Towards better definition, quantification and treatment of fibrosis in heart failure. A scientific roadmap by the Committee of Translational Research of the Heart Failure Association (HFA) of the European Society of Cardiology

Abstract

Fibrosis is a pivotal player in heart failure development and progression. Measurements of (markers of) fibrosis in tissue and blood may help to diagnose and risk stratify patients with heart failure, and its treatment may be effective in preventing heart failure and its progression. A lack of pathophysiological insights and uniform definitions has hampered the research in fibrosis and heart failure. The Translational Research Committee of the Heart Failure Association discussed several aspects of fibrosis in their workshop. Early insidious perturbations such as subclinical hypertension or inflammation may trigger first fibrotic events, while more dramatic triggers such as myocardial infarction and myocarditis give rise to full blown scar formation and ongoing fibrosis in diseased hearts. Aging itself is also associated with a cardiac phenotype that includes fibrosis. Fibrosis is an extremely heterogeneous phenomenon, as several stages of the fibrotic process exist, each with different fibrosis subtypes and a different composition of various cells and proteins — resulting in a very complex pathophysiology. As a result, detection of fibrosis, e.g. using current cardiac imaging modalities or plasma biomarkers, will detect only specific subforms of fibrosis, but cannot capture all aspects of the complex fibrotic process. Furthermore, several anti‐fibrotic therapies are under investigation, but such therapies generally target aspecific aspects of the fibrotic process and suffer from a lack of precision. This review discusses the mechanisms and the caveats and proposes a roadmap for future research.

The vicious cycle of arrhythmia and myocardial fibrosis

“…Cardiac remodelling includes changes in the myocytic compartment (cardiomyocyte hypertrophy) as well as changes in the non‐myocytic compartment (myocardial fibrosis) . Various ‘drivers’ may underpin the remodelling process, and it has been postulated that some triggers have more effects on cardiomyocytes whilst others are more specific to changes outside the cardiomyocyte, but in fact, there is intense cross talk between the two, and several studies have demonstrated that remodelled cardiomyocytes cause fibroblast proliferation and production of extracellular matrix (ECM) .…”

“…Extracellular TGF‐β produced by irregularly paced cardiomyocytes was able to increase production of collagens by cardiac fibroblasts. Both TGF‐β and CTGF are well‐known paracrine inducers of myocardial fibrosis and both play a role in fibroblast to myofibroblast transition (FMT) and fibroblast differentiation . After cleavage, TGF‐β binds to its cellular receptor and SMAD transcription factors are activated, eventually resulting in increased expression of ECM proteins.…”

Figures of the Heart Failure Association (HFA): Dr. Rudolf de Boer, HFA Board Member (2014–2020), Chair of the Basic Science Section (2016–2018), coordinator of the Study Group on Heart Failure with Preserved Ejection Fraction, and member of the HFA study groups of Translational Research and Cardio‐oncology

“…My adoption into ESC and HFA have brought me a lot: I profited both from learning from high‐rank researchers and clinicians as well as from networking. It has been a privilege and very learning to contribute and drive some influential committees and task forces for the development of HFA congresses and meeting programmes, and was able to contribute to position and scientific papers . I am currently member of the Board of the HFA of the ESC since 2014, I have been Chair of the Basic Science Section (2016–2018), I am the coordinator of the HFA Study Group on Heart Failure with Preserved Ejection Fraction, and member of the HFA study groups of Translational Research and Cardio‐oncology.…”

Mechanotransduction in the Cardiovascular System: From Developmental Origins to Homeostasis and Pathology

“…Heart failure is a clinical condition subject to continuous growth due to the elevation of life expectancy worldwide. Myocardial maladaptive remodeling is one of the earliest hallmarks of heart failure, a pathology characterized by inflammation and a progressive fibrosis that negatively affects the contractility of the myocardium, and leads to replacement of myocytes with a stiff fibrotic tissue [37]. In healthy conditions, quiescent cardiac fibroblasts are responsible for renewal of ECM proteins [38].…”