Multimodality Imaging of Constrictive Pericarditis: Pathophysiology and New Concepts.

PURPOSE OF REVIEW: The unique pathophysiological changes of constrictive pericarditis (CP) can now be identified with better imaging modalities, thereby helping in its early diagnosis. Through this review, we outline the pathophysiology of CP and its translation into symptomology and various imaging findings which then are used for both diagnosis and guiding treatment options for CP. RECENT FINDINGS: Multimodality imaging has provided us with the capability to recognize early stages of the disease and identify patients with a potential for reversibility and can be treated with medical management. Additionally, peri-procedural planning and prediction of post-operative complications has been made possible with the use of advanced imaging techniques. Advanced imaging has the potential to play a greater role in identification of patients with reversible disease process and provide peri-procedural risk stratification, thereby improving outcomes for patients with CP.

Post-COVID-19 Cardiovascular Evaluation in National Collegiate Athletic Association Division I Athletes.

OBJECTIVE: To evaluate the necessity of cardiac testing after a COVID-19 diagnosis as it relates to myocarditis in collegiate athletes. DESIGN: Cross-sectional retrospective case series. SETTING: National Collegiate Athletic Association Division I University. PATIENTS: One hundred sixty-five collegiate athletes diagnosed with COVID-19 by reverse transcriptase-polymerase chain reaction or immunoglobulin G antibody between August and December 2020 without exclusion. INTERVENTIONS: All participants underwent cardiac workup consisting of serum troponin, electrocardiogram, transthoracic echocardiogram, and cardiac magnetic resonance (CMR). All results were reviewed by team physicians and sports cardiologists. MAIN OUTCOME MEASURES: Prevalence of myocarditis and abnormality on cardiac testing after COVID-19 infection at a single institution. RESULTS: One (0.61% [95% CI, 0.02%-3.3%] asymptomatic athlete had CMR findings of an age-indeterminate myocardial injury with further cardiac testing being otherwise normal. No athlete had CMR abnormalities consistent with acute myocarditis by the modified Lake Louise Criteria. CONCLUSIONS: Occurrence of myocarditis was lower in this population compared with other studies. No student athlete was permanently disqualified from participation because of testing. A stratified, risk-based testing strategy with CMR may be more appropriate than a universal screening strategy.

Kir1.1 (ROMK) and Kv7.1 (KCNQ1/KvLQT1) are essential for normal gastric acid secretion: importance of functional Kir1.1.

Potassium channels comprise the apical leak pathway supplying extracellular K(+) for exchange with protons by the gastric H(+), K(+)-ATPase and provide potential therapeutic targets for inhibiting gastric acid secretion. The Kir1.1 (ROMK) potassium channel mediates the high capacity K(+) recycling necessary for NaCl reabsorption in the thick ascending limb of the kidney, and this channel exhibits functional and regulatory characteristic well suited for K(+) recycling by gastric parietal cells. We report here that Kir1.1 channels are required for gastric acid secretion and that this channel participates with Kv7.1 (KCNQ1/KvLQT1) in the potassium recycling process. We show that Kir1.1 colocalizes with the ß-subunit of H(+), K(+)-ATPase in gastric parietal cells of Kir1.1 wild-type mice. In Kir1.1-deficient mice, gastric mucosal morphology, as well as parietal cell number, proliferation index, and ultrastructure were normal but secretagogue-stimulated gastric acid secretion in whole stomach and perfused gastric glands was absent. Luminal application of potassium-restored acid secretion in perfused gastric glands from Kir1.1-deficient as well as barium-blocked wild-type mice. In wild-type mice, both luminal Tertiapin-Q, an inhibitor of Kir1.1, as well as XE991, an inhibitor of Kv7.1, reduced proton secretion. We propose that Kir1.1 and Kv7.1 channels collaborate in potassium and current recycling across the apical pole of parietal cells.

Noninvasive detection of macrophages using a nanoparticulate contrast agent for computed tomography.

Sudden fibrous cap disruption of 'high-risk' atherosclerotic plaques can trigger the formation of an occlusive thrombus in coronary arteries, causing acute coronary syndromes. High-risk atherosclerotic plaques are characterized by their specific cellular and biological content (in particular, a high density of macrophages), rather than by their impact on the vessel lumen. Early identification of high-risk plaques may be useful for preventing ischemic events. One major hurdle in detecting high-risk atherosclerotic plaques in coronary arteries is the lack of an imaging modality that allows for the identification of atherosclerotic plaque composition with high spatial and temporal resolutions. Here we show that macrophages in atherosclerotic plaques of rabbits can be detected with a clinical X-ray computed tomography (CT) scanner after the intravenous injection of a contrast agent formed of iodinated nanoparticles dispersed with surfactant. This contrast agent may become an important adjunct to the clinical evaluation of coronary arteries with CT.

Pathological Correlation of a Cardiac Mass with Multimodality Imaging.

Cardiac masses are rarely encountered in clinical practice and can lead to severe hemodynamic consequences. In addition to clinical cues, noninvasive modalities can play an important role in characterization of these masses and therefore their diagnosis and management planning. Here in this case report, we describe the use of various forms of noninvasive imaging techniques to narrow the differential diagnosis and form an operative plan for a cardiac mass later identified as a benign myxoma originating from the right ventricle on histological examination.

Monitoring of arterial wall remodelling in atherosclerotic rabbits with a magnetic resonance imaging contrast agent binding to matrix metalloproteinases.

AIMS: P947 is a gadolinium-based magnetic resonance imaging (MRI) contrast agent with high affinity for several matrix metalloproteinases (MMPs) involved in arterial wall remodelling. We tested whether the intensity of enhancement detected in vivo in the arterial wall with P947 and MRI correlates with actual tissue MMP-related enzymatic activity measured in a rabbit atherosclerotic model subjected to dietary manipulations. METHODS AND RESULTS: Aortas of 15 rabbits in which atherosclerotic lesions were induced by balloon angioplasty and 4 months of hypercholesterolaemic diet were imaged at 'baseline' with P947-enhanced MRI. Atherosclerotic rabbits were divided into three groups: five rabbits were sacrificed ('baseline' group); five rabbits continued to be fed a lipid-supplemented diet ('high-fat' group); and five rabbits were switched from atherogenic to a purified chow diet ('low-fat' group). Four months later, a second P947-enhanced MRI was acquired in the 10 remaining rabbits. A significantly lower signal was detected in the aortic wall of rabbits from the 'low-fat' group as compared with rabbits from the 'high-fat' group (21 ± 6 vs. 46 ± 3%, respectively; P = 0.04). Such differences were not detected with the contrast agent P1135, which lacks the MMP-specific peptide sequence. In addition, the intensity of aortic wall enhancement detected with MRI after injection of P947 strongly correlated with actual MMP-2 gelatinolytic activity measured in corresponding aortic segments using zymography (r = 0.87). CONCLUSION: P947-enhanced MRI can distinguish dietary-induced variations in MMP-related enzymatic activity within plaques in an experimental atherosclerotic model, supporting its utility as a clinical imaging tool for in vivo detection of arterial wall remodelling.

Recombinant high-density lipoprotein formulations.

High-density lipoprotein cholesterol (HDL-C) has emerged as a biomarker of residual cardiovascular disease (CVD) risk in high-risk patients treated with low-density lipoprotein cholesterol (LDL-C)-lowering therapies inclusive of inhibitors of 3-hydroxy-3-methyl-glutaryl-CoA reductase. The evidence for increasing low levels of HDL-C is sparse, and the available data are confounded by metabolic interactions between elevated very low-density lipoprotein (VLDL) and LDL particle concentrations. Despite these limitations, there has been widespread interest in novel strategies that target HDL. One such path has been the development of recombinant HDL formulations that mimic the pre-beta fraction of native HDL, which is the main HDL subclass that mediates cholesterol efflux from lipid-laden macrophages. Various recombinant HDL formulations (apolipoprotein A-1 [apoA-1]-bound phospholipid disks or delipidated HDL particles, mutant apoA-1 proteins, and apoA-1 mimetic peptides) have been investigated in animal studies and some human trials. However, these HDL-modifying therapies require evaluation in clinical trials of atherosclerosis and CVD events. This review presents our current knowledge on novel recombinant therapies, and their future prospects to mitigate atherosclerotic CVD events.

Magnetic resonance molecular imaging of thrombosis in an arachidonic acid mouse model using an activated platelet targeted probe.

OBJECTIVE: Atherosclerotic plaque rupture leads to acute thrombus formation and may trigger serious clinical events such as myocardial infarction or stroke. Therefore, it would be valuable to identify atherothrombosis and vulnerable plaques before the onset of such clinical events. We sought to determine whether the noninvasive in vivo visualization of activated platelets was effective when using a target-specific MRI contrast agent to identify thrombi, hallmarks of vulnerable or high-risk atherosclerotic plaques. METHODS AND RESULTS: Inflammatory thrombi were induced in mice via topical application of arachidonic acid on the carotid. Thrombus formation was imaged with intravital fluorescence microscopy and molecular MRI. To accomplish the latter, a paramagnetic contrast agent (P975) that targets the glycoprotein alpha(IIb)beta(3), expressed on activated platelets, was investigated. The specificity of P975 for activated platelets was studied in vitro. In vivo, high spatial-resolution MRI was performed at baseline and longitudinally over 2 hours after injecting P975 or a nonspecific agent. The contralateral carotid, a sham surgery group, and a competitive inhibition experiment served as controls. P975 showed a good affinity for activated platelets, with an IC(50) (concentration of dose that produces 50% inhibition) value of 2.6 micromol/L. In thrombosed animals, P975 produced an immediate and sustained increase in MRI signal, whereas none of the control groups revealed any significant increase in MRI signal 2 hours after injection. More important, the competitive inhibition experiment with an alpha(IIb)beta(3) antagonist suppressed the MRI signal enhancement, which is indicative for the specificity of P975 for the activated platelets. CONCLUSIONS: P975 allowed in vivo target-specific noninvasive MRI of activated platelets.

Left ventricular mural thrombi with multisystem thrombosis in patients with COVID-19 and myocardial injury: a case series.

BACKGROUND: Cardiovascular and thromboembolic complications have been reported in patients with Coronavirus disease-2019 (COVID-19)-related severe respiratory distress syndrome. Although myocarditis associated with COVID-19 pneumonia has been described, evidence of left ventricular (LV) mural thrombi with other multisystem events has not been reported. CASE SUMMARY: We report two cases with severe COVID-19 pneumonia and myocardial injury with large LV thrombi and other multisystem thrombotic events. The first patient represents an unusual case of large LV apical thrombus without concordant regional wall motion abnormality and mildly reduced LV function. A subsequent inferior ST-elevation myocardial infarction (STEMI) was likely related to either an embolic event or in situ coronary thrombosis. We could not ascertain whether the acute right ventricular dysfunction was due to in situ pulmonary thrombosis or inferior STEMI. The catastrophic cerebrovascular accident was likely an embolic phenomenon. Similarly, the second patient demonstrated multiple large pedunculated thrombi occupying one-third of the LV cavity with moderately reduced LV function. A segmental pulmonary embolism was diagnosed on computed tomography chest, confirming multiple territories of in situ thrombosis. DISCUSSION: COVID-19-related inflammatory cytokine release has been linked to activation of coagulation pathways. Marked elevation of ferritin and C-reactive protein levels in both patients were consistent with evidence of a hyperinflammatory state with 'cytokine storm'. Furthermore, the finding of elevated D-dimer levels lends support to the altered coagulation cascade that plausibly explains the multisystem thrombosis observed in our patients. The direct viral endothelial involvement and subsequent endothelial dysfunction may play an important role in the development of thrombosis in different vascular beds, as seen in our patients.

Annexin A5-functionalized bimodal nanoparticles for MRI and fluorescence imaging of atherosclerotic plaques.

Apoptosis and macrophage burden are believed to correlate with atherosclerotic plaque vulnerability and are therefore considered important diagnostic and therapeutic targets for atherosclerosis. These cell types are characterized by the exposure of phosphatidylserine (PS) at their surface. In the present study, we developed and applied a small micellar fluorescent annexin A5-functionalized nanoparticle for noninvasive magnetic resonance imaging (MRI) of PS exposing cells in atherosclerotic lesions. Annexin A5-mediated target-specificity was confirmed with ellipsometry and in vitro binding to apoptotic Jurkat cells. In vivo T(1)-weighted MRI of the abdominal aorta in atherosclerotic ApoE(-/-) mice revealed enhanced uptake of the annexin A5-micelles as compared to control-micelles, which was corroborated with ex vivo near-infrared fluorescence images of excised whole aortas. Confocal laser scanning microscopy (CLSM) demonstrated that the targeted agent was associated with macrophages and apoptotic cells, whereas the nonspecific control agent showed no clear uptake by such cells. In conclusion, the annexin A5-conjugated bimodal micelles displayed potential for noninvasive assessment of cell types that are considered to significantly contribute to plaque instability and therefore may be of great value in the assessment of atherosclerotic lesion phenotype.

Reproducibility of black blood dynamic contrast-enhanced magnetic resonance imaging in aortic plaques of atherosclerotic rabbits.

PURPOSE: To investigate the short-term reproducibility of black-blood dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) in atherosclerotic rabbits to evaluate the potential of this technique to be a reliable readout of plaque progression and/or regression upon therapeutic intervention. MATERIALS AND METHODS: Atherosclerotic rabbits were imaged at baseline and 24 hours later with DCE-MRI on a 1.5T MRI system. DCE-MRI images were analyzed by calculating the area under the signal intensity versus time curve (AUC). Intraclass correlation coefficients (ICCs) were used to evaluate interscan, intraobserver, and interobserver reproducibility. In addition, the test-retest coefficient of variation (CoV) was evaluated. RESULTS: Statistical analyses showed excellent interscan, intraobserver, and interobserver agreement. All ICCs were greater than 0.75, P < 0.01 indicating excellent agreement between measurements. CONCLUSION: Experimental results show good interscan and excellent intra- and interobserver reproducibility, suggesting that DCE-MRI could be used in preclinical settings as a read-out for novel therapeutic interventions for atherosclerosis. This preliminary work encourages investigating the reproducibility of DCE-MRI also in clinical settings, where it could be used for monitoring high-risk patients and in longitudinal clinical drug trials.

Multimodal clinical imaging to longitudinally assess a nanomedical anti-inflammatory treatment in experimental atherosclerosis.

Atherosclerosis is an inflammatory disease causing great morbidity and mortality in the Western world. To increase the anti-inflammatory action and decrease adverse effects of glucocorticoids (PLP), a nanomedicinal liposomal formulation of this drug (L-PLP) was developed and intravenously applied at a dose of 15 mg/kg PLP to a rabbit model of atherosclerosis. Since atherosclerosis is a systemic disease, emerging imaging modalities for assessing atherosclerotic plaque are being developed. (18)F-Fluoro-deoxy-glucose positron emission tomography and dynamic contrast enhanced magnetic resonance imaging, methods commonly used in oncology, were applied to longitudinally assess therapeutic efficacy. Significant anti-inflammatory effects were observed as early as 2 days that lasted up to at least 7 days after administration of a single dose of L-PLP. No significant changes were found for the free PLP treated animals. These findings were corroborated by immunohistochemical analysis of macrophage density in the vessel wall. In conclusion, this study evaluates a powerful two-pronged strategy for efficient treatment of atherosclerosis that includes nanomedical therapy of atherosclerotic plaques and the application of noninvasive and clinically approved imaging techniques to monitor delivery and therapeutic responses. Importantly, we demonstrate unprecedented rapid anti-inflammatory effects in atherosclerotic lesions after the nanomedical therapy.

Targeted molecular probes for imaging atherosclerotic lesions with magnetic resonance using antibodies that recognize oxidation-specific epitopes.

BACKGROUND: Oxidized low-density lipoprotein plays a key role in the initiation, progression, and destabilization of atherosclerotic plaques and is present in macrophages and the lipid pool. The aim of this study was to assess the feasibility of magnetic resonance imaging of atherosclerotic lesions in mice using micelles containing gadolinium and murine (MDA2 and E06) or human (IK17) antibodies that bind unique oxidation-specific epitopes. METHODS AND RESULTS: MDA2 micelles, E06 micelles, IK17 micelles, nonspecific IgG micelles, and untargeted micelles (no antibody) were prepared and characterized with respect to pharmacokinetics and biodistribution in wild-type and atherosclerotic apolipoprotein E-deficient (apoE(-/-)) mice. Magnetic resonance imaging was performed at 9.4 T over a 96-hour time interval after the administration of 0.075-mmol Gd/kg micelles. MDA2, E06, and IK17 micelles exhibited a longer plasma half-life than IgG or untargeted micelles in apoE(-/-) but not wild-type mice. In apoE(-/-) mice, MDA2 and IK17 micelles showed maximal arterial wall uptake at 72 hours and E06 micelles at 96 hours, manifested by 125% to 231% enhancement in magnetic resonance signal compared with adjacent muscle. Confocal microscopy revealed that MDA2, IK17, and E06 micelles accumulated within atherosclerotic lesions and specifically within macrophages. Intravenous injection of free MDA2 before imaging with MDA2 micelles resulted in significantly diminished magnetic resonance signal enhancement. IgG micelles and untargeted micelles showed minimal enhancement in apoE(-/-) mice. There was no significant signal enhancement with all micelles in wild-type mice. CONCLUSIONS: Magnetic resonance imaging with micelles containing gadolinium and oxidation-specific antibodies demonstrates specific targeting and excellent image quality of oxidation-rich atherosclerotic lesions.

Well-defined, multifunctional nanostructures of a paramagnetic lipid and a lipopeptide for macrophage imaging.

In the field of nanomedicine there is a great demand for technologies that allow the creation of self-assembled structures of which the size and morphology can be accurately controlled. In the current study, we report a nanoparticle platform that is composed of a paramagnetic lipid and a fluorescently labeled lipopeptide. By judiciously controlling the ratio of the aforementioned amphiphilic molecules, a variety of well-defined nanosized supramolecular structures with different sizes and morphologies could be created. The hydrodynamic radii of the different structures were determined by dynamic light scattering. Cryo-TEM revealed the aggregate morphology to vary from small micellar structures to plate-like and even full grown ribbons of which the aspect ratios varied from a diameter of 5-8 nm to structures with a width of up to 25 nm and infinite length. Interestingly, nuclear magnetic resonance dispersion profiling revealed excellent properties for MRI and also showed that the relaxivity of the structures was tunable and morphology dependent. Finally, macrophage cells were treated with two selected nanoparticles and were shown to be avidly taken up. In conclusion we demonstrate a methodology to create structures that (1) are paramagnetic to enable their detection with MRI, (2) exhibit fluorescent properties, (3) can be tuned to defined sizes and shapes, and (4) are efficiently taken up by macrophage cells in vitro.

Atherosclerosis and matrix metalloproteinases: experimental molecular MR imaging in vivo.

PURPOSE: To evaluate the capability of P947, a magnetic resonance (MR) imaging contrast agent that molecularly targets matrix metalloproteinases (MMPs), to aid detection and imaging of MMPs in atherosclerotic lesions in vivo; its specificity compared with that of P1135; expression and distribution of MMPs in atherosclerotic vessels; and in vivo distribution and molecular localization of fluorescent europium (Eu) P947. MATERIALS AND METHODS: The Animal Care and Use Committee approved all experiments. P947 was synthesized by attaching a gadolinium chelate (1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid) to a peptide that specifically binds MMPs. Scrambled form of P947 (P1135) was synthesized by replacing the targeting moiety of P947 with a scrambled peptide lacking the ability to bind MMPs. P947, P1135, and gadoterate meglumine were injected into atherosclerotic apolipoprotein E-deficient and wild-type mice. The aortic MR imaging enhancement produced by the contrast agents was measured at different times and was compared by using one-way analysis of variance. MMP expression was investigated in the aortas by using MMP immunostaining and in situ MMP zymography. A fluorescent form of P947 (Eu-P947) was synthesized to compare the in vivo distribution of the contrast agent (Eu-P947) with specific MMP immunofluorescent staining. RESULTS: MMP-targeted P947 facilitated a 93% increase (P < .001) in MR image signal intensity (contrast-to-noise ratio [CNR], 17.7 compared with 7.7; P < .001) of atherosclerotic lesions in vivo. Nontargeted P1135 (scrambled P947) provided 33% MR image enhancement (CNR, 10.8), whereas gadoterate meglumine provided 5% (CNR, 6.9). Confocal laser scanning microscopy demonstrated colocalization between fluorescent Eu-P947 and MMPs in atherosclerotic plaques. Eu-P947 was particularly present in the fibrous cap region of plaques. CONCLUSION: P947 improved MR imaging for atherosclerosis through MMP-specific targeting. The results were validated and provide support for further assessment of P947 as a potential tool for the identification of unstable atherosclerosis.

Tyrosine polyethylene glycol (PEG)-micelle magnetic resonance contrast agent for the detection of lipid rich areas in atherosclerotic plaque.

Vulnerable or high-risk atherosclerotic plaques often exhibit large lipid cores and thin fibrous caps that can lead to deadly vascular events when they rupture. In this study, polyethylene glycol (PEG)-micelles that incorporate a gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA) amphiphile were used as an MR contrast agent. In an approach inspired by lipoproteins, the micelles were functionalized with tyrosine residues, an aromatic, lipophilic amino acid, to reach the lipid-rich areas of atherosclerotic plaque in a highly efficient manner. These micelles were applied to apolipoprotein E(-/-) (ApoE(-/-)) mice as a model of atherosclerosis. The abdominal aortas of the animals were imaged using T(1)-weighted (T(1)W) high-resolution MRI at 9.4T before and up to 48 h after the administration of the micelles. PEG-micelles modified with 15% tyrosine residues yielded a significant enhancement of the abdominal aortic wall at 6 and 24 h postinjection (pi) as compared to unmodified micelles. Fluorescence microscopy on histological sections of the abdominal aorta showed a correlation between lipid-rich areas and the distribution of the functionalized contrast agent in plaque. Using a simple approach, we demonstrated that lipid-rich areas in atherosclerotic plaque of ApoE(-/-) mice can be detected by MRI using Gd-DTPA micelles.

Evaluation of matrix metalloproteinases in atherosclerosis using a novel noninvasive imaging approach.

OBJECTIVE: Despite great advances in our knowledge, atherosclerosis continues to kill more people than any other disease in the Western world. This is because our means of identifying truly vulnerable patients is limited. Prediction of atherosclerotic plaque rupture may be addressed by MRI of activated matrix metalloproteinases (MMPs), a family of enzymes that have been implicated in the vulnerability of plaques prone to rupture. This study evaluated the ability of the novel gadolinium-based MRI contrast agent P947 to target MMPs in atherosclerotic plaques. METHODS AND RESULTS: The affinity of P947 toward activated MMPs was demonstrated in vitro. The affinity and specificity of P947 toward matrix metalloproteinase (MMP)-rich plaques was evaluated both in vivo using ApoE-/- mice and ex vivo in hyperlipidemic rabbits. Gadolinium content quantification and MRI showed a preferential accumulation of P947 in atherosclerotic lesions compared with the nontargeted reference compound, Gd-DOTA. The ex vivo assay on rabbit plaques revealed a higher uptake of P947. Moreover, using human carotid artery endarterectomy specimens, P947 facilitated discrimination between histologically defined MMP-rich and MMP-poor plaques. An in vivo MRI investigation in mice revealed that P947 greatly improved the ability to visualize and delineate atherosclerotic plaques. CONCLUSIONS: P947 may be a useful tool for the detection and characterization of the MMP-rich atherosclerotic plaques.

Magnetic resonance molecular imaging contrast agents and their application in atherosclerosis.

Heart disease is the most prevalent cause of mortality in the Western world and is most frequently caused by rupture of lesions in the arteries, which are formed by atherosclerosis. Atherosclerosis is a progressive disease, and therefore, there is a strong motivation to be able to image the stages of this disease in vivo. The pathogenesis of this disease is now well established, and a number of markers such as macrophages, vascular adhesion molecules, fibrin, and the alphanubeta3-integrin have been identified that are of particular interest for imaging. Furthermore, the differentiation between the stable and unstable plaque with imaging is a central goal of the field. Contrast can be generated in magnetic resonance imaging through the application of several types of agents such as T1, T2, chemical exchange saturation transfer or 19F-based imaging agents. Subsequent to the discussion of the above topics, we will describe some examples of molecular imaging agents that successfully detect specific markers in atherosclerotic plaques that are of interest in several stages of this disease.