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      Live Intravital Imaging of Cellular Trafficking in the Cardiac Microvasculature—Beating the Odds

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          Abstract

          Although mortality rates from cardiovascular disease in the developed world are falling, the prevalence of cardiovascular disease (CVD) is not. Each year, the number of people either being diagnosed as suffering with CVD or undergoing a surgical procedure related to it, such as percutaneous coronary intervention, continues to increase. In order to ensure that we can effectively manage these diseases in the future, it is critical that we fully understand their basic physiology and their underlying causative factors. Over recent years, the important role of the cardiac microcirculation in both acute and chronic disorders of the heart has become clear. The recruitment of inflammatory cells into the cardiac microcirculation and their subsequent activation may contribute significantly to tissue damage, adverse remodeling, and poor outcomes during recovery. However, our basic understanding of the cardiac microcirculation is hampered by an historic inability to image the microvessels of the beating heart—something we have been able to achieve in other organs for over 100 years. This stems from a couple of clear and obvious difficulties related to imaging the heart—firstly, it has significant inherent contractile motion and is affected considerably by the movement of lungs. Secondly, it is located in an anatomically challenging position for microscopy. However, recent microscopic and technological developments have allowed us to overcome some of these challenges and to begin to answer some of the basic outstanding questions in cardiac microvascular physiology, particularly in relation to inflammatory cell recruitment. In this review, we will discuss some of the historic work that took place in the latter part of last century toward cardiac intravital, before moving onto the advanced work that has been performed since. This work, which has utilized technology such as spinning-disk confocal and multiphoton microscopy, has—along with some significant advancements in algorithms and software—unlocked our ability to image the “business end” of the cardiac vascular tree. This review will provide an overview of these techniques, as well as some practical pointers toward software and other tools that may be useful for other researchers who are considering utilizing this technique themselves.

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          Most cited references 84

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          Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: a report from the Studies of Left Ventricular Dysfunction (SOLVD).

          This study sought to assess proinflammatory cytokine levels in patients in the studies of left ventricular dysfunction trial (SOLVD) in relation to both their New York Heart Association functional classification and their neurohormonal status before randomization. Elevated levels of tumor necrosis factor-alpha have been identified in 30% to 40% of patients with heart failure. However, it is unclear which subsets of patients with heart failure elaborate tumor necrosis factor-alpha. It is also unclear what the mechanism for the increased expression of proinflammatory cytokines is. Tumor necrosis factor-alpha and interleukin-6 levels were analyzed by enzymes-linked immunoassay using randomly selected plasma samples from patients in functional classes I to III who were enrolled in neurohormonal substudies of the SOLVD trial; age-matched healthy subjects served as the control group. Plasma levels of tumor necrosis factor-alpha (p < 0.001) were elevated in patients in functional classes I to III ([mean +/- SD] 1.95 +/- 0.54, 2.63 +/- 0.48, 6.4 +/- 1.9 pg/ml, respectively) compared with age-matched control subjects (0.75 +/- 0.05 pg/ml) and were progressively elevated in relation to decreasing functional status of the patient. Plasma levels of interleukin-6 (p < 0.001) were elevated in patients in functional classes I to III (3.3 +/- 0.55, 6.2 +/- 1.1, 5.22 +/- 0.9 pg/ml, respectively) compared with age-matched control subjects (1.8 +/- 0.5 pg/ml and were progressively elevated in relation to decreasing functional status of the patient. Cox proportional-hazards analysis showed that there was a trend toward significance between plasma tumor necrosis factor-alpha (p < 0.07) and survival, whereas there was no significant relation for plasma interleukin-6 (p < 0.72). Except for atrial natriuretic factor, which correlated weakly (r = 0.23, p = 0.04) with circulating tumor necrosis factor-alpha levels, there was no significance correlation between neurohormonal and proinflammatory cytokine levels. Circulating levels of proinflammatory cytokines increase in patients as their functional heart failure classification deteriorates. Moreover, activation of the neurohumoral axis is unlikely to completely explain the elaboration of proinflammatory cytokines in heart failure.
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            Coronary microvascular dysfunction: an update.

            Many patients undergoing coronary angiography because of chest pain syndromes, believed to be indicative of obstructive atherosclerosis of the epicardial coronary arteries, are found to have normal angiograms. In the past two decades, a number of studies have reported that abnormalities in the function and structure of the coronary microcirculation may occur in patients without obstructive atherosclerosis, but with risk factors or with myocardial diseases as well as in patients with obstructive atherosclerosis; furthermore, coronary microvascular dysfunction (CMD) can be iatrogenic. In some instances, CMD represents an epiphenomenon, whereas in others it is an important marker of risk or may even contribute to the pathogenesis of cardiovascular and myocardial diseases, thus becoming a therapeutic target. This review article provides an update on the clinical relevance of CMD in different clinical settings and also the implications for therapy.
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              Intravital imaging.

              Until recently, the idea of observing life deep within the tissues of a living mouse, at a resolution sufficient to pick out cellular behaviors and molecular signals underlying them, remained a much-coveted dream. Now, a new era of intravital fluorescence microscopy has dawned. In this Primer, we review the technologies that made this revolution possible and demonstrate how intravital imaging is beginning to provide quantitative and dynamic insights into cell biology, immunology, tumor biology, and neurobiology. Copyright © 2011 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                26 November 2019
                2019
                : 10
                Affiliations
                Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham , Birmingham, United Kingdom
                Author notes

                Edited by: Elzbieta Kolaczkowska, Jagiellonian University, Poland

                Reviewed by: Dianne Cooper, Queen Mary University of London, United Kingdom; Justin Deniset, University of Calgary, Canada

                *Correspondence: Dean Philip John Kavanagh d.kavanagh@ 123456bham.ac.uk

                This article was submitted to Inflammation, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2019.02782
                6901937
                Copyright © 2019 Kavanagh and Kalia.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 3, Tables: 1, Equations: 0, References: 96, Pages: 17, Words: 14118
                Categories
                Immunology
                Review

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