Assessment of endothelial damage and dysfunction: observations in relation to heart failure

More than 150 years ago, Virchow proposed that abnormalities in blood flow, vessel wall and blood components predispose to thrombosis, constituting what is now known as ‘Virchow's triad’ for thrombogenesis.1 This rather simplistic view has been continually modified by new discoveries and concepts, as we now know that the process of thrombus formation requires complex interactions involving injury to the vascular endothelium, platelet adherence, aggregation and release, and clotting factor activation, eventually leading to thrombin generation and fibrin formation.2 The endothelium has many vital and diverse (depending on the particular vascular bed) physiological roles, such as regulation of blood vessel tone, permeability, metabolism and haemostasis. Impairment of endothelial function manifests clinically as oedema, hypertension, abnormal vasoconstriction and hypercoagulability. Indeed, it is a widely held view that impaired endothelial function is also the initial step in atherogenesis, which is largely responsible for ischaemic heart disease and thrombotic strokes decades later. Impaired endothelial function is also associated with hypertension, diabetes mellitus and heart failure (regardless of aetiology), although whether as a cause or a consequence is undetermined. Hence, understanding endothelial function is likely to be a key to modifying risk factors of cardiovascular disorders and their sequelae. Nevertheless, the ideal method(s) of assessing endothelial physiology (and, therefore, pathology) remains uncertain. Various indices have been used to assess endothelial activation, dysfunction and damage: the ideal index would not only be specific to the endothelium but would also be stable and easily measurable—the ‘gold standard’ remains uncertain, as available indices quantify different aspects of endothelial physiology. In addition, words such as damage, injury, dysfunction and activation are currently freely used in the study of endothelial cell biology without a clear definition, or even a consensus, of their meaning. Certainly, a continuum is likely to exist between endothelial activation (e.g. by cytokines), endothelial …