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BACKGROUND Blood transfusion can be lifesaving for patients with hemorrhage; however, transfusion requirements for victims of gun violence are poorly understood. STUDY DESIGN AND METHODS In an urban, Level 1 trauma center, 23,422 trauma patients were analyzed in a retrospective cohort study. Patients with gunshot wounds (GSWs) (n = 2,672; 11.4% of trauma patients) were compared to those with non-GSW traumatic injuries from 2005 to 2017, to assess blood utilization. RESULTS The GSW cohort was approximately five times more likely to require transfusion (538 of 2672 [20.1%] vs. 798 of 20,750 [3.9%]; p < 0.0001), and the number of blood component units transfused per patient was approximately 10 times greater (3.3 ± 13.5 vs. 0.31 ± 3.8 units/patient; p < 0.0001), compared to the non-GSW cohort. The risk-adjusted likelihood of requiring high-dose transfusion was greater in the GSW cohort (odds ratio, 2.38; 95% confidence interval, 1.14-5.80), and requirements were increased for all four blood components (red blood cells, platelets, plasma, and cryoprecipitate). Patients with GSWs had approximately 14 times greater overall mortality (653 of 2672 [24.4%] vs. 352 of 20,750 [1.7%]; p < 0.0001]. Compared to non-GSW penetrating injuries (e.g., stab wounds), those with GSWs had approximately four times higher transfusion requirements (3.3 ± 13.5 vs. 0.80 ± 3.8 units/patient; p < 0.0001), and approximately eight times greater overall mortality (653 of 2672 [24.4%] vs. 28 of 956 [2.9%]; p < 0.0001). CONCLUSIONS Compared to other traumatic injuries, GSW injuries are associated with substantially greater blood utilization and mortality. Trauma centers treating GSW injuries should have ready access to all blood components and ability to implement massive transfusions.

Stromal cell-derived factor-1α (SDF-1) has been reported to mediate cardioprotection through the mobilization of stem cells into injured tissue and an increase in local angiogenesis after myocardial infarction. However, little is known regarding whether SDF-1 induces acute protection following global myocardial ischemia/reperfusion (I/R) injury and if so, by what molecular mechanism. SDF-1 binding to its cognate receptor CXCR4 has been shown to activate STAT3 in a variety of cells. STAT3 is a cardioprotective factor and may mediate SDF-1/CXCR4-induced acute protection. We hypothesized that SDF-1 would improve myocardial function through CXCR4-increased STAT3 activation following acute I/R. Isolated mouse hearts were subjected to 25-min global ischemia/40-min reperfusion and divided into groups of 1) vehicle; 2) SDF-1; 3) AMD3100, a CXCR4 inhibitor; 4) SDF-1 + AMD3100; 5) Stattic, a STAT3 inhibitor; 6) SDF-1 + Stattic; 7) cardiomyocyte-restricted ablation of STAT3 (STAT3KO); 8) STAT3KO + SDF-1; 9) Ly294002, an inhibitor of the Akt pathway; and 10) SDF-1 + Ly294002. Reagents were infused into hearts within 5 min before ischemia. SDF-1 administration significantly improved postischemic myocardial functional recovery in a dose-dependent manner. Additionally, pretreatment with SDF-1 reduced cardiac apoptotic signaling and increased myocardial STAT3 activation following acute I/R. Inhibition of the SDF-1 receptor CXCR4 neutralized these protective effects by SDF-1 in hearts subjected to I/R. Notably, inhibition of the STAT3 pathway or use of STAT3KO hearts abolished SDF-1-induced acute protection following myocardial I/R. Our results represent the first evidence that the SDF-1/CXCR4 axis upregualtes myocardial STAT3 activation and, thereby, mediates acute cardioprotection in response to global I/R.

Mesenchymal stem cells (MSCs) protect ischemic tissues in part through paracrine growth factor production. IL-6, which is upregulated in the heart during ischemia, has been shown to enhance stem cell proliferation and migration. The effect of IL-6 on MSC paracrine function, however, remains unknown. In addition, TGF-α increases MSC vascular endothelial growth factor (VEGF) production and may share downstream signaling pathways with IL-6 involving ERK, JNK, and PI3K. We hypothesize that cotreatment with IL-6 and TGF-α will result in greater MSC VEGF production than by either treatment alone via these signaling pathways. Murine MSCs were treated with IL-6 (0.05 ng/mL) with or without TGF-α (250 ng/mL) and in combination with inhibitors of ERKI/II, JNK, and PI3K for 24 h. Vascular endothelial growth factor concentrations in the supernatants were measured using enzyme-linked immunosorbent assay. Phosphorylation of ERK, JNK, and PI3K was measured using Western blot analysis. IL-6 increased MSC VEGF production at a dose of 0.05 ng/mL, and the combination of IL-6 and TGF-α (250 ng/mL) increased VEGF production to a greater extent than IL-6 or TGF-α alone. IL-6 induced phosphorylation of ERK, JNK, and PI3K, and inhibition of each suppressed IL-6-induced VEGF production. TGF-α cotreatment overcame VEGF suppression after ERK2 inhibition but not ERK1, JNK, or PI3K. These data suggest that IL-6 stimulates MSC VEGF production alone and additively with TGF-α via ERK-, JNK-, and PI3K-mediated mechanisms. IL-6 and TGF-α cotreatment may be a useful strategy for enhancing MSC VEGF production and cardioprotection during myocardial ischemia.

Mesenchymal stem cells (MSCs) have been used experimentally and clinically in the treatment of a wide variety of pathologies. It is now clear that a number of different mechanisms contribute to the therapeutic effects exerted by these cells. The ability of MSCs to interact with and modulate the functions of a wide variety of immune cells has been recognized as one such mechanism. The implications that the immunomodulatory properties of MSCs may have for the treatment of solid organ rejection, the Systemic Inflammatory Response Syndrome, cancer, and Crohn’s disease are reviewed herein.

Background Stem cell-based therapies for myocardial ischemia have demonstrated promising early clinical results, but their benefits have been limited in duration due to impaired donor cell engraftment and function. Several strategies have emerged for enhancing stem cell function prior to their therapeutic use particularly with regard to stem cell homing, paracrine function, and survival. This review discusses current understandings of stem cell-mediated cardioprotection as well as methods of enhancing post-transplantation stem cell function and survival through hypoxic preconditioning, genetic manipulation, and pharmacologic pretreatment. Materials and Methods A literature search was performed using the MEDLINE and PubMed databases using the keywords “stem cell therapy,” “myocardial ischemia,” “hypoxic preconditioning,” “paracrine function,” and “stem cell pretreatment.” Studies published in English since January 1990 were selected. In addition, studies were identified from references cited in publications found using the search terms. Results All included studies utilized animal studies and/or in vitro techniques. Stem cell modifications generally targeted stem cell homing (SDF-1, CXCR4), paracrine function (VEGF, angiogenin, Ang-1, HGF, IL-18 binding protein, TNFR1/2), or survival (Akt, Bcl-2, Hsp20, HO-1, FGF-2). However, individual modifications commonly exhibited pleiotropic effects involving some or all of these general categories. Conclusion These strategies for optimizing stem cell-mediated cardioprotection present unique potential sets of advantages and disadvantages for clinical application. Additional questions remain including those that are most efficacious in terms of magnitude and duration of benefit as well as whether combinations may yield greater benefits in both the preclinical and clinical settings.

Toll-like receptors (TLRs) play a key role in innate immune defenses. After activation by foreign pathogens or host-derived molecules, TLRs signal via overlapping or distinct signaling cascades and eventually induce numerous genes involved in a variety of cellular responses. A growing body of evidence suggests that TLR signaling also plays an important role in cardiac ischemia/reperfusion injury. We review our current understanding of the TLR signaling pathways and their roles in the pathophysiology of cardiac ischemia/reperfusion injury, as well as discuss several mechanisms for TLR activation and regulation.

Atrial fibrillation (AF) is the most common chronic arrhythmia in the United States and is associated with high morbidity rates and significant healthcare costs. Although medical therapy for AF modestly reduces complications, cardiac surgery continues to have an important role in the treatment of AF and is constantly evolving. Cardiothoracic surgeons are uniquely positioned to offer effective operations to patients with lone AF, in addition to those undergoing concomitant elective cardiac surgery. This review discusses (1) the burden of AF, (2) classification and electrophysiology of AF, (3) surgical techniques and outcomes, and (4) future directions in surgical therapy.

Toll-like receptor 2 (TLR2), a key component of the innate immune system, is linked to inflammation and myocardial dysfunction after ischemia-reperfusion injury (I/R). Treatment of the heart with mesenchymal stem cells (MSCs) is known to improve myocardial recovery after I/R in part by paracrine factors such as VEGF. However, it is unknown whether TLR2 activation on the MSCs affects MSC-mediated myocardial recovery and VEGF production. We hypothesized that the knockout of TLR2 on the MSCs (TLR2KO MSCs) would 1) improve MSC-mediated myocardial recovery and 2) increase myocardial and MSC VEGF release. With the isolated heart perfusion system, Sprague-Dawley rat hearts were subjected to I/R and received one of three intracoronary treatments: vehicle, male wild-type MSCs (MWT MSCs), or TL2KO MSCs. All treatments were performed immediately before ischemia, and heart function was measured continuously. Postreperfusion, heart homogenates were analyzed for myocardial VEGF production. Contrary to our hypothesis, only MWT MSC treatment significantly improved the recovery of left ventricular developed pressure and the maximal positive and negative values of the first derivative of pressure. In addition, VEGF production was greatest in hearts treated with MWT MSCs. To investigate MSC production of VEGF, MSCs were activated with TNF in vitro and the supernatants collected for ELISA. In vitro basal levels of MSC VEGF production were similar. However, with TNF activation, MWT MSCs produced significantly more VEGF, whereas activated TLR2KO MSC production of VEGF was unchanged. Finally, we observed that MWT MSCs proliferated more rapidly than TLR2KO MSCs. These data indicate that TLR2 may be essential to MSC-mediated myocardial recovery and VEGF production.

The production of growth factors such as vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) by human bone marrow mesenchymal stem cells (MSCs) may play an important role in their paracrine effects on proliferation, differentiation, and protection. NO is produced during ischemia and may affect MSC function. However, it is unknown whether NO alters the production of VEGF and HGF from MSCs. To study this, human MSCs were stimulated to produce growth factors with TNF or LPS with and without various doses of NO donors or NOS inhibitors. We found that FK409, an NO donor, significantly suppressed the production of VEGF and HGF from human MSCs. Vascular endothelial growth factor in the supernatants of cells treated by 20 nM FK409 (497 +/- 19 pg/mL) was significantly lower compared with controls (625 +/- 34 pg/mL). Similarly, NO donor significantly suppressed the amount of HGF from controls (118 +/- 3 to 40 +/- 2 pg/mL) after treatment with 20 nM FK409. NO donor also abolished the augmentation of VEGF production induced by LPS. The amount of VEGF in the supernatant was 571 +/- 11 pg/mL when cells were treated with 20 nM FK409 and LPS (200 ng/mL), which was significantly lower than groups treated with LPS alone (941 +/- 30 pg/mL). This study constitutes an initial report regarding the effect of NO on human MSC growth factor production.

Mesenchymal stem cells (MSCs) possess immunomodulatory properties and may curtail the inflammatory response that characterizes sepsis and other systemic inflammatory states. We aimed to determine whether intravenous infusion of MSCs is associated with reduced inflammation and improved myocardial function in a rat model of endotoxemia. Adult Sprague-Dawley rats were administered saline (vehicle) or LPS (5 mg/kg) via tail vein injection. Treatments, either vehicle or 2 × 10(6) MSCs, were infused 1 h later via tail vein. Animals were randomly assigned to the following groups: (a) vehicle + vehicle (control; n = 6), (b) LPS + vehicle (n = 6), or (c) LPS + MSCs (n = 6). Six hours after induction of endotoxemia, left ventricular ejection fraction (EF) and fractional shortening (FS) was assessed via parasternal short-axis M-mode echocardiography. Hearts and serum were collected for determination of cytokine levels via enzyme-linked immunosorbent assay. Animals injected with LPS + vehicle exhibited depressed cardiac function as indicated by a 26% and 37% reduction in EF and FS from baseline, respectively. Treatment with MSCs was associated with improved cardiac function compared with vehicle treatment as indicated by a reduction in EF and FS of only 10% and 17%, respectively (P < 0.05). Myocardial levels of TNF-α, IL-1β, and IL-6 were elevated in LPS-treated animals versus control. Similarly, serum levels of IL-1β, IL-6, and IL-10 were increased in LPS-treated animals. Treatment with MSCs, however, was associated with significant reductions in serum levels of IL-1β and IL-6 and in myocardial levels of TNF-α, IL-1β, and IL-6. In addition, treatment with MSCs was associated with a further increase in serum IL-10. Infusion of MSCs modulates the systemic inflammatory response and is associated with improved cardiac function during endotoxemia.

Background Transforming growth factor-α (TGF-α) has been shown to augment mesenchymal stem cell-mediated cardioprotection during acute ischemia and reperfusion in isolated heart models. To determine whether this pretreatment strategy would be effective in vivo, we hypothesized that the intramyocardial injection of mesenchymal stem cells pretreated with TGF-α after coronary artery ligation would confer greater preservation of cardiac function, reduction in infarct size, and reduction myocardial inflammation. Methods Sprague-Dawley rats underwent left anterior descending coronary artery ligation. Ischemic border zones were injected 30 minutes later with vehicle (n = 11), 1 million mesenchymal stem cells (n = 9), or mesenchymal stem cells pretreated with TGF-α (250 ng/mL for 24 hours; n=10). Cardiac function was assessed by echocardiography at 7 and 28 days after ligation. Infarct size was measured using triphenyltetrazolium chloride. Ischemic border zone cytokine expression was measured 30 days after infarction. Results Myocardial function after ligation was greatest in hearts injected with cells pretreated with TGF-α in association with reduced ventricular remodeling and infarct size compared with vehicle-injected hearts. Myocardial interleukin 1β, interleukin 6, and TNF-α concentrations were lower, and Bcl-2 expression was higher, in hearts injected with either cell type. Vascular endothelial growth factor and matrix metalloproteinase-2 expression were highest in hearts that received pretreated cells. Conclusions Intramyocardial injection of mesenchymal stem cells pretreated with TGF-α further protects cardiac function and reduces infarct size compared with injection of untreated cells. Pretreating donor cells with TGF-α may be useful for enhancing cell-based therapies for myocardial ischemia.

Stem cell-based therapies offer promising potential for myocardial infarction (MI), but endogenous molecules released in response to injury likely impair posttransplantation stem cell function. Stem cell-mediated cardioprotection occurs in part via paracrine effects, and transforming growth factor-α (TGF-α) has been shown to enhance paracrine function. However, it is unknown whether pretreating stem cells with TGF-α increases stem cell-mediated cardioprotection after acute MI. Mesenchymal stem cells (MSCs) were treated with TGF-α (250 ng/ml) for 24 h. Adult male Sprague-Dawley rat hearts were isolated and perfused using the Langendorff method. MI was induced by ligating the left anterior descending coronary artery. Postligation (30 min), vehicle or 1 × 106MSCs with or without pretreatment were injected in the infarct border zones, and the hearts were perfused for an additional 60 min. Left ventricular function was continuously measured, and infarct size was assessed with Evans blue dye and 2,3,5-triphenyltetrazolium chloride staining. Myocardial production of interleukin (IL)-1β and IL-6 and caspase 3 activation was also measured. Left ventricular function decreased significantly following coronary artery ligation but improved following injection of untreated MSCs and to a greater extent after injection of pretreated MSCs. In addition, the infarct area, myocardial caspase 3 activation, and IL-6 production were lowest in hearts injected with pretreated cells. Intramyocardial injection of TGF-α-pretreated MSCs after acute MI is associated with increased myocardial function and decreased myocardial injury. This strategy may be useful for optimizing the therapeutic efficacy of stem cells for the treatment of acute MI.

Phosphoinositide-3 kinases (PI3Ks) are critical regulatory proteins in the immunologic defense system against sepsis. The PI3K mechanism helps modulate cellular survival, innate and adaptive immunities, inflammation, nuclear factor-κB transcription, and may, in turn, play a protective role in sepsis. Animal studies confirm its role in the prevention of organ dysfunction and improvement of survival outcomes. Further advances in the understanding of this key immunomodulatory pathway may provide valuable insights into the manipulation of cellular function for therapeutic treatment of sepsis and other inflammatory diseases.

Differences in cardiovascular disease outcomes between men and women have long been recognized and attributed, in part, to gender and sex steroids. Gender dimorphisms also exist with respect to the roles of progenitor and stem cells in post-ischemic myocardial and endothelial repair and regeneration. Understanding how these cells are influenced by donor gender and the recipient hormonal milieu may enable researchers to further account for the gender-related disparities in clinical outcomes as well as utilize the beneficial effects of these hormones to optimize transplanted cell function and survival. This review discusses (1) the cardiovascular effects of sex steroids (specifically estradiol and testosterone); (2) the therapeutic potentials of endothelial progenitor cells, mesenchymal stem cells, and embryonic stem cells; and (3) the direct effect of sex steroids on these cell types.