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Funding This work was supported by CUREPLaN, a grant from the Leducq Foundation for Cardiovascular Research (18CVD01 to D.S., E.G.K. and F. S.) , and the American Heart Association (18TPA34230062 to F.S.)

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Rogalska, Malgorzata EAuthor

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Isoform changes of action potential regulators in the ventricles of arrhythmogenic phospholamban-R14del humanized mouse hearts

Publicated to:Metabolism-Clinical And Experimental. 138 155344- - 2023-01-01 138(), DOI: 10.1016/j.metabol.2022.155344

Authors: Rogalska, ME; Vafiadaki, E; Erpapazoglou, Z; Haghighi, K; Green, L; Mantzoros, CS; Hajjar, RJ; Tranter, M; Karakikes, I; Kranias, EG; Stillitano, F; Kafasla, P; Sanoudou, D

Affiliations

Acad Athens, Mol Biol Div, Biomed Res Fdn, Athens 11527, Greece - Author
Barcelona Inst Sci & Technol, Ctr Genom Regulat CRG, Barcelona 08003, Spain - Author
BSRC Alexander Fleming, Inst Fundamental Biomed Res, Athens 16672, Greece - Author
Flagship Pioneering, Cambridge, MA 02142 USA - Author
Harvard Med Sch, Beth Israel Deaconess Med Ctr, Div Endocrinol Diabet & Metab, Boston, MA 02215 USA - Author
Harvard Med Sch, Sect Endocrinol, Boston VA Healthcare Syst, Boston, MA 02215 USA - Author
Natl & Kapodistrian Univ Athens, Attikon Hosp, Dept Internal Med 4, Clin Genom & Pharmacogen Unit,Med Sch, Athens 11527, Greece - Author
Natl & Kapodistrian Univ Athens, Ctr New Biotechnol & Precis Med, Med Sch, Athens 11527, Greece - Author
Stanford Univ, Cardiovasc Inst, Sch Med, 240 Pasteur Dr, Stanford, CA 94304 USA - Author
Stanford Univ, Dept Cardiothorac Surg, Sch Med, 240 Pasteur Dr, Stanford, CA 94304 USA - Author
Univ Cincinnati, Dept Med, Coll Med, Cincinnati, OH 45267 USA - Author
Univ Cincinnati, Dept Pharmacol & Syst Physiol, Coll Med, Cincinnati, OH 45267 USA - Author
Univ Med Ctr Utrecht, Div Heart & Lung, Dept Cardiol, NL-3584 CX Utrecht, Netherlands - Author
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Abstract

Arrhythmogenic cardiomyopathy (ACM) is characterized by life-threatening ventricular arrhythmias and sudden cardiac death and affects hundreds of thousands of patients worldwide. The deletion of Arginine 14 (p.R14del) in the phospholamban (PLN) gene has been implicated in the pathogenesis of ACM. PLN is a key regulator of sarcoplasmic reticulum (SR) Ca2+ cycling and cardiac contractility. Despite global gene and protein expression studies, the molecular mechanisms of PLN-R14del ACM pathogenesis remain unclear. Using a humanized PLNR14del mouse model and human induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs), we investigated the transcriptome-wide mRNA splicing changes associated with the R14del mutation. We identified >200 significant alternative splicing (AS) events and distinct AS profiles were observed in the right (RV) and left (LV) ventricles in PLN-R14del compared to WT mouse hearts. Enrichment analysis of the AS events showed that the most affected biological process was associated with "cardiac cell action potential", specifically in the RV. We found that splicing of 2 key genes, Trpm4 and Camk2d, which encode proteins regulating calcium homeostasis in the heart, were altered in PLN-R14del mouse hearts and human iPSC-CMs. Bioinformatical analysis pointed to the tissue-specific splicing factors Srrm4 and Nova1 as likely upstream regulators of the observed splicing changes in the PLN-R14del cardiomyocytes. Our findings suggest that aberrant splicing may affect Ca2+-homeostasis in the heart, contributing to the increased risk of arrythmogenesis in PLN-R14del ACM.

Keywords

alternative splicingarrhythmiacardiomyopathygenomicsAlternative splicingArrhythmiaCardiac-hypertrophyCardiomyopathyDilated cardiomyopathyDysregulationFailureGeneGenomicsKinase-iiMicroexonsModulationMutationProteinSpinal muscular-atrophy

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Metabolism-Clinical And Experimental due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2023, it was in position 9/186, thus managing to position itself as a Q1 (Primer Cuartil), in the category Endocrinology & Metabolism. Notably, the journal is positioned above the 90th percentile.

From a relative perspective, and based on the normalized impact indicator calculated from World Citations provided by WoS (ESI, Clarivate), it yields a value for the citation normalization relative to the expected citation rate of: 1.13. This indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: ESI Nov 14, 2024)

This information is reinforced by other indicators of the same type, which, although dynamic over time and dependent on the set of average global citations at the time of their calculation, consistently position the work at some point among the top 50% most cited in its field:

  • Field Citation Ratio (FCR) from Dimensions: 4.34 (source consulted: Dimensions Jun 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-06-30, the following number of citations:

  • WoS: 6
  • Scopus: 7

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-06-30:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 14.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 14 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 7.35.
  • The number of mentions on the social network X (formerly Twitter): 6 (Altmetric).

Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: Greece; Israel; Netherlands; United States of America.

There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: First Author (Rogalska, MALGORZATA) .