The fibrosis-cell death axis in heart failure

Abstract

Cardiac stress can induce morphological, structural and functional changes of the heart, referred to as cardiac remodeling. Myocardial infarction or sustained overload as a result of pathological causes such as hypertension or valve insufficiency may result in progressive remodeling and finally lead to heart failure (HF). Whereas pathological and physiological (exercise, pregnancy) overload both stimulate cardiomyocyte growth (hypertrophy), only pathological remodeling is characterized by increased deposition of extracellular matrix proteins, termed fibrosis, and loss of cardiomyocytes by necrosis, apoptosis and/or phagocytosis. HF is strongly associated with age, and cardiomyocyte loss and fibrosis are typical signs of the aging heart. Fibrosis results in stiffening of the heart, conductivity problems and reduced oxygen diffusion, and is associated with diminished ventricular function and arrhythmias. As a consequence, the workload of cardiomyocytes in the fibrotic heart is further augmented, whereas the physiological environment is becoming less favorable. This causes additional cardiomyocyte death and replacement of lost cardiomyocytes by fibrotic material, generating a vicious cycle of further decline of cardiac function. Breaking this fibrosis-cell death axis could halt further pathological and age-related cardiac regression and potentially reverse remodeling. In this review, we will describe the interaction between cardiac fibrosis, cardiomyocyte hypertrophy and cell death, and discuss potential strategies for tackling progressive cardiac remodeling and HF.

Keywords: Cardiomyocyte; Cell death; Fibroblast; Fibrosis; Heart failure; Hypertrophy; Myofibroblast; TGFβ.

Fig. 1

Different types of fibrosis. Mouse cardiac tissue was stained with Masson’s trichrome stain to visualize cardiomyocytes in red and fibrotic fibers in blue. Pictures with interstitial and perivascular fibrosis are from pressure overload (TAC) mouse hearts and replacement fibrosis from mouse hearts with a myocardial infarction. Bar indicates 50 µm

Fig. 2

A simplified depiction of the vicious cycle of myofibroblast activation, impaired cardiac function and cardiomyocyte cell death. This simplified scheme shows in the outer circle (black) the role of myofibroblasts in fibrogenesis and cardiac impairment, whereas the inner processes predominantly reflect paracrine signaling effects. Together, this generates a sustained response of progressive cardiac deterioration. FMT fibroblasts to myofibroblasts transition, IL-6 interleukin-6, IL-33 interleukin-33, FGF2 fibroblast growth factor 2, TGFβ transforming growth factor beta. Lightning symbols indicate stressors acting on the cells

Fig. 3

Suggested three pillars of heart failure treatment. Current standard heart failure (HF) therapy is focused at relief of the initial problem and aims at unloading the heart. Upon detection of HF, the sustained process of cardiac hypertrophy, fibrosis and cardiomyocyte cell death is already ongoing in most patients and cannot be stopped without additional treatment. We therefore suggest that to halt this sustained process, additional therapy will be required that blocks fibrotic processes and improves cardiomyocyte function. FMT fibroblasts to myofibroblasts transition, ECM extracellular matrix