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Noninvasive imaging methods are required to monitor the inflammatory content of atherosclerotic plaques. FEDAA1106 (N-(5-fluoro-2-phenoxyphenyl)-N-(2-(2-fluoroethoxy)-5-methoxybenzyl) acetamide) is a selective ligand for TSPO-18kDa (also known as peripheral benzodiazepine receptor), which is expressed by activated macrophages. We compared 18F-FEDAA1106 and 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG, a marker of glucose metabolism) for positron emission tomographic (PET) imaging of vascular inflammation. This was tested using a murine model in which focal inflammation was induced in the carotid artery via placement of a constrictive cuff. Immunostaining revealed CD68-positive cells (macrophages) at a disturbed flow site located downstream from the cuff. Dynamic PET imaging using 18F-FEDAA1106 or 18F-FDG was registered to anatomic data generated by computed tomographic (CT)/CT angiography. Standardized uptake values were significantly increased at cuffed compared to contralateral arteries using either 18F-FEDAA1106 (p < .01) or FDG (p < .05). However, the 18F-FEDAA1106 signal was significantly higher at the inflamed disturbed flow region compared to the noninflamed uniform flow regions, whereas differences in FDG uptake were less distinct. We conclude that 18F-FEDAA1106 can be used in vivo for detection of vascular inflammation. Moreover, the signal pattern of 18F-FEDAA1106 corresponded with vascular inflammation more specifically than FDG uptake. [ABSTRACT FROM AUTHOR]

Interest in the use of contrast-enhanced MRI to enable in vivo specific characterization of atherosclerotic plaques is increasing. In this study the intrinsic ability of three differently sized gadolinium-based contrast agents to permeate different mouse plaque phenotypes was evaluated with MRI. A tapered cast was implanted around the right carotid artery of apoE mice to induce two different plaque phenotypes: a thin cap fibroatheroma (TCFA) and a non-TCFA lesion. Both plaques were allowed to develop over 6 and 9 weeks, leading to an intermediate and advanced lesion, respectively. Signal enhancement in the carotid artery wall, following intravenous injection of Gd-HP-DO3A as well as paramagnetic micelles and liposomes was evaluated. In vivo T-weighted MRI plaque enhancement characteristics were complemented by fluorescence microscopy and correlated to lesion phenotype. The two smallest contrast agents, i.e. Gd-HP-DO3A and micelles, were found to enhance contrast in T-weighted MR images of all investigated plaque phenotypes. Maximum contrast enhancement ranged between 53 and 70% at 6 min after injection of Gd-HP-DO3A with highest enhancement and longest retention in the non-TCFA lesion. Twenty-four hours after injection of micelles maximum contrast enhancement ranged between 24 and 35% in all plaque phenotypes. Administration of the larger liposomes did not cause significant contrast enhancement in the atherosclerotic plaques. Confocal fluorescence microscopy confirmed the MRI-based differences in plaque permeation between micelles and liposomes. Plaque permeation of contrast agents was strongly dependent on size. Our results implicate that, when equipped with targeting ligands, liposomes are most suitable for the imaging of plaque-associated endothelial markers due to low background enhancement, whereas micelles, which accumulate extravascularly on a long timescale, are suited for imaging of less abundant markers inside plaques. Low molecular weight compounds may be employed for target-specific imaging of highly abundant extravascular plaque-associated targets. Copyright © 2010 John Wiley & Sons, Ltd. In this study the intrinsic ability of three differently sized gadolinium-based contrast agents to permeate different mouse plaque phenotypes was evaluated with MRI. Gd-HP-DO3A and paramagnetic micelles were found to enhance T-weighted MR images of the plaques, whereas paramagnetic liposomes did not cause significant plaque enhancement. This knowledge can be used to improve the design of targeted contrast agents directed towards specific markers of vulnerable and stable plaque. [ABSTRACT FROM AUTHOR]

Focuses on the role of innate and adaptive immunity in atherosclerosis. Details of physiology of innate as well as adaptive immune system; Subdivisions of adaptive immunity system; Description of process of activation of innate and adaptive immunity in atherosclerosis.

Aims The purpose of this study was to investigate the relation between acute coronary flow reduction and arterial wall temperature.Methods and results Five pigs with normal coronary arteries were catheterized. Arterial wall temperature was studied with a thermographic system that uses a 4-thermistor sensor tip. Flow velocity was studied at the same time and place with the temperature measurements, using a Doppler wire. In order to modify the coronary flow, a balloon was gradually inflated proximally to the thermographic sensors. Temperature differences and flow velocities were simultaneously recorded.Flow velocities above an average peak velocity (APV) of 9cm/s were associated with unaffected temperature measurements. At flow velocities around 4cm/s, the wall temperature was increased (ΔT=0.015±0.005oC, P∼0.05), following the heart-rate. When flow velocity dropped further below this value, the local wall temperature was logarithmically increased to a maximum value observed at total vessel occlusion (ΔT=0.188±0.023oC, P<0.001).Conclusion The reduction of coronary flow has an effect on the arterial wall temperature. This effect however, appears only below a critical threshold of APV and in a logarithmic fashion. Above this threshold, temperature measurements should be unaffected from flow reductions and related to the regional temperature heterogeneity. [ABSTRACT FROM PUBLISHER]

Objective: We investigated whether an increased oxygen cost of contractility and/or a decreased myofibrillar efficiency contribute to oxygen wastage of stunned myocardium. Because Ca2+-sensitizers may increase myofibrillar Ca2+-sensitivity without increasing cross-bridge cycling, we also investigated whether EMD 60263 restores myofibrillar efficiency and/or the oxygen cost of contractility. Methods: Regional fiber stress and strain were calculated from mesomyocardially implanted ultrasound crystals and left ventricular pressure in anesthetized pigs (n=18). Regional myocardial oxygen consumption (MVO2) was measured before contractility (end-systolic elastance, Ees) and total myofibrillar work (stress–strain area, SSA) were determined from stress–strain relationships. Atrial pacing at three heart rates and two doses of dobutamine were used to vary SSA and Ees, respectively. After stunning (two times 10-min ischemia followed by 30-min reperfusion), measurements were repeated following infusion of saline (n=8) or EMD 60263 (1.5 mg·kg−1 i.v., n=10). Linear regression was performed using: MVO2=α·SSA+β·Ees+γ·HR−1 (α−1, myofibrillar efficiency; β, oxygen cost of contractility; and γ, basal metabolism/min). Results: Stunning decreased SSA by 57% and Ees by 64%, without affecting MVO2, while increasing α by 71% and β by 134%, without affecting γ. From the wasted oxygen, 72% was used for myofibrillar work and 18% for excitation–contraction coupling. EMD 60263 restored both α and β. Conclusions: Oxygen wastage in stunning is predominantly caused by a decreased myofibrillar efficiency and to a lesser extent by an increased oxygen cost of contractility. Considering that EMD 60263 reversed both causes of oxygen wastage, it is most likely that this drug increases myofibrillar Ca2+-sensitivity without increasing myofibrillar cross-bridge cycling. [ABSTRACT FROM PUBLISHER]

Investigates systolic and diastolic left ventricular function in terms of pressure-volume relationships before and after ischemia. Perfusion of porcine hearts; Energy transformation of the myocardium; Relationship between oxygen consumption and the total mechanical work; Shifting of the systolic pressure-volume relationship and contractile efficiency.

Compares the degree of right and left ventricular stunning induced by a ten-minute occlusion of the left anterior descending coronary artery and the response to subsequent atrial pacing without and with dobutamine. Systemic hemodynamics; Regional contractility; Regional segment length shortening; Regional total mechanical work (PLA).

Objective: In order to determine whether the relatively high oxygen consumption of stunned myocardium is related to decreased mechanical efficiency, myocardial oxygen consumption (MVO2) and its major determinants were studied in 10 open chest anaesthetised pigs. Methods: According to the time varying elastance concept, MVO2 is determined by contractility (Emax) and total mechanical work (PLA), which is the sum of the external work (EW) and potential energy (PE). Mechanical efficiency (EW/MVO2) equals the product of EW/PLA (=efficiency of energy transfer or EET) and PLA/MVO2. Eimx is the slope of the end systolic pressure-segment length relationship, determined by gradually clamping the aorta. PLA is the area enclosed by the end systolic pressure-segment length relationship and the pressure-segment length trajectory. EW is the area of the pressure-segment length loop. Systemic haemodynamics, regional segment shortening, and MVO2 were determined at baseline, during stunning (two sequences of 10 min occlusion and 30 min of reperfusion), after a subsequent 50 beats·min−1 increase in heart rate by atrial pacing and additional infusion of 2 μg·kg−1·min−1 dobutamine. Results: Stunning decreased segment shortening from 18.2(SEM 1.9)% to 10.2(1.5)%, MVO2 from 4.16(0.27) × 102 to 2.84(0.25) × 12 μ·mol·bear−1g−1, and Emax from 47(9) to 23(3) mm Hg·mm−1 (all p < 0.05). PLA decreased by 13(4)%, as EW decreased by 42(6)%, and PE tended to increase. Although EET decreased from 0.58(0.04) to 0.40(0.03) (p < 0.05), there was no decrease in the mechanical efficiency, as an increase in PE caused an increase in PLA/MVo, which compensated for the decrease in EET. Dobutamine infusion increased Emax and EW per beat to 120(23)% and 67(8)% of baseline, respectively, while MVO2 [4.12(0.53) μmol·beat−1·g−1] and EET [0.57(0.04)] returned to baseline. Conclusions: In stunned myocardium, mechanical efficiency is not decreased despite a decrease in EET. The increase in EET after dobutamine may explain the lack of the excessive increase in MVO2.Cardiovascular Research 1993;27:740-747 [ABSTRACT FROM PUBLISHER]

Study objective — The aim as to compare the responses of intracoronary infusions of ATP, an endothelium dependent vasodilator, with adenosine following brief ischaemia (10 min) and reperfusion in a model of myocardial stunning.Design — In group 1 (n=6), coronary blood flow and endocardial (endo) and epicardial (epi) percent segment length shortening were measured in the distribution of the left anterior descending coronary artery before and during maximal intracoronary infusions of either adenosine or ATP (20 (μg·kg−1·min−1). Measurements were obtained before and after myocardial stunning both at control heart rate and during atrial pacing (150 beats·min−1). In group 2 (n=6), myocardial blood flows by microspheres and arterial-venous lactate and oxygen differences were determined following the same ischaemia-reperfusion protocol to characterise transmural changes in blood flow and metabolism in this model of stunning.Experimental material — The experiments were done on 12 anaesthetised swine, weight 25-39 kg.Measurements and main results — In group 1, baseline endo and epi segment length shortening were 16(SD 3)% and 14(6)% and following reperfusion were reduced to 10(4)% and 8(6)% respectively (p<0.05). Prior to stunning, minimal coronary resistances during adenosine and ATP were 0.81(0.40) and 0.76(0.25) mm Hg·min·ml−1 respectively and following reperfusion were 0.86(0.31) (NS) and 0.85(0.23) (NS) mm Hg·min·ml−1 respectively. Infusion of either vasodilator enchanced function by 30% following reperfusion whereas no such effect was observed prior to ischaemia. In group 2, no maldistribution of blood flow was observed following the same ischaemia-reperfusion protocol to account for this vasodilator enhancement in function. Percent lactate extraction values were 29(11)% and 25(14)% at preischaemic control and paced heart rates respectively, and following reperfusion were lowered to 0(12)% without pacing (p<0.05) and −1(34)% during pacing (p<0.05).Conclusions — Brief ischaemia and reperfusion in swine induces myocardial stunning without altering the vasodilator responses of either ATP, an endothelium dependent vasodilator, or adenosine. Recruitment in postischaemic segment length shortening was observed during infusions of both vasodilators at a time when maldistribution of flow was not observed. Possible mechanisms include either enhanced washout of lactate from the reperfused myocardium or greater utilisation of substrates during higher blood flows. [ABSTRACT FROM PUBLISHER]

Background: The presence of smooth muscle fibers on the wall of large arteries would suggest that arterial compliance might change in response to vasoactive substances. The purpose of this study is to determine the basal level of vasomotor tone in these arteries in a commonly used animal preparation and to learn whether the compliance of large conductance arteries can be altered in vivo by vasoactive agents. Methods: Proximal iliac arterial compliance was measured in 7 pentobarbital-anesthetized pigs, before and during local infusions of adenosine and norepinephrine. Luminal area was measured every forty milliseconds by means of a 30 MHz intravascular ultrasound catheter and an automatic edge detection program. Simultaneous high-fidelity pressure measurements were obtained by means of a catheter-tipped pressure microtransducer positioned at the origin of the iliac artery. Linear regression analysis of the area/pressure relationship in two consecutive cardiac cycles (systolic phase only) was performed before and during adenosine and norepinephrine infusions. The slope of the area/pressure regression line was defined as an index of arterial compliance. Measurements after three minutes of infusions of adenosine (5–5000 μg/minute) and norepinephrine (0.001–10 μg/minute) were compared with the control measurements. Results: Even at the highest infusion rate, adenosine did not significantly increase arterial compliance as compared with baseline (25 ±7 vs 19 ±4 mm²/mmHg ⊗ 10-3, respectively, P = ns). In contrast, norepinephrine decreased arterial compliance as compared with the second baseline control (13 ±3 vs 20 ±3 mm²/mmHg ⊗ 10-3 respectively, P < 0.01). Conclusions: In this animal model with pentobarbital anesthesia, arterial compliance may be modified more by the acute infusion of norepinephrine than by adenosine in large conductance arteries such as the proximal iliac. Thus, in this preparation, smooth muscle tone tends to be minimal and arterial compliance near maximal (ie, mostly a passive phenomenon). However, in response to norepinephrine, arterial compliance can decrease significantly as smooth muscle tone increases. Intravascular ultrasound allows continuous and accurate monitoring of these changes of arterial dimensions, suggesting that this technique may be useful in the evaluation of pharmacologically induced changes in the compliance of large arteries by vasoactive agents. [ABSTRACT FROM AUTHOR]

The article discusses research on the JAG1-NOTCH4 pathway sensing of disturbed flow, which enhances atherosclerosis susceptibility by regulating Endothelial cell (EC) heterogeneity, and that the pathway may treat atherosclerosis. Researchers used porcine and murine arteries and cultured human coronary artery EC that disturbed flow activates the JAG1-NOTCH4 signaling pathway. Single-cell ribonucleic acid sequencing in Jag1ECKO mice demonstrated that Jag1 suppresses subsets of ECs.

Evidence is accumulating that calcium-rich microdeposits in the vascular wall might play a crucial role in the onset and progression of atherosclerosis. Here we investigated an atherosclerotic lesion of the carotid artery in an established murine model, i.e. the apolipoprotein E-deficient (APOE) mouse to identify (i) the presence of microcalcifications, if any, (ii) the elemental composition of microcalcifications with special reference to calcium/phosphorus mass ratio and (iii) co-localization of increased concentrations of iron and zinc with microcalcifications. Atherosclerosis was induced by a flow-divider placed around the carotid artery resulting in low and high shear-stress regions. Element composition was assessed with a proton microprobe. Microcalcifications, predominantly present in the thickened intima of the low shear-stress region, were surrounded by areas with normal calcium levels, indicating that calcium-precipitation is a local event. The diameter of intimal microcalcifications varied from 6 to 70 μm. Calcium/phosphorus ratios of microcalcifications varied from 0.3 to 4.8, mainly corresponding to the ratio of amorphous calcium-phosphate. Increased iron and zinc concentrations commonly co-localized with microcalcifications. Our findings indicate that the atherosclerotic process in the murine carotid artery is associated with locally accumulated calcium, iron and zinc. The calcium-rich deposits resemble amorphous calcium phosphate rather than pure hydroxyapatite. We propose that the APOE mouse, in which atherosclerosis was evoked by a flow-divider, offers a useful model to investigate the pathophysiological significance of accumulation of elements such as calcium, iron and zinc. [ABSTRACT FROM AUTHOR]