Background: Atrial fibrillation (AF) is associated with increased thromboembolic risk. More importantly, new onset AF (NAF) has been linked to inflammatory activation, impairment of nitric oxide (NO) signalling and increased generation of reactive oxygen species. Cardiac remodelling and development of AF can be initiated in animal models by infusion of angiotensin II resulting in stimulation of myeloperoxidase (MPO) activity and activation of matrix metalloproteinases. These factors are associated with variable endothelial glycocalyx “shedding” (GS), thus increasing cell permeability and distorting shear sensing in the macro-and micro-vasculature.
Hypotheses: (1) NAF is associated with increased GS relative to chronic AF and (2) the extent of GS in AF is predictable on the basis of inflammation and impairment of NO signalling.
Methods: Plasma levels of syndecan1 (SD1), the most prevalent proteoglycan component of GS, were measured in 59 chronic AF, 31 NAF patients and 23 controls. Determinants of extent of SD1 elevation were sought via univariate followed by multivariate analyses, including (a) markers of inflammation (CRP and MPO levels), (b) indices of NO signalling (plasma asymmetric dimethyl arginine [ADMA], platelet response to a NO donor), and stroke risk (CHA2DS2VASc score).
Results: SD1 levels in NAF were elevated (p = 0.01, 1-way ANOVA) compared to those of chronic AF and controls. In both chronic and NAF patients, there were significant univariate correlations (p < 0.05 in all cases) between SD1 concentrations and patients’ ages, CHA2DS2VASc scores (inverse correlation), MPO levels, platelet response to SNP and ADMA levels. On multivariate analyses, plasma SD1 levels in AF patients were related directly and significantly to MPO and ADMA levels (p = 0.0001 and p = 0.03, respectively).
Conclusions: NAF is associated with increased GS. The extent of GS correlates independently with markers of MPO release and of impairment of NO generation. It is likely that increased GS, whether triggered by MPO or other pro-inflammatory mediators, creates a “vicious cycle” in NAF, potentiating tissue infiltration by neutrophils and further increasing MPO release. This cascade of events may contribute to greater thromboembolic stroke risk in NAF patients.