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Aims: 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. Methods and results: Left ventricular myocardial tissue from ischaemic or non‐ischaemic cardiomyopathy patients undergoing VAD implantation and subsequent cardiac transplantation and non‐failing hearts of the control group were analysed for 4‐hydroxyproline (4OH‐P) content as a marker for collagen protein. In addition, collagen cross‐linking and mRNAs of collagens I and III and transforming growth factor beta‐1 were measured. 4OH‐P content was significantly increased in failing hearts compared with the control group and increased (P < 0.05) after mechanical unloading (nmol/mg tissue, mean ± standard deviation: 16.74 ± 9.68 vs. 7.75 ± 2.39 and 18.57 ± 9.19). However, plotting of the 4OH‐P ratios (post/pre‐VAD) against the collagen content pre‐VAD could be fitted by non‐linear regression. Collagen cross‐linking correlated strongly with the total collagen content in pre‐ and post‐VAD myocardium (r2 = 0.73 and 0.71, respectively). In contrast to the total collagen content, all three mRNAs of fibrotic genes were significantly down‐regulated during VAD support when compared to pre‐VAD. Conclusions: This investigation of a comparably large patient cohort revealed that cardiac fibrosis was strongly increased in heart failure and increased even after mechanical unloading. The mRNAs of collagens I and III are independently regulated from the collagen protein. [ABSTRACT FROM AUTHOR]