Applying the Input Output Analogy to Cardiac Microvasculature in Disease

Endothelial cell activation is a term that was originally coined to describe the increased adhesiveness of cultured endothelial cells that had been pretreated with cytokines. The term today may be more broadly defined as the pheno-typic response of the endothelium to an inflammatory stimulus, usually consisting of some combination of procoagulant and proadhesive properties and loss of barrier function. The term endothelial cell dysfunction was—and to some extent continues to be—used to describe reduced vasodilator reserve in conduit vessels and microvascular resistance vessels in the heart, as observed in atherosclerosis, transplantation, and heart failure. However, the term may be more broadly applied to states in which the endothe-lial phenotype—whether or not it meets the definition of activation—poses a net liability to the host. Thus, whereas endothelial cell activation describes a definable phenotype of the endothelium, endothelial cell dysfunction describes the cost of the phenotype to the organism.

Endothelial cell dysfunction may arise from any number of changes in the extracellular environment and may in turn contribute to progression in pathophysiology (Figure 3). For example, local differences in blood flow (hemodynamics) may conspire with coronary risk factors to modulate endothelial cell phenotype in the coronary arteries as a prelude to atherosclerosis. Takayasu's arteritis is a necrotizing vasculitis that may be associated with aneurismal dilation of the coronary arteries. Recent studies point to a possible role for endothelial-derived metalloproteinases in this syndrome. Many of the risk factors for conduit vessel disease have also been shown to affect microvascular endothelium, including diabetes and hypertension. Microangiopathic hemolytic anemia, as exemplified by thrombotic thrombocytopenic purpura (TTP), may be complicated by widespread occlusion of small arteries in the heart and recurrent cycles of ischemia-reperfusion. TTP is associated with increased apoptosis of endothelial cells in affected organs. The pheno-type of cardiac microvascular endothelial cells has been shown to change in patients with heart failure. Patients with dilated cardiomyopathy have reduced VEGF expression and capillary density. Ischemia-reperfusion injury of the heart is associated with increased ROS generation, decreased NO bioactivity, generation of cytokines and chemokines, complement activation, increased expression of cell adhesion molecules, trafficking of neutrophils and monocytes, mast cell activation, increased permeability, and changes in the ECM. Patients with cardiac syndrome X have reduced coronary microvascular dilatory responses and increased coronary resistance. Sepsis, which is associated with systemic activation of inflammatory and coagulation cascades, may result in abnormalities in systolic and diastolic function. The mechanism does not appear to be related to reduced coronary flow, but rather to the effect of soluble mediators (e.g., input signals) on cardiac endothelium and cardiomyocytes.

Figure 3 Schematic of cardiac endothelium in disease. The endothelium is both affected by and contributes to cardiac pathophysiology. Atherosclerosis affects the large coronary arteries. Diabetes and hypertension affect large- and small-vessel endothelium. Abnormalities in cardiomyocyte function (e.g., hypertrophic cardiomyopathy, myocarditis, and ischemia) may result in altered paracrine signaling in the endothelium and secondary endothelial cell activation and/or dysfunction. Shown is cardiomyocyte production of nitric oxide (NO) and VEGF. Ischemia/reperfusion results in the exposure of the endothelium to myriad signals, including free oxygen radicals (O2-), complement, and cytokines [e.g., interleukin (IL)-8 and monocyte chemoattractant protein (MCP)-1]. Cardiac ischemia may result in increased mobilization and/or uptake of circulating endothelial precursor cells (EPCs) in the cardiac vasculature. (see color insert)

Figure 3 Schematic of cardiac endothelium in disease. The endothelium is both affected by and contributes to cardiac pathophysiology. Atherosclerosis affects the large coronary arteries. Diabetes and hypertension affect large- and small-vessel endothelium. Abnormalities in cardiomyocyte function (e.g., hypertrophic cardiomyopathy, myocarditis, and ischemia) may result in altered paracrine signaling in the endothelium and secondary endothelial cell activation and/or dysfunction. Shown is cardiomyocyte production of nitric oxide (NO) and VEGF. Ischemia/reperfusion results in the exposure of the endothelium to myriad signals, including free oxygen radicals (O2-), complement, and cytokines [e.g., interleukin (IL)-8 and monocyte chemoattractant protein (MCP)-1]. Cardiac ischemia may result in increased mobilization and/or uptake of circulating endothelial precursor cells (EPCs) in the cardiac vasculature. (see color insert)

As a final example of microvascular disorders, endothelial dysfunction plays a critical role in mediating cardiac allograft vasculopathy following heart transplantation.

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