Evidence map›Paper›PMID 26015324›Full record

ArticleJournal of the American Heart Association2015

Use of whole exome sequencing for the identification of Ito-based arrhythmia mechanism and therapy.

Amy C Sturm, Crystal F Kline, Patric Glynn, Benjamin L Johnson, Jerry Curran, Ahmet Kilic, Robert S D Higgins, Philip F Binkley, Paul M L Janssen, Raul Weiss and 6 more

Open access · goldAbstract readCase Reports
PubMed Full text at PMC Publisher
In one paragraph

Article in Journal of the American Heart Association, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.

0numbers the graph read from it
0cells of the map it votes in
8citing papers in PubMed
3.0field-weighted citation impact, top 8% 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

8 citing papers in PubMed, 17 citations in OpenAlex.

  1. Review
  2. Purkinje physiology and pathophysiology.Journal of interventional cardiac electrophysiology : an international journal of arrhythmias and pacing · 2018
    Review
  3. Article
  4. Treat the Patient, Not Just the Cell!Circulation research · 2017
    Review
  5. Review
  6. Article
  7. Genetics of Common Endocrine Disease: The Present and the Future.The Journal of clinical endocrinology and metabolism · 2016
    Review
  8. Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

16 authors at 3 institutions in 2 countries.

Amy C SturmThe Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University Wexner Medical Center, The Ohio State University College of Engineering, Columbus, OH (A.C.S., C.F.K., P.G., B.L.J., J.C., A.K., R.D.H., P.F.B., P.L.J., R.W., S.V.R., T.J.H., C.A.C., P.J.M.) Department of Internal Medicine, The Ohio State University Wexner Medical Center, The Ohio State University College of Engineering, Columbus, OH (A.C.S., P.F.B., R.W., S.V.R., T.J.H., P.J.M.).
Crystal F KlineThe Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University Wexner Medical Center, The Ohio State University College of Engineering, Columbus, OH (A.C.S., C.F.K., P.G., B.L.J., J.C., A.K., R.D.H., P.F.B., P.L.J., R.W., S.V.R., T.J.H., C.A.C., P.J.M.) Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, The Ohio State University College of Engineering, Columbus, OH (C.F.K., J.C., P.L.J., P.J.M.).
Patric GlynnThe Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University Wexner Medical Center, The Ohio State University College of Engineering, Columbus, OH (A.C.S., C.F.K., P.G., B.L.J., J.C., A.K., R.D.H., P.F.B., P.L.J., R.W., S.V.R., T.J.H., C.A.C., P.J.M.) Department of Surgery, The Ohio State University Wexner Medical Center, The Ohio State University College of Engineering, Columbus, OH (P.G., A.K., R.D.H.).
Benjamin L JohnsonThe Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University Wexner Medical Center, The Ohio State University College of Engineering, Columbus, OH (A.C.S., C.F.K., P.G., B.L.J., J.C., A.K., R.D.H., P.F.B., P.L.J., R.W., S.V.R., T.J.H., C.A.C., P.J.M.).
Jerry CurranThe Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University Wexner Medical Center, The Ohio State University College of Engineering, Columbus, OH (A.C.S., C.F.K., P.G., B.L.J., J.C., A.K., R.D.H., P.F.B., P.L.J., R.W., S.V.R., T.J.H., C.A.C., P.J.M.) Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, The Ohio State University College of Engineering, Columbus, OH (C.F.K., J.C., P.L.J., P.J.M.).
Ahmet KilicThe Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University Wexner Medical Center, The Ohio State University College of Engineering, Columbus, OH (A.C.S., C.F.K., P.G., B.L.J., J.C., A.K., R.D.H., P.F.B., P.L.J., R.W., S.V.R., T.J.H., C.A.C., P.J.M.) Department of Surgery, The Ohio State University Wexner Medical Center, The Ohio State University College of Engineering, Columbus, OH (P.G., A.K., R.D.H.).
Robert S D HigginsThe Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University Wexner Medical Center, The Ohio State University College of Engineering, Columbus, OH (A.C.S., C.F.K., P.G., B.L.J., J.C., A.K., R.D.H., P.F.B., P.L.J., R.W., S.V.R., T.J.H., C.A.C., P.J.M.) Department of Surgery, The Ohio State University Wexner Medical Center, The Ohio State University College of Engineering, Columbus, OH (P.G., A.K., R.D.H.).
Philip F BinkleyThe Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University Wexner Medical Center, The Ohio State University College of Engineering, Columbus, OH (A.C.S., C.F.K., P.G., B.L.J., J.C., A.K., R.D.H., P.F.B., P.L.J., R.W., S.V.R., T.J.H., C.A.C., P.J.M.) Department of Internal Medicine, The Ohio State University Wexner Medical Center, The Ohio State University College of Engineering, Columbus, OH (A.C.S., P.F.B., R.W., S.V.R., T.J.H., P.J.M.).
Paul M L JanssenThe Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University Wexner Medical Center, The Ohio State University College of Engineering, Columbus, OH (A.C.S., C.F.K., P.G., B.L.J., J.C., A.K., R.D.H., P.F.B., P.L.J., R.W., S.V.R., T.J.H., C.A.C., P.J.M.) Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, The Ohio State University College of Engineering, Columbus, OH (C.F.K., J.C., P.L.J., P.J.M.).
Raul WeissThe Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University Wexner Medical Center, The Ohio State University College of Engineering, Columbus, OH (A.C.S., C.F.K., P.G., B.L.J., J.C., A.K., R.D.H., P.F.B., P.L.J., R.W., S.V.R., T.J.H., C.A.C., P.J.M.) Department of Internal Medicine, The Ohio State University Wexner Medical Center, The Ohio State University College of Engineering, Columbus, OH (A.C.S., P.F.B., R.W., S.V.R., T.J.H., P.J.M.).
Subha V RamanThe Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University Wexner Medical Center, The Ohio State University College of Engineering, Columbus, OH (A.C.S., C.F.K., P.G., B.L.J., J.C., A.K., R.D.H., P.F.B., P.L.J., R.W., S.V.R., T.J.H., C.A.C., P.J.M.) Department of Internal Medicine, The Ohio State University Wexner Medical Center, The Ohio State University College of Engineering, Columbus, OH (A.C.S., P.F.B., R.W., S.V.R., T.J.H., P.J.M.).
Steven J FowlerCardiovascular Genetics Program, Clinical Cardiac Electrophysiology, New York University Langone Medical Center, New York, NY (S.J.F., S.G.P.) Leon H. Charney Division of Cardiology, New York University Langone Medical Center, New York, NY (S.J.F.).
Silvia G PrioriCardiovascular Genetics Program, Clinical Cardiac Electrophysiology, New York University Langone Medical Center, New York, NY (S.J.F., S.G.P.) Molecular Cardiology, IRCCS Fondazione Salvatore Maugeri, University of Pavia, Italy (S.G.P.) Department of Cardiology, University of Pavia, Italy (S.G.P.).
Thomas J HundThe Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University Wexner Medical Center, The Ohio State University College of Engineering, Columbus, OH (A.C.S., C.F.K., P.G., B.L.J., J.C., A.K., R.D.H., P.F.B., P.L.J., R.W., S.V.R., T.J.H., C.A.C., P.J.M.) Department of Internal Medicine, The Ohio State University Wexner Medical Center, The Ohio State University College of Engineering, Columbus, OH (A.C.S., P.F.B., R.W., S.V.R., T.J.H., P.J.M.) Department of Biomedical Engineering, The Ohio State University, Columbus, OH (T.J.H.).
Cynthia A CarnesThe Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University Wexner Medical Center, The Ohio State University College of Engineering, Columbus, OH (A.C.S., C.F.K., P.G., B.L.J., J.C., A.K., R.D.H., P.F.B., P.L.J., R.W., S.V.R., T.J.H., C.A.C., P.J.M.) College of Pharmacy, Columbus, OH (C.A.C.).
Peter J MohlerThe Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University Wexner Medical Center, The Ohio State University College of Engineering, Columbus, OH (A.C.S., C.F.K., P.G., B.L.J., J.C., A.K., R.D.H., P.F.B., P.L.J., R.W., S.V.R., T.J.H., C.A.C., P.J.M.) Department of Internal Medicine, The Ohio State University Wexner Medical Center, The Ohio State University College of Engineering, Columbus, OH (A.C.S., P.F.B., R.W., S.V.R., T.J.H., P.J.M.) Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, The Ohio State University College of Engineering, Columbus, OH (C.F.K., J.C., P.L.J., P.J.M.).
The Ohio State University Wexner Medical Center · USNYU Langone Health · USThe Ohio State University · US

Funding

Frequency-dependent modulation of cardiac myofilament function in health/diseaseR01HL113084 · NHLBI · OHIO STATE UNIVERSITY · PI JANSSEN, PAULUS ML · 2012 to 2023
$4.6M
Role of spectrin/ankyrin-G complex in myocyte signaling and cardiac excitabilityR01HL083422 · NHLBI · VANDERBILT UNIVERSITY · PI MOHLER, PETER J. · 2006 to 2016
$3.8M
Role of ankyrin-B in human arrhythmiaR01HL084583 · NHLBI · UNIVERSITY OF IOWA · PI MOHLER, PETER J. · 2006 to 2015
$3.4M
EHD proteins in cardiac membrane protein targeting and remodelingR01HL114383 · NHLBI · OHIO STATE UNIVERSITY · PI BOYDEN, PENELOPE ALTMAN, MOHLER, PETER J. · 2013 to 2016
$2.1M
CaMKII-dependent regulation of cardiac excitabilityR01HL114893 · NHLBI · OHIO STATE UNIVERSITY · PI HUND, THOMAS JEFFREY · 2012 to 2016
$1.9M
NHLBI NIH HHS HL083422NHLBI NIH HHS HL084583NHLBI NIH HHS HL113084NHLBI NIH HHS HL114383NHLBI NIH HHS HL114893NHLBI NIH HHS R01 HL083422NHLBI NIH HHS R01 HL084583NHLBI NIH HHS R01 HL113084NHLBI NIH HHS R01 HL114383NHLBI NIH HHS R01 HL114893
6 · The paper itself

Abstract

backgroundIdentified genetic variants are insufficient to explain all cases of inherited arrhythmia. We tested whether the integration of whole exome sequencing with well-established clinical, translational, and basic science platforms could provide rapid and novel insight into human arrhythmia pathophysiology and disease treatment. METHODS AND

resultsWe report a proband with recurrent ventricular fibrillation, resistant to standard therapeutic interventions. Using whole-exome sequencing, we identified a variant in a previously unidentified exon of the dipeptidyl aminopeptidase-like protein-6 (DPP6) gene. This variant is the first identified coding mutation in DPP6 and augments cardiac repolarizing current (Ito) causing pathological changes in Ito and action potential morphology. We designed a therapeutic regimen incorporating dalfampridine to target Ito. Dalfampridine, approved for multiple sclerosis, normalized the ECG and reduced arrhythmia burden in the proband by >90-fold. This was combined with cilostazol to accelerate the heart rate to minimize the reverse-rate dependence of augmented Ito.

conclusionsWe describe a novel arrhythmia mechanism and therapeutic approach to ameliorate the disease. Specifically, we identify the first coding variant of DPP6 in human ventricular fibrillation. These findings illustrate the power of genetic approaches for the elucidation and treatment of disease when carefully integrated with clinical and basic/translational research teams.

Indexed as

Mutation4-AminopyridineAction PotentialsAdultCilostazolDipeptidyl-Peptidases and Tripeptidyl-PeptidasesDrug Therapy, CombinationElectrocardiographyExomeGenetic VariationHeart RateHumansMaleNerve Tissue ProteinsPotassium Channel BlockersPotassium Channels4-AminopyridineCilostazolDipeptidyl-Peptidases and Tripeptidyl-PeptidasesDPP6 protein, humanNerve Tissue ProteinsPotassium Channel BlockersPotassium ChannelsTetrazolesVasodilator Agentsarrhythmiageneticsion channel

Identifiers

PMID26015324
PMCPMC4599408
OpenAlexW1893469292

What OpenQuestion holds

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LicenceCC BY-NC
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.