Diagnostic value of epinephrine test for genotyping LQT1, LQT2, and LQT3 forms of congenital long QT syndrome

Update of Diagnosis and Management of Inherited Cardiac Arrhythmias

“…9 Shimizu et al also reported that the sensitivity (penetrance) by ECG diagnostic criteria was lower in LQT1 (68%) than in either LQT2 (83%) or LQT3 (83%). 10 Therefore, novel tools to unveil latent mutation carriers of LQTS, especially those with LQT1, has long been expected, because identification of patients with latent LQTS may afford the opportunity to initiate potentially life-saving pharmacotherapy and health style modifications. Exercise or catecholamine infusion, such as epinephrine, an α+β adrenergic ago- …”

Clinical Impact of Genetic Studies in Lethal Inherited Cardiac Arrhythmias

“…14 However, the ECG diagnosis at rest has long been reported to miss some patients affected by congenital LQTS, as evidenced by syncopal events occurring among family members with a "normal" QT interval; 15 therefore, provocative testing using catecholamine infusion or exercise was developed to unmask concealed forms of congenital LQTS, before genetic screening became available. [16][17][18][19][20] Genotype in Congenital LQTS Because familial forms of congenital LQTS have long been recognized, a genetic background (inheritance) has long been expected. Since the first 2 genes responsible for LQTS were identified in 1995, 21,22 molecular genetic studies have revealed 12 forms of Romano-Ward-type congenital LQTS caused by mutations in the genes of the potassium, sodium and calcium channels or the membrane adapter located on chromosomes 3, 4, 7, 11, 12, 17, 20 and 21 (Table2).…”

“…54 The differential sensitivity in cardiac events to sympathetic ( -adrenergic) stimulation has been suggested to be caused by the differential response of ventricular repolarization to sympathetic stimulation in both experimental studies employing arterially perfused wedge preparations 45,46 and in clinical studies using catecholamine provocative testing or exercise testing. [16][17][18][19][20] …”

“…The 2 major protocols developed for epinephrine provocative testing include the escalating-dose protocol by Ackerman's group (Mayo protocol), 18,19 and bolus injection followed by brief continuous infusion by my group (Shimizu protocol). 16,17,19 The bolus (Shimizu) protocol was developed on the basis of a differential response of the APD and QT interval to sympathetic stimulation with isoproterenol between experimental models of LQT1, LQT2 and LQT3 using arterially-perfused canine left ventricular wedge preparations. 46 Clinical data from the use of the bolus protocol suggested that sympathetic stimulation produces genotype-specific Genotype-specific responses of the corrected QT (QTc) interval to epinephrine provocative testing in patients with LQT1, LQT2 and LQT3 syndromes.…”

“…16,17,19 Epinephrine remarkably prolongs the QTc interval at peak effect when the heart rate is maximally increased (1-2 min after the bolus injection), and the QTc remains prolonged during the steady-state epinephrine effect (3-5 min) in patients with LQT1. 16,17,19 In LQT1 patients, a paradoxical QT prolongation, defined as an absolute increase in the QT (not QTc) interval, despite a shortening of the RR interval, is often observed during epinephrine infusion. Ackerman et al reported that the paradoxical QT prolongation had a sensitivity of 92.5%, specificity of 86%, positive predictive value of 76%, and negative predictive value of 96% for LQT1 patients vs non-LQT1 patients.…”