Inhaled nitric oxide preserves ventricular function during resuscitation using a percutaneous mechanical circulatory support device in a porcine cardiac arrest model: an echocardiographic myocardial work analysis.

BACKGROUND: Resuscitation using a percutaneous mechanical circulatory support device (iCPR) improves survival after cardiac arrest (CA). We hypothesized that the addition of inhaled nitric oxide (iNO) during iCPR might prove synergistic, leading to improved myocardial performance due to lowering of right ventricular (RV) afterload, left ventricular (LV) preload, and myocardial energetics. This study aimed to characterize the changes in LV and RV function and global myocardial work indices (GWI) following iCPR, both with and without iNO, using 2-D transesophageal echocardiography (TEE) and GWI evaluation as a novel non-invasive measurement. METHODS: In 10 pigs, iCPR was initiated following electrically-induced CA and 10 min of untreated ventricular fibrillation (VF). Pigs were randomized to either 20 ppm (20 ppm, n = 5) or 0 ppm (0 ppm, n = 5) of iNO in addition to therapeutic hypothermia for 5 h following ROSC. All animals received TEE at five pre-specified time-points and invasive hemodynamic monitoring. RESULTS: LV end-diastolic volume (LVEDV) increased significantly in both groups following CA. iCPR alone led to significant LV unloading at 5 h post-ROSC with LVEDV values reaching baseline values in both groups (20 ppm: 68.2 ± 2.7 vs. 70.8 ± 6.1 mL, p = 0.486; 0 ppm: 70.8 ± 1.3 vs. 72.3 ± 4.2 mL, p = 0.813, respectively). LV global longitudinal strain (GLS) increased in both groups following CA. LV-GLS recovered significantly better in the 20 ppm group at 5 h post-ROSC (20 ppm: - 18 ± 3% vs. 0 ppm: - 13 ± 2%, p = 0.025). LV-GWI decreased in both groups after CA with no difference between the groups. Within 0 ppm group, LV-GWI decreased significantly at 5 h post-ROSC compared to baseline (1,125 ± 214 vs. 1,835 ± 305 mmHg%, p = 0.011). RV-GWI was higher in the 20 ppm group at 3 h and 5 h post-ROSC (20 ppm: 189 ± 43 vs. 0 ppm: 108 ± 22 mmHg%, p = 0.049 and 20 ppm: 261 ± 54 vs. 0 ppm: 152 ± 42 mmHg%, p = 0.041). The blood flow calculated by the Impella controller following iCPR initiation correlated well with the pulsed-wave Doppler (PWD) derived pulmonary flow (PWD vs. controller: 1.8 ± 0.2 vs. 1.9 ± 0.2L/min, r = 0.85, p = 0.012). CONCLUSIONS: iCPR after CA provided sufficient unloading and preservation of the LV systolic function by improving LV-GWI recovery. The addition of iNO to iCPR enabled better preservation of the RV-function as determined by better RV-GWI. Additionally, Impella-derived flow provided an accurate measure of total flow during iCPR.

Hemolysis associated with Impella heart pump positioning: In vitro hemolysis testing and computational fluid dynamics modeling.

INTRODUCTION: Short-term mechanical circulatory support devices provide temporary hemodynamic support in heart failure and are increasingly used to enable recovery or as a bridge to decision. Blood damage with mechanical circulatory support devices is influenced by many factors, including the magnitude and duration of shear stress and obstruction to blood flow. This study aimed to evaluate the effects of the Impella CP® heart pump positioning on hemolysis using in vitro hemolysis testing and computational fluid dynamics modeling. METHODS: The in vitro hemolysis testing was conducted per the recommended Food and Drug Administration and American Society for Testing and Materials guidelines. The bench hemolysis testing and computational fluid dynamics simulation analysis were performed for both normal operating (outlet unobstructed) and outlet-obstructed condition of Impella CP (mimicking outlet on the aortic valve due to improper positioning). RESULTS: The modified index of hemolysis was 2.78 ± 0.69 at normal operating conditions compared to 18.7 ± 7.8 when the Impella CP outlet was obstructed (p = 0.002). Computational fluid dynamics modeling showed about three times increase in exposure time to regions of high shear stress when the Impella CP outlet was obstructed compared to unobstructed condition, thus supporting the experimental observations. CONCLUSION: Based on these results, it is recommended to ensure proper placement of Impella CP via regular monitoring using echocardiographic guidance or other methods to minimize the risk of hemolysis associated with an obstructed outflow.

Regulation of Effector Treg Cells in Murine Lupus.

OBJECTIVE: Treg cells need to acquire an effector phenotype to function in settings of inflammation. Whether effector Treg cells can limit disease severity in lupus is unknown. Interferon regulatory factor 4 (IRF-4) is an essential controller of effector Treg cells and regulates their ability to express interleukin-10 (IL-10). In non-Treg cells, IRF-4 activity is modulated by interactions with DEF-6 and its homolog switch-associated protein 70 (SWAP-70). Although mice lacking both DEF-6 and SWAP-70 (double-knockout [DKO] mice) develop lupus, they display normal survival, suggesting that in DKO mice, Treg cells can moderate disease development. The purpose of this study was to investigate whether Treg cells from DKO mice have an increased capacity to become effector Treg cells due to the ability of DEF-6 and SWAP-70 to restrain IRF-4 activity. METHODS: Treg cells were evaluated by fluorescence-activated cell sorting. The B lymphocyte-induced maturation protein 1 (BLIMP-1)/IL-10 axis was assessed by crossing DKO mice with BLIMP-1-YFP-10BiT dual-reporter mice. Deletion of IRF-4 in Treg cells from DKO mice was achieved by generating FoxP3(Cre) IRF-4(fl/fl) DKO mice. RESULTS: The concomitant absence of DEF-6 and SWAP-70 led to increased numbers of Treg cells, which acquired an effector phenotype in a cell-intrinsic manner. In addition, Treg cells from DKO mice exhibited enhanced expression of the BLIMP-1/IL-10 axis. Notably, DKO effector Treg cells survived and expanded as disease progressed. The accumulation of Treg cells from DKO mice was associated with the up-regulation of genes controlling autophagy. IRF-4 was required for the expansion and function of effector Treg cells from DKO mice. CONCLUSION: This study revealed the existence of mechanisms that, by acting on IRF-4, can fine-tune the function and survival of effector Treg cells in lupus. These findings suggest that the existence of a powerful effector Treg cell compartment that successfully survives in an unfavorable inflammatory environment could limit disease development.

Epigenetics and the IRFs: a complex interplay in the control of immunity and autoimmunity.

Effective immune responses require the coordinated activation and differentiation of several cell types, including T-cells, B-cells and myeloid cells. Abnormalities in the appropriate regulation of these processes underlie the pathogenesis of many autoimmune disorders, including systemic lupus erythematosus (SLE). Recent studies have revealed that, in addition to sequence-specific DNA-binding factors, the chromatin landscape of a cell can play a pivotal role in controlling these processes and in regulating the onset of autoimmunity. Interferon regulatory factors (IRFs) are emerging as critical regulators of the activation and differentiation of immune cells and deregulation in the expression and/or function of members of the IRF family has increasingly been linked to the pathogenesis of lupus. In this review, we will provide a brief overview of the role of different IRFs in immune responses and SLE development and discuss studies, which highlight the intricate relationship of this family of transcription factors with the epigenetic machinery.