Recent studies implicate increased cGMP synthesis as a postreceptor contributor to reduced cardiac sympathetic responsiveness. Here we provide the first evidence that modulation of this interaction by cGMP-specific phosphodiesterase PDE5A is also diminished in failing hearts, providing a novel mechanism for blunted beta-adrenergic signaling in this disorder. In normal conscious dogs chronically instrumented for left ventricular pressure-dimension analysis, PDE5A inhibition by EMD82639 had modest basal effects but markedly blunted dobutamine-enhanced systolic and diastolic function. In failing hearts (tachypacing model), however, EMD82639 had negligible effects on either basal or dobutamine-stimulated function. Whole myocardium from failing hearts had 50% lower PDE5A protein expression and 30% less total and EMD92639-inhibitable cGMP-PDE activity. Although corresponding myocyte protein and enzyme activity was similar among groups, the proportion of EMD82639-inhibitable activity was significantly lower in failure cells. Immunohistochemistry confirmed PDE5A expression in both the vasculature and myocytes of normal and failing hearts, but there was loss of z-band localization in failing myocytes that suggested altered intracellular localization. Thus, PDE5A regulation of cGMP in the heart can potently modulate beta-adrenergic stimulation, and alterations in enzyme localization and reduced synthesis may blunt this pathway in cardiac failure, contributing to dampening of the beta-adrenergic response.

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OBJECTIVEAcute subdural hematoma (ASDH) is a leading entity in brain injury. Rodent models mostly lack standard intensive care, while large animal models frequently are only short term. Therefore, the authors developed a long-term, resuscitated porcine model of ASDH-induced brain injury and report their findings.METHODSAnesthetized, mechanically ventilated, and instrumented pigs with human-like coagulation underwent subdural injection of 20 mL of autologous blood and subsequent observation for 54 hours. Continuous bilateral multimodal brain monitoring (intracranial pressure [ICP], cerebral perfusion pressure [CPP], partial pressure of oxygen in brain tissue [PbtO2], and brain temperature) was combined with intermittent neurological assessment (veterinary modified Glasgow Coma Scale [MGCS]), microdialysis, and measurement of plasma protein S100β, GFAP, neuron-specific enolase [NSE], nitrite+nitrate, and isoprostanes. Fluid resuscitation and continuous intravenous norepinephrine were targeted to maintain CPP at pre-ASDH levels. Immediately postmortem, the brains were taken for macroscopic and histological evaluation, immunohistochemical analysis for nitrotyrosine formation, albumin extravasation, NADPH oxidase 2 (NOX2) and GFAP expression, and quantification of tissue mitochondrial respiration.RESULTSNine of 11 pigs survived the complete observation period. While ICP significantly increased after ASDH induction, CPP, PbtO2, and the MGCS score remained unaffected. Blood S100β levels significantly fell over time, whereas GFAP, NSE, nitrite+nitrate, and isoprostane concentrations were unaltered. Immunohistochemistry showed nitrotyrosine formation, albumin extravasation, NOX2 expression, fibrillary astrogliosis, and microglial activation.CONCLUSIONSThe authors describe a clinically relevant, long-term, resuscitated porcine model of ASDH-induced brain injury. Despite the morphological injury, maintaining CPP and PbtO2 prevented serious neurological dysfunction. This model is suitable for studying therapeutic interventions during hemorrhage-induced acute brain injury with standard brain-targeted intensive care.

Controversial evidence is available regarding suitable targets for the arterial O2 tension (PaO2) after traumatic brain injury and/or hemorrhagic shock (HS). We previously demonstrated that hyperoxia during resuscitation from hemorrhagic shock attenuated cardiac injury and renal dysfunction in swine with coronary artery disease. Therefore, this study investigated the impact of targeted hyperoxemia in a long-term, resuscitated model of combined acute subdural hematoma (ASDH)-induced brain injury and HS. The prospective randomized, controlled, resuscitated animal investigation consisted of 15 adult pigs. Combined ASDH plus HS was induced by injection of 0.1 ml/kg autologous blood into the subdural space followed by controlled passive removal of blood. Two hours later, resuscitation was initiated comprising re-transfusion of shed blood, fluids, continuous i.v. noradrenaline, and either hyperoxemia (target PaO2 200 – 250 mmHg) or normoxemia (target PaO2 80 – 120 mmHg) during the first 24 h of the total of 54 h of intensive care. Systemic hemodynamics, intracranial and cerebral perfusion pressures, parameters of brain microdialysis and blood biomarkers of brain injury did not significantly differ between the two groups. According to the experimental protocol, PaO2 was significantly higher in the hyperoxemia group at the end of the intervention period, i.e., at 24 h of resuscitation, which coincided with a higher brain tissue PO2. The latter persisted until the end of observation period. While neurological function as assessed using the veterinary Modified Glasgow Coma Score progressively deteriorated in the control group, it remained unaffected in the hyperoxemia animals, however, without significant intergroup difference. Survival times did not significantly differ in the hyperoxemia and control groups either. Despite being associated with higher brain tissue PO2 levels, which were sustained beyond the intervention period, targeted hyperoxemia exerted neither significantly beneficial nor deleterious effects after combined ASDH and HS in swine with pre-existing coronary artery disease. The unavailability of a power calculation and, thus, the limited number of animals included, are the limitations of the study.

Introduction: Deep sternal wound infections (DSWI) after cardiac surgery pose a significant challenge in reconstructive surgery. In this context, free flaps represent well-established options. The objective of this study was to investigate the clinical outcome after free myocutaneous tensor fasciae latae (TFL) flap reconstruction of sternal defects, with a special focus on surgical complications and donor-site morbidity. Methods: A retrospective chart review focused on patient demographics, operative details, and postoperative complications. Follow-up reexaminations included assessments of the range of motion and muscle strength at the donor-site. Patients completed the Quality of Life 36-item Short Form Health Survey (SF-36) as well as the Lower Extremity Functional Scale (LEFS) questionnaire and evaluated aesthetic and functional outcomes on a 6-point Likert scale. The Vancouver Scar Scale (VSS) and the Patient and Observer Scar Assessment Scales (POSAS) were used to rate scar appearance. Results: A total of 46 patients (mean age: 67 ± 11 years) underwent sternal defect reconstruction with free TFL flaps between January 2010 and March 2021. The mean defect size was 194 ± 43 cm2. The mean operation time was 387 ± 120 min with a flap ischemia time of 63 ± 16 min. Acute microvascular complications due to flap pedicle thromboses occurred in three patients (7%). All flaps could be salvaged without complete flap loss. Partial flap loss of the distal TFL portion was observed in three patients (7%). All three patients required additional reconstruction with pedicled or local flaps. Upon follow-up, the range of motion (hip joint extension/flexion (p = 0.73), abduction/adduction (p = 0.29), and internal/external rotation (p = 0.07)) and muscle strength at the donor-sites did not differ from the contralateral sides (p = 0.25). Patient assessments of aesthetic and functional outcomes, as well as the median SF-36 (physical component summary (44, range of 33 to 57)) and LEFS (54, range if 35 to 65), showed good results with respect to patient comorbidities. The median VSS (3, range of 2 to 7) and POSAS (24, range of 18 to 34) showed satisfactory scar quality and scar appearance. Conclusion: The free TFL flap is a reliable, effective, and, therefore, valuable option for the reconstruction of extensive sternal defects in critically ill patients suffering from DSWIs. In addition, the TFL flap shows satisfactory functional and aesthetic results at the donor-site.