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Background The high incidence of gastrointestinal bleeding (GIB) in patients with ventricular assist devices (VAD) is well known, but there is limited evidence to support the use of proton pump inhibitors (PPIs) or histamine receptor antagonists (H2RA) for preventing GIB in patients with VAD. Materials and methods The surgical ICU and VAD databases within a large regional academic cardiac mechanical support and transplant center were queried for patients who underwent VAD implantation between 2010 and 2014. An observational cohort study was conducted to identify which acid suppressing drug regimen was associated with the fewest number of GIB events within 30 d after VAD implantation: PPI, H2RA, or neither. Secondary outcomes included timing, etiology, and location of GIB. Multivariable logistic regression was used to compare treatment cohorts to GIB. Odds ratios, 95% confidence intervals, and P-values were reported from the model. Results One hundred thirty-eight patients were included for final analysis, 19 of which had a GIB within 30 days of VAD implantation. Both H2RA and PPI use were associated with reduced GIB compared with the cohort with no acid suppressive therapy. In the multivariate analysis, the PPI cohort showed a statistically significant reduction in GIB (Odds ratio 0.18 [95% confidence interval 0.04-0.79] P = 0.026). Conclusions Using PPI postoperatively in patients with new VAD was associated with a reduced incidence of GIB. Given that GIB is a known complication after VAD placement, clinicians should consider the use of acid suppressive therapy for primary prevention.

Background Acute mechanical circulatory support (aMCS) can be a lifesaving therapy for patients with refractory cardiogenic shock. As device safety and technology improve, so will the ability to extend aMCS to patients at remote hospitals. The Intermountain West is unique because of the large geographical area, making transport of critically ill patients a logistical challenge. Methods We reviewed our experience of transporting patients in cardiogenic shock over long distances who had already been placed on aMCS: Impella and extracorporeal membrane oxygenator devices. Survival data was compared to international benchmark data published by the Extracorporeal Life Support Organization. Results A total of 11 patients (91% male; mean age 56 ± 5.4 y) were transported via fixed-wing aircraft to our center. The etiology of cardiogenic shock was ST-elevation myocardial infarction ( n = 4), acutely decompensated chronic systolic heart failure ( n = 4), postcardiotomy shock ( n = 2), and acute myocarditis ( n = 1). Average transport distance was 364 ± 139 miles (585 ± 264 km) and flight time was 170 ± 29 min. All patients were safely transported with no in-transit adverse events. The average duration of aMCS was 6.4 ± 3.3 d. Six patients (54.5%) survived to device explantation and 3 (27.2%) survived to hospital discharge. For comparison, Extracorporeal Life Support Organization benchmark data for adult cardiogenic shock patients report 56% survival to device explantation and 41% to hospital discharge. Conclusions Patient transport with aMCS over long distances can be done safely without serious adverse events using good protocols and well-trained personnel. Although survival data are slightly below benchmark data, they appear reasonable, given the severity of illness and challenges of transferring critically ill patients to an expert center.

Background Heart failure is a leading cause of death but very little is known about right ventricular (RV) failure (RVF) and right ventricular recovery (RVR). A robust animal model of reversible, RVF does not exist, which currently limits research opportunities and clinical progress. We sought to develop an animal model of reversible, pressure-overload RVF to study RVF and RVR. Materials and methods Fifteen New Zealand rabbits underwent implantation of a fully implantable, adjustable, pulmonary artery band. Animals were assigned to the control, RVF, and RVR groups (n = 5 for each). For the RVF and RVR groups, the pulmonary artery bands were serially tightened to create RVF and released for RVR. Echocardiographic, cardiac magnetic resonance imaging, and histologic analysis were performed. Results RV chamber size and wall thickness increased during RVF and regressed during RVR. RV volumes were 1023 μL ± 123 for control, 2381 μL ± 637 for RVF, and 635 μL ± 549 for RVR, and RV wall thicknesses were 0.98 mm ± 0.12 for controls (P = 0.05), 1.72 mm ± 0.60 for RVF, and 1.16 mm ± 0.03 for RVR animals (P = 0.04), respectively. Similarly, heart weight, liver weight, cardiomyocyte size, and the degree of cardiac and hepatic fibrosis increased with RVF and decreased during RVR. Conclusions We report an animal model of chronic, reversible, pressure-overload RVF to study RVF and RVR. This model will be used for preclinical studies that improve our understanding of the mechanisms of RVF and that develop and test RV protective and RVR strategies to be studied later in humans.

Background Clinical and experimental studies have traditionally focused on understanding the mechanisms for why a heart fails. We hypothesize that the pathways involved with myocardial recovery are not simply the reverse of those that cause heart failure. However, determining when and how a decompensated heart can recover remains unknown. Methods Male C57BL/6 mice underwent minimally invasive aortic banding for 3, 4, or 6 wk with or without subsequent band removal for 1 wk (debanding). Physiologic and genomic characterization was performed with intracardiac pressure-volume recordings, rt-PCR, and microarray analysis. Results Heart weight/body weight ratios and PV loops demonstrated a transition from compensated left ventricular hypertrophy to decompensated heart failure between 3 and 4 wk. Pressure-relief afforded by debanding allowed functional recovery and normalization of LVH after both 3 and 4, but not 6 wk of banding. Whole genome microarrays demonstrated 397 genes differentially expressed in recovered hearts, 250 genes differentially expressed in the nonrecoverable (6 wk) hearts, and only 10 genes shared by both processes. In particular, altered expression patterns of apoptotic and metalloproteinase genes correlated with the heart’s ability to functionally recover. Conclusions This clinically-relevant model (1) allows us to temporally and mechanistically characterize the failing heart, (2) demonstrates a unique genomic signature that may predict when a failing heart can recover following pressure relief, and (3) will prove useful as a template for testing therapeutic strategies aimed at recovery of the failing heart.

Background Most cardiovascular studies have implicated the central transcription factor nuclear factor kappa-B (NF-κB) as contributing to the detrimental effects of cardiac injury. This ostensibly negative view of NF-κB competes with its important role in the normal host inflammatory and immune response. Pressure overload, left ventricular hypertrophy (LVH), and heart failure represent a spectrum of disease that has both adaptive and maladaptive components. In contrast to its known effects related to myocardial ischemia–reperfusion, we hypothesized that NF-κB is necessary for the compensatory phase of cardiac remodeling. Methods C57BL6 mice underwent minimally invasive transverse aortic constriction with or without inhibition of the proximal NF-κB kinase, inhibitory kappa-B kinase-β. Isolated cardiomyocytes were cultured. Transthoracic echocardiography was performed on all mice. Results Inhibitory kappa-B kinase-β inhibition successfully decreased cardiomyocyte expression of phosphorylated p65 NF-κB and decreased expression of hypertrophic markers with stimulation in vitro . Three weeks after transverse aortic constriction, the mice treated with inhibitory kappa-B kinase-β inhibition more aggressively developed LVH, as measured by heart weight/body weight ratio, left ventricular mass, and wall thickness. These mice also demonstrated a functional decline, as measured by decreased fractional shortening and ejection fraction. These findings were associated with decreased protein expression of p65 NF-κB. Conclusions Although short-term pressure-overload results in compensatory LVH with normal cardiac function, NF-κB inhibition resulted in increased LVH that was associated with functional deterioration. These observations suggest that NF-κB is an important part of the adaptive phase of LVH, and its inhibition detrimentally affects cardiac remodeling.

Background The inflammatory response to vascular injury is characterized by expression of cytokines, growth factors, and chemokines that conspire to promote vessel remodeling and intimal hyperplasia (IH). Interleukin-10 (IL-10) is a multifunctional cytokine that has several anti-inflammatory properties in vitro. Few studies have evaluated the effects of IL-10 in experimental atherosclerosis. The purpose of the present study was to determine the influence of IL-10 on vascular inflammation and IH following mechanical injury. Methods Wire carotid injury was performed in wild-type (WT) mice with and without IL-10 treatment. Immunohistochemistry, PCR, and ELISA assays were used to examine vessel production of basic fibroblast growth factor (bFGF), monocyte chemotactic protein-1 (MCP-1), and nuclear factor kappa B (NFκB). Vessels were morphometrically analyzed for IH. Results Carotid injury induced early expression of MCP-1 and bFGF that was abrogated in mice treated with IL-10. Similarly, injury-induced expression of NFκB message and protein was attenuated in mice receiving exogenous IL-10. Compared to untreated mice, IL-10 markedly decreased levels of IH. Interestingly, carotid injury in IL-10-deficient mice resulted in an augmented IH response compared to injured WT mice. Conclusions In an in vivo model of direct vascular injury, IL-10 decreased expression of the pro-inflammatory transcription factor, NFκB, and the mitogenic chemokine and growth factor, MCP-1 and bFGF, respectively. These observations were associated with IL-10-induced attenuation of IH. Furthermore, endogenous IL-10 appeared to suppress the injury response. In conclusion, exogenously delivered IL-10 may represent a clinically relevant anti-inflammatory strategy for post-injury intimal hyperplasia.

Elevation of cellular cAMP inhibits lipopolysaccharide(LPS)-stimulated tumor necrosis factor alpha (TNF-alpha) production and increases the expression of interleukin (IL)-10 in mononuclear cells. TNF-alpha gene expression obligates activation of the transcription factor nuclear factor kappaB (NF-kappaB). Exogenous IL-10 inhibits NF-kappaB in monocytes and thus attenuates TNF-alpha production. We examined the role of endogenous IL-10 in the regulation of NF-kappaB activation and TNF-alpha production in human monocytes by cAMP.Human monocytes were stimulated with Escherichia coli LPS (100 ng/ml) with and without forskolin (FSK, 50 microM) or dibutyryl cyclic AMP (dbcAMP, 100 microM). Cytokine (TNF-alpha and IL-10) release was measured by immunoassay. TNF-alpha mRNA was measured by reverse transcription polymerase chain reaction, and NF-kappaB DNA binding activity was assessed by gel mobility shift assay.cAMP-elevating agents inhibited LPS-stimulated TNF-alpha release (0.77 +/- 0.13 ng/10(6) cells in LPS + dbcAMP and 0.68 +/- 0.19 ng/10(6) cells in LPS + FSK, both P0.05 vs 1.61 +/- 0.34 ng/10(6) cells in LPS alone). Conversely, cAMP enhanced LPS-stimulated IL-10 release (100 +/- 21.5 pg/10(6) cells in LPS + dbcAMP and 110 +/- 25.2 pg/10(6) cells in LPS + FSK, both P0.05 vs 53.3 +/- 12.8 pg/10(6) cells in LPS alone). Neither TNF-alpha mRNA expression nor NF-kappaB activation stimulated by LPS was inhibited by the cAMP-elevating agents. Neutralization of IL-10 with a specific antibody did not attenuate the effect of cAMP-elevating agents on TNF-alpha production.The results indicate that cAMP inhibits LPS-stimulated TNF-alpha production through a posttranscriptional mechanism that is independent of endogenous IL-10.

Observational data strongly suggest an association between Chlamydia pneumoniae and atherosclerotic cardiovascular disease. However, few studies have mechanistically linked C. pneumoniae to vascular remodeling. The purpose of the present study was to examine the mechanistic relationship between C. pneumoniae and human vascular smooth muscle cell (VSMC) physiology. We sought to determine the influence of human VSMC infection by C. pneumoniae on (1) VSMC proliferation and (2) activation of the proinflammatory and proliferative transcription factors nuclear factor kappaB (NF-kappaB) and activator protein 1 (AP-1).C. pneumoniae was grown and isolated from Hep 2 cells. Human aortic VSMCs were inoculated with C. pneumoniae in the presence and absence of the azalide antibiotic azithromycin. Cell proliferation was assayed by direct cell counting 48 h following infection. Two hours following infection, nuclear extracts were isolated, and activation of both NF-kappaB and AP-1 was assessed by electrophoretic mobility shift assay.Compared with control, C. pneumoniae infection stimulated VSMC proliferation (P0.05) and induced both NF-kappaB and AP-1 DNA binding activity. These effects were eliminated by concurrent treatment with azithromycin.VSMC infection with C. pneumoniae activates proliferative intracellular signals and stimulates cell growth. These data implicate C. pneumoniae as a pathogenic mediator and a potential therapeutic target in the prevention of atherosclerotic disease.

Hemorrhage and resuscitation has been recognized as an exclusively destructive process which results in multiple organ dysfunction. Although it is well established that endogenous adaptation (preconditioning) mechanisms exist, it is unknown whether hemorrhage and resuscitation induces endogenous adaptive/protective mechanisms in the heart. Furthermore, α 1 -adrenoceptors and nuclear factor κ B (NFKB) have each been implicated in stress-induced signal transduction; however, whether they might be involved in hemorrhage-induced adaptive signal transduction remains unknown. This study tests the hypothesis that H/R activates myocardial NFKB and results in myocardial adaptation via α 1 -adrenoceptors. Rats were briefly (10 min) hemorrhaged to 35 mmHg and resuscitated, sham operated, or neither, with and without prior α 1 -adrenoceptor inhibition (prazosin). Hearts were then isolated and either probed for NFKB activation or subjected to a second insult consisting of global normothermic I/R (20 min/40 min). Antecedent hemorrhage and resuscitation activated myocardial NFKB and improved left ventricular developed pressure, coronary flow, and end diastolic pressure following ischemia-reperfusion (P < 0.05, ANOVA with Bonferroni-Dunn). Hemorrhage-induced adaptation was abolished by prior α 1 -adrenoceptor blockade. This study constitutes the initial demonstration that H/R activates myocardial NFKB and induces adaptive signal transduction against ischemia-reperfusion injury.