Evidence map›Paper›PMID 41032675›Full record

ArticleCardiovascular research2025

RRAD-reduction reveals efficacy of targeting L-type calcium channel regulation for treatment of heart failure.

Garrett Elmore, Sarisha S Lohano, Nicholas M McVay, Bryana M Levitan, Andrea Sebastian, Kyle W Barker, Alec Dupont, Steven W Leung, Riham R E Abouleisa, Pretty R Mathew and 9 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cardiovascular research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
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

0 citing papers in PubMed.

No citing paper in PubMed yet.

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

19 authors.

Garrett ElmoreDepartment of Physiology, University of Kentucky, 741 S. Limestone, Lexington, KY 40536-0298, USA.
Sarisha S LohanoDepartment of Physiology, University of Kentucky, 741 S. Limestone, Lexington, KY 40536-0298, USA.
Nicholas M McVayDepartment of Physiology, University of Kentucky, 741 S. Limestone, Lexington, KY 40536-0298, USA.
Bryana M LevitanDepartment of Physiology, University of Kentucky, 741 S. Limestone, Lexington, KY 40536-0298, USA.
Andrea SebastianDepartment of Physiology, University of Kentucky, 741 S. Limestone, Lexington, KY 40536-0298, USA.
Kyle W BarkerDepartment of Physiology, University of Kentucky, 741 S. Limestone, Lexington, KY 40536-0298, USA.
Alec DupontDepartment of Physiology, University of Kentucky, 741 S. Limestone, Lexington, KY 40536-0298, USA.
Steven W LeungGill Heart and Vascular Institute, University of Kentucky, Lexington, KY 40506, USA.
Riham R E AbouleisaDivision of Cardiothoracic Surgery, Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA.
Pretty R MathewDivision of Cardiothoracic Surgery, Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA.
Austin Wellette-HunsuckerDepartment of Physiology, University of Kentucky, 741 S. Limestone, Lexington, KY 40536-0298, USA.
Austin T MintonDepartment of Physiology, University of Kentucky, 741 S. Limestone, Lexington, KY 40536-0298, USA.
Kenneth S CampbellDepartment of Physiology, University of Kentucky, 741 S. Limestone, Lexington, KY 40536-0298, USA.
Solomon W HarrarDepartment of Statistics, University of Kentucky, Lexington, KY 40506, USA.
Mohammad MehriDepartment of Mechanical and Aerospace Engineering, University of Kentucky, Lexington, KY 40506, USA.
Jonathan F WenkDepartment of Mechanical and Aerospace Engineering, University of Kentucky, Lexington, KY 40506, USA.
Tamer M A MohamedDivision of Cardiothoracic Surgery, Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA.
Douglas A AndresDepartment of Biochemistry, University of Kentucky, Lexington, KY 40506, USA.
Jonathan SatinDepartment of Physiology, University of Kentucky, 741 S. Limestone, Lexington, KY 40536-0298, USA.ORCID 0000-0001-9198-8349

Funding

Induction of Cardiomyocyte Proliferation via Transient Expression of Cell Cycle Factors as a Promising Therapy for Heart FailureR01HL147921 · NHLBI · UNIVERSITY OF LOUISVILLE · PI Tamer M A Mohamed, Jonathan Satin · 2020 to 2026
$5.3M
Length-dependent activation in human myocardiumR01HL149164 · NHLBI · UNIVERSITY OF KENTUCKY · PI CAMPBELL, KENNETH S, TANNER, BERTRAND C.W. · 2020 to 2023
$2.8M
Mechanisms of L-type Calcium Channel Regulation in Heart Health and DiseaseR01HL166280 · NHLBI · UNIVERSITY OF KENTUCKY · PI Jonathan Satin · 2023 to 2026
$2.5M
Defining the major signaling mechanism which controls spontaneous cardiomyocyte proliferation in the Neonatal StageR01HL178610 · NHLBI · BAYLOR COLLEGE OF MEDICINE · PI Tamer M A Mohamed · 2025 to 2026
$1.5M
NHLBI NIH HHS R01 HL147921NHLBI NIH HHS R01 HL149164NHLBI NIH HHS R01 HL166280NHLBI NIH HHS R01 HL178610NIH HHS HL149164NIH HHS HL166280US Department of Defense HT94252310655US Department of Defense W81WXH-20-21-0418
6 · The paper itself

Abstract

aimsHeart failure with reduced ejection fraction (HFrEF) is a major health problem. Increasing L-type calcium channel (LTCC) activity deteriorates heart function; however, myocardial RRAD knockout (cRADΔ/Δ) instills tonic modulated LTCC current (ICa,L) that preserves healthy myocardium. Thus, we chose to challenge the dogma that enhanced trigger Ca2+ is maladaptive. The study objective was to test the hypothesis that modulated ICa,L in cRADΔ/Δ mice rescues dilated cardiomyopathy by providing tonic modulated trigger Ca2+. METHODS AND

resultsMouse and human models were tested. The muscle lim protein knockout mouse (MLPKO) is a murine model of dilated cardiomyopathy (DCM) and HFrEF. The experimental timeline was to induce cRADΔ/Δ after onset of DCM (2.5 months of age) and follow subjects for up to 1-year. Longitudinal echocardiography and cardiac magnetic resonance imaging (CMR) showed that cRADΔ/Δ intervention rescued systolic function. Patch clamp recordings of isolated cardiomyocytes of MLPKO with cRADΔ/Δ demonstrated augmented LTCC activity, along with rescue of dysfunctional Ca2+ handling and sarcomere function. Bulk RNAseq of hearts demonstrated down-regulated pathological signalling cascades and pro-hypertrophic gene expression which comported with the reduction in eccentric hypertrophy observed with gravimetrics, CMR, and echocardiography. RRAD knockdown effects translate from mouse to human heart. Ventricle slices from HFrEF patients were treated with lentiviral shRNA targeting RRAD and recapitulated the inotropic and lusitropic effects observed in the mouse model of DCM.

conclusionInduction of cardiomyocyte-restricted RAD knockout in MLPKO mice after onset of DCM rescued cardiac dysfunction and attenuated pathological remodelling. cRADΔ/Δ intervention provided positive inotropy and lusitropy and reverted transcriptional signatures towards healthy myocardium. This study introduces targeting myocardial RAD regulation of the LTCC as a novel therapeutic strategy for systolic heart failure.

Indexed as

Calcium Channels, L-TypeCalcium SignalingCardiomyopathy, DilatedHeart FailureLIM Domain ProteinsMuscle ProteinsMyocytes, CardiacVentricular Function, LeftAnimalsDisease Models, AnimalFemaleHumansMaleMice, Inbred C57BLMice, Knockoutras ProteinsCacna1d protein, mouseCalcium Channels, L-TypeLIM Domain ProteinsMuscle Proteinsras ProteinsRrad protein, mouseDilated cardiomyopathyHeart failureL-type calcium channelTherapeutic strategy

Identifiers

PMID41032675
PMCPMC12638741

What Socratic holds

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Registered trials

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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 Socratic graph.