Immunomodulatory role of non-neuronal cholinergic signaling in myocardial injury.

Whereas prior studies have demonstrated an important immunomodulatory role for the neuronal cholinergic system in the heart, the role of the non-neuronal cholinergic system is not well understood. To address the immunomodulatory role of the non-neuronal cholinergic system in the heart we used a previously validated diphtheria toxin (DT)-induced cardiomyocyte ablation model (Rosa26-DTMlc2v-Cre mice). DT-injected Rosa26-DTMlc2v-Cre mice were treated with diluent or Pyridostigmine Bromide (PYR), a reversible cholinesterase inhibitor. PYR treatment resulted in increased survival and decreased numbers of MHC-IIlowCCR2+ macrophages in DT-injected Rosa26-DTMlc2v-Cre mice compared to diluent treated Rosa26-DTMlc2v-Cre mice. Importantly, the expression of CCL2/7 mRNA and protein was reduced in the hearts of PYR-treated mice. Backcrossing Rosa26-DTMlc2v-Cre mice with a transgenic mouse line (Chat-ChR2) that constitutively overexpresses the vesicular acetylcholine transporter (VAChT) resulted in decreased expression of Ccl2/7 mRNA and decreased numbers of CD68+ cells in DT-injured Rosa26-DTMlc2v-Cre/Chat-ChR2 mouse hearts, consistent with the pharmacologic studies with PYR. In vitro studies with cultures of LPS-stimulated peritoneal macrophages revealed a concentration-dependent reduction in CCL2 secretion following stimulation with ACh, nicotine and muscarine. Viewed together, these findings reveal a previously unappreciated immunomodulatory role for the non-neuronal cholinergic system in regulating homeostatic responses in the heart following tissue injury.

Infections after trauma are associated with subsequent cardiac injury.

BACKGROUND: Trauma produces profound inflammatory and immune responses. A second hit such as an infection further disrupts the inflammatory cascade. Inflammatory responses, following traumatic injuries, infections, or both, are emerging as biologic mediators of cardiac disease including myocardial ischemia and infarction. Inflammation-induced and stress-related cardiac damage are increasingly recognized in patients with critical illness. It is believed that cardiac dysfunction is the result of alterations in the inflammatory and immune cascades. Urinary tract infections (UTIs) and ventilator-associated pneumonia (VAP) are associated with increased mortality in trauma patients. UTIs and VAPs induced inflammatory responses. We postulate that increased mortality seen in trauma patients with infections is caused by increased rates of cardiac injury. METHODS: This is a retrospective review of prospectively collected data. All trauma patients admitted to the intensive care unit at our Level I trauma center during 5 years were included in the analysis. Proportional hazard regression analysis was performed to predict suspicion of cardiac injury (troponin ordered), any cardiac injury (troponin > 0.15 ng/mL), or severe cardiac injury (troponin > 1 ng/mL) using age, sex, Injury Severity Score (ISS), pulmonary disease (chronic obstructive pulmonary disease), heart failure, hypertension, diabetes, and the presence of a UTI or VAP. A similar proportion hazard regression was performed to predict mortality. RESULTS: In the model to predict any cardiac injury, chronic obstructive pulmonary disease (hazards ratio [HR], 1.9; p = 0.02), ISS (HR, 1.01; p = 0.04), VAP (HR, 5.6; p < 0.01), and UTI (HR, 2.4; p = 0.03) were significant. Neither VAP nor UTI predicted severe cardiac injury. In the model to predict death, any cardiac injury was not associated with mortality, but severe cardiac injury and UTI were associated with mortality as age increased. CONCLUSION: Infectious complications have been associated with increased mortality in trauma patients. Our data demonstrate that development of VAP or UTI is associated with an increased risk of developing cardiac injury in trauma patients, which may contribute to subsequent increased mortality. LEVEL OF EVIDENCE: Prognostic/epidemiologic study, level III.

Myocardial injury and bacterial pneumonia contribute to the pathogenesis of fatal influenza B virus infection.

BACKGROUND: Influenza B virus infection causes rates of hospitalization and influenza-associated pneumonia similar to seasonal influenza A virus infection and accounts for a substantial percentage of all influenza-related hospitalizations and deaths among those aged <18 years; however, the pathogenesis of fatal influenza B virus infection is poorly described. METHODS: Tissue samples obtained at autopsy from 45 case patients with fatal influenza B virus infection were evaluated by light microscopy and immunohistochemical assays for influenza B virus, various bacterial pathogens, and complement components C4d and C9, to identify the cellular tropism of influenza B virus, characterize concomitant bacterial pneumonia, and describe the spectrum of cardiopulmonary injury. RESULTS: Viral antigens were localized to ciliated respiratory epithelium and cells of submucosal glands and ducts. Concomitant bacterial pneumonia, caused predominantly by Staphylococcus aureus, was identified in 38% of case patients and occurred with significantly greater frequency in those aged >18 years. Pathologic evidence of myocardial injury was identified in 69% of case patients for whom cardiac tissue samples were available for examination, predominantly in case patients aged <18 years. CONCLUSIONS: Our findings suggest that bacterial pneumonia and cardiac injury contribute to fatal outcomes after infection with influenza B virus and that the frequency of these manifestations may be age related.