Hepcidin, interleukin-6 and hematological iron markers in males before and after heart surgery.

Anemia of inflammation in patients with acute or chronic acute-phase activation is a common clinical problem. Hepcidin is a peptide shown to be the principal regulator of the absorption and systemic distribution of iron. Main inducers of hepcidin are iron overload, hypoxia and inflammation, where the latter has been linked to hepcidin via increased interleukin-6 (IL-6). This article addresses the impact and time course of postoperative acute-phase reaction in humans following heart surgery on prohepcidin, hepcidin, hematological markers and IL-6 concentrations. Serum concentrations of prohepcidin, hepcidin, IL-6 and hematological iron parameters were studied in five male patients without infection before and after heart surgery. This study, which is the first to report the impact on serum hepcidin and serum prohepcidin concentrations in patients following surgery, clearly demonstrates the induction of hypoferremia due to the postoperative acute-phase reaction. Significant changes were seen for serum iron concentration, transferrin saturation, total iron binding capacity and hemoglobin concentration. A significant increase in ferritin concentration was seen 96-144 h postoperatively. Additionally, there were significant alterations in both serum hepcidin after 96-144 h and serum prohepcidin after 48 h compared with preoperative values. Serum prohepcidin decreased, whereas serum hepcidin increased. In conclusion, changes in serum prohepcidin were followed by an increase in serum hepcidin. This speaks in favor of a chain of action where proteolytic trimming of serum prohepcidin results in increased serum hepcidin. However, hypoferremia appeared prior to the changes in serum prohepcidin and serum hepcidin.

The prevalence of moderate mitral regurgitation in patients undergoing CABG.

OBJECTIVE: The aim of this study was to determine the prevalence of moderate ischemic mitral regurgitation (IMR) in the contemporary CABG population. We also aimed to correlate the effective regurgitant orifice area (ERO) of any regurgitant mitral valve in patients with coronary artery disease with the semiquantitative integrated scale of IMR. DESIGN: From March 15 through June 15, 2006, 510 consecutive CABG patients in three tertiary centres were included in the study. All patients showing any sign of mitral regurgitation (MR) at the referring hospital underwent a preoperative transthoracic echocardiographic estimation of the degree of MR using the integrated scale (1-4) and ERO. RESULTS: IMR was found in 141 patients (28%). The prevalence of moderate 2+ or worse IMR was 4% (95% CI; 2.5-6.1%) and the ERO corresponding to 2+ IMR or more ranged from 5 to 30 mm(2). Fourteen patients had an ERO between 15-30 mm(2). CONCLUSIONS: According to our study, patients with moderate IMR, defined as an ERO between 15-30 mm(2), account for only 2.7% (95% CI; 1.5-4.7%) of a non-emergency CABG population.

Moderate mitral regurgitation in patients undergoing CABG--the MoMIC trial.

BACKGROUND: The presence of mild to moderate ischemic mitral regurgitation (IMR) marks a significantly reduced long-term survival and increased hospitalizations due to heart-failure. However, it is common practice in many institutions to refrain from repairing the mitral valve in these patients. There are no available conclusive data to support this practice, and thus there is a need for an adequately powered randomized trial. STUDY DESIGN: The Moderate Mitral Regurgitation In Patients Undergoing CABG (MoMIC) trial is the first international multi-center, large-scale study to clarify whether moderate IMR in CABG patients should be corrected. A total of 550 CABG patients with moderate IMR are to be randomized to treatment of either CABG alone or CABG plus mitral valve correction. The primary end point is a composite end point of mortality and rehospitalization for heart failure at five years. The inclusion and randomization of patients started in February 2008. IMPLICATION: If correction of moderate IMR in CABG patients proves to be the superior strategy, most patients should be treated accordingly.

The feasibility of left ventricular mechanical support as a bridge to cardiac recovery.

OBJECTIVE: To study the achievability of device weaning in patients receiving left ventricular assist devices (LVADs) as a bridge to transplantation. METHODS: Eighteen consecutive patients receiving a LVAD between September 1997 and June 2002 were included in the study. During a four-month follow-up, patients were repeatedly evaluated with right heart catheterization and echocardiography and, if functional improvement was observed, studied with the device turned off. Cardiac recovery was defined as off-pump LVEF>or=40% together with a significant improvement in invasive haemodynamic measurements (CI>or=2.5 and PCWP

Effect of lung volume reduction surgery for emphysema on diaphragm function.

Preoperative prediction of a successful outcome following lung volume reduction surgery (LVRS) for emphysema is imperfect. One mechanism could be improvement in respiratory muscle function yet controversy exists regarding the magnitude and mechanism of such an improvement. Therefore, we measured diaphragm strength in 18 patients before and after LVRS. Mean (S.D.) FRC fell from 6.53 to 5.40 l (p = 0.0001). Mean sniff transdiaphragmatic pressure increased from 76 to 87 cm H2O (14%, p < 0.03) and mean twitch transdiaphragmatic pressure (Tw Pdi) increased by 2.5 cm H2O at 3 months (12%, p = 0.03). There was a highly significant increase in twitch esophageal pressure (Tw Pes) (60%, p < 0.0001), which was maintained at 12 months (46% increase, p = 0.0004). No change was observed in quadriceps twitch tension in nine subjects in whom it was measured. After LVRS the ratio Tw Pes:Tw Pdi increased from 0.24 to 0.37 at 3 months (p = 0.0003) and 0.36 at 12 months (p = 008). Low values of Sn Pdi, Sn Pes, Tw Pes and a high RV/TLC ratio were the preoperative variables most predictive of improvement in shuttle walking distance. We conclude that LVRS improves diaphragm function primarily by alteration of lung volume. Patients with poor diaphragm function and high RV/TLC ratio preoperatively are most likely to benefit from the procedure.

Difference in resistance to humidity between commonly used dry powder inhalers: an in vitro study.

Multi-dose dry powder inhalers (DPIs) are commonly used in asthma and chronic obstructive lung disease (COPD) treatment. A disadvantage is their sensitivity to humidity. In real life, DPIs are periodically exposed to humid conditions, which may affect aerosol characteristics and lung deposition. This study compared DPI aerosol performance after exposure to humidity. Budesonide (BUD) inhalers (Turbuhaler; Novolizer; Easyhaler) and budesonide/formoterol (BUD/FORM) inhalers (Turbuhaler; Spiromax; Easyhaler) were stored in 75% relative humidity (RH) at both ambient temperature and at -0 °C. Delivered dose (DD) and fine-particle dose (FPD) were tested in vitro before and after storage. BUD inhalers: Turbuhaler and Novolizer showed only small decreases (<15%) in FPD in 40 °C/75% RH, whereas FPD for Easyhaler decreased by >60% (P=0.01) after 1.5 months of storage. Easyhaler also decreased significantly after 6 months of storage in ambient/75%RH by 25% and 54% for DD and FPD, respectively, whereas only small decreases were seen for Turbuhaler and Novolizer (<15%). BUD/FORM inhalers: Turbuhaler and Spiromax DD were unchanged in 40 °C/75% RH, whereas Easyhaler showed a small decrease. FPD (budesonide) decreased for Turbuhaler, Spiromax and Easyhaler by 18%, 10% and 68% (all significant), respectively, at 40 °C/75% RH. In ambient/75%RH, DD was unchanged for all inhalers, whereas FPD (budesonide) decreased for Spiromax (7%, P=0.02) and Easyhaler (34%, (P<0.01)). There are significant differences in device performance after exposure to humid conditions. A clinically relevant decrease of more than half FPD was seen for one of the inhalers, a decrease that may affect patients' clinical outcomes. Prescriber and patient knowledge on device attributes are essential to ensure optimal drug delivery to the lungs.

Comparison of lung volume reduction surgery and physical training on health status and physiologic outcomes: a randomized controlled clinical trial.

STUDY OBJECTIVES: In 1996, researchers in Sweden initiated a collaborative randomized study comparing lung volume reduction surgery (LVRS) and physical training with physical training alone. The primary end point was health status; secondary end points included survival and physiologic measurements. DESIGN: After an initial 6-week physical training program, researchers' patients were randomized to either LVRS (surgical group [SG]) with continued training for 3 months, or to continued training alone (training group [TG]) for 1 year. SETTING: All seven thoracic surgery centers in Sweden. PATIENTS: All patients in Sweden with severe emphysema fulfilling inclusion criteria for LVRS. INTERVENTIONS: Patients randomized to surgery underwent a median sternotomy, except for a few patients in whom thoracotomy or video-assisted thoracoscopy were performed. In the TG, supervised physical training continued for 1 year; in the SG, supervised physical training continued for 3 months postoperatively. MEASUREMENTS AND RESULTS: Fifty-three patients were included in each group. Six in-hospital deaths occurred after surgery (12%), and one more death occurred during follow-up. Two deaths occurred in the TG. The difference in death rates between the groups was not statistically significant. Health status, as measured by St. George Respiratory Questionnaire (SGRQ) [total scale score mean difference at 1 year, 14.7; 95% confidence interval (CI), 9.8 to 19.7] as well as by the Medical Outcomes Study Short-Form General Health Survey (physical function scale score mean difference at 1 year, 19.7; 95% CI, 12.1 to 27.3) was improved from baseline in the SG compared with the TG. FEV(1), residual volume, and shuttle walking test values also improved in the SG but not in the TG after 6 months and 12 months. CONCLUSIONS: In severe emphysema, LVRS can improve health status in survivors but is associated with mortality risk. The effects are stable for at least 1 year. Physical training alone failed to achieve a similar improvement.

Tumor necrosis factor gene polymorphism and cardiac allograft vasculopathy.

BACKGROUND: Cardiac allograft vasculopathy (CAV) limits survival after cardiac transplantation. Tumor necrosis factor-alpha (TNF-alpha) may be a key factor in the development of CAV. Two bi-allelic polymorphisms associated with high TNF-alpha production have been identified in the TNF gene locus, TNFA1/2, at position -308 and TNFB1/2 at +252. We hypothesized that recipient TNFA2 and TNFB2 homozygosity is associated with the development of CAV after heart transplantation. METHODS: TNF gene polymorphisms were analyzed by multiplex fluorescent solid-phase mini-sequencing in 70 cardiac transplant recipients. Recipients homozygous for TNFA2 or TNFB2 (Group A, n = 29) were compared with recipients heterozygous or homozygous for TNFA1 and TNFB1 (Group B, n = 41). Coronary arteriography was performed annually or when indicated. Cumulative freedom from CAV and survival was calculated according to the Kaplan-Meier test. RESULTS: Mean follow-up was 3.8 +/- 0.3 years. In Group A, 11 of 29 recipients (38%) developed CAV compared with 9 of 41 (22%) in Group B (p = 0.12). Cumulative freedom from CAV at 3 years was 42% in Group A and 80% in Group B (p = 0.043). In Group A, 11 of 29 recipients (38%) died during follow-up compared with 4 of 41 (10%) in Group B (p = 0.006). Cumulative survival at 3 years was 72% in Group A and 93% in Group B (p = 0.003). CONCLUSIONS: The results suggest that TNFA2 and TNFB2 allele homozygosity is associated with cardiac allograft vasculopathy and mortality in heart transplant recipients.

Blunted vascular response to endothelin-a receptor blockade in cyclosporine-treated lung transplant recipients.

BACKGROUND: The majority of cyclosporine-treated transplant recipients develop hypertension. Endothelin-1 (ET-1) has been suggested to mediate cyclosporine-induced vasoconstriction when binding to ET-A receptors. We hypothesized that cyclosporine-treated lung transplant recipients have an increased basal vascular resistance and an augmented response to ET-A receptor blockade. METHODS: The selective ET-A receptor blocker BQ-123 (10 and 50 nmol/min) was infused into the brachial artery, alone or in combination with the nitric oxide synthase inhibitor NG-monomethyl-L-arginine acetate (L-NMMA) (2 and 4 micromol/min) in 10 lung transplant recipients without pharmacologically treated hypertension and 8 healthy controls. Forearm blood flow (FBF) was measured by venous occlusion plethysmography and plasma levels of ET-1 were analyzed. RESULTS: Baseline forearm vascular resistance did not differ between recipients and controls (32 +/- 4 vs 42 +/- 7 mmHg/ml/min, p = 0.32). BQ-123 increased FBF in controls but not in recipients (26% +/- 9% vs 5% +/- 11% at 10 nmol/min, p = 0.043 between groups). Coinfusion of BQ-123 and L-NMMA caused a comparable decrease in FBF in recipients and controls (-26% +/- 11%, vs -34% +/- 7%). Baseline ET-1 was higher in recipients (17.2 +/- 1.1 vs 14.7 +/- 0.8 pg/ml, p = 0.038). BQ-123 infusion increased plasma ET-1 in controls but not in recipients (+24% +/- 11% vs -0.4% +/- 6.2%, p = 0.029 between groups). CONCLUSIONS: The results demonstrate that cyclosporine-treated lung transplant recipients have increased plasma levels of ET-1 and a blunted response to ET-A receptor blockade compared with healthy subjects. In contrast, we found no evidence for an increased basal vascular resistance in transplant recipients. These alterations in endothelin handling may contribute to the development of transplant-associated hypertension.

Effects of lung volume reduction surgery on left ventricular diastolic filling and dimensions in patients with severe emphysema.

STUDY OBJECTIVES: Data on the influence of lung volume reduction surgery (LVRS) on cardiac function and hemodynamics are scarce and controversial. Previous studies have focused mainly on right ventricular function and pulmonary hemodynamics. Here, we evaluated the effects of LVRS on left ventricular (LV) end-diastolic filling pattern, dimensions, stiffness, and performance, as well as pulmonary and systemic hemodynamics. DESIGN: A prospective, open, controlled study. PATIENTS: Patients with severe emphysema undergoing LVRS (10 patients). Patients scheduled for pulmonary lobectomy due to carcinoma (ie, the lobectomy group) served as control subjects (10 patients). MEASUREMENTS: LV dimensions and mitral flow velocities were measured by transesophageal, two-dimensional, Doppler echocardiography, and central hemodynamics were measured by a pulmonary artery thermodilution catheter. Measurements were performed during anesthesia in the supine position, before and after surgery, without and with passive leg elevation. RESULTS: Baseline cardiac index (CI) [- 21%], stroke volume index (SVI) [- 31%], stroke work index (SWI) [- 26%], and LV end-diastolic area index (EDAI) [- 15%] were significantly (p < 0.001) lower, whereas LV end-diastolic stiffness (LVEDS) did not differ in the LVRS group compared to the lobectomy group. The time from peak early diastolic filling to zero flow (E-dec time) [58%] and the deceleration slope of early diastolic filling (E-dec slope) [45%] were significantly higher (p < 0.01), whereas peak early diastolic filling velocity (E-max) [- 31%; p < 0.01] and the proportion of E-max vs peak late diastolic filling velocity (A-max) [ie, the E/A ratio] (- 27%; p < 0.001) were significantly lower compared to the lobectomy group. LVRS significantly increased CI (40%; p < 0.001), SVI (34%; p < 0.001), SWI (58%; p < 0.001), LV EDAI (18%; p < 0.001), E-max (44%; p < 0.01), A-max (15%; p < 0.05) and E/A ratio (28%; p < 0.01), decreased E-dec time (- 31%; p < 0.05) and E-dec slope (- 98%; p < 0.01), and had no effect on LVEDS. In the lobectomy group, surgery affected none of these variables. CONCLUSIONS: LV function is impaired in patients with severe emphysema due to small end-diastolic dimensions. LVRS increases LV end-diastolic dimensions and filling, and improves LV function.

Mortality after mitral regurgitation surgery: importance of clinical and echocardiographic variables.

OBJECTIVES: The management of patients with mitral regurgitation (MR) constitutes a challenge due to its heterogeneity in terms of etiology and possible treatment strategies. In the present study, we sought to describe the importance of preoperative echocardiographic and clinical variables in relation to outcome 5 years after surgical treatment of MR. METHODS: The echocardiographic reports (transthoracic) from 298 patients were analyzed and the anatomic lesions were classified into one of three main groups (functional, organic degenerated with hypermobile valve or organic degenerated without hypermobility). 5-year cumulative survival was compared with the expected survival in an age- and gender-matched normal population. Risk functions were determined with a Poisson regression model. RESULTS: Operative mortality was 4.4%, with higher mortality in patients with concomitant coronary artery bypass grafting (CABG) (7.6 vs. 2.2%, P=0.03). Survival after 5 years was 65% in patients with concomitant CABG, compared with the expected 86% (P<0.001), 70 vs. 88% (P<0.001) in patients with preoperative NYHA class III/IV, while survival in patients with NYHA class I/II did not differ from the expected (90 vs. 90%, P=0.56). In patients with a hypermobile valve without CABG, postoperative survival did not differ from the expected (91 vs. 89%, P=0.92). The estimated risk ratio for death, repair versus prosthesis, was 0.57 (95% confidence interval 0.32-1.00, P=0.05). CONCLUSIONS: The present study shows that it is possible, using transthoracic echocardiography and clinical data, to identify patients with an excellent outcome. The adverse effects of severe symptomatology and replacement compared with repair are demonstrated. The findings encourage early intervention before severe symptoms occur, especially if repair is possible.

Cyclosporine C2 levels have impact on incidence of rejection in de novo lung but not heart transplant recipients: the NOCTURNE study.

BACKGROUND: Cyclosporine (CsA) absorption varies early after transplantation and can be accurately assessed by the area under the absorption curve (AUC). The 2-hour post-dose (C2) level of CsA in whole blood is reported to be a useful surrogate marker of CsA AUC in kidney and liver transplant monitoring, but should be further explored in thoracic organ recipients. METHODS: In a 12-month study we included de novo lung (n = 95) and heart (n = 96) recipients. All participants received cyclosporine (Sandimmun Neoral) monitored by C0 and blood was collected for analysis of C2 retrospectively. Abbreviated AUC (AUC(0-4)) was measured at 7 days and 3 months. Primary outcome was C2 relation to the frequency of acute cellular rejection (ACR) needing treatment and possible decline in measured glomerular filtration rate (mGFR). Recipients were divided into lower, middle and upper third C2 groups based on 2-week post-operative values (tertiles T1 to T3). RESULTS: C2 was the most robust substitute for AUC(0-4) in the group of patients studied. For lung, but not heart, recipients there were differences in mean number of ACRs (p = 0.05), incidence of any rejections (p = 0.04), mean number of any rejections (p = 0.001) and time to first rejection (p = 0.03) between T1 and T3. C2 did not predict reduction in mGFR. CONCLUSIONS: C2 is a sensitive predictor for ACR in lung, but not heart, recipients, C2 was not predictive of a decline in mGFR. This study suggests that management of lung recipients by C2 may diminish the number of ACRs.

Prolonged extracorporeal membrane oxygenation and circulatory support as bridge to lung transplant.

A 38-year-old man with progressive alveolitis secondary to polymyositis was treated for 52 days with venovenous and venoarterial extracorporeal membrane oxygenation as a bridge to bilateral lung transplantation. The patient survived, despite multiple complications, and is now back home with good pulmonary function. He is working part-time nearly 3 years post-transplant. This case shows that long-term extracorporeal lung assist is a viable but demanding alternative for bridging patients to pulmonary transplantation. This case also shows that right ventricular failure necessating conversion to veno-arterial assist does not necessarily predict right ventricular failure post-transplant.

Pulmonary hemodynamics as predictors of mortality in patients awaiting lung transplantation.

Lung transplantation (LTx) is a therapeutic option for patients with end-stage lung disease. However, the mortality rate of patients on the waiting list is high. The purpose of this study was to examine the prognostic value of cardio-pulmonary hemodynamics for death in patients awaiting LTx. Retrospectively, 177 patients with advanced lung disease accepted for LTx at Sahlgrenska University Hospital from January 1990 through December 2003 were studied. Patient demographics, pulmonary function tests, gas exchange and hemodynamic variables were included in the analysis. Death while awaiting LTx was the primary endpoint for all analyses. Mean age was 49 +/- 9 years. Main diagnoses were alpha 1 antitrypsin deficiency (n = 56), chronic obstructive pulmonary disease (n = 61), cystic fibrosis (n = 14) and interstitial lung disease (n = 46). Thirty patients died (17%). LTx was performed in 143 cases. By univariate analyses, forced vital capacity (FVC) % of predicted, pulmonary vascular resistance (PVR) and diagnosis were associated with risk for death. In multivariate analysis PVR (HR, 1.22; 95% CI, 1.06-1.41; P = 0.006) and FVC% of predicted (HR, 0.97; 95% CI, 0.94-0.99; P = 0.01) were independently associated with death. Patients with increased PVR and a lower FVC % of predicted awaiting LTx should be considered for a higher organ allocation priority. Assessment of pulmonary hemodynamics needs to be considered during evaluation for LTx.

The relationship between ASAT, CKMB, troponin-T and mortality after cardiac surgery.

OBJECTIVE: To investigate the relationship between ASAT, CKMB, troponin-T and mortality after cardiac surgery. DESIGN: ASAT, CKMB and TnT were analysed in 116 patients. Correlation, sensitivity, specificity and predictive values for permanent myocardial injury (defined as TnT > or = 2.0 microg/l postoperative day four) were calculated. In the second part our clinical protocol (ASAT on postoperative day 1 and TnT on day 3-4 in patients with ASAT above 2.5 microkat/l) was evaluated. Mortality was compared between patients with ASAT < 2.5 microkat/l (ASAT-), 2. ASAT > or = 2.5 microkat/l and TnT < 2.0 microg/l (ASAT+/TnT-) and 3. ASAT > or = 2.5 microkat/l and TnT > or = 2.0 microg/l (ASAT+/TnT+). RESULTS: Both ASAT and CKMB had irrespectively of cut-off level, low positive and high negative predictive value of permanent myocardial injury. Early and mid-term mortality did not differ significantly between ASAT- and ASAT+/TnT- patients. CONCLUSIONS: ASAT and CKMB can be used to exclude but not to diagnose permanent myocardial injury after cardiac surgery. Increased postoperative ASAT in the absence of increased TnT is not associated with worse clinical outcome than after normal postoperative ASAT.

Vascular resistance and endothelial function in cyclosporine-treated lung transplant recipients.

The majority of patients undergoing solid organ transplantation develop hypertension, to which vasoconstriction and impaired endothelial function have been suggested to contribute. We compared basal vascular resistance and nitric oxide-mediated endothelial-dependent and independent vasoreactivity between cyclosporine-treated lung transplant recipients and healthy subjects. Forearm blood flow was measured by venous occlusion plethysmography at rest and during acetylcholine, glyceryltrinitrate and N(G)-monomethyl-L-arginine acetate (L-NMMA) infusion in 11 lung transplant recipients 3-5 years after transplantation and in eight healthy subjects. Forearm vascular resistance (FVR) was calculated. Plasma levels of endothelin-1 (ET-1) and von Willebrand factor (vWf) were analysed. Basal vascular resistance was 40% lower in transplant recipients than in healthy subjects (P = 0.021). Endothelial-dependent and independent vasodilation did not differ. Plasma levels of ET-1 and vWf were higher in transplant recipients (P = 0.009 and P < 0.001 respectively). There was a significant correlation between ET-1 levels and FVR in healthy subjects (r = 0.83, P = 0.042), but not in transplant recipients (r = -0.14, P = 0.70). The findings oppose the theory of generalized vasoconstriction and impaired endothelial function in the pathogenesis of hypertension after transplantation. Increased plasma levels of ET-1 do not cause increased FVR in lung transplant recipients.