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Biomedical subjects

Edward Carmeliet

Publications and source records attributed to Edward Carmeliet.

6 recordsLinked to original sources
PubMed2006

Action potential duration, rate of stimulation, and intracellular sodium.

In the first section of this short review the change of the cardiac action potential (APD) with the rate of stimulation under physiological conditions is described and mechanistically analyzed. A fast phase of adaptation is mainly caused by changes in gating characteristics of ionic currents, and rapid modulation of the Na(+)/Ca(2+) exchanger. The slower phase is largely conditioned by incomplete recovery from inactivation of the late Na(+) current (late I(Na)) and changes in ion concentrations of [K(+)](e), [Na(+)](i), and [Ca(2+)](i), which cause secondary changes in the permeation and the gating of ion channels and flux through transporters. In a second section, an analysis is presented of the rate dependence of APD in pathological conditions and its importance in the genesis of arrhythmias in hypertrophy, heart failure, congenital, and acquired LQT syndromes is summarized. The role of the late I(Na), Na(+), and Ca(2+) overload is emphasized. Special attention is given to the paradoxical transient lengthening of APD in LQT3 syndrome for the sudden increase in rate in this setting. The third section consists of a short commentary on Na(+) and Ca(2+) overload and drugs which block the late I(Na).

Action Potentials↗
PubMed2005

Novel mutation in the Per-Arnt-Sim domain of KCNH2 causes a malignant form of long-QT syndrome.

BACKGROUND: It has been proposed that the highest risk for cardiac events in patients with long-QT syndrome subtype 2 (LQT2) is related to mutations in the pore region of the KCNH2 channel. It has also been suggested that a subpopulation of LQT2 patients may benefit from pharmacological therapy with modified KCNH2 channel-blocking drugs. METHODS AND RESULTS: In a large LQT2 family (n=33), we have identified a novel nonpore missense mutation (K28E) in the Per-Arnt-Sim (PAS) domain of the KCNH2 channel associated with a malignant phenotype: One third of the suspected gene carriers experienced a major cardiac event. Wild-type and K28E-KCNH2 channels were transiently transfected in HEK293 cells. For the mutant channel, whole-cell patch-clamp analysis showed a reduced current density, a negative shift of voltage-dependent channel availability, and an increased rate of deactivation. Western blot analysis and confocal imaging revealed a trafficking deficiency for the mutant channel that could be rescued by the K+ channel blocker E-4031. In cells containing both wild-type and mutant channels, deactivation kinetics were normal. In these cells, reduced current density was restored with E-4031. CONCLUSIONS: Our data suggest that besides pore mutations, mutations in the PAS domain may also exhibit a malignant outcome. Pharmacological restoration of current density is promising as a mutation-specific therapy for patients carrying this trafficking-defective mutant.

Adult↗
PubMed2004

Intracellular Ca(2+) concentration and rate adaptation of the cardiac action potential.

Influx of Ca(2+) ions through the cardiac plasma membrane contributes to the shaping of the action potential plateau and acts as trigger for the release of Ca(2+) ions from the sarcoplasmic reticulum and the initiation of the contractile process. The increased intracellular Ca(2+) concentration feeds back on the channels and transporters in the plasma membrane and modulates the electrical activity. This interaction and its change with rate of pacing is the topic of this review, which is subdivided in three parts. In part I a description is given of different channels and transporters that carry Ca(2+) ions, or are activated-modulated by intracellular Ca(2+) ions. In part II an analysis is given of the changes in action potential duration and shape when stimuli are applied in the relative refractory period (electrical restitution) and when rate is suddenly increased and kept at the higher level until steady-state is obtained. A description of experimental findings in each case is followed by a discussion of possible mechanisms. Part III deals with physiopathological aspects of Ca(2+) handling and discusses recent information on hypertrophy, heart failure and atrial fibrillation.

Action Potentials↗
PubMed2003

Effect of pacing and mexiletine on dispersion of repolarisation and arrhythmias in DeltaKPQ SCN5A (long QT3) mice.

OBJECTIVE: It has been suggested that both pacing and treatment with mexiletine may reduce torsade de pointes (TdP) arrhythmias in patients with long QT syndrome 3 (LQT3), but it is not fully understood how these interventions could prevent TdP. We therefore studied the effects of pacing and mexiletine in mice with a heterozygous knock-in DeltaKPQ SCN5A(Delta/+) deletion (SCN5A-Tg), a murine LQT3 model. METHODS: Three right and left ventricular monophasic action potentials (MAPs) were simultaneously recorded in Langendorff-perfused hearts of SCN5A-Tg and wild type (WT) littermates. AV block was induced, and pacing was performed at baseline and during mexiletine infusion (4 microg/ml). MAP recordings were analysed for action potential duration (APD), APD dispersion, and early afterdepolarisations (EADs) and related to spontaneous arrhythmias. RESULTS: After inducing AV block, SCN5A-Tg hearts were bradycardic [SCN5A-Tg 532+/-60 vs. WT 284+/-48 ms cycle length (CL, mean+/-S.E.M., P<0.05(*))]. EADs occurred in 16/18, and polymorphic ventricular tachycardia (pVT) in 11/18 SCN5A-Tg but not in 19 WT. SCN5A-Tg had longer APD than WT hearts*. At CL of 200 ms and longer, APD dispersion was higher in SCN5A-Tg [dispersion (APD70): 12+/-3 ms vs. 5+/-2 ms at CL=200 ms*], and increased to 35+/-4 ms* directly prior to pVT episodes. Sudden rate accelerations initially increased APD dispersion due to EADs and APD alternans in SCN5A-Tg, but pacing then reduced APD dispersion. Pacing suppressed (n=9/9) and prevented (n=49/50) pVT. Mexiletine shortened APD at long CL*, and suppressed pVT (n=4/5*), but did not prevent pVT during normal rhythm. CONCLUSIONS: Bradycardia, increased dispersion of APD and EADs provoke ventricular ectopy and pVT in SCN5A-Tg hearts. Ventricular pacing reduces APD dispersion, suppresses EADs and prevents pVT in SCN5A-Tg hearts. These effects provide a pathophysiological rationale for pacing in LQT3.

Action Potentials↗