Epinephrine Challenge: Long-Term Evaluation of Test Performance for the Evaluation of Unexplained Cardiac Arrest and Familial Sudden Death.

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.