Albumin Microbubble Persistence During Myocardial Contrast Echocardiography Is Associated With Microvascular Endothelial Glycocalyx Damage

Lindner, Jonathan R.; Ismail, Suad; Spotnitz, William D.; Skyba, Danny M.; Jayaweera, Ananda R.; Kaul, Sanjiv

doi:10.1161/01.cir.98.20.2187

Cited by 77 publications

(63 citation statements)

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“…3,21 Previous studies have described normal appearance (wash-in) rates but delayed decay (wash-out) rates of albumin microbubbles after I-R. 3 These results are consistent with the microbubble/leukocyte interactions observed in the present study. We previously postulated that the disruption of the negatively charged glycocalyx, resulting from oxygenderived free radical formation after I-R, 22 could promote attachment of anionic albumin microbubbles to the endothelial surface.…”

Section: Affinity Of Microbubbles For Inflamed Microvesselssupporting

confidence: 91%

mentioning

confidence: 99%

“…3 The exact mechanism for the persistence of albumin microbubbles in injured tissue is not known. Based on experimental observations, proposed putative mechanisms include charge-specific interactions with the endothelium in regions where the glycocalyx is compromised 3 and direct adherence to exposed subendothelial extracellular matrix. 4 Many different processes contribute to the structural and functional abnormalities of the microcirculation after I-R. Oxygen-derived free radicals play a role in early inflammatory responses after reperfusion and promote leukocyte adhesion.…”

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confidence: 99%

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Microbubble Persistence in the Microcirculation During Ischemia/Reperfusion and Inflammation Is Caused by Integrin- and Complement-Mediated Adherence to Activated Leukocytes

et al. 2000

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Background-Albumin microbubbles that are used for contrast echocardiography persist within the myocardial microcirculation after ischemia/reperfusion (I-R). The mechanism responsible for this phenomenon is unknown. Methods and Results-Intravital microscopy of the microcirculation of exteriorized cremaster muscle was performed in 12 wild-type mice during intravenous injections of fluorescein-labeled microbubbles composed of albumin, anionic lipids, or cationic lipids. Injections were performed at baseline and after 30 to 90 minutes of I-R in 8 mice and 2 hours after intrascrotal tumor necrosis factor-␣ (TNF-␣) in 4 mice. Microbubble adherence at baseline was uncommon (Ͻ2/50 high-power fields). After I-R, adherence increased (PϽ0.05) to 9Ϯ5 and 5Ϯ4 per 50 high-power fields for albumin and anionic lipid microbubbles, respectively, due to their attachment to leukocytes adherent to the venular endothelium. TNF-␣ produced even greater microbubble binding, regardless of the microbubble shell composition. The degree of microbubble attachment correlated (rϭ0.84 to 0.91) with the number of adhered leukocytes. Flow cytometry revealed that microbubbles preferentially attached to activated leukocytes. Albumin microbubble attachment was inhibited by blocking the leukocyte ␤ 2 -integrin Mac-1, whereas lipid microbubble binding was inhibited when incubations were performed in complement-depleted or heat-inactivated serum rather than control serum. Conclusions-Microvascular attachment of albumin and lipid microbubbles in the setting of I-R and TNF-␣-induced inflammation is due to their ␤ 2 -integrin-and complement-mediated binding to activated leukocytes adherent to the venular wall. Thus, microbubble persistence on contrast ultrasonography may be useful for the detection and monitoring of leukocyte adhesion in inflammatory diseases. (Circulation. 2000;101:668-675.)

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Section: Affinity Of Microbubbles For Inflamed Microvesselssupporting

confidence: 91%

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confidence: 99%

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confidence: 99%

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Microbubble Persistence in the Microcirculation During Ischemia/Reperfusion and Inflammation Is Caused by Integrin- and Complement-Mediated Adherence to Activated Leukocytes

et al. 2000

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“…C-reactive protein), promotes scavenger receptor expression, and is one of the major fundamental mediators of inflammation following injury and/or infection. IL-6 is also associated with loss of the cell membrane glycocalyx, which is important in the binding of albumin microbubbles to inflamed vessels (27). The pattern of co-localization of CD36, SRB-1, and TLR-4 to PESDA without co-localization to CD68-expressing monocytes/macrophages (Fig.…”

Section: Discussionmentioning

confidence: 95%

“…It has been demonstrated previously that complement inactivation (heat inactivation of serum) results in a decrease in the binding of microbubbles not only to the endothelium (4) but also to activated leukocytes (11,27). Thus, to extend our understanding of microbubble interactions with scavenger receptors, we hypothesized that binding to scavenger receptors was dependent upon the oxidized nature of PESDA shell proteins (i.e.…”

Section: Discussionmentioning

confidence: 99%

Albumin-based Microbubbles Bind Up-regulated Scavenger Receptors following Vascular Injury

Anderson

Duryee

Anchan

et al. 2010

Journal of Biological Chemistry

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We have shown previously that perfluorocarbon-exposed sonicated dextrose albumin (PESDA) microbubbles bind to injured vascular tissue and can be detected with ultrasound imaging techniques. Prior studies have shown that scavenger receptors (SRs) are regulators of innate and adaptive immune responses and are involved in the progression of vascular disease such as atherosclerosis. In this study, we sought to determine the molecular mechanism of PESDA binding to ballooninjured vasculature. RT-PCR analysis of angioplastied aortas demonstrated a significantly (p < 0.01) increased expression of SRs. Binding to SRs was confirmed using SR-expressing CHO cells, and this binding was blocked by competitive inhibition with the SR-binding ligands oxidized LDL and malondialdehyde-acetaldehyde-modified LDL. Confocal imaging confirmed the co-localization of PESDA microbubbles to CD36, SRB-1, and Toll-like receptor 4, but not to monocytes/macrophages. This study demonstrates that PESDA binds to SRs and that this binding is in major part dependent upon the oxidized nature of PESDA microbubble shell proteins. The extent of SR mRNA expression was increased with injury and associated with microbubble retention as defined by scanning electron microscopy and immunohistochemistry. These findings clarify the mechanisms of how albumin-based microbubbles bind to injured and inflamed vasculature and further support the potential of this imaging technique to detect early vascular innate inflammatory pathophysiologic processes.The complexities of vascular inflammation and disease are multifaceted, and although our current clinical treatments are effective, there is a need to refine patient treatment regimens and risk stratification tools. Standard risk factors for the development of coronary heart disease include age, hypertension, dyslipidemia, diabetes, and tobacco use (1). Although these measures are linked to the development of atheromatous plaques and coronary heart disease, there is an underestimation of subclinical atherosclerosis (2, 3). For example, a substantial proportion of men and women with an intermediate Framingham risk score (10 -19%, 10-year coronary heart disease risk) had a higher than predicted atherosclerotic burden (3). This limitation in the predictive power of the Framingham risk score is postulated to be secondary to the lack of representation of other risk modifiers such as inflammation (2, 3).Currently, there is no gold standard for detecting inflammation within the vascular wall. Perfluorocarbon-exposed sonicated dextrose albumin (PESDA) 2 microbubbles interact with and bind to sites of endothelial dysfunction using contrast pulse sequencing ultrasound (4, 5). However, the mechanism(s) by which albumin-based microbubbles bind and interact with the injured vascular wall has yet to be fully determined. This study details in part the nature of PESDA binding to injured vessels and how this binding may play a role in the non-invasive detection of vascular wall injury and innate inflammatory responses. EXPERIMENTAL PRO...

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2015

Perfusion for Congenital Heart Surgery

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Albumin Microbubble Persistence During Myocardial Contrast Echocardiography Is Associated With Microvascular Endothelial Glycocalyx Damage

Abstract: Sonicated albumin microbubbles persist within the myocardium in situations in which the endothelial glycocalyx is damaged. The measurement of the myocardial transit rate of albumin microbubbles may provide an in vivo assessment of endothelial glycocalyx damage.

Cited by 77 publications

References 31 publications

Microbubble Persistence in the Microcirculation During Ischemia/Reperfusion and Inflammation Is Caused by Integrin- and Complement-Mediated Adherence to Activated Leukocytes

Microbubble Persistence in the Microcirculation During Ischemia/Reperfusion and Inflammation Is Caused by Integrin- and Complement-Mediated Adherence to Activated Leukocytes

Albumin-based Microbubbles Bind Up-regulated Scavenger Receptors following Vascular Injury

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