Exaggerated and prolonged inflammation after myocardial infarction (MI) accelerates left ventricular remodeling. Inflammatory pathways may present a therapeutic target to prevent post-MI heart ...failure. However, the appropriate magnitude and timing of interventions are largely unknown, in part because noninvasive monitoring tools are lacking. Here, we used nanoparticle-facilitated silencing of CCR2, the chemokine receptor that governs inflammatory Ly-6C(high) monocyte subset traffic, to reduce infarct inflammation in apolipoprotein E-deficient (apoE(-/-)) mice after MI. We used dual-target positron emission tomography/magnetic resonance imaging of transglutaminase factor XIII (FXIII) and myeloperoxidase (MPO) activity to monitor how monocyte subset-targeted RNAi altered infarct inflammation and healing.
Flow cytometry, gene expression analysis, and histology revealed reduced monocyte numbers and enhanced resolution of inflammation in infarcted hearts of apoE(-/-) mice that were treated with nanoparticle-encapsulated siRNA. To follow extracellular matrix cross-linking noninvasively, we developed a fluorine-18-labeled positron emission tomography agent ((18)F-FXIII). Recruitment of MPO-rich inflammatory leukocytes was imaged with a molecular magnetic resonance imaging sensor of MPO activity (MPO-Gd). Positron emission tomography/magnetic resonance imaging detected anti-inflammatory effects of intravenous nanoparticle-facilitated siRNA therapy (75% decrease of MPO-Gd signal; P<0.05), whereas (18)F-FXIII positron emission tomography reflected unimpeded matrix cross-linking in the infarct. Silencing of CCR2 during the first week after MI improved ejection fraction on day 21 after MI from 29% to 35% (P<0.05).
CCR2-targeted RNAi reduced recruitment of Ly-6C(high) monocytes, attenuated infarct inflammation, and curbed post-MI left ventricular remodeling.
PET/MRI of Inflammation in Myocardial Infarction Lee, Won Woo, MD, PhD; Marinelli, Brett, BA; van der Laan, Anja M., MD ...
Journal of the American College of Cardiology,
01/2012, Letnik:
59, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Objectives The aim of this study was to explore post–myocardial infarction (MI) myocardial inflammation. Background Innate immune cells are centrally involved in infarct healing and are emerging ...therapeutic targets in cardiovascular disease; however, clinical tools to assess their presence in tissue are scarce. Furthermore, it is currently not known if the nonischemic remote zone recruits monocytes. Methods Acute inflammation was followed in mice with coronary ligation by 18-fluorodeoxyglucose (18 FDG) positron emission tomography/magnetic resonance imaging, fluorescence-activated cell sorting, polymerase chain reaction, and histology. Results Gd-DTPA–enhanced infarcts showed high18 FDG uptake on day 5 after MI. Cell depletion and isolation data confirmed that this largely reflected inflammation; CD11b+ cells had 4-fold higher18 FDG uptake than the infarct tissue from which they were isolated (p < 0.01). Surprisingly, there was considerable monocyte recruitment in the remote myocardium (approximately 104 /mg of myocardium, 5.6-fold increase; p < 0.01), a finding mirrored by macrophage infiltration in the remote myocardium of patients with acute MI. Temporal kinetics of cell recruitment were slower than in the infarct, with peak numbers on day 10 after ischemia. Quantitative polymerase chain reaction showed a robust increase of recruiting adhesion molecules and chemokines in the remote myocardium (e.g., 12-fold increase of monocyte chemoattractant protein-1), although levels were always lower than in the infarct. Finally, matrix metalloproteinase activity was significantly increased in noninfarcted myocardium, suggesting that monocyte recruitment to the remote zone may contribute to post-MI dilation. Conclusions This study shed light on the innate inflammatory response in remote myocardium after MI.
In a cell-free approach to regenerative therapeutics, transient application of paracrine factors in vivo could be used to alter the behavior and fate of progenitor cells to achieve sustained clinical ...benefits. Here we show that intramyocardial injection of synthetic modified RNA (modRNA) encoding human vascular endothelial growth factor-A (VEGF-A) results in the expansion and directed differentiation of endogenous heart progenitors in a mouse myocardial infarction model. VEGF-A modRNA markedly improved heart function and enhanced long-term survival of recipients. This improvement was in part due to mobilization of epicardial progenitor cells and redirection of their differentiation toward cardiovascular cell types. Direct in vivo comparison with DNA vectors and temporal control with VEGF inhibitors revealed the greatly increased efficacy of pulse-like delivery of VEGF-A. Our results suggest that modRNA is a versatile approach for expressing paracrine factors as cell fate switches to control progenitor cell fate and thereby enhance long-term organ repair.
Human transmission of SARS-CoV-2 and emergent variants of concern continue to occur globally, despite mass vaccination campaigns. Public health strategies to reduce virus spread should therefore ...rely, in part, on frequent screening with rapid, inexpensive, and sensitive tests. We evaluated two digitally integrated rapid tests and assessed their performance using stored nasal swab specimens collected from individuals with or without COVID-19. An isothermal amplification assay combined with a lateral flow test had a limit of detection of 10 RNA copies per reaction, and a positive percent agreement (PPA)/negative percent agreement (NPA) during the asymptomatic and symptomatic phases of 100%/100% and 95.83/100%, respectively. Comparatively, an antigen-based lateral flow test had a limit of detection of 30,000 copies and a PPA/NPA during the asymptomatic and symptomatic phases of 82.86%/98.68% and 91.67/100%, respectively. Both the isothermal amplification and antigen-based lateral flow tests had optimized detection of SARS-CoV-2 during the peak period of transmission; however, the antigen-based test had reduced sensitivity in clinical samples with qPCR Ct values greater than 29.8. Low-cost, high-throughput screening enabled by isothermal amplification or antigen-based techniques have value for outbreak control.
Monocytes (Mo) and macrophages (MΦ) are emerging therapeutic targets in malignant, cardiovascular, and autoimmune disorders. Targeting of Mo/MΦ and their effector functions without compromising ...innate immunity's critical defense mechanisms first requires addressing gaps in knowledge about the life cycle of these cells. Here we studied the source, tissue kinetics, and clearance of Mo/MΦ in murine myocardial infarction, a model of acute inflammation after ischemic injury. We found that a) Mo tissue residence time was surprisingly short (20 h); b) Mo recruitment rates were consistently high even days after initiation of inflammation; c) the sustained need of newly made Mo was fostered by extramedullary monocytopoiesis in the spleen; d) splenic monocytopoiesis was regulated by IL-1β; and e) the balance of cell recruitment and local death shifted during resolution of inflammation. Depending on the experimental approach, we measured a 24 h Mo/MΦ exit rate from infarct tissue between 5 and 13% of the tissue cell population. Exited cells were most numerous in the blood, liver, and spleen. Abrogation of extramedullary monocytopoiesis proved deleterious for infarct healing and accelerated the evolution of heart failure. We also detected rapid Mo kinetics in mice with stroke. These findings expand our knowledge of Mo/MΦ flux in acute inflammation and provide the groundwork for novel anti-inflammatory strategies for treating heart failure.
Aim
To study the effectiveness of a brief intervention (BI) associated with the ASSIST (Alcohol Smoking and Substance Involvement Screening Test) for alcohol and illicit drug use as part of a ...systematic screening program implemented in primary care.
Design
A multi‐center randomized open‐label trial stratified using the ASSIST‐specific substance involvement score (for alcohol, scores ranged from 11 to 15 and 16 to 20; and for the other substances from 4 to 12 and 13 to 20).
Setting
A total of 19 primary care centers (n = 520), eight emergency rooms (n = 195) and five police stations (n = 91) were evaluated.
Participants
A total of 12 217 people aged between 19 and 55 years were screened for moderate alcohol and drug use risk as defined by the ASSIST Chilean version. A total of 806 non‐treatment‐seekers were randomized.
Intervention and comparison
ASSIST‐linked BI (n = 400) compared with an informational pamphlet on risk associated with substance use (n = 406).
Measurements
Total ASSIST alcohol and illicit involvement score (ASSIST–AI), and ASSIST‐specific score for alcohol, cannabis and cocaine at baseline and at 3‐month follow‐up.
Findings
Sixty‐two per cent of participants completed follow‐up. An intention‐to‐treat analysis showed no difference between the two groups for the ASSIST–AI score mean difference (MD) = − 0.17, confidence interval (CI) = −1.87, 2.20, either for specific scores alcohol (MD = 0.18, CI = −1.45, 1.10), cannabis (MD = –0.62, CI = −0.89, 2.14) or cocaine (MD = –0.79, CI = −2.89, 4.47).
Conclusion
It is not clear whether a brief intervention associated with the Alcohol Smoking and Substance Involvement Screening Test is more effective than an informational pamphlet in reducing alcohol and illicit substance consumption in non‐treatment‐seeking, primary care users with moderate risk.
Cardiovascular disease (CVD) is responsible for the majority of deaths in the developed world. Particularly, in patients with chronic kidney disease (CKD), the imbalance of calcium and phosphate may ...lead to the acceleration of both vascular and valve inflammation and calcification. One in two patients with CKD are reported as dying from cardiovascular causes due to the resulting acceleration in the development of atherosclerosis plaques. In addition, CKD patients on hemodialysis are prone to aortic valve calcification and often need valve replacement before kidney transplantation. The lysosomal proteases, cathepsins, are composed of 11 cysteine members (cathepsin B, C, F, H, K, L, O, S, V, W, and Z), as well as serine proteases cathepsin A and G, which cleave peptide bonds with serine as the amino acid, and aspartyl proteases D and E, which use an activated water molecule bound to aspartate to break peptide substrate. Cysteine proteases, also known as thiol proteases, degrade protein
the deprotonation of a thiol and have been found to play a significant role in autoimmune disease, atherosclerosis, aortic valve calcification, cardiac repair, and cardiomyopathy, operating within extracellular spaces. This review sought to evaluate recent findings in this field, highlighting how among cathepsins, the inhibition of cathepsin S in particular, could play a significant role in diminishing the effects of CVD, especially for patients with CKD.
The aging myopathy manifests itself with diastolic dysfunction and preserved ejection fraction. We raised the possibility that, in a mouse model of physiological aging, defects in electromechanical ...properties of cardiomyocytes are important determinants of the diastolic characteristics of the myocardium, independently from changes in structural composition of the muscle and collagen framework. Here we show that an increase in the late Na(+) current (INaL) in aging cardiomyocytes prolongs the action potential (AP) and influences temporal kinetics of Ca(2+) cycling and contractility. These alterations increase force development and passive tension. Inhibition of INaL shortens the AP and corrects dynamics of Ca(2+) transient, cell contraction and relaxation. Similarly, repolarization and diastolic tension of the senescent myocardium are partly restored. Thus, INaL offers inotropic support, but negatively interferes with cellular and ventricular compliance, providing a new perspective of the biology of myocardial aging and the aetiology of the defective cardiac performance in the elderly.
Lack of diversity regarding genetic and environmental backgrounds weakens the generalization and clinical applicability of research findings on psychotic disorders. Notably, Latin Americans have been ...generally neglected in genetic studies, comprising less than 2% of genome-wide association study samples. But Latin American populations represent a unique opportunity for research, given the exceptionally high ethnic admixture of this group. Increasing genetic diversity is essential to improve the fine mapping of known regions associated with psychotic disorders, discover novel genetic associations, and replicate studies. Additionally, Latin America is characterized by massive social, political, and economic inequalities, all known risk factors for mental health issues, including psychotic disorders. This article aims to 1) discuss the challenges and advantages of studying Latin America's particular genetic makeup and environmental context; 2) review previous studies conducted in the region; and 3) describe three Latin American research initiatives in progress: the Neuropsychiatric Genetics of Psychosis in Mexican Populations (NeuroMEX), the Paisa, and the Latin American Network for the Study of Early Psychosis (ANDES) studies.
Myeloid cell content in atherosclerotic plaques associates with rupture and thrombosis. Thus, imaging of lesional monocytes and macrophages could serve as a biomarker of disease progression and ...therapeutic intervention.
To noninvasively assess plaque inflammation with dextran nanoparticle (DNP)-facilitated hybrid positron emission tomography/magnetic resonance imaging (PET/MRI).
Using clinically approved building blocks, we systematically developed 13-nm polymeric nanoparticles consisting of cross-linked short chain dextrans, which were modified with desferoxamine for zirconium-89 radiolabeling ((89)Zr-DNP) and a near-infrared fluorochrome (VT680) for microscopic and cellular validation. Flow cytometry of cells isolated from excised aortas showed DNP uptake predominantly in monocytes and macrophages (76.7%) and lower signal originating from other leukocytes, such as neutrophils and lymphocytes (11.8% and 0.7%, P<0.05 versus monocytes and macrophages). DNP colocalized with the myeloid cell marker CD11b on immunohistochemistry. PET/MRI revealed high uptake of (89)Zr-DNP in the aortic root of apolipoprotein E knock out (ApoE(-/-)) mice (standard uptake value, ApoE(-/-) mice versus wild-type controls, 1.9±0.28 versus 1.3±0.03; P<0.05), corroborated by ex vivo scintillation counting and autoradiography. Therapeutic silencing of the monocyte-recruiting receptor C-C chemokine receptor type 2 with short-interfering RNA decreased (89)Zr-DNP plaque signal (P<0.05) and inflammatory gene expression (P<0.05).
Hybrid PET/MRI with a 13-nm DNP enables noninvasive assessment of inflammation in experimental atherosclerotic plaques and reports on therapeutic efficacy of anti-inflammatory therapy.
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