The changes in aortic blood flow induced by PLR predict preload responsiveness in ventilated patients, whereas with arrhythmias and spontaneous breathing activity, respiratory variations of arterial pulse pressure poorly predict preload responsiveness.

The respiratory variation in aortic blood flow reliably predicts fluid responsiveness in patients with sinus rhythm and without breathing activity.

MM overestimates diaphragmatic excursion in comparison to AMM in cardiac surgical patients. Using MM may lead to a lack of recognition of diaphragmatic dysfunction.

P947 (DOTA-Gd-peptide) was recently identified as an MRI contrast agent for the detection and characterization of the matrix metalloproteinases (MMP)-rich atherosclerotic plaques. Because this product displays a broad spectrum affinity for the MMP family, we hypothesized that it may also recognize other metalloproteinases overactivated in vulnerable atherosclerotic plaques. Therefore, this study aimed at describing, at the molecular and cellular level, the interactions between P947 and proteases of atherosclerotic plaques. Fluorimetric assays were used to measure the in vitro affinity of P947 toward recombinant and purified MMPs, angiotensin-converting enzyme (ACE), endothelin-converting enzyme (ECE-1), neutral endopeptidase (NEP), and both aminopeptidases A and N (APA and APN). Using similar fluorimetric assays associated with specific substrates, enzymatic activities were measured in vulnerable and stable plaques collected from human atherosclerotic carotid arteries. Ex vivo affinity of P947 for metalloproteinases in vulnerable lesions was subsequently determined. Interaction between P947 and major cell types present in atherosclerotic plaques was also investigated in different cell lines: PMA-1-differentiated THP-1 (macrophage), Ox-LDL-treated THP-1 (foam cell), Jurkat cell line (lymphocyte), and human umbilical vein endothelial cell (HUVEC, endothelial cell). Molecular targeting of P947 was confirmed by fluorimetry, ICP-MS, and in vitro MRI approaches. Potential application of P947 for detecting atherosclerotic plaques by in vivo MRI was tested in a rabbit model of atherosclerosis. In vitro, P947 displayed affinities for purified MMPs, ACE, ECE-1, NEP, APA, and APN in the micromolar range. Interestingly, MMPs, ACE, and APN exhibited higher activities in vulnerable plaques from human atherosclerotic carotid samples, as compared to stable plaques. ECE-1, NEP, and APA had either no activity or the same low activity in both vulnerable and stable plaques. P947 showed micromolar affinities for MMPs, ACE, and APN secreted by plaque samples. Moreover, P947 bound to THP-1 macrophages and THP-1 foam cells in a concentration-dependent manner and with a higher intensity than the control contrast agents DOTA-Gd or P1135 (DOTA-Gd coupled to a scrambled peptide). In THP-1 macrophages, P947 inhibited largely (70%) and almost completely (95%) MMP and APN activities, respectively, which strongly suggested an MMP- and APN-dependent binding of P947 to these cells. This enzyme-specific binding was confirmed with in vitro MRI. Indeed, the T1 value of THP-1 cells decreased from 2.094 s (macrophages w/o P947) to 2.004 s (macrophages with 1 mM of P947). In addition, the Gd content measured by ICP-MS was 11.01 ± 1.05 fg Gd/macrophage when cells were incubated in the presence of P947 and only 5.18 ± 0.43 fg Gd/macrophage with the control product P1135. The difference of Gd concentration between both contrast agents corresponded to a specific accumulation of 5.83 fg Gd/cell, which may be detected by MRI. MR imaging in the atherosclerosi...

Systolic function is often evaluated by measuring ejection fraction and its preservation is often assimilated with the lack of impairment of systolic left ventricular (LV) function. Considering the left ventricle as a muscular pump, we explored LV function during chronic hypertension independently of increased afterload conditions. Fourteen conscious and chronically instrumented pigs received continuous infusion of either angiotensin II (n = 8) or saline (n = 6) during 28 days. Hemodynamic recordings were regularly performed in the presence and 1 h after stopping angiotensin II infusion to evaluate intrinsic LV function. Throughout the protocol, the mean arterial pressure steadily increased by 55 ± 4 mmHg in angiotensin II-treated animals. There were no significant changes in stroke volume, LV fractional shortening or LV wall thickening, indicating the lack of alterations in LV ejection. In contrast, we observed maladaptive changes with (1) the lack of reduction in isovolumic contraction and relaxation durations with heart rate increases, (2) abnormally blunted isovolumic contraction and relaxation responses to dobutamine and (3) a linear correlation between isovolumic contraction and relaxation durations. None of these changes were observed in saline-infused animals. In conclusion, we provide evidence of impaired LV function with concomitant isovolumic contraction and relaxation abnormalities during chronic hypertension while ejection remains preserved and no sign of heart failure is present. The evaluation under unloaded conditions shows intrinsic LV abnormalities.

To develop a reproducible and stable closed chest model of ischemic cardiogenic shock in sheep, with high survival rate and potential insight into human pathology. We established a protocol for multi-step myocardial alcoholisation of the left anterior descending coronary artery by percutaneous ethanol injection. A thorough hemodynamic assessment was obtained by invasive and non-invasive monitoring devices. Repeated blood samples were obtained to determine haemoglobin and alcohol concentration, electrolytes, blood gas parameters and cardiac troponin I. After sacrifice, tissue was excised for quantification of infarction and histology. Cardiogenic shock was characterized by a significant decrease in mean arterial pressure (− 33%), cardiac output (− 29%), dP/dt max (− 28%), carotid blood flow (− 22%), left ventricular fractional shortening (− 28%), and left ventricle end-systolic pressure-volume relationship (− 51%). Lactate and cardiac troponin I levels increased from 1.4 ± 0.2 to 4.9 ± 0.7 mmol/L (p = 0.001) and from 0.05 ± 0.02 to 14.74 ± 2.59 µg/L (p = 0.001), respectively. All haemodynamic changes were stable over a three-hour period with a 71% survival rate. The necrotic volume (n = 5) represented 24.0 ± 1.9% of total ventricular mass. No sham exhibited any variation under general anaesthesia. We described and characterized, for the first time, a stable, reproducible sheep model of cardiogenic shock obtained by percutaneous intracoronary ethanol administration. Five to 10% of patients presenting with acute myocardial infarction (AMI) develop cardiogenic shock (CS). This population has a high mortality rate (40%-50%) 1 , despite the improvement in survival due to primary reperfusion therapy, optimal pharmacological treatment, intra-aortic balloon pumping and the use of short-term mechanical circulatory support (STMCS) 1. Insights into the pathophysiology of CS remain crucial to the development of new approaches, either pharmacological or mechanical, to reduce local and systemic effects of CS, and to appraise safety and efficacy of novel procedures prior to clinical translation. In this context, large animal models may provide a heuristic methodology to test pathophysiological hypotheses and new therapeutic procedures. These models should mimic human pathology, be reproducible, allow for control of the extent of ischemia, rely on minimally invasive techniques, require short preparation time and easy animal management, lead to impaired cardiac function and be cost-effective. Several models of myocardial infarction exist and are based on coronary artery ligation, coronary artery occlusion (by angiography balloon catheter or embolization), or intra-coronary alcoholisation. However, the current large animal models are suboptimal for several reasons, e.g. high mortality

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Although long-term use of cyclooxygenase (COX)-2 inhibitors may be associated with increased cardiovascular risk, their effects on vascular reactivity in atherosclerosis has remained largely unexplored. The aim of the present study was to evaluate the role of COX-2 induced by an atherosclerotic process, in the local control of vascular tone. New Zealand White rabbits were fed 0.3% cholesterol and subjected to balloon injury of the abdominal aorta. After 2 wk, the aorta was removed and used for organ bath experiments and immunohistochemistry, and the prostaglandins released were measured using enzyme immunoassays. Hypercholesterolemia and vascular injury significantly increased the thickness of the intimal layer, which was associated with an induction of COX-2 immunoreactivity throughout the aortic wall. In these preparations, a significant decrease of the maximal contractions induced by norepinephrine was observed. The norepinephrine-induced contractions of atherosclerotic preparations were restored by the COX inhibitors DuP-697 (0.5 micromol/l) and indomethacin (1.7 micromol/l), to similar contractions as was observed in aortic preparations derived from healthy rabbits. Norepinephrine stimulation of the abdominal aorta was accompanied by increased levels of prostaglandin I(2) but not of prostaglandin E(2), prostaglandin D(2), or thromboxane A(2) in atherosclerotic compared with normal aorta. Selective COX-2 inhibition significantly decreased the prostaglandin I(2) release from atherosclerotic aorta but had no effect on the prostaglandin release from aortic preparations derived from normal rabbits. These observations suggest that the local induction of COX-2 during atherosclerosis decreased the sensitivity to norepinephrine and that COX-2 inhibitors may increase vascular reactivity at sites of atherosclerotic lesions.