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MYL4 identifies intramural anatomy of Purkinje fibers in human hearts

ABSTRACT: ABSTRACTBACKGROUND: Cardiac Purkinje fibers (PFs) orchestrate myocardial synchrony but in regions of myocardial scarring driver ventricular arrhythmia. It is hypothesized that arrhythmias refractory to ablation may be driven by PFs deep in the scarred myocardium. However, knowledge of human PF anatomy remains reliant on data generated in animal models, obscuring understanding of the substrate underpinning dysrhythmia and pacing strategies. OBJECTIVES: Establish and utilize a human biomarker to delineate PF anatomy in humans. METHODS: RNA-sequencing and differential expression analysis of transcriptomes from human hearts (n=10) revealed 99 genes upregulated in PFs versus ventricular myocardium and endocardium. Whole mount megablock cross sectional analysis was performed with cardiac troponin, MYL4, PAS, Masson’s Trichrome, pro-ANP, and GJA5 colocalization. RESULTS: Comparative transcriptomics from human hearts (n=10) identified Myosin light chain 4 (MYL4) as a promising human PF marker for distinguishing conductive from contractile myocardium. Using PF rich bundle branch and subendocardial regions, MYL4 specificity was validated using canonical PF markers in human (n=3), dog (n=3), goat (n=3), and pig (n=3) hearts. Cross sectional histology of the entire human ventricular myocardium uncovered a deep seeded network of transmurally intercalated, MYL4 positive PFs. This previously unrecognized distribution of the cardiac conduction system accounted for over 60% of human myocardial PF content. CONCLUSIONS: Such significant intramural prevalence exposes limitations associated with treatment approaches based on dogma that PF anatomy is restricted to subendocardium. MYL4 here enabled a comprehensive visualization of human cardiac conduction system, offering an intricate bioanatomical map for heart rhythm management.

ORGANISM(S): Homo sapiens

PROVIDER: GSE291597 | GEO | 2025/03/15

REPOSITORIES: GEO

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Project description:Heart failure is associated with high morbidity and mortality and its incidence increases worldwide. MicroRNAs (miRNAs) are potential markers and targets for diagnostic and therapeutic applications, respectively. We determined myocardial and circulating miRNA abundance and its changes in patients with stable and end-stage heart failure before and at different time points after mechanical unloading by a left ventricular assist device (LVAD) by small-RNA-sequencing. MiRNA changes in failing heart tissues partially resembled that of fetal myocardium. Consistent with prototypical miRNAM-bM-^@M-^Starget-mRNA interactions, target mRNA levels were negatively correlated to changes in abundance for highly expressed miRNAs in heart failure and fetal hearts. The circulating small RNA profile was dominated by miRNAs, and fragments of tRNAs and small cytoplasmic RNAs. Heart- and muscle-specific circulating miRNAs (myomirs) increased up to 140-fold in advanced heart failure, which coincided with a similar increase in cardiac troponin I protein, the established marker for heart injury. These extracellular changes nearly completely reversed 3 months following initiation of LVAD support. In stable heart failure, circulating miRNAs showed less than 5-fold differences compared to normal, and myomir and cardiac troponin I levels were only captured near the detection limit. These findings provide the underpinning for miRNA-based therapies and emphasize the usefulness of circulating miRNAs as biomarkers for heart injury performing similar to established diagnostic protein biomarkers. Total RNA isolated from human left ventricular myocardium of failing hearts due to dilated or ischemic cardiomyopathy before and after mechanical unloading by a left ventricular assist device, and fetal myocardium compared to non-failing postnatal myocardium was subjected to multiplexed small RNA-sequencing on the Illumina platform. mRNA gene expression data using Illumina HumanHT-12v4 beadarrays for a subset of the myocardial samples is available (GSE52601).

Project description:This a model from the article: Mathematical models of the electrical action potential of Purkinje fibre cells. Philip Stewart, Oleg V. Aslanidi, Denis Noble, Penelope J. Noble, Mark R. Boyett and Henggui Zhang. Phil. Trans. R. Soc. A 13 June 2009 vol. 367 no. 1896 2225-2255 doi:10.1098/rsta.2008.0283 , Abstract: Early development of ionic models for cardiac myocytes, from the pioneering modification of the Hodgkin–Huxley giant squid axon model by Noble to the iconic DiFrancesco–Noble model integrating voltage-gated ionic currents, ion pumps and exchangers, Ca2+ sequestration and Ca2+-induced Ca2+ release, provided a general description for a mammalian Purkinje fibre (PF) and the framework for modern cardiac models. In the past two decades, development has focused on tissue-specific models with an emphasis on the sino-atrial (SA) node, atria and ventricles, while the PFs have largely been neglected. However, achieving the ultimate goal of creating a virtual human heart will require detailed models of all distinctive regions of the cardiac conduction system, including the PFs, which play an important role in conducting cardiac excitation and ensuring the synchronized timing and sequencing of ventricular contraction. In this paper, we present details of our newly developed model for the human PF cell including validation against experimental data. Ionic mechanisms underlying the heterogeneity between the PF and ventricular action potentials in humans and other species are analysed. The newly developed PF cell model adds a new member to the family of human cardiac cell models developed previously for the SA node, atrial and ventricular cells, which can be incorporated into an anatomical model of the human heart with details of its electrophysiological heterogeneity and anatomical complexity. This model was taken from the CellML repository and automatically converted to SBML. The original model was: CellMLdetails The original CellML model was created by: Penny Noble penny.noble@dpag.ox.ac.uk The University of Oxford This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information. In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not. . To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

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MYL4 identifies intramural anatomy of Purkinje fibers in human hearts

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