Regional Differences in the Small Intestinal Proteome of Control Mice and of Mice Lacking Lysosomal Acid Lipase.

The metabolic contribution of the small intestine (SI) is still unclear despite recent studies investigating the involvement of single cells in regional differences. Using untargeted proteomics, we identified regional characteristics of the three intestinal tracts of C57BL/6J mice and found that proteins abundant in the mouse ileum correlated with the high ileal expression of the corresponding genes in humans. In the SI of C57BL/6J mice, we also detected an increasing abundance of lysosomal acid lipase (LAL), which is responsible for degrading triacylglycerols and cholesteryl esters within the lysosome. LAL deficiency in patients and mice leads to lipid accumulation, gastrointestinal disturbances, and malabsorption. We previously demonstrated that macrophages massively infiltrated the SI of Lal-deficient (KO) mice, especially in the duodenum. Using untargeted proteomics (ProteomeXchange repository, data identifier PXD048378), we revealed a general inflammatory response and a common lipid-associated macrophage phenotype in all three intestinal segments of Lal KO mice, accompanied by a higher expression of GPNMB and concentrations of circulating sTREM2. However, only duodenal macrophages activated a metabolic switch from lipids to other pathways, which were downregulated in the jejunum and ileum of Lal KO mice. Our results provide new insights into the process of absorption in control mice and possible novel markers of LAL-D and/or systemic inflammation in LAL-D.

Genetic deletion of MMP12 ameliorates cardiometabolic disease by improving insulin sensitivity, systemic inflammation, and atherosclerotic features in mice.

BACKGROUND: Matrix metalloproteinase 12 (MMP12) is a macrophage-secreted protein that is massively upregulated as a pro-inflammatory factor in metabolic and vascular tissues of mice and humans suffering from cardiometabolic diseases (CMDs). However, the molecular mechanisms explaining the contributions of MMP12 to CMDs are still unclear. METHODS: We investigated the impact of MMP12 deficiency on CMDs in a mouse model that mimics human disease by simultaneously developing adipose tissue inflammation, insulin resistance, and atherosclerosis. To this end, we generated and characterized low-density lipoprotein receptor (Ldlr)/Mmp12-double knockout (DKO) mice fed a high-fat sucrose- and cholesterol-enriched diet for 16-20 weeks. RESULTS: DKO mice showed lower cholesterol and plasma glucose concentrations and improved insulin sensitivity compared with LdlrKO mice. Untargeted proteomic analyses of epididymal white adipose tissue revealed that inflammation- and fibrosis-related pathways were downregulated in DKO mice. In addition, genetic deletion of MMP12 led to alterations in immune cell composition and a reduction in plasma monocyte chemoattractant protein-1 in peripheral blood which indicated decreased low-grade systemic inflammation. Aortic en face analyses and staining of aortic valve sections demonstrated reduced atherosclerotic plaque size and collagen content, which was paralleled by an improved relaxation pattern and endothelial function of the aortic rings and more elastic aortic sections in DKO compared to LdlrKO mice. Shotgun proteomics revealed upregulation of anti-inflammatory and atheroprotective markers in the aortas of DKO mice, further supporting our data. In humans, MMP12 serum concentrations were only weakly associated with clinical and laboratory indicators of CMDs. CONCLUSION: We conclude that the genetic deletion of MMP12 ameliorates obesity-induced low-grade inflammation, white adipose tissue dysfunction, biomechanical properties of the aorta, and the development of atherosclerosis. Therefore, therapeutic strategies targeting MMP12 may represent a promising approach to combat CMDs.

Acute lung failure during mechanical circulatory support.

The use of venoarterial extracorporal membrane oxygenation and ventricular assist-devices in children with end stage heart failure is well established. The use of a bridge-to-bridge strategy leads to excellent survival rates in pediatric patients. We present an adolescent, who acquired acute respiratory failure, due to possible transfusion related lung injury, and who was successfully treated with venovenous extracorporal membrane oxygenation while on ventricular assist-device support.

Prolonged extracorporeal membrane oxygenation-assisted support provides improved survival in hypothermic patients with cardiocirculatory arrest.

OBJECTIVE: Extracorporeal circulation is considered the gold standard in the treatment of hypothermic cardiocirculatory arrest; however, few centers use extracorporeal membrane oxygenation instead of standard extracorporeal circulation for this indication. The aim of this study was to evaluate whether extracorporeal membrane oxygenation-assisted resuscitation improves survival in patients with hypothermic cardiac arrest. METHODS: A consecutive series of 59 patients with accidental hypothermia in cardiocirculatory arrest between 1987 and 2006 were included. Thirty-four patients (57.6%) were resuscitated by standard extracorporeal circulation, and 25 patients (42.4%) were resuscitated by extracorporeal membrane oxygenation. Accidental hypothermia was caused by avalanche in 22 patients (37.3%), drowning in 22 patients (37.3%), exposure to cold in 8 patients (13.5%), and falling into a crevasse in 7 patients (11.9%). Multivariate logistic regression analysis was used to compare extracorporeal membrane oxygenation with extracorporeal circulation resuscitation, with adjustment for relevant parameters. RESULTS: Restoration of spontaneous circulation was achieved in 32 patients (54.2%). A total of 12 patients (20.3%) survived hypothermia. In the extracorporeal circulation group, 64% of the nonsurviving patients who underwent restoration of spontaneous circulation died of severe pulmonary edema, but none died in the extracorporeal membrane oxygenation group. In multivariate analysis, extracorporeal membrane oxygenation-assisted resuscitation showed a 6.6-fold higher chance for survival (relative risk: 6.6, 95% confidence interval: 1.2-49.3, P = .042). Asphyxia-related hypothermia (avalanche or drowning) was the most predictive adverse factor for survival (relative risk: 0.09, 95% confidence interval: 0.01-0.60, P = .013). Potassium and pH failed to show statistical significance in the multivariate analysis. CONCLUSIONS: Extracorporeal rewarming with an extracorporeal membrane oxygenation system allows prolonged cardiorespiratory support after initial resuscitation. Our data indicate that prolonged extracorporeal membrane oxygenation support reduces the risk of intractable cardiorespiratory failure commonly observed after rewarming.

Biphasic shocks compared with monophasic damped sine wave shocks for direct ventricular defibrillation during open heart surgery.

BACKGROUND: Biphasic waveform shocks are more effective than monophasic shocks for transchest ventricular defibrillation, atrial cardioversion, and defibrillation with implantable defibrillators but have not been studied for open chest, intraoperative defibrillation. This prospective, blinded, randomized clinical study compares biphasic and monophasic shock effectiveness and establishes intraoperative energy dose-response curves. METHODS: Patients undergoing cardiothoracic surgery with bypass cardioplegia were randomly assigned to the monophasic or biphasic shock group. Ventricular fibrillation occurring after aortic clamp removal was treated with escalating energies of 2, 5, 7, 10, and 20 J until defibrillation occurred. If ventricular fibrillation persisted, a 20-J crossover shock of the other waveform was used. RESULTS: Cumulative defibrillation success at 5 J, the primary end point of the study, was higher in the biphasic group than in the monophasic group (25 of 50 vs. 9 of 41 defibrillated; P = 0.011). In addition, the biphasic group required lower threshold energy (6.8 vs. 11.0 J; P = 0.003), less cumulative energy (12.6 vs. 23.4 J; P = 0.002), and fewer shocks (2.5 vs. 3.5; P = 0.002). Crossover-shock effectiveness did not differ between groups. Dose-response curves show biphasic shocks to have higher cumulative success rates at all energies tested. CONCLUSIONS: Biphasic shocks are substantially more effective than monophasic shocks for direct defibrillation. The dose-response curve guides selection of first-shock energy for traditional step-up protocols. Starting at 5 J optimizes for lowest threshold and cumulative energy, whereas 10 or 20 J optimizes for more rapid defibrillation and fewer shocks.

Experience with percutaneous venoarterial cardiopulmonary bypass for emergency circulatory support.

OBJECTIVE: Mechanical circulatory support can maintain vital organ perfusion in patients with cardiac failure unresponsive to standard pharmacologic treatment. The purpose of the current study was to report complication and survival rates in patients supported with emergency percutaneous venoarterial cardiopulmonary bypass because of prolonged cardiogenic shock or cardiopulmonary arrest. DESIGN: Retrospective clinical study. SUBJECTS: A total of 46 patients supported with venoarterial cardiopulmonary bypass, 25 because of cardiogenic shock unresponsive to pharmacologic therapy and 21 because of cardiopulmonary arrest unresponsive to standard advanced cardiac life support. RESULTS: In 41 of the 46 patients (89%), stable extracorporeal circulation was established; in five patients (11%), femoral cannulation was accomplished only after a surgical cutdown. A total of 28 patients were weaned from cardiopulmonary bypass (19 of 25 patients with cardiogenic shock vs. 9 of 21 patients with cardiopulmonary arrest, p =.03), and 13 patients had long-term survival (10 of 25 patients with cardiogenic shock vs. 3 of 21 patients with cardiopulmonary arrest, p =.1). Complications directly related to the use of cardiopulmonary bypass were found in 18 patients (39%), major complications related to femoral cannulation being the most common single cause for bypass-associated morbidity (eight patients, 17%). CONCLUSIONS: Long-term survival rates after emergency percutaneous cardiopulmonary bypass are encouraging in patients with an underlying cardiocirculatory disease amenable to immediate corrective intervention (angioplasty, surgery, transplantation).

Jejunal tissue oxygenation and microvascular flow motion during hemorrhage and resuscitation.

The relationship between flow motion and tissue oxygenation was investigated during hemorrhage/retransfusion with and without dopamine in 14 pigs. During 45% bleed, jejunal microvascular hemoglobin O(2) saturation (HBjO(2)) and mucosal tissue Po(2) (Po(2)muc) were recorded in seven control and seven dopamine-treated animals. Mean arterial pressure and systemic O(2) delivery decreased during hemorrhage and returned to baseline after retransfusion. Hemorrhage decreased Po(2)muc from 33 +/- 2.8 to 13 +/- 1.6 mmHg and HBjO(2) from 53 +/- 4.9% to 32 +/- 3.9%, respectively, in control animals. During reperfusion, Po(2)muc and HBjO(2) remained low. Dopamine increased Po(2)muc from 28 +/- 4.3 to 45 +/- 4.6 mmHg and HBjO(2) from 54 +/- 5.7% to 69 +/- 1.5% and attenuated the decrease in Po(2)muc and HBjO(2) during hemorrhage. After retransfusion, dopamine restored Po(2)muc and HBjO(2) to baseline. Control animals developed rhythmic HBjO(2) oscillations with increasing amplitude (frequency, 4.5 to 7.6 cycles/min) and showed an inverse relationship between Po(2)muc and HBjO(2) oscillation amplitude. Dopamine prevented regular flow motion. The association between decreased Po(2)muc and increased oscillations in HBjO(2) after normalization of systemic hemodynamics and O(2) transport in control animals suggests a cause-and-effect relationship between low tissue Po(2) and flow motion activity within the jejunal microcirculation.

Vasopressin improves survival in a pig model of hypothermic cardiopulmonary resuscitation.

OBJECTIVE: During hypothermic cardiopulmonary resuscitation with a body core temperature <30 degrees C administration of a vasopressor to support coronary perfusion pressure is controversial. The purpose of the current study was to assess the effects of a single 0.4-unit/kg dose of vasopressin on coronary perfusion pressure, defibrillation success, and 1-hr survival in a pig model of hypothermic closed-chest cardiopulmonary resuscitation combined with rewarming. DESIGN: Prospective, randomized study in an established pig model. SETTING: University hospital research laboratory. SUBJECTS: Fifteen 12- to 16-wk-old domestic pigs. INTERVENTIONS: Pigs were surface cooled to a body core temperature of 26 degrees C and ventricular fibrillation was induced. After 15 mins of untreated cardiac arrest, manual closed-chest cardiopulmonary resuscitation and thoracic lavage with 40 degrees C warmed tap water were started. After 3 mins of external chest compression, animals were assigned randomly to receive vasopressin (0.4 units/kg, n = 8; or saline placebo, n = 7). Defibrillation was attempted 10 mins after drug administration. MEASUREMENTS AND MAIN RESULTS: Compared with saline placebo treated-animals, coronary perfusion pressure in vasopressin-treated pigs was significantly higher 90 secs (36 +/- 5 mm Hg vs. 7 +/- 4 mm Hg, p =.000) to 10 mins (24 +/- 4 mm Hg vs. 8 +/- 4 mm Hg, p =.000) after drug administration. Restoration of spontaneous circulation and 1 hr survival were significantly higher in vasopressin animals compared with saline placebo (8 of 8 vasopressin pigs vs. 0 of 7 placebo pigs, p <.001). CONCLUSIONS: A single 0.4-unit/kg dose of vasopressin administered at a body core temperature <30 degrees C significantly improved defibrillation success and 1-hr survival in a pig model of hypothermic cardiopulmonary resuscitation.