Dataset Information

Fibroblasts Slow Conduction Velocity in a Reconstituted Tissue Model of Fibrotic Cardiomyopathy.

ABSTRACT: Myocardial function deteriorates over the course of fibrotic cardiomyopathy, due to electrophysiological and mechanical effects of myofibroblasts that are not completely understood. Although a range of experimental model systems and associated theoretical treatments exist at the levels of isolated cardiomyocytes and planar co-cultures of myofibroblasts and cardiomyocytes, interactions between these cell types at the tissue level are less clear. We studied these interactions through an engineered heart tissue (EHT) model of fibrotic myocardium and a mathematical model of the effects of cellular composition on EHT impulse conduction velocity. The EHT model allowed for modulation of cardiomyocyte and myofibroblast volume fractions, and observation of cell behavior in a three-dimensional environment that is more similar to native heart tissue than is planar cell culture. The cardiomyocyte and myofibroblast volume fractions determined the retardation of impulse conduction (spread of the action potential) in EHTs as measured by changes of the fluorescence of the Ca2+ probe, Fluo-2. Interpretation through our model showed retardation far in excess of predictions by homogenization theory, with conduction ceasing far below the fibroblast volume fraction associated with steric percolation. Results point to an important multiscale structural role of myofibroblasts in attenuating impulse conduction in fibrotic cardiomyopathy.

SUBMITTER: Spencer TM

PROVIDER: S-EPMC6527425 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Fibroblasts Slow Conduction Velocity in a Reconstituted Tissue Model of Fibrotic Cardiomyopathy.

Spencer Teresa M TM Blumenstein Ryan F RF Pryse Kenneth M KM Lee Sheng-Lin SL Glaubke David A DA Carlson Brian E BE Elson Elliot L EL Genin Guy M GM

ACS biomaterials science & engineering 20161018 11

Myocardial function deteriorates over the course of fibrotic cardiomyopathy, due to electrophysiological and mechanical effects of myofibroblasts that are not completely understood. Although a range of experimental model systems and associated theoretical treatments exist at the levels of isolated cardiomyocytes and planar co-cultures of myofibroblasts and cardiomyocytes, interactions between these cell types at the tissue level are less clear. We studied these interactions through an engineered ...[more]

PMID: 31119190

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Project description:BackgroundHypertrophic cardiomyopathy (HCM) is an autosomal dominant genetic disorder, characterized by cardiomyocyte hypertrophy, cardiomyocyte disarray and fibrosis, which has a prevalence of ∼1: 200-500 and predisposes individuals to heart failure and sudden death. The mechanisms through which diverse HCM-causing mutations cause cardiac dysfunction remain mostly unknown and their identification may reveal new therapeutic avenues. MicroRNAs (miRNAs) have emerged as critical regulators of gene expression and disease phenotype in various pathologies. We explored whether miRNAs could play a role in HCM pathogenesis and offer potential therapeutic targets.Methods and resultsUsing high-throughput miRNA expression profiling and qPCR analysis in two distinct mouse models of HCM, we found that miR-199a-3p expression levels are upregulated in mutant mice compared to age- and treatment-matched wild-type mice. We also found that miR-199a-3p expression is enriched in cardiac non-myocytes compared to cardiomyocytes. When we expressed miR-199a-3p mimic in cultured murine primary cardiac fibroblasts and analyzed the conditioned media by proteomics, we found that several extracellular matrix (ECM) proteins (e.g., TSP2, FBLN3, COL11A1, LYOX) were differentially secreted (data are available via ProteomeXchange with identifier PXD042904). We confirmed our proteomics findings by qPCR analysis of selected mRNAs and demonstrated that miR-199a-3p mimic expression in cardiac fibroblasts drives upregulation of ECM gene expression, including Tsp2, Fbln3, Pcoc1, Col1a1 and Col3a1. To examine the role of miR-199a-3p in vivo, we inhibited its function using lock-nucleic acid (LNA)-based inhibitors (antimiR-199a-3p) in an HCM mouse model. Our results revealed that progression of cardiac fibrosis is attenuated when miR-199a-3p function is inhibited in mild-to-moderate HCM. Finally, guided by computational target prediction algorithms, we identified mRNAs Cd151 and Itga3 as direct targets of miR-199a-3p and have shown that miR-199a-3p mimic expression negatively regulates AKT activation in cardiac fibroblasts.ConclusionsAltogether, our results suggest that miR-199a-3p may contribute to cardiac fibrosis in HCM through its actions in cardiac fibroblasts. Thus, inhibition of miR-199a-3p in mild-to-moderate HCM may offer therapeutic benefit in combination with complementary approaches that target the primary defect in cardiac myocytes.

Project description:BackgroundRipple mapping displays every deflection of a bipolar electrogram and enables the visualization of conduction channels (RMCC) within postinfarction ventricular scar to guide ventricular tachycardia (VT) ablation. The utility of RMCC identification for facilitation of VT ablation in the setting of arrhythmogenic right ventricular cardiomyopathy (ARVC) has not been described.ObjectiveWe sought to (a) identify the slow conduction channels in the endocardial/epicardial scar by ripple mapping and (b) retrospectively analyze whether the elimination of RMCC is associated with improved VT-free survival, in ARVC patients.MethodsHigh-density right ventricular endocardial and epicardial electrograms were collected using the CARTO 3 system in sinus rhythm or ventricular pacing and reviewed for RMCC. Low-voltage zones and abnormal myocardium in the epicardium were identified by using standardized late-gadolinium-enhanced (LGE) magnetic resonance imaging (MRI) signal intensity (SI) z-scores.ResultsA cohort of 20 ARVC patients that had undergone simultaneous high-density right ventricular endocardial and epicardial electrogram mapping was identified (age 44 ± 13 years). Epicardial scar, defined as bipolar voltage less than 1.0 mV, occupied 47.6% (interquartile range [IQR], 30.9-63.7) of the total epicardial surface area and was larger than endocardial scar, defined as bipolar voltage less than 1.5 mV, which occupied 11.2% (IQR, 4.2 ± 17.8) of the endocardium (P < 0.01). A median 1.5 RMCC, defined as continuous corridors of sequential late activation within scar, were identified per patient (IQR, 1-3), most of which were epicardial. The median ratio of RMCC ablated was 1 (IQR, 0.6-1). During a median follow-up of 44 months (IQR, 11-49), the ratio of RMCC ablated was associated with freedom from recurrent VT (hazard ratio, 0.01; P = 0.049). Among nine patients with adequate MRI, 73% of RMCC were localized in LGE regions, 24% were adjacent to an area with LGE, and 3% were in regions without LGE.ConclusionSlow conduction channels within endocardial or epicardial ARVC scar were delineated clearly by ripple mapping and corresponded to critical isthmus sites during entrainment. Complete elimination of RMCC was associated with freedom from VT.

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Fibroblasts Slow Conduction Velocity in a Reconstituted Tissue Model of Fibrotic Cardiomyopathy.

Publications

Fibroblasts Slow Conduction Velocity in a Reconstituted Tissue Model of Fibrotic Cardiomyopathy.

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