First Human Use of RUC-4: A Nonactivating Second-Generation Small-Molecule Platelet Glycoprotein IIb/IIIa (Integrin αIIbß3) Inhibitor Designed for Subcutaneous Point-of-Care Treatment of ST-Segment-Elevation Myocardial Infarction.

Background Despite reductions in door-to-balloon times for primary coronary intervention, mortality from ST-segment-elevation myocardial infarction has plateaued. Early pre-primary coronary intervention treatment of ST-segment-elevation myocardial infarction with glycoprotein IIb/IIIa inhibitors improves pre-primary coronary intervention coronary flow, limits infarct size, and improves survival. We report the first human use of a novel glycoprotein IIb/IIIa inhibitor designed for subcutaneous first point-of-care ST-segment-elevation myocardial infarction treatment. Methods and Results Healthy volunteers and patients with stable coronary artery disease receiving aspirin received escalating doses of RUC-4 or placebo in a sentinel-dose, randomized, blinded fashion. Inhibition of platelet aggregation (IPA) to ADP (20 µmol/L), RUC-4 blood levels, laboratory evaluations, and clinical assessments were made through 24 hours and at 7 days. Doses were increased until reaching the biologically effective dose (the dose producing ≥80% IPA within 15 minutes, with return toward baseline within 4 hours). In healthy volunteers, 15 minutes after subcutaneous injection, mean±SD IPA was 6.9%+7.1% after placebo and 71.8%±15.0% at 0.05 mg/kg (n=6) and 84.7%±16.7% at 0.075 mg/kg (n=6) after RUC-4. IPA diminished over 90 to 120 minutes. In patients with coronary artery disease, 15 minutes after subcutaneous injection of placebo or 0.04 mg/kg (n=2), 0.05 mg/kg (n=6), and 0.075 mg/kg (n=18) of RUC-4, IPA was 14.6%±11.7%, 53.6%±17.0%, 76.9%±10.6%, and 88.9%±12.7%, respectively. RUC-4 blood levels correlated with IPA. Aspirin did not affect IPA or RUC-4 blood levels. Platelet counts were stable and no serious adverse events, bleeding, or injection site reactions were observed. Conclusions RUC-4 provides rapid, high-grade, limited-duration platelet inhibition following subcutaneous administration that appears to be safe and well tolerated. Registration URL: https://www.clini​caltr​ials.gov; Unique identifier: NTC03844191.

Melt Electrowriting of Complex 3D Anatomically Relevant Scaffolds.

The manufacture of fibrous scaffolds with tailored micrometric features and anatomically relevant three-dimensional (3D) geometries for soft tissue engineering applications remains a great challenge. Melt electrowriting (MEW) is an advanced additive manufacturing technique capable of depositing predefined micrometric fibers. However, it has been so far inherently limited to simple planar and tubular scaffold geometries because of the need to avoid polymer jet instabilities. In this work, we surmount the technical boundaries of MEW to enable the manufacture of complex fibrous scaffolds with simultaneous controlled micrometric and patient-specific anatomic features. As an example of complex geometry, aortic root scaffolds featuring the sinuses of Valsalva were realized. By modeling the electric field strength associated with the MEW process for these constructs, we found that the combination of a conductive core mandrel with a non-conductive 3D printed model reproducing the complex geometry minimized the variability of the electric field thus enabling the accurate deposition of fibers. We validated these findings experimentally and leveraged the micrometric resolution of MEW to fabricate unprecedented fibrous aortic root scaffolds with anatomically relevant shapes and biomimetic microstructures and mechanical properties. Furthermore, we demonstrated the fabrication of patient-specific aortic root constructs from the 3D reconstruction of computed tomography clinical data.

Impact of intracoronary bone marrow cell therapy on left ventricular function in the setting of ST-segment elevation myocardial infarction: a collaborative meta-analysis.

AIMS: The objective of the present analysis was to systematically examine the effect of intracoronary bone marrow cell (BMC) therapy on left ventricular (LV) function after ST-segment elevation myocardial infarction in various subgroups of patients by performing a collaborative meta-analysis of randomized controlled trials. METHODS AND RESULTS: We identified all randomized controlled trials comparing intracoronary BMC infusion as treatment for ST-segment elevation myocardial infarction. We contacted the principal investigator for each participating trial to provide summary data with regard to different pre-specified subgroups [age, diabetes mellitus, time from symptoms to percutaneous coronary intervention, infarct-related artery, LV end-diastolic volume index (EDVI), LV ejection fraction (EF), infarct size, presence of microvascular obstruction, timing of cell infusion, and injected cell number] and three different endpoints [change in LVEF, LVEDVI, and LV end-systolic volume index (ESVI)]. Data from 16 studies were combined including 1641 patients (984 cell therapy, 657 controls). The absolute improvement in LVEF was greater among BMC-treated patients compared with controls: [2.55% increase, 95% confidence interval (CI) 1.83-3.26, P < 0.001]. Cell therapy significantly reduced LVEDVI and LVESVI (-3.17 mL/m², 95% CI: -4.86 to -1.47, P < 0.001; -2.60 mL/m², 95% CI -3.84 to -1.35, P < 0.001, respectively). Treatment benefit in terms of LVEF improvement was more pronounced in younger patients (age <55, 3.38%, 95% CI: 2.36-4.39) compared with older patients (age ≥ 55 years, 1.77%, 95% CI: 0.80-2.74, P = 0.03). This heterogeneity in treatment effect was also observed with respect to the reduction in LVEDVI and LVESVI. Moreover, patients with baseline LVEF <40% derived more benefit from intracoronary BMC therapy. LVEF improvement was 5.30%, 95% CI: 4.27-6.33 in patients with LVEF <40% compared with 1.45%, 95% CI: 0.60 to 2.31 in LVEF ≥ 40%, P < 0.001. No clear interaction was observed between other subgroups and outcomes. CONCLUSION: Intracoronary BMC infusion is associated with improvement of LV function and remodelling in patients after ST-segment elevation myocardial infarction. Younger patients and patients with a more severely depressed LVEF at baseline derived most benefit from this adjunctive therapy.

Patients with coronary artery disease unsuitable for revascularization: definition, general principles, and a classification.

In the present report, we review the phenotypes of coronary artery disease (CAD) patients unsuitable for revascularization procedures. We then analyze these phenotypes and propose a simple angiographic-based classification for patients with CAD unsuitable for revascularization. Under this classification, the following four distinct angiographic phenotypes are proposed: (1) suspected cardiac syndrome X; (2) limited territory at risk; (3) diffuse thread-like coronary atherosclerosis; and (4) end-stage CAD. It is hoped that such a classification system, as well as the general principles described in this report, will help to standardize the collection of epidemiological data on patients with refractory angina (RFA) and advanced CAD. It is also hoped that this system will be useful to extend the principles of clinical equipoise to the development of clinical trials of innovative therapies or devices for the treatment of RFA. Finally, we anticipate that the elaboration of this system, the first of its type in the literature, will stimulate discussion of what we feel to be a subject that has received insufficient attention in the literature, and ultimately to improved management of a challenging patient population.

Bivalirudin versus heparin and glycoprotein IIb/IIIa inhibition among patients with renal impairment undergoing percutaneous coronary intervention (a subanalysis of the REPLACE-2 trial).

Among patients who undergo percutaneous coronary intervention, renal impairment is associated with an excessive risk of bleeding and ischemic events. Bivalirudin provides comparable suppression of ischemic events with a decrease in bleeding events compared with heparin and glycoprotein IIb/IIIa inhibition. We examined the relation between adverse events, renal impairment, and antithrombotic therapy within a randomized comparison. The Second Randomized Evaluation in PCI Linking Bivalirudin to Reduced Clinical Events per-protocol study population was assessed. Renal function was defined as calculated creatinine clearance <60 ml/min. Events within the overall study population and within each study arm were assessed. Thirty-day events by renal function were compared by chi-square test and logistic regression. Late mortality was compared by log-rank test. Interaction analyses were performed. Among 5,710 patients, renal impairment was associated with increased ischemic events (hazard ratio 1.45, 95% confidence interval 1.13 to 1.88, p = 0.004), bleeding complications (hazard ratio 1.72, 95% confidence interval 1.06 to 2.80, p = 0.028), and excessive 12-month mortality (hazard ratio 3.85, 95% confidence interval 2.67 to 5.54, p <0.001). Bivalirudin provided suppression of ischemic events that was comparable to heparin and glycoprotein IIb/IIIa inhibition regardless of renal impairment. Fewer bleeding events with bivalirudin were also evident irrespective of renal dysfunction. No interaction between treatment assignment, bleeding or ischemic complications, and renal impairment was observed. The safety and efficacy of bivalirudin compared with heparin and planned glycoprotein IIb/IIIa inhibition in this high-risk group are comparable and consistent with the results of the overall trial.