ArticleJournal of personalized medicine2021
Impaired Right Ventricular Calcium Cycling Is an Early Risk Factor in R14del-Phospholamban Arrhythmias.
Article in Journal of personalized medicine, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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The trial behind it
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Who cites it
12 citing papers in PubMed, 24 citations in OpenAlex.
- Genetic landscape of phospholamban cardiomyopathies.Frontiers in cell and developmental biology · 2025Review
- The phospholamban R14del generates pathogenic aggregates by impairing autophagosome-lysosome fusion.Cellular and molecular life sciences : CMLS · 2024Article
- Reassessing the Mechanisms of PLN-R14del Cardiomyopathy: From Calcium Dysregulation to S/ER Malformation.JACC. Basic to translational science · 2024Review
- Article
- Deep neural network-based clustering of deformation curves reveals novel disease features in PLN pathogenic variant carriers.The international journal of cardiovascular imaging · 2023Article
- Therapeutic Targets and Personalized Medicine in Cardiac Disease.Journal of personalized medicine · 2023Article
- Myofilament Alterations Associated with Human R14del-Phospholamban Cardiomyopathy.International journal of molecular sciences · 2023Article
- Evolving cardiovascular genetic counseling needs in the era of precision medicine.Frontiers in cardiovascular medicine · 2023Article
- Phospholamban R14del disease: The past, the present and the future.Frontiers in cardiovascular medicine · 2023Review
- Isoform changes of action potential regulators in the ventricles of arrhythmogenic phospholamban-R14del humanized mouse hearts.Metabolism: clinical and experimental · 2023Article
- Gene editing reverses arrhythmia susceptibility in humanized PLN-R14del mice: modelling a European cardiomyopathy with global impact.Cardiovascular research · 2022Article
- Aberrant PLN-R14del Protein Interactions Intensify SERCA2a Inhibition, Driving Impaired CaInternational journal of molecular sciences · 2022Article
Corrections and comments
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Authors and funding
22 authors at 5 institutions in 3 countries.
Funding
Abstract
The inherited mutation (R14del) in the calcium regulatory protein phospholamban (PLN) is linked to malignant ventricular arrhythmia with poor prognosis starting at adolescence. However, the underlying early mechanisms that may serve as prognostic factors remain elusive. This study generated humanized mice in which the endogenous gene was replaced with either human wild type or R14del-PLN and addressed the early molecular and cellular pathogenic mechanisms. R14del-PLN mice exhibited stress-induced impairment of atrioventricular conduction, and prolongation of both ventricular activation and repolarization times in association with ventricular tachyarrhythmia, originating from the right ventricle (RV). Most of these distinct electrocardiographic features were remarkably similar to those in R14del-PLN patients. Studies in isolated cardiomyocytes revealed RV-specific calcium defects, including prolonged action potential duration, depressed calcium kinetics and contractile parameters, and elevated diastolic Ca-levels. Ca-sparks were also higher although SR Ca-load was reduced. Accordingly, stress conditions induced after contractions, and inclusion of the CaMKII inhibitor KN93 reversed this proarrhythmic parameter. Compensatory responses included altered expression of key genes associated with Ca-cycling. These data suggest that R14del-PLN cardiomyopathy originates with RV-specific impairment of Ca-cycling and point to the urgent need to improve risk stratification in asymptomatic carriers to prevent fatal arrhythmias and delay cardiomyopathy onset.
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Registered trials
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.