracellular cAMP concentration and inhibited suppression of cAMP by adenosine. No mutations were identi~ed in G ai2 from myocardial tis- sue samples remote from the arrhythmogenic site or from peripheral lymphocytes. These results demon- strate that a somatic cell mutation in the cAMP-de- pendent signal transduction pathway, occurring during myocardial development, may be the etiology for some forms of RVOT tachycardia. Diagnosis It is important to differentiate RVOT tachycardia from arrhythmogenic right ventricular dysplasia (ARVD) This work was supported in part by the National Institutes of Health (R01 HL56139) and the Michael Wolk Foundation. Address correspondence to: Bruce B. Lerman, M.D., Division of Cardiology, Starr 4, The New York Hospital - Cornell Medical Center, 525 East 68 th Street, New York, NY 10021. E-mail: bler- man@mail.med.cornell.edu 210 Cardiac Electrophysiology Review 1999;3:210–214 © Kluwer Academic Publishers, Boston