Optical coherence tomography-based complex characteristics of TCFA and microchannel were the potential predictors of subsequent progression of NSCPs in patients with CAD.

Background-Renal dysfunction is commonly accompanied by a worsening of atherosclerosis; however, the underlying molecular mechanism is not fully understood. We examined the role played by soluble fms-like tyrosine kinase-1 (sFlt-1), an endogenous antagonist of the proatherogenic cytokine placental growth factor (PlGF), in the worsening of atherosclerosis in patients with renal dysfunction and in an animal model of renal failure. Methods and Results-In this study, 329 patients who received cardiac catheterization and 76 patients who underwent renal biopsy were enrolled. Both plasma sFlt-1 levels and renal sFlt-1 mRNA expression were positively correlated with estimated glomerular filtration rate (PϽ0.01). The PlGF/sFlt-1 ratio was negatively correlated with estimated glomerular filtration rate (PϽ0.01), whereas plasma PlGF levels were not affected by it. The PlGF/sFlt-1 ratio was significantly higher in patients with multivessel coronary artery disease than in patients with single-vessel or no coronary artery disease. The reduction of circulating sFlt-1 and renal sFlt-1 mRNA levels was confirmed in five-sixths (5/6)-nephrectomized apolipoprotein E-deficient mice that developed experimental renal dysfunction. Atherosclerotic plaque area and macrophage infiltration into the plaque were significantly higher in 5/6 -nephrectomized apolipoprotein E-deficient mice than in control mice, but replacement therapy with recombinant sFlt-1 significantly reduced both plaque formation and macrophage infiltration. Conclusions-The present study demonstrates that a reduction in the circulating levels of sFlt-1 is associated with the worsening of atherosclerosis that accompanies renal dysfunction. (Circulation. 2009;120:2470-2477.)Key Words: atherosclerosis Ⅲ coronary disease Ⅲ growth substances Ⅲ heart failure Ⅲ kidney C hronic kidney disease is a worldwide public health problem not only because it leads to end-stage renal failure 1-3 but also because it is an independent risk factor for atherosclerosis-related cardiovascular events. 4,5 Accumulating evidence indicates that atherosclerosis is often worsened in patients with renal dysfunction, 6 -9 and the risk of cardiovascular disease increases sharply as the estimated glomerular filtration rate (eGFR) declines. 10 Additionally, more than 50% of deaths among end-stage renal failure patients are due to cardiovascular events. 11 Although it is clear that most cardiovascular events associated with renal dysfunction result from atherosclerosis, the underlying molecular mechanism responsible for the worsening of atherosclerosis in chronic kidney disease is not yet fully understood. Consequently, an effective therapeutic strategy is still lacking. Clinical Perspective on p 2477Fms-like tyrosine kinase 1 (Flt-1), which is a receptor tyrosine kinase and a member of the vascular endothelial growth factor (VEGF) receptor family, 12 is a specific receptor for placental growth factor (PlGF) and VEGF-A. Soluble Flt-1 (sFlt-1), which consists of the 6 extracellular immunoglobulin-like domains ...

Placental growth factor is rapidly produced in infarct myocardium, especially by endothelial cells during the acute phase of myocardial infarction. Placental growth factor might be over-expressed to compensate the acute ischemic damage, and appears to then act to improve LVEF during the chronic phase.

Both BNP and NT-proBNP are useful biomarkers for mortality and cardiovascular events, but NT-proBNP may be superior to BNP for CKD stages 4-5.

Patients with chronic kidney disease (CKD) die of cardiovascular diseases for unknown reasons. Blood vessel formation in plaques and its relationship with plaque stability could be involved with signaling through the Flt-1 receptor and its ligands, vascular endothelial growth factor, and the closely related placental growth factor (PlGF). Flt-1 also exists as a circulating regulatory splice variant short-inhibitory form (sFlt-1) that serves as a decoy receptor, thereby inactivating PlGF. Heparin releases sFlt-1 by displacing the sFlt-1 heparin-binding site from heparin sulfate proteoglycans. Heparin could provide diagnostic inference or could also induce an antiangiogenic state. In the present study, postheparin sFlt-1 levels were lower in CKD patients than in control subjects. More importantly, sFlt-1 levels were inversely related to atherosclerosis in CKD patients, and this correlation was more robust after heparin injection, as verified by subsequent cardiovascular events. Knockout of apolipoprotein E (ApoE) and/or sFlt-1 showed that the absence of sFlt-1 worsened atherogenesis in ApoE-deficient mice. Thus, the relationship between atherosclerosis and PlGF signaling, as regulated by sFlt-1, underscores the underappreciated role of heparin in sFlt-1 release. These clinical and experimental data suggest that novel avenues into CKD-dependent atherosclerosis and its detection are warranted.