We present evidence that the 0.5 microm thick gel layer, lining the inner wall of healthy blood vessels, the glycocalyx, is the first line of defence against atherothrombotic disease. All blood vessel linings are coated with this gel, a highly negatively charged structure, rich in anionic sites mostly represented by the sialic acid moieties of glycoproteins and the sulphate and carboxyl groups of heparan-sulphate proteoglycans. Blood flow in arteries is associated with a shear stress at the glycocalyx, which signals the underlying endothelial cells to release nitric oxide (NO), an anti-atherogenic factor. Sites of low shear stress in the arterial tree are more susceptible to atheroma due to lack of NO generation through this mechanism, whereas exercise, by increasing blood flow and shear stress, is protective. We postulate that risk factors for atherothrombosis act by impairing glycocalyx function. That luminal hyperglycaemia causes glycocalyx dysfunction has already been shown; we postulate this to be the first step in the atherothrombotic process in patients with diabetes mellitus and metabolic syndrome (insulin resistance). There is also evidence of glycocalyx defects from exposure to oxidized low-density lipoprotein. We postulate that other risk factors will have a similar action on the glycocalyx as the initiating factor in the disease process, e.g. smoking, hyperlipidaemias and hyperhomocystenaemia. These predictions can now be tested in a large animal model of shear-stress-mediated arterial dilatation.

P1 was interpreted as the expression of accumulation of activator in an internal release store; P3 was interpreted as a manifestation of negative feedback control of activator entry by the released activator itself, and the slow recovery to P4 as due to the slow lengthening of action potential duration and/or recovery from accumulation of an intracellular metabolite or ion.

Fourteen patients undergoing routine cardiac catheterisation were paced at a steady frequency; after this test, stimuli were introduced with a variable preceding interval (test pulse interval). The QT interval of the electrocardiogram and the duration of the monophasic action potential of the right ventricle were measured. QT interval is a function of action potential duration; the two variables were very closely correlated in this study. Both these variables increased in duration with increasing test pulse interval. A biphasic response, as previously reported, was not seen. An increase in steady state pacing frequency caused QT interval and action potential duration to decrease for any given R-R interval. When frequency of stimulation was suddenly increased and then maintained, there was an immediate action potential shortening followed by a further more gradual shortening occurring over several minutes. These results imply that a simple correction of QT interval for heart rate (QTc) is inadequate. It is concluded that the relation between action potential duration (or QT interval) and heart rate depends on both the instantaneous interval between beats and the duration of the prevailing heart rate.