Epinephrine Challenge

BACKGROUND: The diagnostic implications of a positive epinephrine challenge for long QT syndrome (LQTS) or catecholaminergic polymorphic ventricular tachycardia (CPVT) are not well understood. Test interpretation is challenging, and false positives may be substantial. OBJECTIVES: This study sought to assess the test performance of epinephrine challenge for the diagnosis of LQTS and CPVT, utilizing long-term follow up. METHODS: The sensitivity, specificity, positive likelihood ratio (LR+), and negative likelihood ratio (LR-) of epinephrine challenge for the diagnosis of LQTS and CPVT were assessed in consecutive patients from the Hearts in Rhythm Organization registry, comparing to final working diagnosis according to guideline-derived diagnostic criteria, incorporating repeat phenotyping, and informed by targeted genetic testing over long-term follow-up. RESULTS: A total of 376 consecutive patients undergoing epinephrine challenge were followed for a mean duration of 8.6 ± 5.3 years (250 patients with unexplained cardiac arrest [UCA] and 176 first-degree relatives). The sensitivity, specificity, LR+, and LR- of epinephrine for the diagnosis of LQTS, compared with final working diagnosis, were 90%, 79%, 4.4 (95% CI: 3.4-5.6), and 0.1 (95% CI: 0.0-0.4), respectively. QT prolongation with epinephrine demonstrated no significant correlation with end-recovery QTc on exercise stress testing. The sensitivity, specificity, LR+, and LR- of epinephrine for the diagnosis of CPVT, compared with final working diagnosis, were 62%, 93%, 8.9 (95% CI: 5.2-16.6), and 0.4 (95% CI: 0.2-0.8), respectively. A pathogenic LQTS variant was identified in only 15% of genotyped patients with a positive epinephrine challenge for LQTS, and a pathogenic CPVT variant in only 13% of patients with a positive epinephrine challenge for CPVT. Most patients with a positive epinephrine challenge for LQTS or CPVT had a "non-LQTS/CPVT" final working diagnosis (either UCA, unaffected, or an alternative Inherited arrhythmia syndrome). CONCLUSIONS: A positive epinephrine challenge demonstrated mild-moderate agreement with a final diagnosis of LQTS and CPVT. Most patients with an initial positive test result had their diagnosis revised to UCA, unaffected, or an alternative diagnosis over long-term follow-up. This study suggests that epinephrine challenge has limited utility as a "rule-in" test but may retain value in its negative predictive value for the UCA population.