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Calcific aortic valve disease (CAVD) is increasingly prevalent worldwide with significant morbidity and mortality. Therapeutic options beyond surgical valve replacement are currently limited. In 2011, the National Heart Lung and Blood Institute assembled a working group on aortic stenosis. This group identified CAVD as an actively regulated disease process in need of further study. As a result, the Alliance of Investigators on CAVD was formed to coordinate and promote CAVD research, with the goals of identifying individuals at risk, developing new therapeutic approaches, and improving diagnostic methods. The group is composed of cardiologists, geneticists, imaging specialists, and basic science researchers. This report reviews the current status of CAVD research and treatment strategies with identification of areas in need of additional investigation for optimal management of this patient population.

Background: The neuropilin-like, Discoidin, CUB and LCCL domain containing 2 (DCBLD2) is a transmembrane protein with an unusually long signal sequence (SS) composed of N-terminal (N) and C-terminal (C) subdomains, separated by a transition (tra) subdomain. DCBLD2 interacts with VEGFR-2 and regulates VEGF-induced endothelial cell signaling, proliferation and migration, as well as angiogenesis. The exact mechanisms by which DCBLD2 interacts with VEGFR2 to modulate VEGF signaling remain unclear., Methods: Searching for VEGFR2 interacting DCBLD2 domains, we generated various constructs containing different DCBLD2 domain combinations and conducted co-immunoprecipitation and signaling studies in HEK 293T and endothelial cells. Several peptides were synthesized based on the identified domain, and their effect on VEGF signaling was assessed in vitro in cell culture and in vivo using matrigel plug and corneal micropocket assays. The effect of the lead peptide was further evaluated using a murine hindlimb ischemia model., Results: DCBLD2 SS interacted with VEGFR2 and promoted VEGF signaling. SS was not cleaved in the mature DCBLD2 and its hydrophobic transmembrane 'traC' segment, but not the 'N' subdomain, was involved in DCBLD2-VEGFR2 interaction. The smallest unit in DCBLD2 SS that interacts with VEGFR2 was the L5VL5 sequence. Even after the central valine was removed, the L10 sequence mimicked the DCBLD2 SS traC's effect on VEGF-signaling, while shorter or longer poly-leucine sequences were less effective. Finally, a synthetic traC peptide enhanced VEGF signaling in vitro, promoted VEGF-induced angiogenesis in vivo, and improved blood flow recovery following hindlimb ischemia., Conclusion: DCBLD2 SS along with its derivative peptides can promote VEGFR2 signaling and angiogenesis. Synthetic peptides based on DCBLD2 SS hold promise as therapeutic agents for regulating angiogenesis. Importantly these findings refine the traditional view of signal sequences as mere targeting elements, revealing a role in cellular signaling. This opens new avenues for research and therapeutic strategies.

Abdominal aortic aneurysm (AAA) is defined as abnormal dilation of the infrarenal abdominal aortic diameter to 3.0 cm or greater. The natural history of AAA consists of progressive expansion and potential rupture. Although most AAAs are clinically silent, a pulsatile abdominal mass identified on physical examination may indicate the presence of an AAA. When an AAA is suspected, an imaging study is essential to confirm the diagnosis. This document reviews the relative appropriateness of various imaging procedures for the initial evaluation of suspected AAA. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation., (Copyright © 2023 American College of Radiology. Published by Elsevier Inc. All rights reserved.)

Calcific aortic valve disease (CAVD) is a prevailing disease with increasing occurrence and no known medical therapy. Dcbld2 -/- mice have a high prevalence of bicuspid aortic valve (BAV), spontaneous aortic valve calcification, and aortic stenosis (AS). 18 F-NaF PET/CT can detect the aortic valve calcification process in humans. However, its feasibility in preclinical models of CAVD remains to be determined. Here, we sought to validate 18 F-NaF PET/CT for tracking murine aortic valve calcification and leveraged it to examine the development of calcification with aging and its interdependence with BAV and AS in Dcbld2 -/- mice. Methods: Dcbld2 -/- mice at 3-4 mo, 10-16 mo, and 18-24 mo underwent echocardiography, 18 F-NaF PET/CT ( n = 34, or autoradiography ( n = 45)), and tissue analysis. A subset of mice underwent both PET/CT and autoradiography ( n = 12). The aortic valve signal was quantified as SUV max on PET/CT and as percentage injected dose per square centimeter on autoradiography. The valve tissue sections were analyzed by microscopy to identify tricuspid and bicuspid aortic valves. Results: The aortic valve 18 F-NaF signal on PET/CT was significantly higher at 18-24 mo ( P < 0.0001) and 10-16 mo ( P < 0.05) than at 3-4 mo. Additionally, at 18-24 mo BAV had a higher 18 F-NaF signal than tricuspid aortic valves ( P < 0.05). These findings were confirmed by autoradiography, with BAV having significantly higher 18 F-NaF uptake in each age group. A significant correlation between PET and autoradiography data (Pearson r = 0.79, P < 0.01) established the accuracy of PET quantification. The rate of calcification with aging was significantly faster for BAV ( P < 0.05). Transaortic valve flow velocity was significantly higher in animals with BAV at all ages. Finally, there was a significant correlation between transaortic valve flow velocity and aortic valve calcification by both PET/CT ( r = 0.55, P < 0.001) and autoradiography ( r = 0.45, P < 0.01). Conclusion: 18 F-NaF PET/CT links valvular calcification to BAV and aging in Dcbld2 -/- mice and suggests that AS may promote calcification. In addition to addressing the pathobiology of valvular calcification, 18 F-NaF PET/CT may be a valuable tool for evaluation of emerging therapeutic interventions in CAVD., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Objectives: Ruptured abdominal aortic aneurysms (rAAA) are associated typically with a large sac diameter; however, some patients experience rupture before reaching operative thresholds for elective repair. We aim to investigate the characteristics and outcomes of patients who experience small rAAA., Methods: The Vascular Quality Initiative database for open AAA repair and endovascular aneurysm repair from 2003 to 2020 were reviewed for all rAAA cases. Based on the 2018 Society for Vascular Surgery guidelines on operative size thresholds for elective repair, patients with infrarenal aneurysms of less than 5.0 cm in women or less than 5.5 cm in men were categorized as a small rAAA. Patients who met operative thresholds or had a concomitant iliac diameter 3.5 cm or greater were categorized as a large rAAA. Patient characteristics and perioperative as well as long-term outcomes were compared via univariate regression. Inverse probability of treatment weighting using propensity scores was used to examine the relationship between rAAA size and adverse outcomes., Results: There were 3962 cases that met inclusion criteria, with 12.2% small rAAA. The mean aneurysm diameter was 42.3 mm and 78.5 mm in the small and large rAAA groups, respectively. Patients in the small rAAA group were significantly more likely to be younger, African American, have a lower body mass index, and had significantly higher rates of hypertension. Small rAAA were more likely to be repaired via endovascular aneurysm repair (P = .001). Hypotension was significantly less likely in patients with small rAAA (P<.001). Rates of perioperative myocardial infarction (P < .001), total morbidity (P < .004) and mortality (P < .001) were significantly higher for large rAAA cases. After propensity matching, there was no significant difference in mortality between the two groups, but smaller rAAA was associated with lower rates of myocardial infarction (odds ratio, 0.50; 95% confidence interval, 0.31-0.82). On long-term follow-up, no difference in mortality was noted between the two groups., Conclusions: Patients presenting with small rAAA represent 12.2% of all rAAA and are more likely to be African American. Small rAAA is associated with similar risk of perioperative and long-term mortality compared with rupture at larger size after risk adjustment., (Copyright © 2023 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Peculiar electron-phonon interaction characteristics underpin the ultrahigh mobility 1 , electron hydrodynamics 2-4 , superconductivity 5 and superfluidity 6,7 observed in graphene heterostructures. The Lorenz ratio between the electronic thermal conductivity and the product of the electrical conductivity and temperature provides insight into electron-phonon interactions that is inaccessible to past graphene measurements. Here we show an unusual Lorenz ratio peak in degenerate graphene near 60 kelvin and decreased peak magnitude with increased mobility. When combined with ab initio calculations of the many-body electron-phonon self-energy and analytical models, this experimental observation reveals that broken reflection symmetry in graphene heterostructures can relax a restrictive selection rule 8,9 to allow quasielastic electron coupling with an odd number of flexural phonons, contributing to the increase of the Lorenz ratio towards the Sommerfeld limit at an intermediate temperature sandwiched between the low-temperature hydrodynamic regime and the inelastic electron-phonon scattering regime above 120 kelvin. In contrast to past practices of neglecting the contributions of flexural phonons to transport in two-dimensional materials, this work suggests that tunable electron-flexural phonon couping can provide a handle to control quantum matter at the atomic scale, such as in magic-angle twisted bilayer graphene 10 where low-energy excitations may mediate Cooper pairing of flat-band electrons 11,12 ., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Matrix metalloproteinase (MMP)-12 is highly expressed in abdominal aortic aneurysms and its elastolytic function has been implicated in the pathogenesis. This concept is challenged, however, by conflicting data. Here, we sought to revisit the role of MMP-12 in abdominal aortic aneurysm., Methods: Apoe -/- and Mmp12 -/- / Apoe -/- mice were infused with Ang II (angiotensin). Expression of neutrophil extracellular traps (NETs) markers and complement component 3 (C3) levels were evaluated by immunostaining in aortas of surviving animals. Plasma complement components were analyzed by immunoassay. The effects of a complement inhibitor, IgG-FH 1-5 (factor H-immunoglobulin G), and macrophage-specific MMP-12 deficiency on adverse aortic remodeling and death from rupture in Ang II-infused mice were determined., Results: Unexpectedly, death from aortic rupture was significantly higher in Mmp12 -/- / Apoe -/- mice. This associated with more neutrophils, citrullinated histone H3 and neutrophil elastase, markers of NETs, and C3 levels in Mmp12 -/- aortas. These findings were recapitulated in additional models of abdominal aortic aneurysm. MMP-12 deficiency also led to more pronounced elastic laminae degradation and reduced collagen integrity. Higher plasma C5a in Mmp12 -/- mice pointed to complement overactivation. Treatment with IgG-FH 1-5 decreased aortic wall NETosis and reduced adverse aortic remodeling and death from rupture in Ang II-infused Mmp12 -/- mice. Finally, macrophage-specific MMP-12 deficiency recapitulated the effects of global MMP-12 deficiency on complement deposition and NETosis, as well as adverse aortic remodeling and death from rupture in Ang II-infused mice., Conclusions: An MMP-12 deficiency/complement activation/NETosis pathway compromises aortic integrity, which predisposes to adverse vascular remodeling and abdominal aortic aneurysm rupture. Considering these new findings, the role of macrophage MMP-12 in vascular homeostasis demands re-evaluation of MMP-12 function in diverse settings.

Background: Matrix metalloproteinases (MMPs) play a key role in the pathogenesis of abdominal aortic aneurysm (AAA). Imaging aortic MMP activity, especially using positron emission tomography to access high sensitivity, quantitative data, could potentially improve AAA risk stratification. Here, we describe the design, synthesis, characterization, and evaluation in murine AAA and human aortic tissue of a first-in-class MMP-targeted positron emission tomography radioligand, 64 Cu-RYM2., Methods: The broad spectrum MMP inhibitor, RYM2 was synthetized, and its potency as an MMP inhibitor was evaluated by a competitive inhibition assay. Toxicology studies were performed. Tracer biodistribution was evaluated in a murine model of AAA induced by angiotensin II infusion in Apolipoprotein E-deficient mice. 64 Cu-RYM2 binding to normal and aneurysmal human aortic tissues was assessed by autoradiography., Results: RYM2 functioned as an MMP inhibitor with nanomolar affinities. Toxicology studies showed no adverse reaction in mice. Upon radiolabeling with Cu-64, the resulting tracer was stable in murine and human blood in vitro. Biodistribution and metabolite analysis in mice showed rapid renal clearance and acceptable in vivo stability. In vivo positron emission tomography/computed tomography in a murine model of AAA showed a specific aortic signal, which correlated with ex vivo measured MMP activity and Cd68 gene expression. 64 Cu-RYM2 specifically bound to normal and aneurysmal human aortic tissues in correlation with MMP activity., Conclusions: 64 Cu-RYM2 is a first-in-class MMP-targeted positron emission tomography tracer with favorable stability, biodistribution, performance in preclinical AAA, and importantly, specific binding to human tissues. These data set the stage for 64 Cu-RYM2-based translational imaging studies of vessel wall MMP activity, and indirectly, inflammation, in AAA.

The COVID-19 causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has a critical surface protein called spike protein (S protein), which is the target of many vaccines and drugs developments. Among non-structural proteins of SARS-CoV-2, main protease (M pro ) has drawn much attention to itself for designing antiviral drugs since it is very crucial for the virus replication in host cells. In the first part of the present study, the application of metal-organic frameworks (MOFs), one of the developing nanomaterials in the deformation and consequently inhibition of S protein binding to the receptor, angiotensin-converting enzyme 2 (ACE 2), is investigated. In this line, various S protein inhibitors were designed virtually, including ZIF, UIO, and IRMOF that their interactions with S protein and were investigated using molecular dynamics (MD) simulation. The results revealed that ZIF is the best candidate among the investigated MOFs with the least amount of energy interference with S protein. In the second part, the interaction of three-dimensional (3D) MOFs (such as ZIF, IRMOF, and HKUST) with SARS-CoV-2 M pro was investigated. HKUST had the most potent interaction with M pro and showed more promise in deforming this protein's secondary structure among all materials tested. Furthermore, we investigated the interaction of HKUST-OH with M pro to determine the effect of functionalization. The findings of this study could be used in future studies to introduce bioconjugates of MOFs and biological molecules (e.g., antibody or nanobody) or to use MOFs as carriers for antiviral drug delivery., (© 2022. The Author(s).)

Mechanical homeostasis emerges following normal development of the arterial wall and requires thereafter a slow balanced degradation and deposition of extracellular matrix constituents within an unchanging mechanical state. Recent findings suggest that homeostasis is compromised in arterial aging, which contributes to the structural stiffening that is characteristic of aged central arteries. Matrix metalloproteinases (MMPs) have strong proteolytic activity and play fundamental roles in matrix turnover. Here, we use Mmp12 -/- mice to examine effects of a potent metalloelastase, MMP-12, on the biomechanical phenotype of the thoracic and abdominal aorta in young and naturally aged mice. A key finding is that germline deletion of the gene (Mmp12) that encodes MMP-12 alters biomechanical properties from normal more in young adult than in older adult mice. Consequently, percent changes in biomechanical properties during aortic aging are greater in wild-type than in MMP-12 deficient mice, though with similar overall decreases in elastic energy storage and distensibility and increases in calculated pulse wave velocity. Reduced elastic energy storage compromises the ability of the aorta to augment antegrade and retrograde blood flow while an increased pulse wave velocity can adversely affect end organs, both conditions being characteristic of aortic aging in humans. In summary, MMP-12 is fundamental for establishing homeostatic values of biomechanical metrics in the aorta and its absence leads to a pre-aged aortic phenotype in young mice., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Cardiovascular imaging is evolving in response to systemwide trends toward molecular characterization and personalized therapies. The development of new radiotracers for PET and SPECT imaging is central to addressing the numerous unmet diagnostic needs that relate to these changes. In this 2-part review, we discuss select radiotracers that may help address key unmet clinical diagnostic needs in cardiovascular medicine. Part 1 examined key technical considerations pertaining to cardiovascular radiotracer development and reviewed emerging radiotracers for perfusion and neuronal imaging. Part 2 covers radiotracers for imaging cardiovascular inflammation, thrombosis, fibrosis, calcification, and amyloidosis. These radiotracers have the potential to address several unmet needs related to the risk stratification of atheroma, detection of thrombi, and the diagnosis, characterization, and risk stratification of cardiomyopathies. In the first section, we discuss radiotracers targeting various aspects of inflammatory responses in pathologies such as myocardial infarction, myocarditis, sarcoidosis, atherosclerosis, and vasculitis. In a subsequent section, we discuss radiotracers for the detection of systemic and device-related thrombi, such as those targeting fibrin (e.g., 64 Cu-labeled fibrin-binding probe 8). We also cover emerging radiotracers for the imaging of cardiovascular fibrosis, such as those targeting fibroblast activation protein (e.g., 68 Ga-fibroblast activation protein inhibitor). Lastly, we briefly review radiotracers for imaging of cardiovascular calcification ( 18 F-NaF) and amyloidosis (e.g., 99m Tc-pyrophosphate and 18 F-florbetapir)., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: miRNA therapeutics have gained attention during the past decade. These oligonucleotide treatments can modulate the expression of miRNAs in vivo and could be used to correct the imbalance of gene expression found in human diseases such as obesity, metabolic syndrome, and atherosclerosis. The in vivo efficacy of current anti-miRNA technologies hindered by physiological and cellular barriers to delivery into targeted cells and the nature of miRNAs that allows one to target an entire pathway that may lead to deleterious off-target effects. For these reasons, novel targeted delivery systems to inhibit miRNAs in specific tissues will be important for developing effective therapeutic strategies for numerous diseases including atherosclerosis., Methods: We used pH low-insertion peptide (pHLIP) constructs as vehicles to deliver microRNA-33-5p (miR-33) antisense oligonucleotides to atherosclerotic plaques. Immunohistochemistry and histology analysis was performed to assess the efficacy of miR-33 silencing in atherosclerotic lesions. We also assessed how miR-33 inhibition affects gene expression in monocytes/macrophages by single-cell RNA transcriptomics., Results: The anti-miR-33 conjugated pHLIP constructs are preferentially delivered to atherosclerotic plaque macrophages. The inhibition of miR-33 using pHLIP-directed macrophage targeting improves atherosclerosis regression by increasing collagen content and decreased lipid accumulation within vascular lesions. Single-cell RNA sequencing analysis revealed higher expression of fibrotic genes ( Col2a1, Col3a1, Col1a2, Fn1 , etc) and tissue inhibitor of metalloproteinase 3 ( Timp3 ) and downregulation of Mmp12 in macrophages from atherosclerotic lesions targeted by pHLIP-anti-miR-33., Conclusions: This study provides proof of principle for the application of pHLIP for treating advanced atherosclerosis via pharmacological inhibition of miR-33 in macrophages that avoid the deleterious effects in other metabolic tissues. This may open new therapeutic opportunities for atherosclerosis-associated cardiovascular diseases via selective delivery of other protective miRNAs.

In late 2019, coronavirus disease 2019 (COVID-19) was caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Spike protein is one of the surface proteins of SARS-CoV-2 that is essential for its infectious function. Therefore, it received lots of attention for the preparation of antiviral drugs, vaccines, and diagnostic tools. In the current study, we use computational methods of chemistry and biology to study the interaction between spike protein and its receptor in the body, angiotensin-I-converting enzyme-2 (ACE2). Additionally, the possible interaction of two-dimensional (2D) nanomaterials, including graphene, bismuthene, phosphorene, p-doped graphene, and functionalized p-doped graphene, with spike protein is investigated. The functionalized p-doped graphene nanomaterials were found to interfere with spike protein better than the other tested nanomaterials. In addition, the interaction of the proposed nanomaterials with the main protease (M pro ) of SARS-CoV-2 was studied. Functionalized p-doped graphene nanomaterials showed more capacity to prevent the activity of M pro . These 2D nanomaterials efficiently reduce the transmissibility and infectivity of SARS-CoV-2 by both the deformation of the spike protein and inhibiting the M pro . The results suggest the potential use of 2D nanomaterials in a variety of prophylactic approaches, such as masks or surface coatings, and would deserve further studies in the coming years., (© 2021. The Author(s).)

The development of new radiotracers for PET and SPECT is central to addressing unmet diagnostic needs related to systemwide trends toward molecular characterization and personalized therapies in cardiovascular medicine. In the following 2-part review, we discuss select emerging radiotracers that may help address important unmet diagnostic needs in central areas of cardiovascular medicine, such as heart failure, arrhythmias, valvular disease, atherosclerosis, and thrombosis. Part 1 examines key technical considerations pertaining to cardiovascular radiotracer development and reviews emerging radiotracers for perfusion and neuronal imaging. Highlights of this work include discussions on the development of 18 F-flurpiridaz, an emerging PET perfusion tracer, and the development of 18 F-based radiotracers for cardiovascular neuronal imaging, such as 18 F-flubrobenguane. Part 2 of this review covers emerging radiotracers for the imaging of inflammation, fibrosis, thrombosis, calcification, and cardiac amyloidosis., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

The most widespread, malignant, and deadliest type of glial tumor is glioblastoma multiforme (GBM). Despite radiation, chemotherapy, and radical surgery, the median survival of afflicted individuals is about 12 months. Unfortunately, existing therapeutic interventions are abysmal. Dexamethasone (Dex), a synthetic glucocorticoid, has been used for many years to treat brain edema and inflammation caused by GBM. Several investigations have recently shown that Dex also exerts antitumoral effects against GBM. On the other hand, more recent disputed findings have questioned the long-held dogma of Dex treatment for GBM. Unfortunately, steroids are associated with various undesirable side effects, including severe immunosuppression and metabolic changes like hyperglycemia, which may impair the survival of GBM patients. Current ideas and concerns about Dex's effects on GBM cerebral edema, cell proliferation, migration, and its clinical outcomes were investigated in this study., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Expression of a neuropilin-like protein, DCBLD2, is reduced in human calcific aortic valve disease (CAVD). DCBLD2-deficient mice develop bicuspid aortic valve (BAV) and CAVD, which is more severe in BAV mice compared with tricuspid littermates. In vivo and in vitro studies link this observation to up-regulated bone morphogenic protein (BMP)2 expression in the presence of DCBLD2 down-regulation, and enhanced BMP2 signaling in BAV, indicating that a combination of genetics and BAV promotes aortic valve calcification and stenosis. This pathway may be a therapeutic target to prevent CAVD progression in BAV., Competing Interests: This work was supported by grants from the National Institutes of Health (NIH) grants R01AG065917 and R01HL138567. and Department of Veterans Affairs grant I0-BX004038. Dr Salarian was supported by National Institutes of Health training grant 5T32HL007950. The resources of the Yale Translational Research Imaging Center, funded in part by National Institutes of Health grant 1S10RR018039, were used for this study. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

COVID-19 and the renin-angiotensin system (RAS) are linked by angiotensin-converting enzyme 2 (ACE2), a key enzyme in RAS that has been validated as a SARS-CoV-2 receptor. Functional ACE1/ACE2 gene polymorphisms may lead to the imbalance between ACE/ACE2 ratio and thus generating RAS imbalance that is associated with higher degrees of lung damage in ARDS that may contribute to the COVID-19 infection outcome. Herein, we investigated the role of RAS gene polymorphisms, ACE1 (A2350G) and ACE2 (G8790A) as risk predictors for susceptibility and severity of COVID-19 infection. A total of 129 included: negative controls without a history of COVID-19 infection (n = 50), positive controls with a history of COVID-19 infection who were not hospitalized (n = 35), and patients with severe COVID-19 infection who were hospitalized in the intensive care unit (n = 44). rs4343 of ACE and rs2285666 of ACE2 were genotyped using PCR-RFLP method. Our results indicated that susceptibility to COVID-19 infection was associated with age, GG genotype of A2350G (Pa = 0.01; OR 4.7; 95% CI 1.4-15.1 and Pc = 0.040; OR 2.5; 95% CI 1.05-6.3) and GG genotype of G8790A (Pa = 0.044; OR 6.17; 95% CI 1.05-35.71 and Pc = 0.0001; OR 5.5; 95% CI 2.4-12.4). The G allele of A2350G (Pa = 0.21; OR 1.74; 95% CI 0.73-4.17 and Pc = 0.007; OR 2.1; 95% CI 1.2-3.5) and G allele of G8790A (Pa = 0.002; OR 4.26; 95% CI 1.7-10.65 and Pc = 0.0001; OR 4.7; 95% CI 2.4-9.2) were more frequent in ICU-admitted patients and positive control group. Also lung involvement due to COVID-19 infection was associated with age and the comorbidities such as diabetes. In conclusion, our findings support the association between the wild genotype (GG) of ACE2 and homozygote genotype (GG) of ACE1 and sensitivity to COVID-19 infection, but not its severity. However, confirmation of this hypothesis requires further studies with more participants., (© 2022. The Author(s).)

Objective: The current guidelines recommend elective abdominal aortic aneurysm (AAA) repair at 5.5 cm for men and 5.0 cm for women. However, rupture can occur in patients with an aneurysm smaller than these size thresholds. In the present study, we investigated the proportion of AAAs that rupture at sizes less than elective operative thresholds and compared the outcomes of repair with those of aneurysms that had ruptured at a larger size. Our hypothesis was that the rupture of small AAAs carries mortality similar to that of rupture at larger sizes., Methods: The American College of Surgeons National Surgical Quality Improvement Program targeted vascular files for open AAA repair and endovascular aneurysm repair (EVAR) were reviewed for all cases of ruptured AAAs (rAAAs) from 2011 to 2018. The patients were divided into two groups: those with small AAAs that had ruptured at a size less than the current size guidelines for elective repair and those with large AAAs that had ruptured at a size that had met the criteria for elective repair. Univariate analyses were conducted to compare the comorbidities and perioperative outcomes of infrarenal rAAA repair between the groups. Multivariable logistic regression was performed to examine the differences in mortality between small and large rAAAs after controlling for confounding variables., Results: Of the 1612 rAAA repairs, 167 (10.4%) were small rAAAs. The proportion of small rAAAs did not significantly change during the study period (P = .15). The large rAAA group was more likely to have juxtarenal or suprarenal aneurysms compared with the small rAAA group (27% vs 16%; P = .001). A comparison of infrarenal rAAAs only demonstrated that the mean small rAAA (n = 141) diameter was 4.1 cm in the women and 4.5 cm in the men compared with the large rAAAs (n = 1051), with a mean diameter of 7.1 cm in women and 8.3 cm in men (P < .01 for the women; P < .01 for the men). The patients in the small rAAA group had had a significantly lower body mass index but were more likely to be African American and to have hypertension. The small rAAA group was more likely to present without hypotension and to have undergone EVAR. The repair of small rAAAs was associated with lower bleeding and mortality and a shorter mean operative time but with more readmissions. Multivariable regression analysis demonstrated that size was not associated with outcome after adjusting for other variables., Conclusions: Of all AAA repairs classified as treating rupture, 10% were for patients with small AAAs. Patients with small rAAA were less likely to present with hypotension and were more likely to have undergone EVAR. Further research into sac morphology and more sensitive imaging modalities might help identify small rAAAs at high risk of rupture that would benefit from elective repair., (Copyright © 2021 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

An interactive crosstalk between tumor and stroma cells is essential for metastatic melanoma progression. We evidenced that ESDN/DCBLD2/CLCP1 plays a crucial role in endothelial cells during the spread of melanoma. Precisely, increased extravasation and metastasis formation were revealed in ESDN-null mice injected with melanoma cells, even if the primary tumor growth, vessel permeability, and angiogenesis were not enhanced. Interestingly, improved adhesion of melanoma cells to ESDN-depleted endothelial cells was observed, due to the presence of higher levels of E-selectin transcripts/proteins in ESDN-defective cells. In accordance with these results, anticorrelation was observed between ESDN and E-selectin in human endothelial cells. Most importantly, our data revealed that cimetidine, an E-selectin inhibitor, was able to block cell adhesion, extravasation, and metastasis formation in ESDN-null mice, underlying a major role of ESDN in E-selectin transcription upregulation, which according to our data, may presumably be linked to STAT3. Based on our results, we propose a protective role for ESDN during the spread of melanoma and reveal its therapeutic potential., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Driver-directed therapeutics have revolutionized cancer treatment, presenting similar or better efficacy compared to traditional chemotherapy and substantially improving quality of life. Despite significant advances, targeted therapy is greatly limited by resistance acquisition, which emerges in nearly all patients receiving treatment. As a result, identifying the molecular modulators of resistance is of great interest. Recent work has implicated protein kinase C (PKC) isozymes as mediators of drug resistance in non-small cell lung cancer (NSCLC). Importantly, previous findings on PKC have implicated this family of enzymes in both tumor-promotive and tumor-suppressive biology in various tissues. Here, we review the biological role of PKC isozymes in NSCLC through extensive analysis of cell-line-based studies to better understand the rationale for PKC inhibition. PKC isoforms α, ε, η, ι, ζ upregulation has been reported in lung cancer, and overexpression correlates with worse prognosis in NSCLC patients. Most importantly, PKC isozymes have been established as mediators of resistance to tyrosine kinase inhibitors in NSCLC. Unfortunately, however, PKC-directed therapeutics have yielded unsatisfactory results, likely due to a lack of specific evaluation for PKC. To achieve satisfactory results in clinical trials, predictive biomarkers of PKC activity must be established and screened for prior to patient enrollment. Furthermore, tandem inhibition of PKC and molecular drivers may be a potential therapeutic strategy to prevent the emergence of resistance in NSCLC.

Inflammation plays a major role in the pathogenesis of several vascular pathologies, including abdominal aortic aneurysm (AAA). Evaluating the role of inflammation in AAA pathobiology and potentially outcome in vivo requires non-invasive tools for high-resolution imaging. We investigated the feasibility of X-ray computed tomography (CT) imaging of phagocytic activity using nanoparticle contrast agents to predict AAA outcome. Methods: Uptake of several nanoparticle CT contrast agents was evaluated in a macrophage cell line. The most promising agent, Exitron nano 12000, was further characterized in vitro and used for subsequent in vivo testing. AAA was induced in Apoe -/- mice through angiotensin II (Ang II) infusion for up to 4 weeks. Nanoparticle biodistribution and uptake in AAA were evaluated by CT imaging in Ang II-infused Apoe -/- mice. After imaging, the aortic tissue was harvested and used from morphometry, transmission electron microscopy and gene expression analysis. A group of Ang II-infused Apoe -/- mice underwent nanoparticle-enhanced CT imaging within the first week of Ang II infusion, and their survival and aortic external diameter were evaluated at 4 weeks to address the value of vessel wall CT enhancement in predicting AAA outcome. Results: Exitron nano 12000 showed specific uptake in macrophages in vitro . Nanoparticle accumulation was observed by CT imaging in tissues rich in mononuclear phagocytes. Aortic wall enhancement was detectable on delayed CT images following nanoparticle administration and correlated with vessel wall CD68 expression. Transmission electron microscopy ascertained the presence of nanoparticles in AAA adventitial macrophages. Nanoparticle-induced CT enhancement on images obtained within one week of AAA induction was predictive of AAA outcome at 4 weeks. Conclusions: By establishing the feasibility of CT-based molecular imaging of phagocytic activity in AAA, this study links the inflammatory signal on early time point images to AAA evolution. This readily available technology overcomes an important barrier to cross-sectional, longitudinal and outcome studies, not only in AAA, but also in other cardiovascular pathologies and facilitates the evaluation of modulatory interventions, and ultimately upon clinical translation, patient management., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Glioblastoma multiforme (GBM), as one of the immunosuppressive and common intrinsic brain tumors in adults, remains an intractable malignancy to manage. Since the standard of care for treatment, which includes surgery and chemoradiation, has not provided a sustainable and durable response in affected patients, seeking novel therapeutic approaches to treat GBM seems imperative. Immunotherapy, a breakthrough for cancer treatment, has become an attractive tool for combating cancer with the potential to access the blood-brain-barrier (BBB). In this regard, programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1), as major immunological checkpoints, have drawn considerable interest due to their effectiveness in a spectrum of highly-aggressive neoplasms through negative regulation of the T-cell-mediated immune response. Nevertheless, due to the immunosuppressive microenvironment of GBM, the efficacy of these immune checkpoint inhibitors (ICIs), when used as monotherapy, has been unfavorable and lacks sufficient beneficial outcomes for GBM patients. A variety of clinical studies are attempting to evaluate the combination of ICIs (neoadjuvant/adjuvant) and existing treatment guidelines to strengthen their effectiveness; however, the exact mechanism of this signaling axis affects the consequences of immune therapy remains elusive. This review provides an overview of the PD-1/PD-L1 pathway, currently approved ICIs for clinical use, preclinical and clinical trials of PD-1/PD-L1 as monotherapy, and when used concomitantly with other GBM treatments., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The prevalence of cardiovascular diseases (CVD) is increased in subjects with post-traumatic stress disorder (PTSD). Vascular inflammation mediates CVD and may be assessed by 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging. In this pilot study, we investigated whether subjects with PTSD have enhanced vascular and systemic inflammation compared to healthy controls, as assessed by FDG PET imaging., Methods: A prospective group of 16 subjects (9 PTSD and 7 controls, age 34 ± 7) without prior history of CVD underwent FDG PET/CT imaging. The presence of PTSD symptoms at the time of the study was confirmed using PTSD checklist for DSM-5 (PCL5) questionnaire. Blood samples were collected to determine blood glucose, lipid and inflammatory biomarkers (tumor necrosis factor α, interleukin-1β, and interleukin-6) levels. FDG signal in the ascending aorta, amygdala, spleen and bone marrow was quantified., Results: The two groups matched closely with regards to cardiovascular risk factors. The inflammatory biomarkers were all within the normal range. There was no significant difference in FDG signal in the aorta (target to background ratio: 2.40 ± 0.29 and 2.34 ± 0.29 for control and PTSD subjects, difference: - 0.06, 95% confidence interval of difference: - 0.38 to 0.26), spleen, bone marrow, or amygdala between control and PTSD subjects. There was no significant correlation between aortic and amygdala FDG signal. However, a significant positive correlation existed between amygdala, splenic, and bone marrow FDG signal., Conclusion: This pilot, small study did not reveal any difference in vascular or systemic inflammation as assessed by FDG PET imaging between PTSD and healthy control subjects. Because of the small number of subjects, a modest increase in vascular inflammation, which requires larger scale studies to establish, cannot be excluded. The correlation between FDG signal in amygdala, spleen and bone marrow may reflect a link between amygdala activity and systemic inflammation.

Macrophage elastase [matrix metalloproteinase (MMP)-12] is the most upregulated MMP in abdominal aortic aneurysm (AAA) and, hence, MMP-12-targeted imaging may predict AAA progression and rupture risk. Here, we report the design, synthesis, and evaluation of three novel hydroxamate-based selective MMP-12 inhibitors (CGA, CGA-1, and AGA) and the methodology to obtain MMP-12 selectivity from hydroxamate-based panMMP inhibitors. Also, we report two 99m Tc-radiotracers, 99m Tc-AGA-1 and 99m Tc-AGA-2, derived from AGA. 99m Tc-AGA-2 displayed faster blood clearance in mice and better radiochemical stability compared to 99m Tc-AGA-1. Based on this, 99m Tc-AGA-2 was chosen as the lead tracer and tested in murine AAA. 99m Tc-AGA-2 uptake detected by autoradiography was significantly higher in AAA compared to normal aortic regions. Specific binding of the tracer to MMP-12 was demonstrated through ex vivo competition. Accordingly, this study introduces a novel family of selective MMP-12 inhibitors and tracers, paving the way for further development of these agents as therapeutic and imaging agents.

Background: The hot line services were developed in response to the perceived need for 24-hour help services in crises ranging from suicide to unwanted pregnancy. This study is aimed at analyzing the strengths, weaknesses, challenges, and suggestions of improving the performance of the help centers from the perspective of key stakeholders., Methods: We conducted a qualitative study to elicit the key informants' opinion regarding the performance of Iranian hot-lines. All the conversations were audio-recorded with the permission of the participants. To reach the saturation limit, the number of interviews was completed in the saturation of data. Data was gathered from 15 individual in-depth interviews. Collecting and analyses of data was based on content analysis through which simultaneously during texts open coding, main concepts were extracted and then in axial coding similar concepts were categorized., Results: According to the study results, there is no specific and independent system for assessing the hot- lines. One of the major weaknesses was the lack of standard protocols. Most participants believed that most of these guidelines came from the general principles of counseling and are not standard. As another point, the existence of referral services is one of the main problems of counseling lines. The most important suggestion from the majority of experts were the development of services and modification of their investments., Conclusions: The findings, in addition to providing the applied data for policy-making in the health system, will significantly contribute to the creation of scientific, technical, and skillful personnel in the community of researchers., Competing Interests: There are no conflicts of interest., (Copyright: © 2020 International Journal of Preventive Medicine.)

2-deoxy-2- [ 18 F] fluoro-D-glucose (FDG) PET is commonly used for the assessment of vessel wall inflammation. Guidelines for analysis of arterial wall FDG signal recommend the use of the average of maximal standardized uptake value (mean SUV max ) and target-to-blood (mean TBR max ) ratio. However, these methods have not been validated against a gold standard such as tissue activity ex vivo or net uptake rate of FDG (K i ) obtained using kinetic modeling. We sought to evaluate the accuracy of mean SUV max and mean TBR max for aortic wall FDG signal quantification in comparison with the net uptake rate of FDG., Methods: Dynamic PET data from 13 subjects without prior history of cardiovascular disease who enrolled in a study of vascular inflammation were used for this analysis. Ex vivo measurement of plasma activity was used as the input function and voxel-by-voxel Patlak analysis was performed with t* = 20 minute to obtain the K i image. The FDG signal in the ascending aortic wall was quantified on PET images following recent guidelines for vascular imaging to determine mean SUV max and mean TBR max ., Results: The K i in the ascending aortic wall did not correlate with mean SUV max (r = 0.10, P = NS), but correlated with mean TBR max (r = 0.82, P < 0.001) (Figure 1B). K i and K i&#95;max strongly correlated (R = 0.96, P < 0.0001) and similar to K i , K i&#95;max did not correlate with mean SUV max (r = 0.17, P = NS), but correlated with mean TBR max (r = 0.83, P < 0.001)., Conclusions: Kinetic modeling supports the use of mean TBR max as a surrogate for the net uptake rate of FDG in the arterial wall. These results are relevant to any PET imaging agent, regardless of the biological significance of the tracer uptake in the vessel wall.

Glioblastoma multiforme (GBM) is the most hostile tumor in the central nervous system. Unfortunately, the prognosis of GBM patients is poor following surgical interventions, chemotherapy, and radiotherapy. Consequently, more efficient and effective treatment options for the treatment of GBM need to be explored. Zerumbone, as a sesquiterpene derived from Zingiber zerumbet Smith, has substantial cytotoxic and antiproliferative activities in some types of cancer. Here, we show that exposure of GBM cells (U-87 MG) to Zerumbone demonstrated significant growth inhibition in a concentration-dependent manner. Zerumbone also induced apoptosis and caused cell cycle arrest of human GBM U-87 MG cells in the G2/M phase of the cell cycle. In detail, the apoptotic process triggered by Zerumbone involved the upregulation of proapoptotic Bax and the suppression of antiapoptotic Bcl-2 genes expression as determined by qRT-PCR. Moreover, Zerumbone enhanced the generation of reactive oxygen species (ROS), and N-acetyl cysteine (NAC), as an antioxidant, reversed the ROS-induced cytotoxicity of U-87 MG cells. The Western blot analysis suggested that Zerumbone activated the NF- κ B p65, which was partly inhibited by NAC treatment. Collectively, our results confirmed that Zerumbone induces cytotoxicity by ROS generation. Thus, the study raises the possibility of Zerumbone as a potential natural agent for treating GBM due to its ability to induce cytotoxicity., Competing Interests: All the authors declare no conflict of interest., (Copyright © 2020 Mohammad Jalili-Nik et al.)

Matrix metalloproteinase-12 (MMP-12) is highly upregulated in several inflammatory diseases, including abdominal aortic aneurysm (AAA). Here we report four novel 99m Tc-labeled radiotracers derived from a highly selective competitive MMP-12 inhibitor. These tracers in their 99g Tc version were assessed in vitro on a set of human metalloproteases and displayed high affinity and selectivity toward MMP-12. Their radiolabeling with 99m Tc was shown to be efficient and stable in both buffer and mouse blood. The tracers showed major differences in their biodistribution and blood clearance. On the basis of its in vivo performance, [ 99m Tc]- 1 was selected for evaluation in murine AAA, where MMP-12 gene expression is upregulated. Autoradiography of aortae at 2 h postinjection revealed high uptake of [ 99m Tc]- 1 in AAA relative to adjacent aorta. Tracer uptake specificity was demonstrated through in vivo competition. This study paves the way for further evaluation of [ 99m Tc]- 1 for imaging AAA and other MMP-12-associated diseases.

Previous work has reported the important links between cellular bioenergetics and the development of chronic kidney disease, highlighting the potential for targeting metabolic functions to regulate disease progression. More recently, it has been shown that alterations in fatty acid oxidation (FAO) can have an important impact on the progression of kidney disease. In this work, we demonstrate that loss of miR-33, an important regulator of lipid metabolism, can partially prevent the repression of FAO in fibrotic kidneys and reduce lipid accumulation. These changes were associated with a dramatic reduction in the extent of fibrosis induced in 2 mouse models of kidney disease. These effects were not related to changes in circulating leukocytes because bone marrow transplants from miR-33-deficient animals did not have a similar impact on disease progression. Most important, targeted delivery of miR-33 peptide nucleic acid inhibitors to the kidney and other acidic microenvironments was accomplished using pH low insertion peptides as a carrier. This was effective at both increasing the expression of factors involved in FAO and reducing the development of fibrosis. Together, these findings suggest that miR-33 may be an attractive therapeutic target for the treatment of chronic kidney disease.

Background: Myocardial perfusion imaging (MPI) often employs attenuation-correction computed tomography (CTAC) to reduce attenuation artifacts and improve specificity. While there is no specific guideline on how they should be reported, incidental noncardiac findings identified on these scans may be clinically significant. The prevalence of these findings in veterans is not currently known. In addition, variability in reporting these findings may depend on the interpreting physician's specialty., Methods: To guide future decision-making, CTACs in veterans referred for MPI were prospectively evaluated in a quality-control project for a set of prespecified actionable incidental findings by cardiologists and a radiologist., Results: On the 771 scans performed over eight months, 285 incidental noncardiac findings were identified by the interpreting cardiologists and 378 were identified by the interpreting radiologist. Pulmonary nodules were the most common occurring in 20% of studies read by the radiologist. Interreader agreements between cardiologists and the radiologist were poor for pulmonary nodules ≥ 10 mm and hiatal hernias; fair for pulmonary nodules < 10 mm, extracardiac masses, and aortic aneurysms; and moderate for pleural plaques., Conclusion: Incidental noncardiac findings on CTACs are common in our veteran population. Overall interobserver agreement in identifying these findings between cardiologists and radiologists is fair. Specific guidelines are needed on how CTACs should be read and reported.

PET-based cardiac nuclear imaging plays a large role in the management of ischemic heart disease. Compared with conventional single-photon emission CT myocardial perfusion imaging, PET provides superior accuracy in diagnosis of coronary artery disease and, with the incorporation of myocardial blood flow and coronary flow reserve, adds value in assessing prognosis for established coronary and microvascular disease. This review describes these and other uses of PET in ischemic heart disease, including assessing myocardial viability in ischemic cardiomyopathy. Developments in novel PET flow tracers and molecular imaging tools to assess atherosclerotic plaque vulnerability, vascular calcification, and vascular remodeling also are described., (Published by Elsevier Inc.)

Matrix metalloproteinases (MMPs) are involved in tissue remodeling. Accordingly, MMP inhibitors and related radiolabeled analogs are important tools for MMP-targeted imaging and therapy in a number of diseases. Herein, we report design, synthesis, and evaluation of a new Arginine-containing macrocyclic hydroxamate analog, RYM, its hydrazinonicotinamide conjugate, RYM1 and 99m Tc-labeled analog 99m Tc-RYM1 for molecular imaging. RYM exhibited potent inhibition against a panel of recombinant human (rh) MMPs in vitro. RYM1 was efficiently labeled with 99m TcO 4 - to give 99m Tc-RYM1 in a high radiochemical yield and high radiochemical purity. RYM1 and its decayed labeling product displayed similar inhibition potencies against rhMMP-12. Furthermore, 99m Tc-RYM1 exhibited specific binding with lung tissue from lung-specific interleukin-13 transgenic mice, in which MMP activity is increased in conjunction with tissue remodeling and inflammation. The results support further development of such new water-soluble Arginine-containing macrocyclic hydroxamate MMP inhibitors for targeted imaging and therapy.

Calcific aortic valve disease (CAVD) can progress to symptomatic aortic stenosis in a subset of patients. The severity of aortic stenosis and the extent of valvular calcification can be evaluated readily by echocardiography, CT, and MRI using well-established imaging protocols. However, these techniques fail to address optimally other important aspects of CAVD, including the propensity for disease progression, risk of complications in asymptomatic patients, and the effect of therapeutic interventions on valvular biology. These gaps may be addressed by molecular imaging targeted at key biological processes such as inflammation, remodeling, and calcification that mediate the development and progression of CAVD. In this review, recent advances in valvular molecular imaging, including 18 F-fluorodeoxyglucose (FDG) and 18 F-sodium fluoride (NaF) PET, and matrix metalloproteinase-targeted SPECT imaging in the preclinical and clinical settings are presented and discussed.

As the second term of our commitment to Journal begins, we, the editors, would like to reflect on a few topics that have relevance today. These include prognostication and paradigm shifts; Serial testing: How to handle data? Is the change in perfusion predictive of outcome and which one? Ischemia-guided therapy: fractional flow reserve vs perfusion vs myocardial blood flow; positron emission tomography (PET) imaging using Rubidium-82 vs N-13 ammonia vs F-18 Flurpiridaz; How to differentiate microvascular disease from 3-vessel disease by PET? The imaging scene outside the United States, what are the differences and similarities? Radiation exposure; Special issues with the new cameras? Is attenuation correction needed? Are there normal databases and are these specific to each camera system? And finally, hybrid imaging with single-photon emission tomography or PET combined with computed tomography angiography or coronary calcium score. We hope these topics are of interest to our readers.

Objective: Despite the early promising results of 18 F-fluorodeoxyglucose positron emission tomography for assessment of vessel wall inflammation, its accuracy in prospective identification of vulnerable plaques has remained limited. Additionally, previous studies have indicated that 18 F-fluorodeoxyglucose uptake alone may not allow for accurate identification of specific macrophage activation states. We aimed to determine whether combined measurement of glucose and glutamine accumulation-the 2 most important bioenergetic substrates for macrophages-improves the distinction of macrophage inflammatory states and can be utilized to image atherosclerosis., Approach and Results: Murine peritoneal macrophages (MΦ) were activated ex vivo into proinflammatory states with either lipopolysaccharide (MΦ LPS ) or interferon-γ+tumor necrosis factor-α (MΦ IFN-γ+TNF-α ). An alternative polarization phenotype was induced with interleukin-4 (MΦ IL-4 ). The pronounced increase in 2-deoxyglucose uptake distinguishes MΦ LPS from MΦ IFN-γ+TNF-α , MΦ IL-4 , and unstimulated macrophages (MΦ 0 ). Despite having comparable levels of 2-deoxyglucose accumulation, MΦ IL-4 can be distinguished from both MΦ IFN-γ+TNF-α and MΦ 0 based on the enhanced glutamine accumulation, which was associated with increased expression of a glutamine transporter, Slc1a5 . Ex vivo autoradiography experiments demonstrated distinct and heterogenous patterns of 18 F-fluorodeoxyglucose and 14 C-glutamine accumulation in atherosclerotic lesions of low-density lipoprotein receptor-null mice fed a high-fat diet., Conclusions: Combined assessment of glutamine and 2-deoxyglucose accumulation improves the ex vivo identification of macrophage activation states. Combined ex vivo metabolic imaging demonstrates heterogenous and distinct patterns of substrate accumulation in atherosclerotic lesions. Further studies are required to define the in vivo significance of glutamine uptake in atherosclerosis and its potential application in identification of vulnerable plaques., (© 2017 American Heart Association, Inc.)

Matrix metalloproteinases (MMPs) play a key role in abdominal aortic aneurysm (AAA) development. Accordingly, MMP-targeted imaging provides important information regarding vessel wall biology in the course of aneurysm development. Given the small size of the vessel wall and its proximity with blood, molecular imaging of aneurysm optimally requires highly sensitive tracers with rapid blood clearance. To this end, we developed a novel hydrosoluble zwitterionic MMP inhibitor, RYM, on the basis of which a pan-MMP tracer, RYM1, was designed. Here, we describe the development and preclinical evaluation of RYM1 in comparison with RP805, a commonly used pan-MMP tracer in murine models of aneurysm. Methods: The macrocyclic hydroxamate-based pan-MMP inhibitor coupled with 6-hydrazinonicotinamide, RYM1, was synthesized and labeled with 99m Tc. Radiochemical stability of 99m Tc-RYM1 was evaluated by radio-high-performance liquid chromatography analysis. Tracer blood kinetics and biodistribution were compared with 99m Tc-RP805 in C57BL/6J mice ( n = 10). 99m Tc-RYM1 binding to aneurysm and specificity were evaluated by quantitative autoradiography in apolipoprotein E-deficient (apoE -/- ) mice with CaCl 2 -induced carotid aneurysm ( n = 11). Angiotensin II-infused apoE -/- ( n = 16) mice were used for small-animal SPECT/CT imaging. Aortic tissue MMP activity and macrophage marker CD68 expression were assessed by zymography and reverse-transcription polymerase chain reaction. Results: RYM1 showed nanomolar range inhibition constants for several MMPs. 99m Tc-RYM1 was radiochemically stable in mouse blood for 5 h and demonstrated rapid renal clearance and lower blood levels in vivo compared with 99m Tc-RP805. 99m Tc-RYM1 binding to aneurysm and its specificity were shown by autoradiography in carotid aneurysm. Angiotensin II infusion in apoE -/- mice for 4 wk resulted in AAA formation in 36% (4/11) of surviving animals. In vivo 99m Tc-RYM1 small-animal SPECT/CT images showed higher uptake of the tracer in AAA than nondilated aortae. Finally, aortic uptake of 99m Tc-RYM1 in vivo correlated with aortic MMP activity and CD68 expression. Conclusion: The newly developed pan-MMP inhibitor-based tracer 99m Tc-RYM1 displays favorable pharmacokinetics for early vascular imaging and enables specific detection of inflammation and MMP activity in aneurysm., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

Aneurysms of the thoracic and abdominal aorta are common and can be associated with significant morbidity and mortality when complications, including dissection, rupture, or thrombosis, occur. Current approaches to diagnosis and risk stratification rely on measurements of aneurysm size and rate of growth, often using various imaging modalities, which may be suboptimal in identifying patients at the highest and lowest risk of complications. Targeting the biological processes underlying aneurysm formation and expansion with molecular imaging offers an exciting opportunity to characterize aortic aneurysms beyond size and address current gaps in our approach to diagnosis and treatment. In this review, we summarize the epidemiology and biology of aortic aneurysms and highlight the role of molecular imaging in furthering our understanding of aneurysm pathogenesis and its potential future role in guiding management.