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IntroductionThe detection of atherosclerotic plaques at risk for disruption will be greatly enhanced by molecular probes that target vessel wall biomarkers. Here, we test if fluorescently-labeled Activatable Cell Penetrating Peptides (ACPPs) could differentiate stable plaques from vulnerable plaques that disrupt, forming a luminal thrombus. Additionally, we test the efficacy of a combined ACPP and MRI technique for identifying plaques at high risk of rupture.Methods and ResultsIn an atherothrombotic rabbit model, disrupted plaques were identified with in vivo MRI and co-registered in the same rabbit aorta with the in vivo uptake of ACPPs, cleaved by matrix metalloproteinases (MMPs) or thrombin. ACPP uptake, mapped ex vivo in whole aortas, was higher in disrupted compared to non-disrupted plaques. Specifically, disrupted plaques demonstrated a 4.5~5.0 fold increase in fluorescence enhancement, while non-disrupted plaques showed only a 2.2~2.5 fold signal increase. Receiver operating characteristic (ROC) analysis indicates that both ACPPs (MMP and thrombin) show high specificity (84.2% and 83.2%) and sensitivity (80.0% and 85.7%) in detecting disrupted plaques. The detection power of ACPPs was improved when combined with the MRI derived measure, outward remodeling ratio.ConclusionsOur targeted fluorescence ACPP probes distinguished disrupted plaques from stable plaques with high sensitivity and specificity. The combination of anatomic, MRI-derived predictors for disruption and ACPP uptake can further improve the power for identification of high-risk plaques and suggests future development of ACPPs with molecular MRI as a readout.

BackgroundTo utilize a rabbit model of plaque disruption to assess the accuracy of different magnetic resonance sequences [T1-weighted (T1W), T2-weighted (T2W), magnetization transfer (MT) and diffusion weighting (DW)] at 11.7 T for the ex vivo detection of size and composition of thrombus associated with disrupted plaques.MethodsAtherosclerosis was induced in the aorta of male New Zealand White rabbits (n = 17) by endothelial denudation and high-cholesterol diet. Subsequently, plaque disruption was induced by pharmacological triggering. Segments of infra-renal aorta were excised fixed in formalin and examined by ex vivo magnetic resonance imaging (MRI) at 11.7 T and histology.ResultsMRI at 11.7 T showed that: (i) magnetization transfer contrast (MTC) and diffusion weighted images (DWI) detected thrombus with higher sensitivity compared to T1W and T2W images [sensitivity: MTC = 88.2%, DWI = 76.5%, T1W = 66.6% and T2W = 43.7%, P < 0.001]. Similarly, the contrast-to-noise (CNR) between the thrombus and the underlying plaque was superior on the MTC and DWI images [CNR: MTC = 8.5 ± 1.1, DWI = 6.0 ± 0.8, T1W = 1.8 ± 0.5, T2W = 3.0 ± 1.0, P < 0.001]; (ii) MTC and DWI provided a more accurate detection of thrombus area with histology as the gold-standard [underestimation of 6% (MTC) and 17.6% (DWI) compared to an overestimation of thrombus area of 53.7% and 46.4% on T1W and T2W images, respectively]; (iii) the percent magnetization transfer rate (MTR) correlated with the fibrin (r = 0.73, P = 0.003) and collagen (r = 0.9, P = 0.004) content of the thrombus.ConclusionsThe conspicuity of the thrombus was increased on MTC and DW compared to T1W and T2W images. Changes in the %MTR and apparent diffusion coefficient can be used to identify the organization stage of the thrombus.

Study Objectives: We tested the hypothesis that implementation of a protocol combining risk-stratification, treatment with the direct acting oral anticoagulant rivaroxaban, and defined follow-up would increase the number of PE patients discharged directly from the emergency department (ED) or ED observation unit (EDOU) after pulmonary embolism (PE) diagnosis, but would not be associated with increased mortality, major bleeding or hospital readmission among those discharged. Methods: We performed a multicenter study (NCT02532387) of patients diagnosed with PE or DVT in the EDs of two large, urban teaching hospitals, for 16 months before and after implementing our outpatient PE treatment protocol in October 2015. Physicians were educated about the protocol, but decisions regarding outpatient treatment were at physician discretion. Subjects were identified using a combination of screening in the ED and review of medical records. PE and DVT were objectively confirmed by imaging. Outpatient treatment was defined as discharge from the ED or EDOU. We used Fisher's Exact tests to compare proportions of patients with PE and DVT discharged before and after protocol implementation. We used the total number of patients diagnosed with DVT or PE as the denominators for our analyses. We performed pre-planned subgroup analyses according to: hospital, DVT and PE, and patients discharged directly from the ED (ie, not EDOU). We performed safety analyses analyzing the proportion of deaths, major bleeding events, and hospital readmission in the subgroup of discharged patients. Results: We enrolled 2318 patients with PE or DVT; 1073 (46%) before and 1245 (54%) after protocol implementation. Mean age (59AE17 vs. 60AE17), the proportions of female (49% vs. 49%), white race (76% vs. 81%) and PE diagnosis (59% vs. 56%) were similar before and after. The proportion of PE patients discharged from the ED or EDOU increased after protocol implementation (66 [10.5%] vs. 104 [14.8%], p¼0.02). At one hospital, the increase was more pronounced (40 [12.2%] vs. 70 [19.9%], p¼0.007). The proportion of DVT patients discharged from the ED or EDOU did not change (223 [50.5%] vs. 283 [50.4%], p¼0.54), but more DVT (136 [30.8%] vs. 200 [37.0%], p¼0.04) and PE (34 [5.4%] vs. 57 [8.1%], p¼0.05) were discharged directly from the ED after protocol implementation. Most patients (n¼201 [58.9%]) were discharged on rivaroxaban after protocol implementation; a significant increase vs. before protocol implementation (n¼32 [24.2%]), p<0.001. There was no change in 7-day mortality (0 [0%] vs. 1 [0.3%], p¼1.00), major bleeding (0 [0%] vs. 1 [0.26%], p¼1.00), or hospital readmissions (26 [9.0%] vs. 24 [6.2%], p¼0.17) among discharged patients before and after protocol implementation. Conclusions: Real-world implementation of an outpatient treatment protocol, combining risk stratification and rivaroxaban treatment, increases the proportion of PE patients who can safely be discharged from the ED.

Conclusions: In hospitalized acute medically ill patients without suspected VTE, D-dimer levels increased with advancing age, without an increase in inhospital VTE events. Proportion of patients who received anticoagulation was similar across all age groups, but older patients (75 y) were more likely to receive heparin. Further analyses may provide more insights into understanding the relationship between D-dimer levels, age, anticoagulation therapy, and VTE events.