Differential Behaviors of Atrial Versus Ventricular Fibroblasts A Potential Role for Platelet-Derived Growth Factor in Atrial-Ventricular Remodeling Differences
TL;DR: Atrial fibroblasts behave differently than ventricular fibro Blasts over a range of in vitro and in vivo paradigms, with atrial Fibroblast showing enhanced reactivity that may explain greater atrial fibrotic responses.
Abstract: Background— In various heart disease paradigms, atria show stronger fibrotic responses than ventricles. The possibility that atrial and ventricular fibroblasts respond differentially to pathological stimuli has not been examined. Methods and Results— We compared various morphological, secretory, and proliferative response indexes of canine atrial versus ventricular fibroblasts. Cultured atrial fibroblasts showed faster cell surface area increases, distinct morphology at confluence, and greater α-smooth muscle actin expression than ventricular fibroblasts. Atrial fibroblast proliferation ([3H]thymidine incorporation) responses were consistently greater for a range of growth factors, including fetal bovine serum, platelet-derived growth factor (PDGF), basic fibroblast growth factor, angiotensin II, endothelin-1, and transforming growth factor-β1. Normal atrial tissue showed larger myofibroblast density compared with ventricular tissue, and the difference was exaggerated by congestive heart failure. Congesti...
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TL;DR: 3D computational models used to determine the mechanisms by which fibrosis underlies the degradation of a pulmonary vein ectopic beat into AF found that the occurrence of gap junction remodeling and the subsequent conduction slowing in the fibrotic lesions was a necessary but not sufficient condition for AF development.
114 citations
Cites background from "Differential Behaviors of Atrial Ve..."
...For one, atrial fibroblasts have a greater tendency to differentiate into activated myofibroblasts both in vitro and in vivo compared to ventricular fibroblasts (44), one explanation for why atria exhibit a more sensitive fibrotic response than ventricles in disease progression (45)....
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University of Münster1, Leiden University2, Uppsala University3, Johns Hopkins University4, St George's, University of London5, Maastricht University6, University of Duisburg-Essen7, Otto-von-Guericke University Magdeburg8, Goethe University Frankfurt9, University of Birmingham10, Université de Montréal11, University of Washington12, Dresden University of Technology13, Ludwig Maximilian University of Munich14, University of Crete15, Case Western Reserve University16, University of Hamburg17
TL;DR: Empirical observations suggest that AF is still associated with a doubling of mortality, even after adjustment for confounders, and this observation from the last millennium appears to continue into current randomized trials in AF patients.
Abstract: Atrial fibrillation (AF) is already an endemic disease, and its prevalence is soaring, due to both an increasing incidence of the arrhythmia and an age-related increase in its prevalence. Indeed, 1–2% of the population suffer from AF at present, and the number of affected individuals is expected to double or triple within the next two to three decades both in Europe and in the USA.1–4 Although epidemiological data for other parts of the world are less robust, a similar increase in AF in the community can be assumed in other countries.
Atrial fibrillation causes marked morbidity and mortality on a population basis. Epidemiological observations suggest that AF is still associated with a doubling of mortality, even after adjustment for confounders.2,5 This observation from the last millennium appears to continue into current randomized trials in AF patients. Also, AF is the single most important risk factor for ischaemic stroke. Furthermore, strokes associated with AF result more often in death or permanent disability than strokes that occur as a result of other aetiologies.6–9 The presence of AF is also associated with a marked reduction in everyday functioning and quality of life.10–13
The harm associated with AF and the perceived detrimental effects of the arrhythmia on general health contrast with the outcome of six trials that compared a ‘rate control’ therapy strategy, aiming at accepting AF and controlling the ventricular rate, with an antiarrrhythmic drug-based ‘rhythm control’ therapy strategy, aiming at maintenance of the ‘natural’ sinus rhythm. Apart from a slight improvement in 6 min walk test in a small trial14 and post hoc analyses,15 the outcome of patients randomized to rhythm control therapy was not better than patients randomized to rate control therapy,14,16–20 …
111 citations
TL;DR: It appears that fibrosis progresses despite compensatory changes in the TGF-β-signaling pathway, which may offer the opportunity to selectively interfere with the atrial remodeling process at different stages.
105 citations
Cites background from "Differential Behaviors of Atrial Ve..."
...Importantly, experimental data have shown, that these findings cannot simply be transferred to the atrial level [8–10]....
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TL;DR: It is found that perinatal fibroblasts and endothelial cells proliferate at similar rates and regardless of the injury model, fibroblast proliferation peaks within the first week after injury, a time window similar to the period of the inflammatory phase.
103 citations
TL;DR: The contribution of the fetal epicardial gene program will be discussed in the context of fibroblast origin in development and following injury, primarily focusing on Tcf21 and C/EBP.
99 citations
Cites background from "Differential Behaviors of Atrial Ve..."
...Compared to ventricular fibroblasts, atrial fibroblasts display a more robust response to congestive heart failure [11,12]....
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TL;DR: It is shown that cardiac fibrosis is associated with the emergence of fibroblasts originating from endothelial cells, suggesting an endothelial-mesenchymal transition (EndMT) similar to events that occur during formation of the atrioventricular cushion in the embryonic heart.
Abstract: Cardiac fibrosis, associated with a decreased extent of microvasculature and with disruption of normal myocardial structures, results from excessive deposition of extracellular matrix, which is mediated by the recruitment of fibroblasts. The source of these fibroblasts is unclear and specific anti-fibrotic therapies are not currently available. Here we show that cardiac fibrosis is associated with the emergence of fibroblasts originating from endothelial cells, suggesting an endothelial-mesenchymal transition (EndMT) similar to events that occur during formation of the atrioventricular cushion in the embryonic heart. Transforming growth factor-β1 (TGF-β1) induced endothelial cells to undergo EndMT, whereas bone morphogenic protein 7 (BMP-7) preserved the endothelial phenotype. The systemic administration of recombinant human BMP-7 (rhBMP-7) significantly inhibited EndMT and the progression of cardiac fibrosis in mouse models of pressure overload and chronic allograft rejection. Our findings show that EndMT contributes to the progression of cardiac fibrosis and that rhBMP-7 can be used to inhibit EndMT and to intervene in the progression of chronic heart disease associated with fibrosis.
1,908 citations
TL;DR: Experimental CHF strongly promotes the induction of sustained AF by causing interstitial fibrosis that interferes with local conduction, with important potential implications for understanding, treating, and preventing AF related to CHF.
Abstract: Background—Studies of atrial fibrillation (AF) due to atrial tachycardia have provided insights into the remodeling mechanisms by which “AF begets AF” but have not elucidated the substrate that initially supports AF before remodeling occurs. We studied the effects of congestive heart failure (CHF), an entity strongly associated with clinical AF, on atrial electrophysiology in the dog and compared the results with those in dogs subjected to rapid atrial pacing (RAP; 400 bpm) with a controlled ventricular rate (AV block plus ventricular pacemaker at 80 bpm). Methods and Results—CHF induced by 5 weeks of rapid ventricular pacing (220 to 240 bpm) increased the duration of AF induced by burst pacing (from 8±4 seconds in control dogs to 535±82 seconds; P<0.01), similar to the effect of 1 week of RAP (713±300 seconds). In contrast to RAP, CHF did not alter atrial refractory period, refractoriness heterogeneity, or conduction velocity at a cycle length of 360 ms; however, CHF dogs had a substantial increase in th...
1,343 citations
TL;DR: Cultured fetal and adult human fibroblasts maintained key features of HOX gene expression patterns established during embryogenesis, suggesting that HOX genes may direct topographic differentiation and underlie the detailed positional memory in fibro Blasts.
Abstract: A fundamental feature of the architecture and functional design of vertebrate animals is a stroma, composed of extracellular matrix and mesenchymal cells, which provides a structural scaffold and conduit for blood and lymphatic vessels, nerves, and leukocytes. Reciprocal interactions between mesenchymal and epithelial cells are known to play a critical role in orchestrating the development and morphogenesis of tissues and organs, but the roles played by specific stromal cells in controlling the design and function of tissues remain poorly understood. The principal cells of stromal tissue are called fibroblasts, a catch-all designation that belies their diversity. We characterized genome-wide patterns of gene expression in cultured fetal and adult human fibroblasts derived from skin at different anatomical sites. Fibroblasts from each site displayed distinct and characteristic transcriptional patterns, suggesting that fibroblasts at different locations in the body should be considered distinct differentiated cell types. Notable groups of differentially expressed genes included some implicated in extracellular matrix synthesis, lipid metabolism, and cell signaling pathways that control proliferation, cell migration, and fate determination. Several genes implicated in genetic diseases were found to be expressed in fibroblasts in an anatomic pattern that paralleled the phenotypic defects. Finally, adult fibroblasts maintained key features of HOX gene expression patterns established during embryogenesis, suggesting that HOX genes may direct topographic differentiation and underlie the detailed positional memory in fibroblasts.
1,055 citations
TL;DR: The two PDGF null phenotypes reveal analogous morphogenetic functions for myofibroblast-type cells in lung and kidney organogenesis, and show that PDGF-B is required in the ontogeny of kidney mesangial cells.
854 citations
TL;DR: TGF-beta induces proliferation of connective tissue cells at low concentrations by stimulating autocrine PDGF-AA secretion, which at higher concentrations of TGF- beta, is decreased by down-regulation of PDGF receptor alpha subunits and perhaps by direct growth inhibition.
760 citations