Mechanisms of torsades de pointes

TY - CHAP

T1 - Mechanisms of torsades de pointes

AU - Hancox, Jules C.

AU - Curtis, Michael J.

N1 - Publisher Copyright: © 2022 Elsevier Inc. All rights reserved.

PY - 2022/1/1

Y1 - 2022/1/1

N2 - This chapter considers mechanisms of torsades de pointes (TdP) linked to delayed ventricular repolarization. Major ionic conductances contributing to action potential repolarization are summarized. The key role of IKr as an anti-target in drug-induced long QT syndrome (diLQTS) is considered, as is more recent evidence implicating late Na current (INa,L) enhancement as an additional mechanism by which chronic drug exposure can prolong ventricular action potentials. Factors influencing repolarization reserve, heterogeneity (dispersion) of repolarization and formation of early afterdepolarizations (EADs) are described. Evidence for TdP triggers and maintenance mechanisms from models of congenital LQTS variants 1–3 is discussed. Models of and issues pertaining to evaluation of TdP in diLQTS are then considered, including the use of surrogate measures as exemplified by the TRiAD model. Across the different forms of LQTS considered, EADs are strongly implicated as trigger events for TdP, whilst dispersion of repolarization is a likely maintenance substrate.

AB - This chapter considers mechanisms of torsades de pointes (TdP) linked to delayed ventricular repolarization. Major ionic conductances contributing to action potential repolarization are summarized. The key role of IKr as an anti-target in drug-induced long QT syndrome (diLQTS) is considered, as is more recent evidence implicating late Na current (INa,L) enhancement as an additional mechanism by which chronic drug exposure can prolong ventricular action potentials. Factors influencing repolarization reserve, heterogeneity (dispersion) of repolarization and formation of early afterdepolarizations (EADs) are described. Evidence for TdP triggers and maintenance mechanisms from models of congenital LQTS variants 1–3 is discussed. Models of and issues pertaining to evaluation of TdP in diLQTS are then considered, including the use of surrogate measures as exemplified by the TRiAD model. Across the different forms of LQTS considered, EADs are strongly implicated as trigger events for TdP, whilst dispersion of repolarization is a likely maintenance substrate.

KW - Dispersion of repolarization

KW - EAD

KW - Early afterdepolarization

KW - hERG

KW - I

KW - LQTS

KW - QT interval

KW - Reentry

KW - Repolarization reserve

KW - Torsades de pointes

UR - http://www.scopus.com/inward/record.url?scp=85138023979&partnerID=8YFLogxK

U2 - 10.1016/B978-0-12-821446-6.00002-X

DO - 10.1016/B978-0-12-821446-6.00002-X

M3 - Chapter

AN - SCOPUS:85138023979

SN - 9780128214619

SP - 51

EP - 77

BT - Torsades de Pointes

PB - Elsevier

ER -