Evidence map›Paper›PMID 22539774›Full record

ArticleScience translational medicine2012

Suppression of phosphoinositide 3-kinase signaling and alteration of multiple ion currents in drug-induced long QT syndrome.

Zhongju Lu, Chia-Yen C Wu, Ya-Ping Jiang, Lisa M Ballou, Chris Clausen, Ira S Cohen, Richard Z Lin

Open access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Science translational medicine, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 106 papers.

0numbers the graph read from it
0cells of the map it votes in
106citing papers in PubMed
7.6field-weighted citation impact, top 2% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

106 citing papers in PubMed, 173 citations in OpenAlex.

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46 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

7 authors at 1 institution in 1 country.

Zhongju LuDepartment of Physiology and Biophysics and the Institute for Molecular Cardiology, Stony Brook University, Stony Brook, NY 11794, USA.
Chia-Yen C Wu
Ya-Ping Jiang
Lisa M Ballou
Chris Clausen
Ira S Cohen
Richard Z Lin
Northport VA Medical Center · US

Funding

Memory, Remodeling and Ventricular ArrhythmiasR01HL067101 · NHLBI · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI ROSEN, MICHAEL R. · 2001 to 2010
$6.3M
Novel ion channel approaches to reentrant arrythymiasR01HL094410 · NHLBI · STATE UNIVERSITY NEW YORK STONY BROOK · PI COHEN, IRA S · 2009 to 2013
$3.8M
Gq-Coupled Receptors Inhibit PI 3-Kinase/Akt Signaling PathwayR01DK062722 · NIDDK · STATE UNIVERSITY NEW YORK STONY BROOK · PI LIN, RICHARD Z · 2002 to 2012
$3.1M
NHLBI NIH HHS HL67101NHLBI NIH HHS HL94410NHLBI NIH HHS R01 HL067101NHLBI NIH HHS R01 HL094410NIDDK NIH HHS DK62722NIDDK NIH HHS R01 DK062722
6 · The paper itself

Abstract

Many drugs, including some commonly used medications, can cause abnormal heart rhythms and sudden death, as manifest by a prolonged QT interval in the electrocardiogram. Cardiac arrhythmias caused by drug-induced long QT syndrome are thought to result mainly from reductions in the delayed rectifier potassium ion (K(+)) current I(Kr). Here, we report a mechanism for drug-induced QT prolongation that involves changes in multiple ion currents caused by a decrease in phosphoinositide 3-kinase (PI3K) signaling. Treatment of canine cardiac myocytes with inhibitors of tyrosine kinases or PI3Ks caused an increase in action potential duration that was reversed by intracellular infusion of phosphatidylinositol 3,4,5-trisphosphate. The inhibitors decreased the delayed rectifier K(+) currents I(Kr) and I(Ks), the L-type calcium ion (Ca(2+)) current I(Ca,L), and the peak sodium ion (Na(+)) current I(Na) and increased the persistent Na(+) current I(NaP). Computer modeling of the canine ventricular action potential showed that the drug-induced change in any one current accounted for less than 50% of the increase in action potential duration. Mouse hearts lacking the PI3K p110α catalytic subunit exhibited a prolonged action potential and QT interval that were at least partly a result of an increase in I(NaP). These results indicate that down-regulation of PI3K signaling directly or indirectly via tyrosine kinase inhibition prolongs the QT interval by affecting multiple ion channels. This mechanism may explain why some tyrosine kinase inhibitors in clinical use are associated with increased risk of life-threatening arrhythmias.

Indexed as

Phosphoinositide-3 Kinase InhibitorsAction PotentialsAnimalsCalcium Channels, L-TypeClass I Phosphatidylinositol 3-KinasesComputer SimulationDelayed Rectifier Potassium ChannelsDogsElectrocardiographyFemaleLong QT SyndromeMaleMiceMice, KnockoutModels, CardiovascularMyocytes, CardiacCalcium Channels, L-TypeClass I Phosphatidylinositol 3-KinasesDelayed Rectifier Potassium Channelsphosphatidylinositol 3,4,5-triphosphatePhosphatidylinositol 3-KinasesPhosphatidylinositol PhosphatesPhosphoinositide-3 Kinase InhibitorsPik3ca protein, mousePik3cb protein, mouseProtein Kinase InhibitorsSodium Channel BlockersSodium Channels

Identifiers

PMID22539774
PMCPMC3494282
OpenAlexW2169631942

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.