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BACKGROUND: The evolution of myocardial scar and its arrhythmogenic potential postinfarct is incompletely understood. OBJECTIVES: This study sought to investigate scar and border zone (BZ) channels evolution in an animal ischemia-reperfusion injury model using late gadolinium enhancement cardiac magnetic resonance (LGE-CMR). METHODS: Five swine underwent 90-minute balloon occlusion of the mid-left anterior descending artery, followed by LGE-CMR at day (d) 3, d30, and d58 postinfarct. Invasive electroanatomic mapping (EAM) was performed at 2 months. Topographical reconstructions of LGE-CMR were analyzed for left ventricular core and BZ scar, BZ channel geometry, and complexity, including transmurality, orientation, and number of entrances/exits. RESULTS: LVEF reduced from 48.0% ± 1.8% to 41.3% ± 2.3% postinfarct. Total scar mass reduced over time (P = 0.008), including BZ (P = 0.002) and core scar (P = 0.05). A total of 72 BZ channels were analyzed across all animals and timepoints. Channel length (P = 0.05) and complexity (P = 0.02) reduced progressively from d3 to d58. However, at d58, 64% of channels were newly formed and 36% were midmyocardial. Conserved channels were initially longer and more complex. All LGE-CMR channels colocalized to regions of maximal decrement on EAM, with significantly greater decrement (115 ± 31 ms vs 83 ± 29 ms; P < 0.001) and uncovering of split potentials (24.8% vs 2.6%; P < 0.001) within channels. In total, 3 of 5 animals had inducible VT and tended to have more channels with greater midmyocardial involvement and functional decrement than those without VT. CONCLUSIONS: BZ channels form early postinfarct and demonstrate evolutionary complexity and functional conduction slowing on EAM, highlighting their arrhythmogenic potential. Some channels regress in complexity and length, but new channels form at 2 months' postinfarct, which may be midmyocardial, reflecting an evolving, 3-dimensional substrate for VT. LGE-CMR may help identify BZ channels that may support VT early postinfarct and lead to sudden death.
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Single-cell technology has allowed researchers to probe tissue complexity and dynamics at unprecedented depth in health and disease. However, the generation of high-dimensionality single-cell atlases and virtual three-dimensional tissues requires integrated reference maps that harmonize disparate experimental designs, analytical pipelines, and taxonomies. Here, we present a comprehensive single-cell transcriptome integration map of cardiac fibrosis, which underpins pathophysiology in most cardiovascular diseases. Our findings reveal similarity between cardiac fibroblast (CF) identities and dynamics in ischemic versus pressure overload models of cardiomyopathy. We also describe timelines for commitment of activated CFs to proliferation and myofibrogenesis, profibrotic and antifibrotic polarization of myofibroblasts and matrifibrocytes, and CF conservation across mouse and human healthy and diseased hearts. These insights have the potential to inform knowledge-based therapies.
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Fibroblastos , Fibrosis , Análisis de la Célula Individual , Transcriptoma , Animales , Análisis de la Célula Individual/métodos , Humanos , Fibroblastos/metabolismo , Ratones , Miocardio/metabolismo , Miocardio/patología , Miofibroblastos/metabolismo , Miofibroblastos/patología , Perfilación de la Expresión GénicaRESUMEN
Purpose To assess the correlation between noninvasive cardiac MRI-derived parameters with pressure-volume (PV) loop data and evaluate changes in left ventricular function after myocardial infarction (MI). Materials and Methods Sixteen adult female swine were induced with MI, with six swine used as controls and 10 receiving platelet-derived growth factor-AB (PDGF-AB). Load-independent measures of cardiac function, including slopes of end-systolic pressure-volume relationship (ESPVR) and preload recruitable stroke work (PRSW), were obtained on day 28 after MI. Cardiac MRI was performed on day 2 and day 28 after infarct. Global longitudinal strain (GLS) and global circumferential strain (GCS) were measured. Ventriculo-arterial coupling (VAC) was derived from PV loop and cardiac MRI data. Pearson correlation analysis was performed. Results GCS (r = 0.60, P = .01), left ventricular ejection fraction (LVEF) (r = 0.60, P = .01), and cardiac MRI-derived VAC (r = 0.61, P = .01) had a significant linear relationship with ESPVR. GCS (r = 0.75, P < .001) had the strongest significant linear relationship with PRSW, followed by LVEF (r = 0.67, P = .005) and cardiac MRI-derived VAC (r = 0.60, P = .01). GLS was not significantly correlated with ESPVR or PRSW. There was a linear correlation (r = 0.82, P < .001) between VAC derived from cardiac MRI and from PV loop data. GCS (-3.5% ± 2.3 vs 0.5% ± 1.4, P = .007) and cardiac MRI-derived VAC (-0.6 ± 0.6 vs 0.3 ± 0.3, P = .001) significantly improved in the animals treated with PDGF-AB 28 days after MI compared with controls. Conclusion Cardiac MRI-derived parameters of MI correlated with invasive PV measures, with GCS showing the strongest correlation. Cardiac MRI-derived measures also demonstrated utility in assessing therapeutic benefit using PDGF-AB. Keywords: Cardiac MRI, Myocardial Infarction, Pressure Volume Loop, Strain Imaging, Ventriculo-arterial Coupling Supplemental material is available for this article. © RSNA, 2024.
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Modelos Animales de Enfermedad , Infarto del Miocardio , Animales , Femenino , Porcinos , Infarto del Miocardio/diagnóstico por imagen , Infarto del Miocardio/fisiopatología , Imagen por Resonancia Magnética/métodos , Función Ventricular Izquierda/fisiología , Volumen Sistólico/fisiología , Daño por Reperfusión Miocárdica/fisiopatología , Daño por Reperfusión Miocárdica/diagnóstico por imagen , Imagen por Resonancia Cinemagnética/métodosRESUMEN
Doxorubicin is a commonly used anti-cancer drug used in treating a variety of malignancies. However, a major adverse effect is cardiotoxicity, which is dose dependent and can be either acute or chronic. Doxorubicin causes injury by DNA damage, the formation of free reactive oxygen radicals and induction of apoptosis. Our aim is to induce expression of the multidrug resistance-associated protein 1 (MRP1) in cardiomyocytes derived from human iPS cells (hiPSC-CM), to determine whether this will allow cells to effectively remove doxorubicin and confer cardioprotection. We generated a lentivirus vector encoding MRP1 (LV.MRP1) and validated its function in HEK293T cells and stem cell-derived cardiomyocytes (hiPSC-CM) by quantitative PCR and western blot analysis. The activity of the overexpressed MRP1 was also tested, by quantifying the amount of fluorescent dye exported from the cell by the transporter. We demonstrated reduced dye sequestration in cells overexpressing MRP1. Finally, we demonstrated that hiPSC-CM transduced with LV.MRP1 were protected against doxorubicin injury. In conclusion, we have shown that we can successfully overexpress MRP1 protein in hiPSC-CM, with functional transporter activity leading to protection against doxorubicin-induced toxicity.