The stimulus for this Editorial Comment was provided by the recent publication in Cardiovascular Drugs and Therapy of an original research report from Grushko et al. [10], delineating the results of experiments related to the potential role of monocyte activation as a pivotal component of the inflammatory response to AHF. In a group of patients hospitalised with AHF, compared with control subjects, they investigated the mechanisms whereby concomitant monocyte activation (classically triggered by liposaccharide (LPS)-Toll-like receptor 4 (TLR-4) interaction) occurs in such patients. Unfortunately, the clinical characteristics of the 17 AHF patients studied are not well-described; other than that, their mean left ventricular ejection fraction was 20%. The implication, therefore, is of the occurrence of acute-on-chronic heart failure, often with past histories of hypertension and/or of known ischaemic heart disease. In particular, we have no information as to the extent of hypoxia at presentation in these patients, which might have served as an indirect measure of the extent of fluid extravasation into the lungs. In a sense, these clinical data alter the interpretation of the results of the study, because it is already known that patients with severe chronic heart failure exhibit evidence of damage to the eGC [11]. Only 5 control subjects were studied, limiting the power of the study.

The initial finding was that plasma concentrations of the eGC component heparan sulphate were significantly greater in plasma of AHF patients than in that of control subjects. It is not at all clear why similar findings were not made for other eGC components (hyaluronan and syndecan-1). Although hyaluronan levels were not elevated, the levels in individual patients correlated directly and significantly with hsCRP concentrations, thus suggesting a nexus with extent of inflammatory activation.

More importantly, plasma concentrations of heparan sulphate were directly correlated with monocyte expression of CD14, a marker of monocyte activation. The authors therefore went on to investigate whether activation of monocytes from normal subjects (via exposure to LPS, a ligand of TLR4) also induced changes in the monocyte glycocalyx (mGC). Indeed, content of mGC was substantially reduced, suggesting that monocyte activation led to shedding of much of the mGC. The next question was whether these released fragments might in turn contribute to overall inflammation in AHF. Indeed, it was found that disruption of the mGC was associated with amplification of monocyte activation, triggering release of TNFα and of IL-6.

The results of this study therefore provide evidence that AHF is associated not only with eGC damage but also with monocyte activation, which results in mGC damage (Fig. 1A–C). Furthermore, damage to the mGC creates a ‘vicious cycle’ effect, further increasing monocyte activation and monocyte production of inflammatory cytokines (Fig. 1C). The overall associated pathophysiological consequences of these processes are schematized in Fig. 2.

Schematic representation of changes within vascular lumen/endothelial glycocalyx and endothelium occurring under redox stress, as associated with acute heart failure (AHF). A Note constituents of normal endothelial glycocalyx. B Note (1) enzymes cleaving glycocalyx components (heparanase, matrix metalloproteinases (MMPs), hyaluronidase). (2) Monocyte activation and permeation of glycocalyx by Toll-like receptor 4 (TLR4) in the presence of redox stress. Because of resultant glycocalyx permeation, monocytes penetrate endothelial cells with partial differentiation into macrophages. C Details of changes at level of monocyte including positive feedback

Schematic view of changes at levels of vascular lumen, eGC, endothelial cells, and within vascular smooth muscle, in association with redox stress. Note. Contribution of monocyte glycocalyx shedding to overall process

What remains to be elucidated at this stage? First, we need to know more about the extent of individual versus coordinated overall control of the various components of glycocalyx shedding associated with acute inflammatory states, which include not only heart failure (acute and chronic) but also acute myocardial ischaemia due to acute myocardial infarction [12] or acute exacerbations of coronary artery spasm [6]. Perhaps of greatest interest, TakoTsubo Syndrome, which usually presents as an acute coronary syndrome and evolves into a prolonged myocarditis-like condition with associated myocardial infiltration by neutrophils and macrophages, is associated with marked release of syndecan-1 into plasma, indicative of eGC ‘shedding’ [13]. Furthermore, eGC ‘shedding’ has been extensively documented in association with sepsis and the acute phase of COVID-19 infection. In none of these conditions has the question of how the better-known phenomenon of eGC damage might interact directly rather than indirectly with activation and transmigration of neutrophils and monocytes, or indeed with the pro-inflammatory effects of the resultant accumulation of tissue macrophages. Together, Figs. 1 and 2 schematize our current understanding of this complex process of circulatory disturbance through impaired microvascular rheology, vascular permeabilization with efflux of not only fluid but also of inflammatory cells, and platelet activation/adhesion/aggregation [5].

It is also more apparent than ever that the (patho)physiological roles of activated monocytes per se need to be considered, rather than simply considering monocyte activation as a precursor to conversion to macrophages with a spectrum ranging from pro- to anti-inflammatory properties.