Fever Accentuates Transmural Dispersion of Repolarization and Facilitates Development of Early Afterdepolarizations and Torsade de Pointes Under Long-QT Conditions

Abstract

Background-The arrhythmogenic effects of hyperthermia have been highlighted in the Brugada syndrome but remain largely unexplored in other arrhythmic syndromes. The present study examines the effect of hyperthermia on transmural dispersion of action potential duration (TD-APD), early afterdepolarization (EAD) activity, and torsade de pointes (TdP) under long-QT conditions. Methods and Results-Standard and floating glass microelectrodes were used to record action potentials from epicardial, M cell, and endocardial regions of the arterially perfused left ventricle wedge, from tissue slices isolated from these regions, and from isolated Purkinje fibers. A transmural ECG was simultaneously recorded across the wedge. Under baseline conditions and in the presence of I Ks block (chromanol 293B), hyperthermia (39°C to 40°C) abbreviated APD in tissue slices from all 3 regions. In the presence of I Kr block (E-4031), hyperthermia prolonged APD and induced or augmented EADs in M cell and Purkinje preparations at pacing cycle lengths Ն800 ms but abbreviated APD in epicardium and endocardium, resulting in a marked accentuation of TD-APD. Ryanodine prevented the hyperthermiainduced EAD. In perfused wedge preparations, hyperthermia abbreviated APD throughout both in the absence or presence of I Kr or I Ks block and did not induce EADs or TdP. Combined I Kr and I Ks block increased TD-APD and induced EADs (4/12) and spontaneous TdP (3/12) at 36°C to 37°C; hyperthermia (39°C to 40°C) further accentuated TD-APD and facilitated the development of EAD activity (9/12) and TdP (6/12). Conclusions-Our findings suggest that hyperthermia can be associated with an increased arrhythmic risk when the repolarization reserve of the myocardium is compromised.

Inappropriate Pacing Inhibition Triggered by QT Prolongation due to T Wave Oversensing in an ICD Recipient Presenting with Long QT Syndrome

“…However, the fever induced QT interval prolongation has been reported in patients with type 2 but not in patients with type 1 LQTS. Furthermore, an experimental study using a perfusion wedge model of type 1 LQTS showed that hyperthermia abbreviated the action potential duration of the left ventricular myocardium (9). Therefore; other unknown factors might be associated with the further QT interval prolongation in this patient.…”

Impact of dosing regimen of custirsen, an antisense oligonucleotide, on safety, tolerability and cardiac repolarization in healthy subjects

“…ECGs were centrally read by an external laboratory (eResearch Technology, Inc., Philadelphia, PA, USA). Baseline ECG data were collected in triplicate on day 1 at 0 (pre-dose), 2, 4, 6, 8, 12, 16, 20 and 24 h (after placebo infusion) and on day 8 at 0 (predose), 2,4,6,8,12,16,20,24,30,36 and 48 h (after custirsen infusion). Pre-dose ECGs were collected after dexamethasone administration (in the premedication group) and before custirsen or placebo infusion.…”

“…Samples were collected within 15 min prior to the start of custirsen infusion and at 2,4,6,8,12,16,20,24,30,36 and 48 h after the start of infusion to match Holter ECG data collection, and on day 15 follow-up. PK parameters (area under the plasma concentration vs. …”

A hot topic

“…99,104 The link between hyperthermia and arrhythmias is complex, and there is evidence that elevated temperature increases the transmural dispersion gradient of repolarization, precipitating arrhythmias. 100 While there are no specific LQT3 Na V 1.5 mutations identified which display enhanced temperature sensitivities, biophysical analysis close to physiological temperature is recommended for characterization of these mutations in vivo.…”