Endothelial dysfunction in cardiovascular disease and Flammer syndrome-similarities and differences

Abstract

The endothelium has increasingly been recognized as a smart barrier and a key regulator of blood flow in micro- and macrovascular beds. Endothelial dysfunction marks a stage of atherosclerosis and is an important prognostic marker for cardiovascular disease. Yet, some people who tend to be slim and physically active and with rather low blood pressure show a propensity to respond to certain stimuli such as emotional stress with endothelial-mediated vascular dysregulation (Flammer syndrome). This leads to characteristic vascular symptoms such as cold hands but also a risk for vascular-mediated diseases such as normal-tension glaucoma. It is the aim of this review to delineate the differences between Flammer syndrome and its "counterpart" endothelial dysfunction in the context of cardiovascular diseases.

Keywords: Atherosclerosis; Endothelium; Flammer syndrome; Glaucoma; Patient stratification; Predictive diagnostics; Primary vascular dysregulation.

Fig. 1

The endothelium actively sends relaxing/dilating and constrictive signals to the smooth muscle cells. Three central pathways are outlined: The constituent endothelial nitric oxide synthase (eNOS, NOS III) is regulated by endocrine and paracrine effects such as endothelin-1 (ETR, ET-1) and acetylcholine (ACh) as well as shear stress via pertussis toxin-sensitive G_q/i pathways, calcium, and calmodulin. Nitric oxide (NO) signals relaxation, but uncoupling can lead to increased oxidative stress (H ₂ O ₂). The endothelial cells also evoke hyperpolarization of the cell membrane of smooth muscle cells (endothelium-dependent hyperpolarization factor (EDHF)). Cyclooxygenase 1 (COX) produces eicosanoids that have in the case of prostacyclin (PGI ₂) relaxing effects through cyclic AMP or constrictive effects particularly for thromboxane A₂ (TXA ₂). Angiotensin II (A II) has direct (by angiotensin receptor 1 (AT1)) or indirect constrictive effects through ET-1

Fig. 2

Method of flow-mediated dilation to measure endothelial dysfunction. The graph shows the diameter at baseline (A), during 5 min of cuff inflation (B), and the reactive hyperemic vasodilation with initial vasoconstriction (C). The diameters were measured on a longitudinal section of the brachial conduit artery in 2D mode. The measurements are automatically computed by FMD Studio (Quipu srl, Pisa)

Fig. 3

Static retinal vessel analysis by semi-automatically tracing all vessels in a range of 0.5 to 1 its diameter around the optic disc. By dividing the sum of diameters of arterioles and venules, the arteriovenous ratio is calculated. The “Atherosclerosis in Community Study” (ARIC) has widely validated association of the arteriovenous ratio with cardiovascular risk and outcome. Normal values are age-dependent and lie in a range of 0.75–1 [55]

Fig. 4

Description of dynamic retinal vessel analysis. a Video automated tracing of marked arteriole (red) and venula (blue) for tracing during flicker light. b Relative diameter over time: baseline, dilatation due to flicker light (during gray-shaded area) expressed as relative diameter compared to baseline (100%), and return to baseline. Of note, normal values are in a range of 2–12% and a 19% increment in radius will double the volume flow rate according to Poiseuille’s law. Also baseline amplitude, slope, and postdilatative contraction can be measured [65]. Importantly, both arterial and venous (c) dilatative response have been linked to disease [66, 67]. Green line: normal range, red/blue lines: normal flicker-induced arterial/venous dilatation, dark gray line: pathological, blunted response to flicker light