Non-invasive in vivo imaging of myocardial apoptosis and necrosis

Simonsen

Arthritis Care & Research

et al. 2016

Objective. Cardiac events are a major cause of death in patients with idiopathic inflammatory myopathies. The study objective was in a controlled setting to describe cardiac abnormalities by noninvasive methods in a cohort of patients with polymyositis (PM) or dermatomyositis (DM) and to identify predictors for cardiac dysfunction. Methods. In a cross-sectional study, 76 patients with PM/DM and 48 matched healthy controls (HCs) were assessed by serum levels of cardiac troponin I, electrocardiography, Holter monitoring, echocardiography with tissue Doppler imaging, and quantitative cardiac Results. Compared to HCs, patients with PM/DM more frequently had left ventricular diastolic dysfunction (LVDD) (12% versus 0%; P 5 0.02) and longer QRS and QT intervals (P 5 0.007 and P < 0.0001, respectively). In multivariate analysis, factors associated with LVDD were age (P 5 0.001), disease duration (P 5 0.004), presence of myositis-specific or -associated autoantibodies (P 5 0.05), and high cardiac 99m Tc-PYP uptake (P 5 0.006). In multivariate analysis of the pooled data for patients and HCs, a diagnosis of PM/DM (P < 0.0001) was associated with LVDD. Conclusion. Patients with PM or DM had an increased prevalence of cardiac abnormalities compared to HCs. LVDD was a common occurrence in PM/DM patients and correlated to disease duration. In addition, the association of LVDD with myositis-specific or -associated autoantibodies and high cardiac 99m Tc-PYP uptake supports the notion of underlying autoimmunity and myocardial inflammation in patients with PM/DM.

Section: Discussionmentioning

confidence: 99%

Cardiac Abnormalities in Adult Patients With Polymyositis or Dermatomyositis as Assessed by Noninvasive Modalities

Simonsen

Arthritis Care & Research

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

“…Annexin V, which is used for noninvasive apoptosis detection in myocardial infarction and inflammatory myocardial diseases (20), was used as a control. By using a low concentration of TPP-HDL-apoA-I-QD NPs, significant detection of apoptotic macrophages was observed (Fig.…”

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confidence: 99%

Biodegradable synthetic high-density lipoprotein nanoparticles for atherosclerosis

Marrache

Dhar

2013

141

127

Atherosclerosis remains one of the most common causes of death in the United States and throughout the world because of the lack of early detection. Macrophage apoptosis is a major contributor to the instability of atherosclerotic lesions. Development of an apoptosis targeted high-density lipoprotein (HDL)-mimicking nanoparticle (NP) to carry contrast agents for early detection of vulnerable plaques and the initiation of preventative therapies that exploit the vascular protective effects of HDL can be attractive for atherosclerosis. Here, we report the construction of a synthetic, biodegradable HDL-NP platform for detection of vulnerable plaques by targeting the collapse of mitochondrial membrane potential that occurs during apoptosis. This HDL mimic contains a core of biodegradable poly(lactic-co-glycolic acid), cholesteryl oleate, and a phospholipid bilayer coat that is decorated with triphenylphosphonium (TPP) cations for detection of mitochondrial membrane potential collapse. The lipid layer provides the surface for adsorption of apolipoprotein (apo) A-I mimetic 4F peptide, and the core contains diagnostically active quantum dots (QDs) for optical imaging. In vitro uptake, detection of apoptosis, and cholesterol binding studies indicated promising detection ability and therapeutic potential of TPP-HDL-apoA-I-QD NPs. In vitro studies indicated the potential of these NPs in reverse cholesterol transport. In vivo biodistribution and pharmacokinetics indicated favorable tissue distribution, controlled pharmacokinetic parameters, and significant triglyceride reduction for i.v.-injected TPP-HDL-apoA-I-QD NPs in rats. These HDL NPs demonstrate excellent biocompatibility, stability, nontoxic, and nonimmunogenic properties, which prove to be promising for future translation in early plaque diagnosis and might find applications to prevent vulnerable plaque progression.espite advances in both primary and secondary prevention, atherosclerosis (1) remains one of the leading causes of morbidity and mortality in the Western world because of the lack of early detection and targeted therapy. In general, atherosclerosis is a result of excess cholesterol circulating in the bloodstream. At the cellular level, atherosclerotic plaque formation is caused by cholesterol consumption and foam cell formation by macrophages situated within the intimal layers of the arteries (2). The term "vulnerable plaque" designates a plaque at high risk of disruption leading to thrombosis. Identification of vulnerable plaques before the thrombus formation is essential to enable the development of treatment modalities. One intriguing possibility for the development of image-guided therapies of coronary heart diseases (CHDs) is through high-density lipoproteins (HDLs), because of its function in the reverse cholesterol transport (RCT) pathway (3, 4). Along with apolipoprotein (apo) E, which promotes cholesterol efflux from foam cells, apoA-I-containing HDL facilitate the transport of cholesterol from lesions. Development of targeted HDL nanoparticles ...

Journal of Nuclear Medicine

“…Annexi n-V labeled with 99m Tc was developed to image ongoing apoptotic cell death in vivo via specific binding to exposed phosphatidylserine with a high affinity (1)(2)(3)(4)(5)(6)(7). In healthy cells, phosphatidylserine is actively transported from the outer to the inner leaflet of the cell membrane by an aminophospholipid translocase.…”

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confidence: 99%

Effect of Postconditioning on Myocardial 99mTc-Annexin-V Uptake: Comparison with Ischemic Preconditioning and Caspase Inhibitor Treatment

Taki¹,

Higuchi²,

Kawashima³

et al. 2007

99m Tc-Annexin-V imaging has been proved to be feasible to detect phosphatidylserine, which externalizes on the outer cell membrane early in the process of apoptosis. To determine whether postconditioning suppresses myocardial cell damage or apoptosis, we evaluated the intensity and distribution of 99m Tc-annexin-V uptake after postconditioning in a rat model of ischemia and reperfusion and compared the effect to that of ischemic preconditioning and pretreatment with caspase inhibitor. Methods: In control rats (n 5 13), after thoracotomy the left coronary artery was occluded for 20 min followed by reperfusion for 30 or 90 min and injection of 99m Tc-annexin-V (80-150 MBq). One hour later, to verify the area at risk, 201 Tl (0.74 MBq) was injected intravenously just beyond the left coronary artery reocclusion, and the rats were sacrificed 1 min later. In the groups of rats with various interventions, postconditioning (n 5 11) was performed just after the reperfusion, and preconditioning (n 5 11) and caspase inhibitor treatment (n 5 11) were performed before ischemia. Dual-tracer autoradiography was performed to assess 99m Tc-annexin-V uptake and area at risk. Results: In all control rats, intense 99m Tc-annexin-V uptake was observed in the area at risk (uptake ratios at 30 or 90 min after reperfusion, 4.15 6 1.89 and 3.70 6 1.41, respectively). Postconditioning suppressed 99m Tc-annexin-V uptake (uptake ratios at 30 or 90 min after reperfusion, 2.09 6 0.56, P , 0.05, and 1.88 6 0.69, P , 0.05, respectively). Preconditioning also suppressed uptake (uptake ratios at 30 and 90 min after reperfusion, 1.17 6 0.29, P , 0.005, and 1.33 6 0.74, P , 0.01, respectively), as did caspase inhibitor (uptake ratios at 30 and 90 min after reperfusion, 2.08 6 0.50, P , 0.05, and 1.27 6 0.24, P , 0.005, respectively). In all interventions, the percentage of cells positive on deoxyuride-59-triphosphate biotin nick end labeling and histologic changes with myocardial cell degeneration and cell infiltrations were suppressed markedly. Conclusion: These data indicate that 99m Tcannexin-V imaging may be a way to monitor myocardial injury and its response to novel therapeutic interventions including postconditioning, preconditioning, and antiapoptotic therapy.