Background Non-thrombotic platelet-endothelial interactions may contribute to atherosclerotic plaque development, although in vivo studies examining mechanism without platelet pre-activation are lacking. Using in vivo molecular imaging at various stages of atherosclerosis, we quantified platelet-endothelial interactions and evaluated the contribution of major adhesion pathways. Methods and Results Mice deficient for the LDL-receptor and Apobec-1 were studied as an age-dependent model of atherosclerosis at 10, 20, 30, and 40 wks of age, which provided progressive increase in stage from very early fatty streak (10 wks) to large complex plaques without rupture (40 wks). Platelet-targeted contrast ultrasound molecular imaging of the thoracic aorta performed with microbubbles targeted to GPIbα demonstrated selective signal enhancement as early as 10 weeks of age. This signal increased progressively with age (almost 8-fold increase from 10 to 40 weeks, ANOVA p<0.001). Specificity for platelet targeting was confirmed by the reduction in platelet-targeted signal commensurate with the decrease in platelet count after immunodepletion with anti-GPIb or anti-CD41 antibody. Inhibition of P-selectin in 20 and 40 wk atherosclerotic mice resulted in a small (15-30%) reduction in platelet signal. Molecular imaging with microbubbles targeted to the A1 domain of von Willebrand factor (VWF) demonstrated selective signal enhancement at all time points which did not significantly increase with age. Treatment of 20 and 40 week mice with recombinant ADAMTS13 eliminated platelet and VWF molecular imaging signal. Conclusions Platelet-endothelial interactions occur in early atherosclerosis. These interactions are in part due to endothelial VWF large multimers which can be reversed with exogenous ADAMTS13.
Background In diabetes mellitus reduced perfusion and capillary surface area in skeletal muscle, which is a major glucose storage site, contributes to abnormal glucose homeostasis. Using contrast-enhanced ultrasound (CEU) we investigated whether abdominal adipose tissue perfusion is abnormal in insulin resistance (IR) and correlates with glycemic control. Methods and Results Abdominal adipose tissue and skeletal muscle CEU perfusion imaging was performed in obese IR (db/db) mice at 11-12 or 14-16 weeks of age, and in control lean mice. Time-intensity data were analyzed to quantify microvascular blood flow (MBF) and capillary blood volume (CBV). Blood glucose response over one hour was measured after insulin challenge (1 u/Kg, I.P.). Compared to control mice, db/db mice at 11-12 and 14-16 weeks had a higher glucose concentration area-under-the-curve after insulin (11.8±2.8, 20.6±4.3, and 28.4±5.9 mg·min/dL [×1000], respectively, p=0.0002), and also had lower adipose MBF (0.094±0.038, 0.035±0.010, and 0.023±0.01 mL/min/g, p=0.0002) and CBV (1.6±0.6, 1.0±0.3, and 0.5±0.1 mL/100 g, p=0.0017). The glucose area-under-the-curve correlated in a non-linear fashion with both adipose and skeletal muscle MBF and CBV. There were significant linear correlations between adipose and muscle MBF (r=0.81) and CBV (r=0.66). Adipocyte cell volume on histology was 25-fold higher in 14-16 week db/db versus control mice. Conclusions Abnormal adipose MBF and CBV in IR can be detected by CEU and correlates with the degree of impairment in glucose storage. Abnormalities in adipose tissue and muscle appear to be coupled. Impaired adipose tissue perfusion is in part explained by an increase in adipocyte size without proportional vascular response.
Introduction Vaso-occlusive events play a role in the pathophysiology of sickle cell disease (SCD) and are a potential target for new therapies. There is strong evidence that platelet and endothelial activation as well as microvascular dysfunction contribute to this process. Techniques capable of spatially and temporally assessing basal or provoked tissue hypoperfusion in animal models or in patients with SCD would be valuable for evaluating new therapies. Contrast enhanced ultrasound (CEU) is a non-invasive imaging technique that relies on the ultrasound detection of microbubble contrast agents during their microvascular transit. In this study we hypothesized that CEU perfusion imaging would provide a biologic readout for abnormalities in skeletal muscle perfusion in a murine model of SCD. Materials and Methods NY1DD mice with either homozygous (n=16) or heterozygous (n=18) gene deletion of murine β globin that also transgenically express human α and βsglobin were studied at 8-10 weeks of age, while C57/BL6 mice (n=7) were used as controls. Animals were studied under basal conditions only if they appeared healthy and not in distress or pain crisis equivalent. Mice were anesthetized with inhaled isoflurane and a jugular vein was cannulated for contrast administration. CEU perfusion imaging of the proximal hindlimb adductor muscles and the myocardium was performed using continuous intravenous infusions of lipid-shelled decafluorobutane microbubbles. Time-activity curves from real-time imaging following a disruptive high power ultrasound pulse sequence was used to quantify both microvascular blood flow (MBF) and its parametric components: functional microvascular blood volume (MBV) and flux rate (β). Skeletal muscle CEU was performed at rest and during electrostimulated contractile exercise at 1 Hz. Spatial analysis of perfusion was done to assess average percent area of perfusion per areas of tissue. High-frequency echocardiography was performed to evaluate LV dimensions and stroke volume. Results Skeletal muscle MBF was significantly lower in NY1DD mice compared to controls, the extent of which was similar for the two NY1DD cohorts (MBF= 1.11±0.84, 0.58±0.77, 0.48±0.35 for control, homozygous, and heterozygous NY1DD mice, respectively; Kruskall-Wallis p<0.05). Microbubble microvascular flux rate was similarly reduced by approximately half in both NY1DD groups compared to controls (p<0.01). Skeletal muscle MBV was reduced only in the homozygous NY1DD mice (approximately 70% the volume of controls). Spatial analysis of MBV revealed coarse rather than diffuse spatial hypoperfusion in the homozygous NY1DD mice, indicating lack of perfusion downstream from large intramuscular vascular units. Electrostimulated exercise produced a significant increase in skeletal muscle MBF in all groups, although hyperemic blood flow remained 60-70% lower than controls for both NY1DD groups. In contrast to skeletal muscle perfusion, myocardial MBF was increased in NY1DD mice, largely due to increased flux rate. Echocardiography demonstrated a similar stroke volume and cardiac output between animals. Conclusions CEU perfusion imaging can be used to non-invasively detect microvascular abnormalities in murine models of SCD. Even under basal resting conditions, there is a reduction in skeletal muscle MBF. The reduction in microvascular flux rate under basal conditions and presence of MBF reserve in mice with SCD strongly suggest that abnormalities in MBF at rest were to a large extent functional in nature rather than obstructive. From spatial analysis, this appears to involve medium to large intravascular units. CEU will likely provide important insight into the pathophysiology of worsening vaso-occlusive events during crisis and may also potentially be used to assess the efficacy of new treatments for SCD. Disclosures: No relevant conflicts of interest to declare.
This chapter is dedicated to the dosing of medications in patients with chronic kidney disease. It is important for clinicians to have a working understanding of basic pharmacokinetic and pharmacodynamic principles to ensure patients with chronic kidney disease achieve the therapeutic target without toxicity. This chapter will provide a systematic approach to medication dosing in patients with chronic kidney disease by obtaining a medical history and performing a thorough physical examination, calculating an accurate assessment of renal function, determining loading dose, determining a maintenance dose, and monitoring drug levels if indicated. Specific pharmacologic considerations in the setting of renal insufficiency along with drug removal by dialysis are also outlined.
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