The vasculature: a therapeutic target in heart failure?

Abstract

It is well established that the vasculature plays a crucial role in maintaining oxygen and nutrients supply to the heart. Increasing evidence further suggests that the microcirculation has additional roles in supporting a healthy microenvironment. Heart failure is well known to be associated with changes and functional impairment of the microvasculature. The specific ablation of protective signals in endothelial cells in experimental models is sufficient to induce heart failure. Therefore, restoring a healthy endothelium and microcirculation may be a valuable therapeutic strategy to treat heart failure. This review article will summarize the current understanding of the vascular contribution to heart failure with reduced or preserved ejection fraction. Novel therapeutic approaches including next generation pro-angiogenic therapies and non-coding RNA therapeutics, as well as the targeting of metabolites or metabolic signalling, vascular inflammation and senescence will be discussed.

Keywords: Angiogenesis; MicroRNAs; Microcirculation; Non-coding RNAs.

Figure 1

Compared characteristics of the microvasculature in different pathological diseases. Ischaemic HF shows a reduced capillary density with inflamed endothelium. There is massive cardiomyocyte death plus a hypertrophic compensatory effect on the remote zone. Furthermore, there is invasion of bone marrow-derived macrophages. First, there is a compensatory hypertrophy characterized by an increase of capillary density and cardiomyocyte increased size followed by a maladaptive hypertrophy is characterized by capillary rarefaction and an inflamed endothelium, interstitial fibrosis and the presence of bone marrow-derived macrophages. Moreover, the cardiomyocytes are hypertrophic and there is sporadic cardiomyocyte death. Finally, HFpEF is also characterized by reduced capillary density and inflamed endothelium. This is accompanied by interstitial fibrosis, sporadic cardiomyocyte death, and hypertrophy. HFpEF hearts also show the presence of bone marrow-derived macrophages.

Figure 2

Schematic of the different mechanisms regulating vascular homeostasis in the heart and the molecular players involved in them. There mechanism specific for the maintenance of vascular homeostasis like the endothelial metabolism, angiogenesis and the formation of collaterals, or the signals involved in atherosclerosis and inflammation. Other mechanisms like nutrient transport or the effect on cardiomyocyte relaxation have an effect directly on cardiomyocytes.

Figure 3

Graphical scheme of the different strategies to improve microcirculatory dysfunction in the HF.