Caliber and fitness of the axillary artery as a conduit for large-bore cardiovascular procedures.

OBJECTIVES: We sought to describe the caliber and vascular health of the subclavian and axillary arteries as related to their potential utilization in complex cardiovascular procedures. BACKGROUND: Patients referred for advanced catheter-based therapies frequently have lower extremity peripheral vascular disease that may prohibit the use of large bore arterial catheters. Utilization of the upper extremity peripheral vasculature is rarely considered as an alternative access strategy. This may be due in part to a lack of familiarity with the thoracic vasculature. METHODS AND RESULTS: 208 consecutive patients undergoing routine CTA prior to transcatheter aortic valve replacement were retrospectively evaluated in a systematic analysis of upper and lower extremity vasculature. Minimal luminal diameters (MLDs) for the axillary arteries and iliofemoral arteries were 6.0 ± 1.1 mm and 6.6 ± 1.8 mm respectively. Compared to the iliofemoral arteries, the axillary arteries demonstrated substantially lower rates of significant stenosis (2% vs. 12%, p < 0.01) and significantly lower rates of moderate to severe calcification disease (9% vs. 64%, p < 0.01). Diabetes and tobacco use were independently associated with smaller axillary artery caliber by MLD (p < 0.01) but not with significant stenotic disease. CONCLUSIONS: The axillary arteries are slightly smaller but less frequently diseased than the corresponding iliofemoral vessels.

Antigen-specific in vitro expansion of factor VIII-specific regulatory T cells induces tolerance in hemophilia A mice.

BACKGROUND: Following protein replacement therapy, one-third of severe hemophilia A patients develop antibodies to factor VIII (FVIII), which also hinders the efficacy of gene therapy. Regulatory T cells (Tregs) have a naturally suppressive function that potentially reduces the immune response to FVIII therapy. Furthermore, antigen-specific Tregs are functionally much more potent than polyclonal cells. Adoptive transfer of antigen-specific Tregs can effectively suppress anti-FVIII antibody responses. OBJECTIVE: Develop a clinically feasible protocol to enrich and expand Tregs specific to FVIII for suppressing anti-FVIII immune responses. METHODS: Regulatory T cells are isolated from FVIII-sensitized mice, sorted on CD25high markers, and expanded specifically with FVIII, antigen-presenting cells, and interleukin 2 (IL 2). Subsequently, Tregs are further cultured with anti-CD3/anti-CD28 beads, anti-Crry antibodies, and IL 2 to achieve 10-fold to 20-fold expansion. Expanded Tregs are characterized and tested for their suppressive activity in vitro and in vivo. RESULTS: In vitro FVIII-specific suppressive assays indicate that FVIII specifically expanded Tregs are more suppressive than non-specifically expanded and naive Tregs. Adoptive transfer of expanded Tregs into HemA mice showed that FVIII-specifically expanded Tregs are significantly more potent in suppressing anti-FVIII immune responses in FVIII plasmid-treated HemA mice. Moreover, the FVIII-specific immune tolerance is maintained after a secondary challenge with FVIII plasmid. CONCLUSIONS: Our results demonstrate that the FVIII-specific sensitization and expansion protocol yields more potent Tregs to suppress anti-FVIII antibody responses and induce long-term tolerance to FVIII, increasing the potential for adoptive Treg cell therapy to modulate anti-FVIII immune responses.

Embolic stroke of undetermined source correlates to atrial fibrosis without atrial fibrillation.

OBJECTIVE: To examine the hypothesis that atrial fibrosis and associated atrial cardiopathy may be in the causal pathway of cardioembolic stroke independently of atrial fibrillation (AF) by comparing atrial fibrosis burden between patients with embolic stroke of undetermined source (ESUS), patients with AF, and healthy controls. METHODS: We used late-gadolinium-enhancement MRI to compare atrial fibrosis in 10 patients with ESUS against 10 controls (no stroke, no AF) and 10 patients with AF. Fibrosis was compared between groups, controlling for stroke risk factors. RESULTS: Mean age was 51 ± 15 years, and 43% of participants were female. Patients with ESUS had more atrial fibrosis than controls (16.8 ± 5.7% vs 10.6 ± 5.7%, p = 0.019) and similar fibrosis compared to patients with AF (17.8 ± 4.8%, p = 0.65). Odds ratios of ESUS per quartile of fibrosis were 3.22 (95% CI [CI] 1.11-9.32, p = 0.031, unadjusted) and 3.17 (95% CI 1.05-9.52, p = 0.041, CHA2DVASc score adjusted). Patients with >12% fibrosis had a higher percentage of ESUS (77.8% vs 27.3%, p = 0.02), and patients with >20% fibrosis had the highest proportion of ESUS (4 of 5). CONCLUSIONS: Patients with ESUS exhibit similar atrial fibrosis compared to patients with AF and more fibrosis than healthy controls. Fibrosis is associated with ESUS after controlling for stroke risk factors, supporting the hypothesis that fibrosis is in the causal pathway of cardioembolic stroke independently of AF. Prospective studies are needed to assess the role of anticoagulation in primary and secondary stroke prevention in patients with high atrial fibrosis.

Performance of coronary angiography and intervention after out of hospital cardiac arrest.

AIMS: Out of Hospital Cardiac Arrest (OHCA) is frequently attributed to coronary artery disease, thus guidelines recommend coronary angiography (CAG) for survivors of OHCA. However, the real-world application of these guidelines is unknown, and we sought to evaluate CAG practices in the contemporary OHCA population. METHODS: The Clinical Outcomes Assessment Program (COAP), a Washington State public reporting system, and the Cardiac Arrest Registry to Enhance Survival (CARES), a national registry of OHCA, were matched to characterize OHCA presentations between 2014 and 2015. Adults presenting to PCI-capable centers after OHCA were included. Logistic regression analyses were performed to assess predictors of undergoing CAG after OHCA. RESULTS: 2361 subjects were included with 729 (31%) proceeding to CAG, and 354 (15%) receiving PCI. The majority had return of spontaneous circulation (ROSC) at hospital arrival without identified ST elevations (72.2%). Of those with ST elevations and ROSC, 69% underwent CAG. OHCAs without ST elevations underwent CAG in 29.6% and PCI in 12.6%. After adjustment, older patients (aOR 0.73, 95% CI 0.72-0.84 per decade) and women (aOR 0.53, 95% CI 0.41-0.67) were less likely to proceed to CAG. Patients with witnessed arrest (aOR 2.07, 95% CI 1.62-2.67), VT/VF (aOR 6.11, 95% CI 4.85-7.69), ST elevations (aOR 3.82, 95% CI 2.71-5.38) and sustained ROSC (aOR 3.64, 95% CI 2.62-5.04) were more likely to undergo CAG. CONCLUSION: Only one-third of patients presenting to PCI-capable hospitals underwent CAG after OHCA. Patient selection for an invasive strategy after OHCA appeared to be heavily influenced by pre-hospital presentation variables.

Prolonging pulse duration in ultrasound-mediated gene delivery lowers acoustic pressure threshold for efficient gene transfer to cells and small animals.

While ultrasound-mediated gene delivery (UMGD) has been accomplished using high peak negative pressures (PNPs) of 2 MPa or above, emerging research showed that this may not be a requirement for microbubble (MB) cavitation. Thus, we investigated lower-pressure conditions close to the MB inertial cavitation threshold and focused towards further increasing gene transfer efficiency and reducing associated cell damage. We created a matrix of 21 conditions (n = 3/cond.) to test in HEK293T cells using pulse durations spanning 18 µs-36 ms and PNPs spanning 0.5-2.5 MPa. Longer pulse duration conditions yielded significant increase in transgene expression relative to sham with local maxima between 20 J and 100 J energy curves. A similar set of 17 conditions (n = 4/cond.) was tested in mice using pulse durations spanning 18 µs-22 ms and PNPs spanning 0.5-2.5 MPa. We observed local maxima located between 1 J and 10 J energy curves in treated mice. Of these, several low pressure conditions showed a decrease in ALT and AST levels while maintaining better or comparable expression to our positive control, indicating a clear benefit to allow for effective transfection with minimized tissue damage versus the high-intensity control. Our data indicates that it is possible to eliminate the requirement of high PNPs by prolonging pulse durations for effective UMGD in vitro and in vivo, circumventing the peak power density limitations imposed by piezo-materials used in US transducers. Overall, these results demonstrate the advancement of UMGD technology for achieving efficient gene transfer and potential scalability to larger animal models and human application.

Early Transcatheter Aortic Valve Function With and Without Therapeutic Anticoagulation.

OBJECTIVES: Prosthetic leaflet thrombosis is a growing concern in transcatheter aortic valve replacement (TAVR). Given the uncertainty of best practices for antiplatelet and anticoagulation therapies in the post-TAVR period, additional evidence regarding the impact of anticoagulation on prosthetic valve function after TAVR is needed. METHODS: Patients undergoing native-valve TAVR at a single academic institution between 2012 and 2015 were analyzed based on any anticoagulant use at hospital discharge post TAVR. Changes in prosthetic valve peak velocity and mean gradient were assessed based on transthoracic echocardiograms performed immediately following valve implant and at 4-week follow-up. Multivariate regression analyses were performed to explore the impact of anticoagulation status on early TAVR valve performance. RESULTS: For 403 patients, there were no available data to analyze. Of those, 29.6% were discharged on anticoagulation. Following TAVR, the average mean prosthetic valve gradient was 11.8 ± 5.6 mm Hg and peak velocity was 2.33 ± 0.52 m/s. There were no significant differences between anticoagulated and non-anticoagulated groups in the mean or peak gradients or velocity immediately following implant or at 4 weeks, which remained true following multivariate adjustment (P=.80 for delta mean gradient; P=.91 for delta peak velocity). CONCLUSION: Our data suggest that the absence of anticoagulation is not associated with short-term degradation in TAVR performance and do not support the routine use of anticoagulation following native-valve TAVR.