Implantable Defibrillator System Shock Function, Mortality, and Cause of Death After Magnetic Resonance Imaging.

BACKGROUND: Studies have shown that magnetic resonance imaging (MRI) does not have clinically important effects on the device parameters of non-MRI-conditional implantable cardioverter-defibrillators (ICDs). However, data on non-MRI-conditional ICD detection and treatment of arrhythmias after MRI are limited. OBJECTIVE: To examine if non-MRI-conditional ICDs have preserved shock function of arrhythmias after MRI. DESIGN: Prospective cohort study. (ClinicalTrials.gov: NCT01130896). SETTING: 1 center in the United States. PATIENTS: 629 patients with non-MRI-conditional ICDs enrolled consecutively between February 2003 and January 2015. INTERVENTIONS: 813 total MRI examinations at a magnetic field strength of 1.5 Tesla using a prespecified safety protocol. MEASUREMENTS: Implantable cardioverter-defibrillator interrogations were collected after MRI. Clinical outcomes included arrhythmia detection and treatment, generator or lead exchanges, adverse events, and death. RESULTS: During a median follow-up of 2.2 years from MRI to latest available ICD interrogation before generator or lead exchange in 536 patients, 4177 arrhythmia episodes were detected, and 97 patients received ICD shocks. Sixty-one patients (10% of total) had 130 spontaneous ventricular tachycardia or fibrillation events terminated by ICD shocks. A total of 210 patients (33% of total) are known to have died (median, 1.7 years from MRI to death); 3 had cardiac arrhythmia deaths where shocks were indicated without direct evidence of device dysfunction. LIMITATIONS: Data were acquired at a single center and may not be generalizable to other clinical settings and MRI facilities. Implantable cardioverter-defibrillator interrogations were not available for a subset of patients; adjudication of cause of death relied solely on death certificate data in a subset. CONCLUSION: Non-MRI-conditional ICDs appropriately treated detected tachyarrhythmias after MRI. No serious adverse effects on device function were reported after MRI. PRIMARY FUNDING SOURCE: Johns Hopkins University and National Institutes of Health.

Effect of Diffuse Subendocardial Hypoperfusion on Left Ventricular Cavity Size by 13N-Ammonia Perfusion PET in Patients With Hypertrophic Cardiomyopathy.

Vasodilator-induced transient left ventricular (LV) cavity dilation by positron emission tomography (PET) is common in patients with hypertrophic cardiomyopathy (HC). Because most patients with PET-LV cavity dilation lack obstructive epicardial coronary artery disease, we hypothesized that vasodilator-induced subendocardial hypoperfusion resulting from microvascular dysfunction underlies this result. To test this hypothesis, we quantified myocardial blood flow (MBF) (subepicardial, subendocardial, and global MBF) and left ventricular ejection fraction (LVEF) in 104 patients with HC without significant coronary artery disease, using 13NH3-PET. Patients with HC were divided into 2 groups, based on the presence/absence of LV cavity dilation (LVvolumestress/LVvolumerest >1.13). Transient PET-LV cavity dilation was evident in 52% of patients with HC. LV mass, stress left ventricular outflow tract gradient, mitral E/E', late gadolinium enhancement, and prevalence of ischemic ST-T changes after vasodilator were significantly higher in patients with HC with LV cavity dilation. Baseline LVEF was similar in the 2 groups, but LV cavity dilation+ patients had lower stress-LVEF (43 ± 11 vs 53 ± 10; p <0.001), lower stress-MBF in the subendocardial region (1.6 ± 0.7 vs 2.3 ± 1.0 ml/min/g; p <0.001), and greater regional perfusion abnormalities (summed difference score: 7.0 ± 6.1 vs 3.9 ± 4.3; p = 0.004). The transmural perfusion gradient, an indicator of subendocardial perfusion, was similar at rest in the 2 groups. Notably, LV cavity dilation+ patients had lower stress-transmural perfusion gradients (0.85 ± 0.22, LV cavity dilation+ vs 1.09 ± 0.39, LV cavity dilation-; p <0.001), indicating vasodilator-induced subendocardial hypoperfusion. The stress-transmural perfusion gradient, global myocardial flow reserve, and stress-LVEF were associated with LV cavity dilation. In conclusion, diffuse subendocardial hypoperfusion and myocardial ischemia resulting from microvascular dysfunction contribute to development of transient LV cavity dilation in HC.

Inhibitory receptor expression on memory CD8 T cells following Ad vector immunization.

T cells are an important component of immune responses, and their function is influenced by their expression of inhibitory receptors. Immunization with alternative serotype adenovirus (Ad) vectors induces highly functional T cell responses with lower programmed cell death 1 (PD-1) expression and increased boostability relative to Ad5 vectors. However, a detailed phenotypic characterization of other inhibitory receptors is lacking, and it is unknown whether Ad5-induced CD8 T cells eventually recover function with time. In this report, we measure the expression of various inhibitory receptors and memory markers during early and late time points following vaccination with Ad5 and alternative serotype Ad vectors. CD8 T cells induced by Ad5 exhibited increased expression of the inhibitory receptor Tim-3 and showed decreased central memory differentiation as compared with alternative serotype Ad vectors, even a year following immunization. Moreover, relative to Ad5-primed mice, Ad26-primed mice exhibited substantially improved recall of SIV Gag-specific CD8 T cell responses following heterologous boosting with MVA or Ad35 vectors. We also demonstrate that low doses of Ad5 priming resulted in more boostable immune responses with lower PD-1 expression as compared to high Ad5 doses, suggesting a role for vector dose in influencing immune dysfunction following Ad5 vaccination. These data suggest that Ad5 vectors induce a long-term pattern of immune exhaustion that can be partly overcome by lowering vector dose and modulating inhibitory signals.

Augmented replicative capacity of the boosting antigen improves the protective efficacy of heterologous prime-boost vaccine regimens.

UNLABELLED: Prime-boost immunization regimens have proven efficacious at generating robust immune responses. However, whether the level of replication of the boosting antigen impacts the magnitude and protective efficacy of vaccine-elicited immune responses remains unclear. To evaluate this, we primed mice with replication-defective adenovirus vectors expressing the lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP), followed by boosting with either LCMV Armstrong, which is rapidly controlled, or LCMV CL-13, which leads to a more prolonged exposure to the boosting antigen. Although priming of naive mice with LCMV CL-13 normally results in T cell exhaustion and establishment of chronic infection, boosting with CL-13 resulted in potent recall CD8 T cell responses that were greater than those following boosting with LCMV Armstrong. Furthermore, following the CL-13 boost, a greater number of anamnestic CD8 T cells localized to the lymph nodes, exhibited granzyme B expression, and conferred improved protection against Listeria and vaccinia virus challenges compared with the Armstrong boost. Overall, our findings suggest that the replicative capacity of the boosting antigen influences the protective efficacy afforded by prime-boost vaccine regimens. These findings are relevant for optimizing vaccine candidates and suggest a benefit of robustly replicating vaccine vectors. IMPORTANCE: The development of optimal prime-boost vaccine regimens is a high priority for the vaccine development field. In this study, we compared two boosting antigens with different replicative capacities. Boosting with a more highly replicative vector resulted in augmented immune responses and improved protective efficacy.

Alternative serotype adenovirus vaccine vectors elicit memory T cells with enhanced anamnestic capacity compared to Ad5 vectors.

The failure of the adenovirus serotype 5 (Ad5) vector-based human immunodeficiency virus type 1 (HIV-1) vaccine in the STEP study has led to the development of adenovirus vectors derived from alternative serotypes, such as Ad26, Ad35, and Ad48. We have recently demonstrated that vaccines using alternative-serotype Ad vectors confer partial protection against stringent simian immunodeficiency virus (SIV) challenges in rhesus monkeys. However, phenotypic differences between the T cell responses elicited by Ad5 and those of alternative-serotype Ad vectors remain unexplored. Here, we report the magnitude, phenotype, functionality, and recall capacity of memory T cell responses elicited in mice by Ad5, Ad26, Ad35, and Ad48 vectors expressing lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP). Our data demonstrate that memory T cells elicited by Ad5 vectors were high in magnitude but exhibited functional exhaustion and decreased anamnestic potential following secondary antigen challenge compared to Ad26, Ad35, and Ad48 vectors. These data suggest that vaccination with alternative-serotype Ad vectors offers substantial immunological advantages over Ad5 vectors, in addition to circumventing high baseline Ad5-specific neutralizing antibody titers.