Simple steatosis sensitizes cholestatic rats to liver injury and dysregulates bile salt synthesis and transport.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder. It is uncertain if simple steatosis, the initial and prevailing form of NAFLD, sensitizes the liver to cholestasis. Here, we compared the effects of obstructive cholestasis in rats with a normal liver versus rats with simple steatosis induced by a methionine/choline-deficient diet. We found that plasma liver enzymes were higher and hepatic neutrophil influx, inflammation, and fibrosis were more pronounced in animals with combined steatosis and cholestasis compared to cholestasis alone. Circulating bile salt levels were markedly increased and hepatic bile salt composition shifted from hydrophilic tauro-ß-muricholate to hydrophobic taurocholate. This shift was cytotoxic for HepG2 hepatoma cells. Gene expression analysis revealed induction of the rate-limiting enzyme in bile salt synthesis, cytochrome P450 7a1 (CYP7A1), and modulation of the hepatic bile salt transport system. In conclusion, simple steatosis sensitizes the liver to cholestatic injury, inflammation, and fibrosis in part due to a cytotoxic shift in bile salt composition. Plasma bile salt levels were elevated, linked to dysregulation of bile salt synthesis and enhanced trafficking of bile salts from the liver to the systemic circulation.

Hemodynamic and ventilatory responses during exercise in chronic thromboembolic disease.

BACKGROUND: Patients with chronic thromboembolic disease (CTED) may suffer from exercise intolerance without pulmonary hypertension at rest. Pulmonary endarterectomy (PEA) for symptomatic CTED results in improvement of symptoms and quality of life. Neither the pathophysiology of the exercise limitation nor the underlying mechanisms of the PEA-induced improvement have been studied previously. OBJECTIVES: We studied hemodynamic and ventilatory responses upon exercise in 14 patients with CTED. After 1 year, we studied the underlying physiologic mechanisms of the PEA-induced symptomatic improvement. METHODS: Cardiopulmonary exercise testing (CPET) was performed during right heart catheterization, and noninvasive CPET was performed 1 year postoperatively. RESULTS: During exercise, we observed abnormal pulmonary vascular responses, that is, a steep mean pulmonary artery pressure/cardiac output (2.7 ± 1.2 mm Hg·min·L(-1)), and low pulmonary vascular compliance (2.8 ± 1.1 mL·mm Hg(-1)); mean pulmonary artery pressure/cardiac output slope correlated with dead-space ventilation (r = 0.586; P = .028) and ventilatory equivalents for carbon dioxide slope (r = .580; P = .030). Postoperatively, the improvement observed in exercise capacity was related to improvements in CPET-derived parameters pointing to restoration of right ventricle stroke volume response (oxygen pulse: 11.7 ± 3.1 to 13.3 ± 3.3; P = .027; heart rate response: 80.9 ± 12.4 to 72.0 ± 5.7; P = .003); and, indicating improved ventilatory efficiency, the ventilatory equivalents for carbon dioxide slope decreased from 38.2 ± 3.6 to 32.8 ± 7.0 (P = .014). CONCLUSIONS: Patients with CTED showed an abnormal pulmonary vascular response to exercise and a decreased ventilatory efficiency. Responses after PEA point to restoration of right ventricle stroke volume response and ventilatory efficiency.

Reduced force of diaphragm muscle fibers in patients with chronic thromboembolic pulmonary hypertension.

Patients with pulmonary hypertension (PH) suffer from inspiratory muscle weakness. However, the pathophysiology of inspiratory muscle dysfunction in PH is unknown. We hypothesized that weakness of the diaphragm, the main inspiratory muscle, is an important contributor to inspiratory muscle dysfunction in PH patients. Our objective was to combine ex vivo diaphragm muscle fiber contractility measurements with measures of in vivo inspiratory muscle function in chronic thromboembolic pulmonary hypertension (CTEPH) patients. To assess diaphragm muscle contractility, function was studied in vivo by maximum inspiratory pressure (MIP) and ex vivo in diaphragm biopsies of the same CTEPH patients (N = 13) obtained during pulmonary endarterectomy. Patients undergoing elective lung surgery served as controls (N = 15). Muscle fiber cross-sectional area (CSA) was determined in cryosections and contractility in permeabilized muscle fibers. Diaphragm muscle fiber CSA was not significantly different between control and CTEPH patients in both slow-twitch and fast-twitch fibers. Maximal force-generating capacity was significantly lower in slow-twitch muscle fibers of CTEPH patients, whereas no difference was observed in fast-twitch muscle fibers. The maximal force of diaphragm muscle fibers correlated significantly with MIP. The calcium sensitivity of force generation was significantly reduced in fast-twitch muscle fibers of CTEPH patients, resulting in a ∼40% reduction of submaximal force generation. The fast skeletal troponin activator CK-2066260 (5 µM) restored submaximal force generation to levels exceeding those observed in control subjects. In conclusion, diaphragm muscle fiber contractility is hampered in CTEPH patients and contributes to the reduced function of the inspiratory muscles in CTEPH patients.

Evaluating the endoscopic reference score for eosinophilic esophagitis: moderate to substantial intra- and interobserver reliability.

BACKGROUND AND STUDY AIMS: Recently the Endoscopic Reference Score (EREFS) for endoscopic assessment of eosinophilic esophagitis was introduced, with good interobserver agreement for most signs. The EREFS has not yet been evaluated by other investigators and intraobserver agreement has not been assessed. The aim of this study was to further validate the EREFS by assessing interobserver and intraobserver agreement of endoscopic signs in patients with eosinophilic esophagitis. PATIENTS AND METHODS: High-quality endoscopic images were made of the esophagus of 30 patients with eosinophilic esophagitis (age 36 years, range 23 - 46 years; 5 female), 6 of whom were in remission. At least three depersonalized images per patient were incorporated into a slideshow. Images were scored by four expert and four trainee endoscopists who were blinded to the patients' conditions. Interobserver agreement was assessed. After 4 weeks, the images were rescored in a different order to assess intraobserver agreement. RESULTS: Interobserver agreement was substantial for rings (κ 0.70), white exudates (κ 0.63), and crepe paper esophagus (κ 0.62), moderate for furrows (κ 0.49) and strictures (κ 0.54), and slight for edema (κ 0.12). Intraobserver agreement was substantial for rings (median κ 0.64, IQR 0.46 - 0.70), furrows (median κ 0.69, IQR 0.50 - 0.89), and crepe paper esophagus (median κ 0.69, IQR 0.62 - 0.83), moderate for white exudates (median κ 0.58, IQR 0.54 - 0.71) and strictures (median κ 0.54, IQR 0.33 - 0.70), and less than chance for edema (median κ 0.00, IQR 0.00 - 0.29). Inter- and intraobserver agreement was not substantially different between expert and trainee endoscopists. CONCLUSIONS: Using the EREFS, endoscopic signs of eosinophilic esophagitis were scored consistently by expert and trainee endoscopists.

Effect of pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension on stroke volume response to exercise.

In pulmonary hypertension, exercise is limited by an impaired right ventricular (RV) stroke volume response. We hypothesized that improvement in exercise capacity after pulmonary endarterectomy (PEA) for chronic thromboembolic pulmonary hypertension (CTEPH) is paralleled by an improved RV stroke volume response. We studied the extent of PEA-induced restoration of RV stroke volume index (SVI) response to exercise using cardiac magnetic resonance imaging (cMRI). Patients with CTEPH (n = 18) and 7 healthy volunteers were included. Cardiopulmonary exercise testing and cMRI were performed before and 1 year after PEA. For cMRI studies, pre- and post-operatively, all patients exercised at 40% of their preoperative cardiopulmonary exercise testing-assessed maximal workload. Post-PEA patients (n = 13) also exercised at 40% of their postoperative maximal workload. Control subjects exercised at 40% of their predicted maximal workload. Preoperatively, SVI (n = 18) decreased during exercise from 35.9 ± 7.4 to 33.0 ± 9.0 ml·m(2) (p = 0.023); in the control subjects, SVI increased (46.6 ± 7.6 vs 57.9 ± 11.8 ml·m(-2), p = 0.001). After PEA, the SVI response (ΔSVI) improved from -2.8 ± 4.6 to 4.0 ± 4.6 ml·m(2) (p <0.001; n = 17). On exercise at 40% of the postoperative maximal workload, SVI did not increase further and was still significantly lower compared with controls. Moreover, 4 patients retained a negative SVI response, despite (near) normalization of their pulmonary hemodynamics. The improvement in SVI response was accompanied by an increased exercise tolerance and restoration of RV remodeling. In conclusion, in CTEPH, exercise is limited by an impaired stroke volume response. PEA induces a restoration of SVI response to exercise that appears, however, incomplete and not evident in all patients.

Bosentan treatment is associated with improvement of right ventricular function and remodeling in chronic thromboembolic pulmonary hypertension.

BACKGROUND: Medical pretreatment before pulmonary endarterectomy (PEA) can optimize right ventricular (RV) function and may improve postoperative outcome in high-risk patients. Using cardiac magnetic resonance imaging (cMRI), we determined whether the dual endothelin-1 antagonist bosentan improves RV function and remodeling in patients with chronic thromboembolic pulmonary hypertension (CTEPH) who waited for PEA. HYPOTHESIS: We hypothesized that medical therapy prior to PEA will be associated with improvements in RV remodeling and function. METHODS: In this pilot study, 15 operable CTEPH patients were randomly assigned to either bosentan (n = 8) or no bosentan (n = 7, control) for 16 weeks, next to "best standard of care." Both before and after treatment, RV stroke volume index (RVSVI), RV ejection fraction (RVEF), RV mass, RV isovolumic relaxation time (rIVRT), leftward ventricular septal bowing (LVSB), and left ventricular ejection fraction (LVEF) were determined using cMRI. RESULTS: After 16 weeks, the change (Δ) from baseline (median [range]) in the studied cMRI parameters differed significantly between the bosentan group and the controls: Δ RVSVI: 6 [-4-11] vs 1 [-6-3] mL/m(-2) ; Δ RVEF: 8 [-10-15] vs -4 [-7-5]%; Δ RV mass: -3 [-6--2] vs 2 [-1-3] g/m(-2) ; Δ rIVRT: -30 [-130-20] vs 10 [-30-30] msec; Δ LVSB: 0.03 [-0.03-0.13] vs -0.03[-0.08-0.04] cm(-1) ; and Δ LVEF: 8 [-5-17] vs -2 [-14-2]% (all P < 0.05). The change from baseline in mean pulmonary artery pressure (-11 [-17-11] vs 5 [-6-21] mm Hg, P < 0.05) and 6-minute walk distance (20 [3-88] vs -4 [-40-40] m, P < 0.05) also differed significantly. CONCLUSIONS: In CTEPH, compared with control, treatment with bosentan for 16 weeks was associated with a significant improvement in cMRI parameters of RV function and remodelling.

Clinical outcomes after percutaneous or surgical revascularisation of unprotected left main coronary artery-related acute myocardial infarction: a single-centre experience.

OBJECTIVES: We evaluated 30-day and 1-year clinical outcomes after percutaneous or surgical coronary revascularisation in patients with unprotected left main coronary artery (ULMCA)-related acute myocardial infarction (AMI). DESIGN: Single-centre registry. PATIENTS: Between January 1998 and December 2008, 84 patients with ULMCA-related AMI underwent revascularisation treatment in our institution (55 underwent percutaneous coronary intervention (PCI), 29 underwent coronary artery bypass graft surgery (CABG)). METHODS: One-year clinical follow-up was obtained for all patients. Univariable and multivariable analyses were performed to find predictors for 30-day mortality and treatment allocation. RESULTS: In the PCI-group, all-cause mortality was 64% at 30 days and 69% at 1 year. In the CABG-group, this was 24% at 30 days and 1 year. Independent predictors of 30-day mortality were cardiogenic shock (HR 2.83), thrombolysis in MI (TIMI) 0/1 flow (HR 2.27) and diabetes mellitus (HR 2.65). Treatment allocation to PCI was primarily determined by TIMI 0/1 flow on baseline angiogram (OR 150). In patients with TIMI 2/3 flow on initial angiogram, treatment allocation was determined by presentation with cardiogenic shock (OR 5.61), year of inclusion (OR 1.72), and distal/bifurcation disease (OR 0.11). CONCLUSIONS: Thirty-day mortality was high in patients presenting with an ULMCA-related AMI, both in the PCI as in the CABG-treatment group. Presentation with cardiogenic shock, TIMI 0/1 flow on initial angiogram and diabetes mellitus were independently predicting of 30-day mortality, whereas treatment allocation was primarily determined by presentation with TIMI 0/1 flow.

Clinical outcome after surgical or percutaneous revascularization in coronary bypass graft failure.

AIMS: To describe long-term outcome following surgical and percutaneous revascularization in graft failure. METHODS: We analyzed consecutive patients with graft failure after heart-team assignment to percutaneous coronary intervention (PCI) or redo coronary artery bypass grafting (CABG) between 2003 and 2008. The primary endpoint was the composite of death, myocardial infarction (MI) or target vessel revascularization (TVR). Kaplan-Meier event rate estimates were calculated up to a 5-year follow-up. Independent predictors for outcomes were identified by backward selection in a multivariable Cox proportional hazard model. RESULTS: We identified 287 patients treated for graft failure: 243 with PCI and 44 with redo CABG. Patients undergoing PCI more frequently presented with ST-elevated myocardial infarction (STEMI) (P < 0.001), multivessel disease (P < 0.001), vein graft failure (P = 0.04), a history of MI (P < 0.001) and shorter time-to-graft failure (P = 0.001). Bare-metal stents (BMS) were used in 81.3% of the PCI-treated lesions and drug-eluting stents (DES) in 18.7%. The median follow-up was 3.9 years. Five-year rate of composite all-cause death, MI or TVR was 57.6% after PCI and 51% after CABG (P = 0.51). Repeat revascularization [TVR and target lesion revascularization (TLR)] was 30.7 and 21.3% after PCI, and 8.0 and 3.2% following CABG (P = 0.009; P = 0.008). In the PCI group, BMS was associated with higher rates of TVR (35.1 vs. 12.6%; P = 0.04) and TLR (24.8 vs. 7.6%; P = 0.04), but similar rate of death or MI compared with DES. Independent predictors for the primary outcome were creatinine [hazard ratio 1.008 per µmol/l, 95% confidence interval (CI) 1.005-1.011, P < 0.001] and peak creatine kinase MB (hazard ratio 1.001 per U/l, 95% CI 1.000-1.002, P = 0.027). CONCLUSION: Clinical outcomes are similarly poor after heart-team triage for surgical or percutaneous intervention in patients with graft failure. Repeat revascularization occurred more frequent after PCI, particularly following BMS implantation.

The role of recalibration response shift in explaining bodily pain in cancer patients undergoing invasive surgery: an empirical investigation of the Sprangers and Schwartz model.

OBJECTIVE: This study aims to explain bodily pain using the Sprangers and Schwartz theoretical model (1999) on quality of life (QL) and response shift in its entirety. Response shift refers to the phenomenon that the meaning of a person's self-evaluation changes over time. In this model, response shift mediates effects of changes in health status (catalysts), stable characteristics of the person (antecedents), and coping mechanisms (mechanisms) on QL. METHODS: Cancer patients (202) were assessed prior to and 3 months following surgery. Measures were for catalysts: type of operation and possibility of tumor resection; for antecedents: age, duration of pain, optimism, and rigidity; for mechanisms: post-traumatic growth, social comparisons, social support, denial, and acceptance; and for QL: bodily pain; for response shift: the pretest-minus-thentest bodily pain score, further referred to as recalibration response shift. Structural equation modeling and sequential regression analyses were used. RESULTS: The final model reached close fit (RMSEA = 0.03; 90% CI = 0.000-0.071; χ2 (18) = 21.13; p = 0.27). Significant effects were found for catalysts on mechanisms, antecedents on mechanisms, mechanisms on response shift, and response shift on bodily pain. Four extra model effects had to be permitted. Using sequential regression analysis, recalibration response shift added 4.4% to the total amount of 29.8% explained variance of bodily pain. CONCLUSIONS: Many effects as hypothesized by the model were found. Recalibration response shift had a unique albeit small contribution to the explanation of bodily pain.

Plasma brain natriuretic peptide as a biomarker for haemodynamic outcome and mortality following pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension.

OBJECTIVES: In chronic thromboembolic pulmonary hypertension (CTEPH), right ventricular (RV) dysfunction is associated with increased morbidity and mortality following pulmonary endarterectomy. Plasma brain natriuretic peptide (BNP) levels were previously shown to correlate with RV (dys)function. We hypothesized that BNP can be used as a non-invasive biomarker to identify patients at 'high risk' for postoperative morbidity and mortality. METHODS: We studied the postoperative outcome in 73 consecutive patients. Patients were divided into three groups based on previously determined cut-off levels: BNP <11.5, indicating normal RV function (ejection fraction [EF] ≥45%), BNP >48.5 pmol/l, indicating RV dysfunction (right ventricular ejection fraction <30%) and BNP 11.5-48.5 pmol/l. Postoperative 'bad outcome' was defined as the presence of either residual pulmonary hypertension (PH) or (all-cause) mortality. RESULTS: Plasma BNP >48.5 pmol/l was shown to be an independent predictor of 'bad outcome'. Compared with BNP <11.5 pmol/l, BNP >48.5 pmol/l identified patients at higher risk for (all-cause) mortality (17 vs 0%; P = 0.009) and residual PH (56 vs 20%; P < 0.004). Also, the durations of mechanical ventilation and intensive care unit stay were significantly longer in patients with BNP >48.5 pmol/ml. CONCLUSIONS: Plasma BNP levels may be of use as a non-invasive biomarker reflecting RV dysfunction, next to other well-recognized (invasive) parameters, for better preoperative risk stratification of CTEPH patients.

Cholestasis is associated with hepatic microvascular dysfunction and aberrant energy metabolism before and during ischemia-reperfusion.

AIMS: The aim was to investigate the impact of ischemia-reperfusion (I/R) on intrahepatic oxidative stress, oxidative phosphorylation, and nucleotide metabolism in relation to liver damage and inflammation in cholestatic rats to elucidate the molecular mechanisms responsible for post-I/R pathogenesis during cholestasis. RESULTS: Pre-I/R cholestatic livers exhibited mild hepatopathology in the form of oxidative/nitrosative stress, perfusion defects, necrosis and apoptosis, inflammation, and fibrosis. Plasma bilirubin concentration in cholestatic livers was 190 µM. I/R in cholestatic livers exacerbated hepatocellular damage and leukocyte infiltration. However, myeloperoxidase activity in neutrophils at 6 h reperfusion was not elevated in cholestatic livers compared to pre-I/R levels and to control (Ctrl) livers. At 6 h reperfusion, cholestatic livers exhibited severe histological damage, which was absent in Ctrl livers. Despite a lower antioxidative capacity after I/R, no cardiolipin peroxidation and equivalent reduced glutathione/oxidized glutathione ratios and Hsp70 levels were found in cholestatic livers versus Ctrls. Bilirubin acted as a potent and protective antioxidant. Postischemic resumption of oxidative phosphorylation in Ctrl livers proceeded rapidly and encompassed reactive hyperemia, which was significantly impaired in cholestatic livers owing to extensive vasoconstriction and perfusion defects. Normalization of intrahepatic energy status and nucleotide-based metabolic cofactors was delayed in cholestatic livers during reperfusion. Innovation and CONCLUSIONS: Cholestatic livers possess sufficient antioxidative capacity to ameliorate radical-mediated damage during I/R. I/R-induced damage in cholestatic livers is predominantly caused by microvascular perfusion defects rather than exuberant oxidative/nitrosative stress. The forestalled rate of oxidative phophorylation and recovery of bioenergetic and possibly metabolic parameters during the early reperfusion phase are responsible for extensive liver damage.

Pulmonary endarterectomy normalizes interventricular dyssynchrony and right ventricular systolic wall stress.

BACKGROUND: Interventricular mechanical dyssynchrony is a characteristic of pulmonary hypertension. We studied the role of right ventricular (RV) wall stress in the recovery of interventricular dyssynchrony, after pulmonary endarterectomy (PEA) in chronic thromboembolic pulmonary hypertension (CTEPH). METHODS: In 13 consecutive patients with CTEPH, before and 6 months after pulmonary endarterectomy, cardiovascular magnetic resonance myocardial tagging was applied. For the left ventricular (LV) and RV free walls, the time to peak (Tpeak) of circumferential shortening (strain) was calculated. Pulmonary Artery Pressure (PAP) was measured by right heart catheterization within 48 hours of PEA. Then the RV free wall systolic wall stress was calculated by the Laplace law. RESULTS: After PEA, the left to right free wall delay (L-R delay) in Tpeak strain decreased from 97 ± 49 ms to -4 ± 51 ms (P < 0.001), which was not different from normal reference values of -35 ± 10 ms (P = 0.18). The RV wall stress decreased significantly from 15.2 ± 6.4 kPa to 5.7 ± 3.4 kPa (P < 0.001), which was not different from normal reference values of 5.3 ± 1.39 kPa (P = 0.78). The reduction of L-R delay in Tpeak was more strongly associated with the reduction in RV wall stress (r = 0.69,P = 0.007) than with the reduction in systolic PAP (r = 0.53, P = 0.07). The reduction of L-R delay in Tpeak was not associated with estimates of the reduction in RV radius (r = 0.37,P = 0.21) or increase in RV systolic wall thickness (r = 0.19,P = 0.53). CONCLUSION: After PEA for CTEPH, the RV and LV peak strains are resynchronized. The reduction in systolic RV wall stress plays a key role in this resynchronization.

Omega-3 fatty acids reduce hepatic steatosis and consequently attenuate ischemia-reperfusion injury following partial hepatectomy in rats.

AIM: The aim of this study was to investigate omega-3 fatty acids (FAs) treatment of experimental steatosis and the consequent effect on ischemia-reperfusion (IR) injury. BACKGROUND: Fatty livers are more susceptible to IR injury and display decreased regenerative capacity. Consequently, restrictions exist for patients with fatty livers to undergo a major hepatectomy or to participate in living donor liver transplantation. Until recently, weight reduction constituted the only proven therapy for patients with fatty livers. METHODS: Steatosis was induced by a 3-wk methionine/choline-deficient diet, followed by oral administration of omega-3 FAs (Omega-3), standard lipid solution (Lipid), or NaCl (Saline) during 2 wk. Control animals received a standard diet without treatment. Rats underwent partial (70%) hepatic IR combined with partial hepatectomy (PHx) of the non-ischemic lobes (30%) followed by 24-h reperfusion. RESULTS: Histological analysis revealed mild (5-33%) macrovesicular steatosis in omega-3-treated animals vs. severe (>66%) macrovesicular steatosis in both Lipid and Saline groups. Following IR/PHx, omega-3-treated rats exhibited reduced serum ALT levels after 6- and 24-h reperfusion, a reduced hepatic TNF-α content, and an improved anti-oxidative capacity. CONCLUSIONS: Omega-3 treatment significantly reduces experimental hepatic steatosis and associated pathophysiological features, resulting in significantly reduced IR injury following PHx.

Concurrent high-dose radiotherapy with low-dose chemotherapy in patients with non-small cell lung cancer of the superior sulcus.

BACKGROUND AND PURPOSE: In the treatment of patients with tumours of the sulcus superior (SST), achieving local control is essential because residual or recurrent disease is associated with severe locoregional problems. This study evaluates the efficacy of concurrent daily low-dose cisplatin (6 mg/m(2)) and high-dose radiotherapy (66 Gy) followed by surgical resection in selected patients. MATERIAL AND METHODS: Clinical charts, imaging and pathology reports were retrospectively reviewed. Survival was analysed using the Kaplan-Meier method. RESULTS: Forty-nine patients with stage II/III SST were treated with concurrent high-dose radiotherapy and low-dose chemotherapy (CRT). Mean follow-up was 49 months (range 2-152). Nineteen patients underwent additional resection after CRT. In 53% a pathological complete response (pCR) was observed (10/19 pts). Acute severe toxicity occurred in 49% (9/19 pts). Late severe toxicity occurred in 3 patients. The 2- and 5-year overall survival was 74% and 33%, respectively. Local tumour control was 100%. Thirty patients received CRT only. Acute severe toxicity occurred in 23% (7/30 pts). Treatment-related mortality was 2%. The 2- and 5-year overall survival was 31% and 18%, respectively. Locoregional disease-free survival was 48% at 5 years. CONCLUSIONS: Concurrent high-dose (66 Gy) radiotherapy and daily low-dose cisplatin was associated with a high pCR rate. Excellent local control was achieved after additional resection in selected patients. However, the occurrence of severe toxicity in long-term survivors after concurrent chemoradiation followed by surgery must be considered.

Time course of restoration of systolic and diastolic right ventricular function after pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension.

BACKGROUND: In chronic thromboembolic pulmonary hypertension, right ventricular (RV) pressure overload causes RV remodeling and dysfunction. Successful pulmonary endarterectomy (PEA) initiates restoration of RV remodeling and global function. Little is known on the restoration of systolic and diastolic RV function. Using transthoracic echocardiography, we studied the time course and extent of postoperative restoration of systolic and diastolic RV function. METHODS: In chronic thromboembolic pulmonary hypertension (n = 55, 36 women, age 52 ± 14 years), transthoracic echocardiography was performed before PEA (pre-PEA) and 2 weeks, 3 months, and 1 year postoperatively. RESULTS: Two weeks postoperatively, RV afterload and dimension had decreased significantly, without further improvement during follow-up. Global RV function, expressed by the myocardial performance index, showed a gradual improvement (from pre-PEA 0.58 ± 0.29 to 0.45 ± 0.38, 0.39 ± 0.19, and 0.37 ± 0.18). In contrast, 2 weeks after PEA systolic RV function, as assessed by tricuspid annular plane systolic velocity excursion and peak tricuspid annular systolic velocity of the RV, had worsened, with a subsequent incomplete restoration during follow-up: tricuspid annular plane systolic velocity excursion from 19.3 ± 5.0 to 12.4 ± 2.5, 15.3 ± 3.0, and 16.8 ± 2.9 mm and systolic velocity of the right ventricle from 11.4 ± 3.0 to 9.6 ± 2.0, 10.0 ± 1.8, and 10.3 ± 1.7 cm/s. Postoperative diastolic RV function also showed a biphasic response: tricuspid inflow-to-annulus ratio from 6.1 ± 3.0 to 9.5 ± 3.5, 6.8 ± 2.4, and 6.3 ± 2.2 cm/s. Dynamics and ultimate level of restoration of systolic and diastolic RV function were similar in patients with and without residual pulmonary hypertension. CONCLUSIONS: Postoperative reduction in RV afterload caused an immediate improvement in RV dimension and global function. In contrast, systolic and diastolic RV function deteriorated after PEA with subsequently a gradual yet incomplete restoration during 1-year follow-up.

Longitudinal follow-up of six-minute walk distance after pulmonary endarterectomy.

BACKGROUND: The 6-minute walk test is a useful tool to assess functional outcome after pulmonary endarterectomy (PEA) in chronic thromboembolic pulmonary hypertension. However, little is known about the longitudinal dynamics in functional improvement. We performed a longitudinal follow-up of 6-minute walk distance, New York Heart Association functional class, and echocardiography after PEA. METHODS: We studied 71 patients with chronic thromboembolic pulmonary hypertension who underwent PEA. A 6-minute walk test and echocardiography were performed before PEA, at 3 months after, and at annual follow-up. At the time of this report, 52 patients had returned for 2-year follow-up, 32 for 3-year follow-up, 23 for 4-year follow-up, and 11 for 5-year follow-up. RESULTS: Preoperatively, the 6-minute walk distance (6-MWD) correlated with hemodynamic severity of disease (mean pulmonary artery pressure: r = -0.55, p < 0.001); total pulmonary resistance: r = -0.59, p < 0.001) After PEA, 6-MWD increased from 440 ± 109 to 524 ± 83 meters at 1 year (n = 71, p < 0.001). Further improvement was observed from 523 ± 87 meters at 1 year to 536 ± 91 meters at 2 years (n = 52, p < 0.012). After 2 years, no further improvement was observed. At 1 year, the change in 6-MWD from baseline correlated significantly with the change observed in pulmonary hemodynamics. Changes in 6-MWD and hemodynamics were more pronounced in patients with residual pulmonary hypertension after PEA, despite the worse absolute outcome. CONCLUSIONS: In patients with chronic thromboembolic pulmonary hypertension, 6-MWD showed a gradual improvement up to 2 years after PEA. Patients with residual pulmonary hypertension benefited most from treatment, despite the worse absolute outcome.

A comparative study of intraductal papillary neoplasia of the biliary tract and pancreas.

Intraductal papillary mucinous neoplasm of the pancreas is a rare but well-established entity in contrast to intraductal papillary mucinous neoplasm of the biliary tract. The aim of this study was to compare the clinicopathologic features of intraductal papillary mucinous neoplasms of the biliary tract and of the pancreas. Twenty patients who underwent resection for intraductal papillary mucinous neoplasm of the biliary tract were compared with 29 cases resected for intraductal papillary mucinous neoplasm of the pancreas. Clinicopathologic characteristics and resection specimens of all patients were reassessed and immunohistochemically screened for expression of a distinct set of tumor markers. Median ages of patients with intraductal papillary mucinous neoplasms of the biliary tract and of the pancreas were 66 and 62 years, respectively (P < .05). Twelve patients with intraductal papillary mucinous neoplasm of the biliary tract (60%) had neoplasms with infiltrating carcinoma, compared with 6 patients with intraductal papillary mucinous neoplasm of the pancreas (21%, P < .05). Cytokeratin 7 and 20 expressions were equal in biliary and pancreatic intraductal papillary mucinous neoplasms. Cytokeratin 20 expression was mainly found in intestinal-type tumors. Gastric, pancreaticobiliary, and oncocytic subtypes were all observed in the intraductal papillary mucinous neoplasm of the biliary tract group. The distribution was significantly different from the intraductal papillary mucinous neoplasm of the pancreas group. The 3-year overall survival rate of malignant biliary and pancreatic intraductal papillary mucinous neoplasm was 63% and 65%, respectively (P = .798). Positive lymph nodes and a high expression of membranous mucin were associated with a significantly shorter overall survival in patients with malignant intraductal papillary mucinous neoplasm. Finally, p53 and Ki67 proliferation index were both associated with the carcinogenesis of intraductal papillary mucinous neoplasm, whereas DPC4 and CDX2 were not. Clinicopathologic features of intraductal papillary mucinous neoplasm of the biliary tract largely resemble those of intraductal papillary mucinous neoplasm of the pancreas, although intraductal papillary mucinous neoplasm of the biliary tract was associated with a higher malignancy rate at the time of surgical treatment. The level of membranous mucin expression and positive lymph nodes are significant prognosticators in patients with malignant intraductal papillary mucinous neoplasm.

Surgical management and outcome of patients with chronic thromboembolic pulmonary hypertension: results from an international prospective registry.

OBJECTIVE: Pulmonary endarterectomy is a curative surgical treatment option for the majority of patients with chronic thromboembolic pulmonary hypertension. The current surgical management and postoperative outcome of patients enrolled in an international registry on chronic thromboembolic pulmonary hypertension were investigated. METHODS: The registry included newly diagnosed (≤6 months) consecutive patients with chronic thromboembolic pulmonary hypertension from February 2007 to January 2009. RESULTS: A total of 679 patients were registered from 1 Canadian and 26 European centers, of whom 386 (56.8%) underwent surgery. The median age of patients undergoing surgery was 60 years, and 54.1% were male. Previous pulmonary embolism was confirmed for 79.8% of patients. Perioperative complications occurred in 189 patients (49.2%): infection (18.8%), persistent pulmonary hypertension (16.7%), neurologic (11.2%) or bleeding (10.2%) complications, pulmonary reperfusion edema (9.6%), pericardial effusion (8.3%), need for extracorporeal membrane oxygenation (3.1%), and in-hospital mortality due to perioperative complications (4.7%). Documented 1-year mortality was 7%. Preoperative exercise capacity was predictive of 1-year mortality. Postoperative pulmonary vascular resistance predicted in-hospital and 1-year mortality. In patients evaluated within 1 year after surgery, the median pulmonary vascular resistance had decreased from 698 to 235 dyn x s x cm(-5) (95% confidence limit, 640-874 and 211-255, respectively, n = 70) and the median 6-minute walk distance had increased from 362 to 459 m (95% confidence limit, 340-399 and 440-473, respectively, n = 168). New York Heart Association functional class improved with most patients progressing from class III/IV to class I/II. CONCLUSIONS: Pulmonary endarterectomy is associated with a low in-hospital mortality rate and improvements in hemodynamics and exercise capacity.

Reversal of hepatic steatosis by omega-3 fatty acids measured non-invasively by (1) H-magnetic resonance spectroscopy in a rat model.

BACKGROUND AND AIM: Living donors with marked (> 33%) macrovesicular steatosis (MaS) are excluded from living donor liver transplantation procedures. Experimental studies have shown that the development of steatosis can be prevented by supplementation with omega-3 fatty acids (FA), but no studies have investigated the reduction of steatosis using omega-3 FA. The aim of the present study was to investigate whether administration of omega-3 FA is effective in reducing steatosis. METHODS: After fatty liver (FL) induction by a 3-week methionine/choline-deficient (MCD) diet, male Wistar rats were daily administered per gavage omega-3 FA (FL+Omega-3), omega-3-poor lipid solution (FL+Lipid), or NaCl (FL+NaCl) during 2 weeks. Control animals received standard chow without treatment. Determination of steatosis degree was performed before, during, and after treatment by clinical 3.0 T ¹H-magnetic resonance spectroscopy (¹H-MRS) and by histology and gas chromatography at the end of the 2-week treatment period. RESULTS: Hepatic fat content (¹H-MRS) was significantly reduced after 1 and 2 weeks of omega-3 FA treatment. Histological analysis revealed a mild (5-33%) MaS degree in omega-3-treated animals vs severe (> 66%) MaS in the FL+Lipid and FL+NaCl groups. Hepatic omega-6 : 3 FA ratio and total FA content were reduced in the FL+Omega-3 group. Furthermore, de novo lipogenesis (C16, C16 : 1ω7, C18 : 1ω9) was also lowered. The reduction in hepatic fat content was associated with decreased lobular inflammation and hepatic tumor necrosis factor- α and interleukin levels as well as an increased antioxidative capacity. CONCLUSION: Omega-3 FA are capable of reversing severe hepatic MaS and ameliorating pathophysiological features of non-alcoholic steatohepatitis such as hepatocellular damage, lobular inflammation, and a reduced antioxidative capacity.

Surveillance and epidemiology of surgical site infections after cardiothoracic surgery in The Netherlands, 2002-2007.

OBJECTIVE: Surgical site infections after cardiothoracic surgery substantially increase the risk for illness, mortality, and costs. Surveillance of surgical site infections might assist in the prevention of these infections. This study describes the Dutch surveillance methods and results of data collected between 2002 and 2007. METHODS: Three cardiothoracic procedures were included: coronary artery bypass graft procedures, valve surgery, and a combination of coronary artery bypass graft procedures with concomitant valve surgery. The surgical site infections were divided into sternal and harvest-site infections. Postdischarge surveillance of surgical site infections was mandatory for sternal wounds and elective for harvest-site wounds, with a follow-up period of 42 postoperative days. Multivariate logistic regression was used for risk factor analysis of coronary artery bypass grafts, with adjustment for random variation among hospitals. RESULTS: Eight of the 16 Dutch cardiothoracic centers participated and collected data on 4066 procedures and 183 surgical site infections, revealing a surgical site infection rate of 2.4% for sternal wounds and 3.2% for harvest sites. Sixty-one percent of all surgical site infections were recorded after discharge. For sternal surgical site infections after coronary artery bypass graft procedures, the significant risk factors were rethoracotomy, diabetes, preoperative length of stay, and obesity; for harvest-site infections, the most relevant risk factor was a long time on extracorporeal circulation. Adjusted surgical site infection rates regarding coronary artery bypass graft procedures varied between hospitals from 0.0% to 9.7%. CONCLUSIONS: Large differences were found in surgical site infection rates between Dutch hospitals, which indicate room for improvement. The follow-up of patients after hospital discharge reduces underestimation of surgical site infection rates.