Cell-Specific Pathways Supporting Persistent Fibrosis in Heart Failure

Farris, Stephen; Don, Creighton W.; Helterline, Deri; Costa, Christopher R.; Plummer, Tabitha; Steffes, Susanne; Mahr, Claudius; Mokadam, Nahush A.; Stempien‐Otero, April

doi:10.1016/j.jacc.2017.05.040

Cited by 37 publications

(29 citation statements)

References 34 publications

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“…DCM patients with extended LGE, that is, those showing an expanded myocardial fibrosis, were less likely to develop LVRR even once pharmacotherapy was started . Replacement fibrosis in myocardium spreads to fill the site of dropping cardiomyocytes via the actions by fibroblasts and macrophages; however, DCM patients without LGE showed recovery of LV function and cavity size. Following the decision to treat those without LGE at baseline CMR with appropriate oral treatment for HF, none developed LGE at the CMR review 2 years later .…”

Section: Discussionmentioning

confidence: 99%

Long‐term prognostic value of ultrastructural features in dilated cardiomyopathy: comparison with cardiac magnetic resonance

et al. 2020

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Aims This study aims to determine the implications associated with long-term prognosis of heart failure (HF) in patients with dilated cardiomyopathy (DCM) presenting initially as decompensated HF. We stratified the phase of DCM patients without late gadolinium enhancement (LGE) based on ultrastructural changes in cardiomyocytes. Methods and results Left ventricular (LV) endomyocardial biopsy was performed in 55 consecutive DCM patients with initial decompensated HF. Ultrastructural changes in cardiomyocytes detected by electron microscopy were compared with data including LGE with cardiac magnetic resonance and HF recurrence. Of the 55 DCM patients, 24 (44%) showed LGE, and 26 (47%) showed recurrence decompensated HF, while 23 patients (42%) showed autophagic vacuoles in cardiomyocytes by electron microscopy. Multivariate analysis identified atrial fibrillation [hazard ratio (HR), 3.40; 95% confidence interval (CI), 1.45-7.98], haemoglobin level (HR, 0.82; 95% CI, 0.68-0.99), beta-blocker use (HR, 0.18; 95% CI, 0.05-0.74), and autophagic vacuoles (HR, 0.25; 95% CI, 0.09-0.65) as predictors of HF recurrence in the total patient population. In patients without LGE, only autophagic vacuoles were independent predictors of readmission because of HF (HR, 0.29; 95% CI, 0.09-0.90). In patients with LGE, atrial fibrillation (HR, 19.10; 95% CI, 2.97-123.09), and mid-linear LGE (HR, 12.96; 95% CI, 2.02-82.94) were independent predictors of readmission because of HF. Conclusions In DCM patients with LGE, characterised by progression of LV remodelling, the LGE pattern was a predictor of HF recurrence, whereas in patients without LGE, absence of autophagic vacuoles was a predictor of HF recurrence.

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Section: Discussionmentioning

confidence: 99%

Long‐term prognostic value of ultrastructural features in dilated cardiomyopathy: comparison with cardiac magnetic resonance

et al. 2020

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“…We and others showed previously that the use of angiotensin-converting enzyme inhibitors has limited impact on myocardial fibrosis in VAD patients. 10,26 In this study, most patients received an antifibrotic medication during VAD therapy and a few did not receive any medications. However, the comparison of total collagen data between patients with or without antifibrotic medications revealed no significant difference which confirms our earlier data.…”

Section: Discussionmentioning

confidence: 94%

Mechanical circulatory support does not reduce advanced myocardial fibrosis in patients with end‐stage heart failure

Kassner

Oezpeker

Gummert

et al. 2020

European J of Heart Fail

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Mechanical unloading by ventricular assist devices (VADs) has become increasingly important for the therapy of end-stage heart failure during the last decade. However, VAD support was claimed to be associated with partial reverse remodelling. Unfortunately, the literature describes the contradictory effects of VAD systems on cardiac fibrosis, a hallmark of cardiac remodelling. To clarify these inconsistent results, the effects on cardiac fibrosis before and after mechanical unloading in 125 patients were examined.

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“…1I ). To examine whether this upregulation in MBNL1 is generalizable to human heart failure, cardiac fibroblasts were isolated from left ventricular biopsies taken from patients receiving left ventricular assist devices-a human cardiac tissue source rich in fibroblasts that have transitioned to a myofibroblast state (Farris et al, 2017). Relative to healthy human fibroblasts there was a significant increase in MBNL1 expression in failing cardiac fibroblasts ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Fibroblast State Reversal By MBNL1-Dependent Transcriptome Modification Regulates Cardiac Repair

Bugg

Bretherton

Beach

et al. 2021

Preprint

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SUMMARYDynamic fibroblast state transitions are responsible for the heart’s fibrotic response to injury, raising the possibility that tactical control of these transitions could alter maladaptive fibrotic outcomes. Transcriptome maturation by the RNA binding protein Muscleblind Like 1 (MBNL1) has emerged as a potential driver of differentiated cell states. Here genetic lineage tracing of myofibroblasts in the injured heart demonstrated that gains in MBNL1 function corresponded to profibrotic fibroblast states. Similarly, in mice cardiac fibroblast specific MBNL1 overexpression induced a transcriptional myofibroblast profile in healthy cardiac fibroblasts that prevented the fibroproliferative phase of cardiac wound healing. By contrast loss of MBNL1 reverted cardiac fibroblasts to a pro-proliferative epicardial progenitor state that limited cardiac fibrosis following myocardial infarction. This progenitor state transition was associated with an MBNL1-dependent destabilization of the mesenchymal transition gene, Sox9. These findings suggest that MBNL1 regulation of the fibroblast transcriptome drives state transitions underlying cardiac fibrosis and repair.

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Cell-Specific Pathways Supporting Persistent Fibrosis in Heart Failure

Cited by 37 publications

References 34 publications

Long‐term prognostic value of ultrastructural features in dilated cardiomyopathy: comparison with cardiac magnetic resonance

Long‐term prognostic value of ultrastructural features in dilated cardiomyopathy: comparison with cardiac magnetic resonance

Mechanical circulatory support does not reduce advanced myocardial fibrosis in patients with end‐stage heart failure

Fibroblast State Reversal By MBNL1-Dependent Transcriptome Modification Regulates Cardiac Repair

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