Myocardial damage as a consequence of cardiotropic viruses leads to a broad variety of clinical presentations and is still a complicated condition to diagnose and treat. Whereas the extracellular matrix protein Secreted Protein Acidic and Rich in Cysteine or SPARC has been implicated in hypertensive and ischemic heart disease by modulating collagen production and cross-linking, its role in cardiac inflammation and endothelial function is yet unknown. Absence of SPARC in mice resulted in increased cardiac inflammation and mortality, and reduced cardiac systolic function upon coxsackievirus-B3 induced myocarditis. Intra-vital microscopic imaging of the microvasculature of the cremaster muscle combined with electron microscopic imaging of the microvasculature of the cardiac muscle uncovered the significance of SPARC in maintaining endothelial glycocalyx integrity and subsequent barrier properties to stop inflammation. Moreover, systemic administration of recombinant SPARC restored the endothelial glycocalyx and consequently reversed the increase in inflammation and mortality observed in SPARC KO mice in response to viral exposure. Reducing the glycocalyx in vivo by systemic administration of hyaluronidase, an enzyme that degrades the endothelial glycocalyx, mimicked the barrier defects found in SPARC KO mice, which could be restored by subsequent administration of recombinant SPARC. In conclusion, the secreted glycoprotein SPARC protects against adverse cardiac inflammation and mortality by improving the glycocalyx function and resulting endothelial barrier function during viral myocarditis.

Patients with MVA can be characterized by microvascular glycocalyx dysfunction using sublingual microscopy. The strong correlation between sublingual PBR responsiveness and myocardial perfusion reserve suggests that the glycocalyx may play an important role in the regulation of microvascular volume for myocardial perfusion and supports the concept of impaired glycocalyx barrier properties in MVA.

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Experimental evidence suggests gender differences in atherogenic susceptibility. Given the role of the endothelial glycocalyx in vascular homeostasis, we compared in the present study systemic glycocalyx volumes in anesthetized female (F; n=6) and male (M; n=7) C57Bl/6 mice (~25 g body weigth (BW)). Systemic glycocalyx volume (Vg, in ml/kg BW) was determined from the difference in distribution volume (Vd, in ml/kg BW) of FITC‐labelled 70 kDa dextrans (D70), used as plasma tracer, and Texas Red‐labelled 40 kDa dextrans (D40), which have full access to the glycocalyx domain. Tracers were simultaneously infused into the jugular vein and Vd calculated from the initial plasma concentration. Vd for D70 was not different between F (33 ± 4) and M (38 ± 1), but Vd for D40 was smaller (P=0.05) in F (37 ± 4) compared to M (46 ± 2), resulting in a smaller (P<0.005) Vg in F (3.7 ± 0.9) than in M (8.0 ± 0.7). True circulating plasma volume (Vp, in ml/kg BW) was subsequently derived from the dilution of NaF labelled red blood cells and hematocrit, and was not different between F (26 ± 2, n=4) and M (26 ± 2, n=5). In conclusion, our data show the presence of a gender difference in systemic glycocalyx volume in mice. The 50% reduction in glycocalyx volume in female mice might underlie their increased susceptibility to the development of atherosclerosis. Supported by Established Investigatorship from Netherlands Heart Foundation (#2005T037, to HV).

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