Prediction of the transition from stable to acute coronary syndromes driven by vascular inflammation, thrombosis with subsequent microembolization, and vessel occlusion leading to irreversible myocardial damage is still an unsolved problem. Here, we introduce a multi-targeted and multi-color nanotracer platform technology that simultaneously visualizes evolving danger patterns in the development of progressive coronary inflammation and atherothrombosis prior to spontaneous myocardial infarction in mice. Individual ligand-equipped perfluorocarbon nanoemulsions are used as targeting agents and are differentiated by their specific spectral signatures via implementation of multi chemical shift selective 19F MRI. Thereby, we are able to identify areas at high risk of and predictive for consecutive development of myocardial infarction, at a time when no conventional parameter indicates any imminent danger. The principle of this multi-targeted approach can easily be adapted to monitor also a variety of other disease entities and constitutes a technology with disease-predictive potential.
Inflammatory cell infiltration is central to healing after acute myocardial infarction (AMI). The relation of regional inflammation to edema, infarct size (IS), microvascular obstruction (MVO), intramyocardial hemorrhage (IMH), and regional and global LV function is not clear. Here we noninvasively characterized regional inflammation and contractile function in reperfused AMI in pigs using fluorine (19F) cardiovascular magnetic resonance (CMR). Adult anesthetized pigs underwent left anterior descending coronary artery instrumentation with either 90 min occlusion (n = 17) or without occlusion (sham, n = 5). After 3 days, in surviving animals a perfluorooctyl bromide nanoemulsion was infused intravenously to label monocytes/macrophages. At day 6, in vivo 1H-CMR was performed with cine, T2 and T2* weighted imaging, T2 and T1 mapping, perfusion and late gadolinium enhancement followed by 19F-CMR. Pigs were sacrificed for subsequent ex vivo scans and histology. Edema extent was 35 ± 8% and IS was 22 ± 6% of LV mass. Six of ten surviving AMI animals displayed both MVO and IMH (3.3 ± 1.6% and 1.9 ± 0.8% of LV mass). The 19F signal, reflecting the presence and density of monocytes/macrophages, was consistently smaller than edema volume or IS and not apparent in remote areas. The 19F signal-to-noise ratio (SNR) > 8 in the infarct border zone was associated with impaired remote systolic wall thickening. A whole heart value of 19F integral (19F SNR × milliliter) > 200 was related to initial LV remodeling independently of edema, IS, MVO, and IMH. Thus, 19F-CMR quantitatively characterizes regional inflammation after AMI and its relation to edema, IS, MVO, IMH and regional and global LV function and remodeling.
Fluorine-19 magnetic resonance imaging (19F MRI) with intravenously applied perfluorooctyl bromide-nanoemulsions (PFOB-NE) has proven its feasibility to visualize inflammatory processes in experimental disease models. This approach is based on the properties of monocytes/macrophages to ingest PFOB-NE particles enabling specific cell tracking in vivo. However, information on safety (cellular function and viability), mechanism of ingestion and impact of specific disease environment on PFOB-NE uptake is lacking. This information is, however, crucial for the interpretation of 19F MRI signals and a possible translation to clinical application. To address these issues, whole blood samples were collected from patients with acute ST-elevation myocardial infarction (STEMI), stable coronary artery disease (SCAD) and healthy volunteers. Samples were exposed to fluorescently-labeled PFOB-NE and particle uptake, cell viability and migration activity was evaluated by flow cytometry and MRI. We were able to show that PFOB-NE is ingested by human monocytes in a time- and subset-dependent manner via active phagocytosis. Monocyte function (migration, phagocytosis) and viability was maintained after PFOB-NE uptake. Monocytes of STEMI and SCAD patients did not differ in their maximal PFOB-NE uptake compared to healthy controls. In sum, our study provides further evidence for a safe translation of PFOB-NE for imaging purposes in humans.
Patients with acute ischemic stroke (AIS) present an increased incidence of systemic inflammatory response syndrome and release of Troponin T coinciding with cardiac dysfunction. The nature of the cardiocirculatory alterations remains obscure as models to investigate systemic interferences of the brain-heart-axis following AIS are sparse. Thus, this study aims to investigate acute cardiocirculatory dysfunction and myocardial injury in mice after reperfused AIS. Ischemic stroke was induced in mice by transient right-sided middle cerebral artery occlusion (tMCAO). Cardiac effects were investigated by electrocardiograms, 3D-echocardiography, magnetic resonance imaging (MRI), invasive conductance catheter measurements, histology, flow-cytometry, and determination of high-sensitive Troponin T (hsTnT). Systemic hemodynamics were recorded and catecholamines and inflammatory markers in circulating blood and myocardial tissue were determined by immuno-assay and flow-cytometry. Twenty-four hours following tMCAO hsTnT was elevated 4-fold compared to controls and predicted long-term survival. In parallel, systolic left ventricular dysfunction occurred with impaired global longitudinal strain, lower blood pressure, reduced stroke volume, and severe bradycardia leading to reduced cardiac output. This was accompanied by a systemic inflammatory response characterized by granulocytosis, lymphopenia, and increased levels of serum-amyloid P and interleukin-6. Within myocardial tissue, MRI relaxometry indicated expansion of extracellular space, most likely due to inflammatory edema and a reduced fluid volume. Accordingly, we found an increased abundance of granulocytes, apoptotic cells, and upregulation of pro-inflammatory cytokines within myocardial tissue following tMCAO. Therefore, reperfused ischemic stroke leads to specific cardiocirculatory alterations that are characterized by acute heart failure with reduced stroke volume, bradycardia, and changes in cardiac tissue and accompanied by systemic and local inflammatory responses.
BACKGROUND: “Spaceflight associated neuro-ocular syndrome” (SANS) represents a challenging health condition in modern space medicine. Forty-eight percent of astronauts are diagnosed with SANS after long-term space missions. The pathophysiological mechanism seems to be multifactorial, and yet remains unknown. In this proof-of-concept study we plan to investigate retinal microcirculatory changes in weightlessness and aim to identify their role in the development of SANS. METHODS AND DESIGN: Healthy individuals will take part in a parabolic flight campaign, which recreates fractioned total weightlessness periods. The airplane is specifically equipped, and designed for the execution of parabolic flight maneuvers and scientific research in microgravity. Retinal microcirculation will be assessed with a modified fundus camera, which allows dynamic vessel analysis. We will additionally measure intra-ocular pressure and hemodynamic changes during each phase of the flight. Blood samples will be analyzed at baseline, one hour and 24 hours after exposure to weightlessness. CONCLUSIONS: This pilot study aims to investigate the feasibility of retinal microcirculation assessment during varying gravity. Results of this study may generate insights whether venous stasis in the eye, surrogated by the dilatation of retinal vessels and increase in intraocular pressure as signs of venous insufficiency, may potentially contribute to the development of SANS.
Background Aortic stiffness has demonstrated an independent prediction of adverse cardiovascular events after ST-segment elevation myocardial infarction (STEMI) [1]. The general impact of the comorbidities diabetes mellitus (DM), chronic kidney disease (CKD), anemia on aortic stiffness is well known [2,3]. Therefore, the present study aimed to investigate the influence of metabolic comorbidities on cardiovascular magnetic resonance (CMR)-derived aortic parameters early and 6 months after STEMI. Methods From the prospective STEMI pathway, 161 patients (mean age: 63.7 years; 75% male) with initial CMR 5 days after STEMI were included. 105 patients pursued in a 6-month follow-up CMR. Aortic stiffness was assessed using different parameters: 1) pulse wave velocity (PWV) from velocity-encoded phase-contrast images, 2) aortic distensibility, and 3) radial strain from the ascending aorta obtained from cine images. DM was diagnosed when either pre-existing, HbA1c ≥6.5% at index hospitalization or 2-hour OGCT ≥200 mg/dl. CKD was present when glomeruli filtration rate (GFR) was less than 60 ml/min/m2, Anemia was defined according to WHO classifications. Results Of the 161 patients, 46 presented with anemia at admission, 79 with anemia at day 5, 26 with CKD and 57 with DM. Initial anemia resulted in a significantly lower distensibility (p=0.003) and aortic strain (p=0.02). A correlation between initial haemoglobin levels and distensibility (r=0.253; p=0.002) was found. CKD Patients showed a lower distensibility (p=0.012). There were correlations between GFR and PWV (r=−0.298; p<0.001), distensibility (r=0.370; p<0.001), and radial strain (r=−0.388; p<0.001). After 6 month this significant correlation remained. The DM group showed higher PWV values (p=0.02) and a lower radial strain (p=0.003). PWV showed a correlation with the 2-hour OGCT value (r=0.249; p=0.011) while the radial strain correlated with HbA1c (r=0.216; p=0.007). After multivariable analyses, diabetes remained the only significant predictor to show higher PWV (p=0.004) and poorer radial strain values (p=0.0045) while initial anemia remained the only significant predictor of lower distensibility (p=0.0033). Aortic stiffness parameters did not show any changes after 6 months in all groups. Only NTproBNP 5 days after STEMI correlated significantly with 6-months PWV (r=0.247; p=0.02), radial strain (r=0.36; p=0.001), distensibility (r=−0.226; p=0.018). Conclusion Anemia, DM and CKD show a detrimental impact on values of aortic stiffness early after STEMI. Diabetes remains the only significant predictor of higher PWV and poorer radial strain values after multivariable analysis while initial anemia remains significant predictor of lower distensibility. After 6 months none of the groups showed improvement in aortic stiffness parameters. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Sonderforschungsbereich 1116
Early macrophage rich vascular inflammation is a key feature in the pathophysiology of restenosis after angioplasty.19F MRI with intravenously applied perfluorooctyl bromide-nanoemulsion (PFOB-NE) could offer ideal features for serial imaging of the inflammatory response after angioplasty. We aimed to non-invasively image monocyte/macrophage infiltration in response to angioplasty in pig carotid arteries using Fluorine-19 magnetic resonance imaging (19F MRI) to assess early inflammatory response to mechanical injury. Early macrophage rich vascular inflammation is a key feature in the pathophysiology of restenosis after angioplasty.19F MRI with intravenously applied perfluorooctyl bromide-nanoemulsion (PFOB-NE) could offer ideal features for serial imaging of the inflammatory response after angioplasty. In eight minipigs, injury of the right carotid artery was induced by either balloon oversize angioplasty only (BA, n=4) or in combination with endothelial denudation (BA + ECDN, n=4). PFOB-NE was administered intravenously three days after injury followed by1H and19F MRI to assess vascular inflammatory burden at day six. Vascular response to mechanical injury was validated using immunohistology. Angioplasty was successfully induced in all eight pigs. Response to injury was characterized by positive remodeling with predominantly adventitial wall thickening and adventitial infiltration of monocytes/macrophages.19F signal could be detectedin vivoin four pigs following BA + ECDN with a robust signal-to-noise ratio (SNR) of 14.7 ± 4.8.Ex vivoanalysis revealed a linear correlation of19F SNR to local monocyte/macrophage cell density. Minimum detection limit of infiltrated monocytes/macrophages was as about 400 cells/mm2. Therefore,19F MRI enables quantification of monocyte/macrophage infiltration after vascular injury with sufficient sensitivity. This might open an avenue to non-invasively monitor inflammatory response to mechanical injury after angioplasty and thus to identify individuals with distinct patterns of vascular inflammation promoting restenosis.One Sentence Summary19F MRI enables radiation-free quantification of monocyte/macrophage infiltration after vascular injury with sufficient sensitivity.
Background: Assessment of left ventricular (LV) function and volume after ST-segment elevation myocardial infarction (STEMI) is recommended to guide clinical decision within and after hospitalization. Early after STEMI, initial LV reshaping and hypokinesia may affect analysis of LV function. A comparative evaluation of left ventricular ejection fraction (LVEF) and stroke volume (SV) by different imaging modalities to assess LV function early after STEMI has not been performed so far. Methods: LV function was assessed by LVEF and SV using serial imaging within 24h and 5 days after STEMI with cineventriculography (CVG), 2-dimensional echocardiography (2DE), 2D and 3D cardiovascular magnetic resonance (2D/3D) in 82 patients. Respective parameters were compared between modalities and to 3D gold standard CMR. Results: 2D analyses of LVEF using CVG and 2DE as well as 2D CMR yielded uniform results within 24h and 5 days of STEMI. SV assessment between CVG and 2DE at day 1 after STEMI was comparable, whereas values for SV were higher using 2D CMR on all occasions (p<0.01 all). This was due to higher LVEDV measurements. LVEF by 2D versus 3D CMR was comparable, 3D CMR yielded consistently higher volumetric values. This was not influenced by infarct location or infarct size. Conclusions Early after STEMI, 2D analysis of LVEF yielded robust results across all imaging techniques implying that CVG, 2DE, and 2D CMR can be used interchangeably in this setting. SV measurements to assess cardiac function differed substantially between imaging techniques due to higher intermodality-differences of absolute volumetric measurements.
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