Growth Differentiation Factor-15 (GDF-15) Levels Are Associated with Cardiac and Renal Injury in Patients Undergoing Coronary Artery Bypass Grafting with Cardiopulmonary Bypass

Objective

Growth differentiation factor-15 (GDF-15) has been identified as a strong marker of cardiovascular disease; however, no data are available concerning the role of GDF-15 in the occurrence of organ dysfunction during coronary artery bypass grafting (CABG) associated with cardiopulmonary bypass (CPB).

Methods

Five arterial blood samples were taken sequentially in 34 patients from anesthesia induction (IND) until 24 h after arrival at the intensive care unit (ICU). Plasma levels of GDF-15, follistatin-like 1 (FLST1), myeloperoxidases (MPO), hydroperoxides and plasma antioxidant status (PAS) were measured at each time-point. Markers of cardiac (cardiac-troponin I, cTnI) and renal dysfunction (neutrophil gelatinase-associated lipocalin, NGAL) and other classical biological factors and clinical data were measured.

Results

Plasma GDF-15 levels increased gradually during and after surgery, reaching nearly three times the IND levels in the ICU (3,075±284 ng/L vs. 1,061±90 ng/L, p<0.001). Plasma MPO levels increased dramatically during surgery, attaining their highest level after unclamping (UNCLAMP) (49±11 ng/mL vs. 1,679±153 ng/mL, p<0.001) while PAS significantly decreased between IND and UNCLAMP (p<0.05), confirming the high oxidative status induced by this surgical procedure. ICU levels of GDF-15 correlated positively with cTnI and NGAL (p = 0.006 and p = 0.036, respectively), and also with hemoglobin and estimated glomerular filtration rate (eGFR). Among all the post-operative biomarkers available, only eGFR, NGAL and GDF-15 measured at ICU arrival were significantly associated with the onset of acute kidney injury (AKI). Patients with a EuroSCORE >3 were shown to have higher GDF-15 levels.

Conclusions

During cardiac surgery associated with CPB, GDF-15 levels increased substantially and were associated with markers of cardiac injury and renal dysfunction.     

Cardiac Function in Patients with Early Cirrhosis during Maximal Beta-Adrenergic Drive: A Dobutamine Stress Study

Background and aim

Cardiac dysfunction in patients with early cirrhosis is debated. We investigated potential cardiac dysfunction by assessing left ventricular systolic performance during a dobutamine stress test in patients with early cirrhosis.

Patients and methods

Nineteen patients with Child A and B cirrhosis (9 with non-alcoholic cirrhosis) and 7 matched controls were included. We used cardiac magnetic resonance imaging to assess left ventricular volumes and cardiac output (CO) at rest and during maximal heart rate induced by increasing dosages of dobutamine and atropine.

Results

Patients with cirrhosis and controls had an equal stress response, the heart rate and ejection fraction increased similarly and maximal heart rate was reached in all. At rest CO was higher in Child B patients than controls. During maximal stress, Child B patients had higher CO (10.6±2.7 vs. 8.0±1.8 L/min), left ventricle end diastolic volume (90±25 vs. 67±16 mL), left ventricular end diastolic volume (10±4 vs. 6±2 mL) and stroke volume (80±23 vs. 61±15 mL) than Child A patients. The systemic vascular resistance was lower in Child B than Child A patients (670±279 vs. 911±274 dyne*s*cm⁻⁵). The left ventricle mass increased by 5.6 gram per model for end stage liver disease (MELD) point. MELD score correlated with the end diastolic and systolic volume, CO, and stroke volume at rest and at stress (all p<0.05).

Conclusion

In patients with early cirrhosis the chronotropoic and inotropic response to pharmacological stress induced by dobutamine is normal. With progression of the disease, the mass of the heart increases along with increase in cardiac volumes.     

Raised Plasma Robo4 and Cardiac Surgery-Associated Acute Kidney Injury

Objective

Endothelial dysfunction associated with systemic inflammation can contribute to organ injury/failure following cardiac surgery requiring cardiopulmonary bypass (CPB). Roundabout protein 4 (Robo4), an endothelial-expressed transmembrane receptor and regulator of cell activation, is an important inhibitor of endothelial hyper-permeability. We investigated the hypothesis that plasma levels of Robo4 are indicative of organ injury, in particular acute kidney injury (AKI), after cardiac surgery.

Methods

Patients (n = 32) undergoing elective cardiac surgery with CPB were enrolled, prospectively. Plasma Robo4 concentrations were measured pre-, 2 and 24 h post-operatively, using a commercially available ELISA. Plasma and endothelial markers of inflammation [interleukin (IL) -6, -8, -10: von Willibrand factor (vWF) and angiopoeitin-2 (Ang-2)] and the AKI marker, neutrophil gelatinase-associated lipocalin (NGAL), were also measured by ELISA.

Results

Plasma Robo4 increased significantly (p<0.001) from pre-operative levels of 2515±904 pg/ml to 4473±1915 pg/ml, 2 h after surgery; and returned to basal levels (2682±979 pg/ml) by 24 h. Plasma cytokines, vWF and NGAL also increased 2 h post-operatively and remained elevated at 24 h. Ang-2 increased 24 h post-operatively, only. There was a positive, significant correlation (r = 0.385, p = 0.0298) between Robo-4 and IL-10, but not other cytokines, 2 h post-operatively. Whilst raised Robo4 did not correlate with indices of lung dysfunction or other biomarkers of endothelial activation; there was a positive, significant correlation between raised (2 h) plasma NGAL and Robo4 (r = 0.4322, p = 0.0135). When patients were classed as AKI or non-AKI either using NGAL cut-off of 150 ng/ml, or the AKI Network (AKIN) clinical classification; plasma Robo4 was significantly higher (p = 0.0073 and 0.003, respectively) in AKI vs. non-AKI patients (NGAL cut-off: 5350±2191 ng/ml, n = 16 vs. 3595±1068 pg/ml, n = 16; AKIN: 6546 pg/ml, IQR 5025–8079, n = 6; vs. 3727 pg/ml, IQR 1962–3727, n = 26) subjects.

Conclusion

Plasma Robo4 levels are increased, transiently, following cardiac surgery requiring CPB; and higher levels in patients with AKI suggest a link between endothelial dysregulation and onset of AKI.     

Elevated Soluble VEGF Receptor sFlt-1 Correlates with Endothelial Injury in IgA Nephropathy

Background

Endothelial injury, which may present clinically as hypertension, proteinuria and increased von Willebrand Factor (vWF) level, is a common manifestation in IgA nephropathy (IgAN). However, causal factors for endothelial injury in IgAN are not completely understood. An imbalance of vascular endothelial growth factor/Soluble fms-like tyrosine kinase-1 (VEGF/sFlt-1) has been observed in many diseases with endothelial dysfunction, including pre-eclampsia and diabetic retinopathy, but whether it contributes to endothelial injury in IgAN requires further exploration.

Methods

Initially, 96 IgAN patients and 22 healthy volunteers were enrolled as a discovery cohort. VEGF/sFlt-1, sFlt-1 and VEGF levels were compared between patients with IgAN and healthy volunteers to explore the underlying factors that contribute to endothelial injury in IgAN. The identified contributor (sFlt-1) was further confirmed in a replication cohort, which included 109 IgAN patients and 30 healthy volunteers. Correlations of sFlt-1 with hypertension, proteinuria, Oxford-E score and plasma vWF were further evaluated in the combined 205 patients with IgAN.

Results

VEGF/sFlt-1 levels were significantly lower in IgAN patients than healthy volunteers (0.33±0.27 vs. 0.43±0.22, p = 0.02) in the discovery cohort. Within the ratio, plasma sFlt-1 levels were significantly elevated (101.18±25.19 vs. 79.73±18.85 pg/ml, p<0.001), but plasma VEGF levels showed no significant differences. Elevated sFlt-1 levels in the replication cohort were confirmed in IgAN patients (93.40±39.78 vs. 71.92±15.78 pg/ml, p<0.001). Plasma sFlt-1 levels in IgAN patients correlated with proteinuria (severe (>3.5 g/d) vs. moderate (1–3.5 g/d) vs. mild (<1 g/d) proteinuria: 115.95±39.09 vs. 99.89±28.55 vs. 83.24±33.92 pg/ml; severe vs. mild: p<0.001, moderate vs. mild p = 0.001, severe vs. moderate: p = 0.014), hypertension (with vs. without hypertension: 107.87±31.94 vs. 87.32±32.76 pg/ml, p = 0.015) and vWF levels (r = 0.161, p = 0.021).

Conclusions

The present study found elevated sFlt-1 in IgAN patients and further identified its correlation with proteinuria, hypertension and vWF levels. These results suggested that elevated sFlt-1 contributes to endothelial injury in IgAN.     

Serum Autotaxin Is a Parameter for the Severity of Liver Cirrhosis and Overall Survival in Patients with Liver Cirrhosis – A Prospective Cohort Study

Background

Autotaxin (ATX) and its product lysophosphatidic acid (LPA) are considered to be involved in the development of liver fibrosis and elevated levels of serum ATX have been found in patients with hepatitis C virus associated liver fibrosis. However, the clinical role of systemic ATX in the stages of liver cirrhosis was unknown. Here we investigated the relation of ATX serum levels and severity of cirrhosis as well as prognosis of cirrhotic patients.

Methods

Patients with liver cirrhosis were prospectively enrolled and followed until death, liver transplantation or last contact. Blood samples drawn at the day of inclusion in the study were assessed for ATX content by an enzyme-linked immunosorbent assay. ATX levels were correlated with the stage as well as complications of cirrhosis. The prognostic value of ATX was investigated by uni- and multivariate Cox regression analyses. LPA concentration was determined by liquid chromatography-tandem mass spectrometry.

Results

270 patients were enrolled. Subjects with liver cirrhosis showed elevated serum levels of ATX as compared to healthy subjects (0.814±0.42 mg/l vs. 0.258±0.40 mg/l, P<0.001). Serum ATX levels correlated with the Child-Pugh stage and the MELD (model of end stage liver disease) score and LPA levels (r = 0.493, P = 0.027). Patients with hepatic encephalopathy (P = 0.006), esophageal varices (P = 0.002) and portal hypertensive gastropathy (P = 0.008) had higher ATX levels than patients without these complications. Low ATX levels were a parameter independently associated with longer overall survival (hazard ratio 0.575, 95% confidence interval 0.365–0.905, P = 0.017).

Conclusion

Serum ATX is an indicator for the severity of liver disease and the prognosis of cirrhotic patients.     

Right Ventricular Function Quantification in Takotsubo Cardiomyopathy Using Two-Dimensional Strain Echocardiography

Aims

This study sought to characterize global and regional right ventricular (RV) myocardial function in patients with Takotsubo cardiomyopathy (TC) using 2D strain imaging.

Methods

We compared various parameters of RV and left ventricular (LV) systolic function between 2 groups of consecutive patients with TC at initial presentation and upon follow-up. Group 1 had RV involvement and group 2 did not have RV involvement.

Results

At initial presentation, RV peak systolic longitudinal strain (RVPSS) and RV fractional area change (RVFAC) were significantly lower in group 1 (−13.2±8.6% vs. −21.8±5.4%, p = 0.001; 30.7±9.3% vs. 43.5±6.3%, p = 0.001) and improved significantly upon follow-up. Tricuspid annular plane systolic excursion (TAPSE) did not differ significantly at initial presentation between both groups (14.8±4.1 mm vs. 17.9±3.5 mm, p = 0.050). Differences in regional systolic RV strain were only observed in the mid and apical segments. LV ejection fraction (LVEF) and LV global strain were significantly lower in group 1 (36±8% vs. 46±10%, p = 0.006 and −5.5±4.8% vs. −10.2±6.2%, p = 0.040) at initial presentation. None of the parameters were significantly different between the 2 groups upon follow-up. A RVPSS cut-off value of >−19.1% had a sensitivity of 85% and a specificity of 71% to discriminate between the 2 groups.

Conclusion

In TC, RVFAC, RVPSS, LVEF and LV global strain differed significantly between patients with and without RV dysfunction, whereas TAPSE did not. 2 D strain imaging was feasible for the assessment of RV dysfunction in TC and could discriminate between patients with and without RV involvement in a clinically meaningful way.     

Baseline MELD Score Predicts Hepatic Decompensation during Antiviral Therapy in Patients with Chronic Hepatitis C and Advanced Cirrhosis

Background and Aims

In patients with advanced liver cirrhosis due to chronic hepatitis C virus (HCV) infection antiviral therapy with peginterferon and ribavirin is feasible in selected cases only due to potentially life-threatening side effects. However, predictive factors associated with hepatic decompensation during antiviral therapy are poorly defined.

Methods

In a retrospective cohort study, 68 patients with HCV-associated liver cirrhosis (mean MELD score 9.18±2.72) were treated with peginterferon and ribavirin. Clinical events indicating hepatic decompensation (onset of ascites, hepatic encephalopathy, upper gastrointestinal bleeding, hospitalization) as well as laboratory data were recorded at baseline and during a follow up period of 72 weeks after initiation of antiviral therapy. To monitor long term sequelae of end stage liver disease an extended follow up for HCC development, transplantation and death was applied (240weeks, ±SD 136weeks).

Results

Eighteen patients (26.5%) achieved a sustained virologic response. During the observational period a hepatic decompensation was observed in 36.8%. Patients with hepatic decompensation had higher MELD scores (10.84 vs. 8.23, p<0.001) and higher mean bilirubin levels (26.74 vs. 14.63 µmol/l, p<0.001), as well as lower serum albumin levels (38.2 vs. 41.1 g/l, p = 0.015), mean platelets (102.64 vs. 138.95/nl, p = 0.014) and mean leukocytes (4.02 vs. 5.68/nl, p = 0.002) at baseline as compared to those without decompensation. In the multivariate analysis the MELD score remained independently associated with hepatic decompensation (OR 1.56, 1.18–2.07; p = 0.002). When the patients were grouped according to their baseline MELD scores, hepatic decompensation occurred in 22%, 59%, and 83% of patients with MELD scores of 6–9, 10–13, and >14, respectively. Baseline MELD score was significantly associated with the risk for transplantation/death (p<0.001).

Conclusions

Our data suggest that the baseline MELD score predicts the risk of hepatic decompensation during antiviral therapy and thus contributes to decision making when antiviral therapy is discussed in HCV patients with advanced liver cirrhosis.     

Total Beta-Adrenoceptor Knockout Slows Conduction and Reduces Inducible Arrhythmias in the Mouse Heart

Introduction

Beta-adrenoceptors (β-AR) play an important role in the neurohumoral regulation of cardiac function. Three β-AR subtypes (β₁, β₂, β₃) have been described so far. Total deficiency of these adrenoceptors (TKO) results in cardiac hypotrophy and negative inotropy. TKO represents a unique mouse model mimicking total unselective medical β-blocker therapy in men. Electrophysiological characteristics of TKO have not yet been investigated in an animal model.

Methods

In vivo electrophysiological studies using right heart catheterisation were performed in 10 TKO mice and 10 129SV wild type control mice (WT) at the age of 15 weeks. Standard surface ECG, intracardiac and electrophysiological parameters, and arrhythmia inducibility were analyzed.

Results

The surface ECG of TKO mice revealed a reduced heart rate (359.2±20.9 bpm vs. 461.1±33.3 bpm; p<0.001), prolonged P wave (17.5±3.0 ms vs. 15.1±1.2 ms; p = 0.019) and PQ time (40.8±2.4 ms vs. 37.3±3.0 ms; p = 0.013) compared to WT. Intracardiac ECG showed a significantly prolonged infra-Hisian conductance (HV-interval: 12.9±1.4 ms vs. 6.8±1.0 ms; p<0.001). Functional testing showed prolonged atrial and ventricular refractory periods in TKO (40.5±15.5 ms vs. 21.3±5.8 ms; p = 0.004; and 41.0±9.7 ms vs. 28.3±6.6 ms; p = 0.004, respectively). In TKO both the probability of induction of atrial fibrillation (12% vs. 24%; p<0.001) and of ventricular tachycardias (0% vs. 26%; p<0.001) were significantly reduced.

Conclusion

TKO results in significant prolongations of cardiac conduction times and refractory periods. This was accompanied by a highly significant reduction of atrial and ventricular arrhythmias. Our finding confirms the importance of β-AR in arrhythmogenesis and the potential role of unspecific beta-receptor-blockade as therapeutic target.     

Non-Invasive Detection of Coronary Endothelial Response to Sequential Handgrip Exercise in Coronary Artery Disease Patients and Healthy Adults

Objectives

Our objective is to test the hypothesis that coronary endothelial function (CorEndoFx) does not change with repeated isometric handgrip (IHG) stress in CAD patients or healthy subjects.

Background

Coronary responses to endothelial-dependent stressors are important measures of vascular risk that can change in response to environmental stimuli or pharmacologic interventions. The evaluation of the effect of an acute intervention on endothelial response is only valid if the measurement does not change significantly in the short term under normal conditions. Using 3.0 Tesla (T) MRI, we non-invasively compared two coronary artery endothelial function measurements separated by a ten minute interval in healthy subjects and patients with coronary artery disease (CAD).

Methods

Twenty healthy adult subjects and 12 CAD patients were studied on a commercial 3.0 T whole-body MR imaging system. Coronary cross-sectional area (CSA), peak diastolic coronary flow velocity (PDFV) and blood-flow were quantified before and during continuous IHG stress, an endothelial-dependent stressor. The IHG exercise with imaging was repeated after a 10 minute recovery period.

Results

In healthy adults, coronary artery CSA changes and blood-flow increases did not differ between the first and second stresses (mean % change ±SEM, first vs. second stress CSA: 14.8%±3.3% vs. 17.8%±3.6%, p = 0.24; PDFV: 27.5%±4.9% vs. 24.2%±4.5%, p = 0.54; blood-flow: 44.3%±8.3 vs. 44.8%±8.1, p = 0.84). The coronary vasoreactive responses in the CAD patients also did not differ between the first and second stresses (mean % change ±SEM, first stress vs. second stress: CSA: −6.4%±2.0% vs. −5.0%±2.4%, p = 0.22; PDFV: −4.0%±4.6% vs. −4.2%±5.3%, p = 0.83; blood-flow: −9.7%±5.1% vs. −8.7%±6.3%, p = 0.38).

Conclusion

MRI measures of CorEndoFx are unchanged during repeated isometric handgrip exercise tests in CAD patients and healthy adults. These findings demonstrate the repeatability of noninvasive 3T MRI assessment of CorEndoFx and support its use in future studies designed to determine the effects of acute interventions on coronary vasoreactivity.     

Renal Hyperfiltration and Systemic Blood Pressure in Patients with Uncomplicated Type 1 Diabetes Mellitus

Background

Patients with type 1 diabetes mellitus (DM) and renal hyperfiltration also exhibit systemic microvascular abnormalities, including endothelial dysfunction. The effect of renal hyperfiltration on systemic blood pressure (BP) is less clear. We therefore measured BP, renal hemodynamic function and circulating renin angiotensin aldosterone system (RAAS) mediators in type 1 DM patients with hyperfiltration (n = 36, DM-H, GFR≥135 ml/min/1.73 m²) or normofiltration (n = 40, DM-N), and 56 healthy controls (HC). Since renal hyperfiltration represents a state of intrarenal RAAS activation, we hypothesized that hyperfiltration would be associated with higher BP and elevated levels of circulating RAAS mediators.

Methods

BP, glomerular filtration rate (GFR - inulin), effective renal plasma flow (paraaminohippurate) and circulating RAAS components were measured in DM-H, DM-N and HC during clamped euglycemia (4–6 mmol/L). Studies were repeated in DM-H and DM-N during clamped hyperglycemia (9–11 mmol/L).

Results

Baseline GFR was elevated in DM-H vs. DM-N and HC (167±6 vs. 115±2 and 115±2 ml/min/1.73 m², p<0.0001). Baseline systolic BP (SBP, 117±2 vs. 111±2 vs. 109±1, p = 0.004) and heart rate (76±1 vs. 67±1 vs. 61±1, p<0.0001) were higher in DM-H vs. DM-N and HC. Despite higher SBP in DM-H, plasma aldosterone was lower in DM-H vs. DM-N and HC (42±5 vs. 86±14 vs. 276±41 ng/dl, p = 0.01). GFR (p<0.0001) and SBP (p<0.0001) increased during hyperglycemia in DM-N but not in DM-H.

Conclusions

DM-H was associated with higher heart rate and SBP values and an exaggerated suppression of systemic aldosterone. Future work should focus on the mechanisms that explain this paradox in diabetes of renal hyperfiltration coupled with systemic RAAS suppression.     

Effect of Meal Ingestion on Liver Stiffness in Patients with Cirrhosis and Portal Hypertension

Background and Aims

Liver stiffness is increasingly used in the non-invasive evaluation of chronic liver diseases. Liver stiffness correlates with hepatic venous pressure gradient (HVPG) in patients with cirrhosis and holds prognostic value in this population. Hence, accuracy in its measurement is needed. Several factors independent of fibrosis influence liver stiffness, but there is insufficient information on whether meal ingestion modifies liver stiffness in cirrhosis. We investigated the changes in liver stiffness occurring after the ingestion of a liquid standard test meal in this population.

Methods

In 19 patients with cirrhosis and esophageal varices (9 alcoholic, 9 HCV-related, 1 NASH; Child score 6.9±1.8), liver stiffness (transient elastography), portal blood flow (PBF) and hepatic artery blood flow (HABF) (Doppler-Ultrasound) were measured before and 30 minutes after receiving a standard mixed liquid meal. In 10 the HVPG changes were also measured.

Results

Post-prandial hyperemia was accompanied by a marked increase in liver stiffness (+27±33%; p<0.0001). Changes in liver stiffness did not correlate with PBF changes, but directly correlated with HABF changes (r = 0.658; p = 0.002). After the meal, those patients showing a decrease in HABF (n = 13) had a less marked increase of liver stiffness as compared to patients in whom HABF increased (n = 6; +12±21% vs. +62±29%,p<0.0001). As expected, post-prandial hyperemia was associated with an increase in HVPG (n = 10; +26±13%, p = 0.003), but changes in liver stiffness did not correlate with HVPG changes.

Conclusions

Liver stiffness increases markedly after a liquid test meal in patients with cirrhosis, suggesting that its measurement should be performed in standardized fasting conditions. The hepatic artery buffer response appears an important factor modulating postprandial changes of liver stiffness. The post-prandial increase in HVPG cannot be predicted by changes in liver stiffness.     

Urothelial Dysfunction and Increased Suburothelial Inflammation of Urinary Bladder Are Involved in Patients with Upper Urinary Tract Urolithiasis – Clinical and Immunohistochemistry Study

Objectives

To investigate the urothelial dysfunction and inflammation of urinary bladder in patients with upper urinary tract (UUT) urolithiasis through the results of cystoscopic hydrodistension and immunohistochemistry study.

Methods

Ninety-one patients with UUT urolithiasis underwent cystoscopic hydrodistension before the stone surgery. Immunofluorescence staining of E-cadherin, zonula occludens-1 (ZO-1), tryptase (mast cell activation), and TUNEL (urothelial apoptosis) were performed in 42 patients with glomerulations after hydrodistension, 10 without glomerulations, and 10 controls.

Results

Of the 91 patients, 62 (68.2%) developed glomerulations after hydrodistension. Lower urinary tract symptoms (LUTS) were present in 53.8% patients, in whom significantly smaller maximal anesthetic bladder capacity (MBC) was noted. Patients with middle or lower 1/3 ureteral stones had a significantly higher glomerulation rate (88.6% vs. 55.4%, p<0.01) and lower MBC (618.4±167.6 vs. 701.2±158.4 ml, p = 0.027) than those with upper 1/3 ureteral or renal stones. Patients with UUT urolithiasis had significantly lower expression of E-cadherin (26.2±14.8 vs. 42.4±16.7) and ZO-1 (5.16±4.02 vs. 11.02±5.66); and higher suburothelial mast cell (13.3±6.8 vs. 1.3±1.2) and apoptotic cell (2.6±2.5 vs. 0.1±0.3) numbers than in controls (all p<0.01).

Conclusions

Urothelial dysfunction and increased suburothelial inflammation and apoptosis are highly prevalent in the bladders of UUT urolithiasis patients, indicating inflammation cross-talk between UUT and urinary bladder. Patients with UUT urolithiaisis concomitant with LUTS had a smaller MBC, which may explain the presence of irritative bladder symptoms.     

Soluble TNF-Alpha-Receptors I Are Prognostic Markers in TIPS-Treated Patients with Cirrhosis and Portal Hypertension

Background

TNFα levels are increased in liver cirrhosis even in the absence of infection, most likely owing to a continuous endotoxin influx into the portal blood. Soluble TNFα receptors (sTNFR type I and II) reflect release of the short-lived TNFα, because they are cleaved from the cells after binding of TNFα. The aims were to investigate the circulating levels of soluble TNFR-I and -II in cirrhotic patients receiving TIPS.

Methods

Forty-nine patients with liver cirrhosis and portal hypertension (12 viral, 37 alcoholic) received TIPS for prevention of re-bleeding (n = 14), therapy-refractory ascites (n = 20), or both (n = 15). Portal and hepatic venous blood was drawn in these patients during the TIPS procedure and during the control catheterization two weeks later. sTNFR-I and sTNFR-II were measured by ELISA, correlated to clinical and biochemical characteristics.

Results

Before TIPS insertion, sTNFR-II levels were lower in portal venous blood than in the hepatic venous blood, as well as in portal venous blood after TIPS insertion. No significant differences were measured in sTNFR-I levels. Hepatic venous levels of sTNFR-I above 4.5 ng/mL (p = 0.036) and sTNFR-II above 7 ng/mL (p = 0.05) after TIPS insertion were associated with decreased survival. A multivariate Cox-regression survival analysis identified the hepatic venous levels of sTNFR-I (p = 0.004) two weeks after TIPS, and Child score (p = 0.002) as independent predictors of mortality, while MELD-score was not.

Conclusion

Hepatic venous levels of sTNFR-I after TIPS insertion may predict mortality in patients with severe portal hypertension.     

Burnt Sugarcane Harvesting – Cardiovascular Effects on a Group of Healthy Workers,Brazil

Background

Brazil is the world''s largest producer of sugarcane. Harvest is predominantly manual, exposing workers to health risks: intense physical exertion, heat, pollutants from sugarcane burning.

Design

Panel study to evaluate the effects of burnt sugarcane harvesting on blood markers and on cardiovascular system.

Methods

Twenty-eight healthy male workers, living in the countryside of Brazil were submitted to blood markers, blood pressure, heart rate variability, cardiopulmonary exercise testing, sympathetic nerve activity evaluation and forearm blood flow measures (venous occlusion plethysmography) during burnt sugarcane harvesting and four months later while they performed other activities in sugar cane culture.

Results

Mean participant age was 31±6.3 years, and had worked for 9.8±8.4 years on sugarcane work. Work during the harvest period was associated with higher serum levels of Creatine Kinase – 136.5 U/L (IQR: 108.5–216.0) vs. 104.5 U/L (IQR: 77.5–170.5), (p = 0.001); plasma Malondialdehyde–7.5±1.4 µM/dl vs. 6.9±1.0 µM/dl, (p = 0.058); Glutathione Peroxidase – 55.1±11.8 Ug/Hb vs. 39.5±9.5 Ug/Hb, (p<0.001); Glutathione Transferase– 3.4±1.3 Ug/Hb vs. 3.0±1.3 Ug/Hb, (p = 0.001); and 24-hour systolic blood pressure – 120.1±10.3 mmHg vs. 117.0±10.0 mmHg, (p = 0.034). In cardiopulmonary exercise testing, rest-to-peak diastolic blood pressure increased by 11.12 mmHg and 5.13 mmHg in the harvest and non-harvest period, respectively. A 10 miliseconds reduction in rMSSD and a 10 burst/min increase in sympathetic nerve activity were associated to 2.2 and 1.8 mmHg rises in systolic arterial pressure, respectively.

Conclusion

Work in burnt sugarcane harvesting was associated with changes in blood markers and higher blood pressure, which may be related to autonomic imbalance.     

The Role of Whole Blood Impedance Aggregometry and Its Utilisation in the Diagnosis and Prognosis of Patients with Systemic Inflammatory Response Syndrome and Sepsis in Acute Critical Illness

Objective

To assess the prognostic and diagnostic value of whole blood impedance aggregometry in patients with sepsis and SIRS and to compare with whole blood parameters (platelet count, haemoglobin, haematocrit and white cell count).

Methods

We performed an observational, prospective study in the acute setting. Platelet function was determined using whole blood impedance aggregometry (multiplate) on admission to the Emergency Department or Intensive Care Unit and at 6 and 24 hours post admission. Platelet count, haemoglobin, haematocrit and white cell count were also determined.

Results

106 adult patients that met SIRS and sepsis criteria were included. Platelet aggregation was significantly reduced in patients with severe sepsis/septic shock when compared to SIRS/uncomplicated sepsis (ADP: 90.7±37.6 vs 61.4±40.6; p<0.001, Arachadonic Acid 99.9±48.3 vs 66.3±50.2; p = 0.001, Collagen 102.6±33.0 vs 79.1±38.8; p = 0.001; SD ± mean)). Furthermore platelet aggregation was significantly reduced in the 28 day mortality group when compared with the survival group (Arachadonic Acid 58.8±47.7 vs 91.1±50.9; p<0.05, Collagen 36.6±36.6 vs 98.0±35.1; p = 0.001; SD ± mean)). However haemoglobin, haematocrit and platelet count were more effective at distinguishing between subgroups and were equally effective indicators of prognosis. Significant positive correlations were observed between whole blood impedance aggregometry and platelet count (ADP 0.588 p<0.0001, Arachadonic Acid 0.611 p<0.0001, Collagen 0.599 p<0.0001 (Pearson correlation)).

Conclusions

Reduced platelet aggregometry responses were not only significantly associated with morbidity and mortality in sepsis and SIRS patients, but also correlated with the different pathological groups. Whole blood aggregometry significantly correlated with platelet count, however, when we adjust for the different groups we investigated, the effect of platelet count appears to be non-significant.     

Fibrin Clot Structure and Platelet Aggregation in Patients with Aspirin Treatment Failure

Background

Aspirin is a cornerstone in prevention of cardiovascular events and modulates both platelet aggregation and fibrin clot formation. Some patients experience cardiovascular events whilst on aspirin, often termed aspirin treatment failure (ATF). This study evaluated both platelet aggregation and fibrin clot structure in patients with ATF.

Methods

We included 177 stable coronary artery disease patients on aspirin monotherapy. Among these, 116 (66%) had ATF defined as myocardial infarction (MI) whilst on aspirin. Platelet aggregation was assessed by Multiplate® aggregometry and VerifyNow®, whereas turbidimetric assays and scanning electron microscopy were employed to study fibrin clot characteristics.

Results

Enhanced platelet aggregation was observed in patients with ATF compared with non-MI patients following stimulation with arachidonic acid 1.0 mM (median 161 (IQR 95; 222) vs. 97 (60; 1776) AU*min, p = 0.005) and collagen 1.0 µg/mL (293 (198; 427) vs. 220 (165; 370) AU*min, p = 0.03). Similarly, clot maximum absorbance, a measure of fibrin network density, was increased in patients with ATF (0.48 (0.41; 0.52) vs. 0.42 (0.38; 0.50), p = 0.02), and this was associated with thinner fibres (mean ± SD: 119.7±27.5 vs. 127.8±31.1 nm, p = 0.003) and prolonged lysis time (552 (498; 756) vs. 519 (468; 633) seconds; p = 0.02). Patients with ATF also had increased levels of C-reactive protein (CRP) (1.34 (0.48; 2.94) and 0.88 (0.32; 1.77) mg/L, p = 0.01) compared with the non-MI group. Clot maximum absorbance correlated with platelet aggregation (r = 0.31–0.35, p-values<0.001) and CRP levels (r = 0.60, p<0.001).

Conclusions

Patients with aspirin treatment failure showed increased platelet aggregation and altered clot structure with impaired fibrinolysis compared with stable CAD patients without previous MI. These findings suggest that an increased risk of aspirin treatment failure may be identified by measuring both platelet function and fibrin clot structure.     

Coronary Collateral Circulation in Patients of Coronary Ectasia with Significant Coronary Artery Disease

Objectives

Patients with coronary ectasia (CE) usually have coexisting coronary stenosis resulting in myoischemia. Coronary collateral plays an important role in protecting myocardium from ischemia and reducing cardiovascular events. However, limited studies investigate the role of CE in coronary collaterals development.

Methods

We evaluated 1020 consecutive patients undergoing coronary angiography and 552 patients with significant coronary artery disease (SCAD), defined as diameter stenosis more than 70%, were finally analyzed. CE is defined as the ectatic diameter 1.5 times larger than adjacent reference segment. Rentrop collateral score was used to classify patients into poor (grades 0 and 1) or good (grades 2 and 3) collateral group.

Results

73 patients (13.2%) had CE lesions which were most located in the right coronary artery (53.4%). Patients with CE had a lower incidence of diabetes (43.8% vs 30.1%, p = 0.03), higher body mass index (25.4±3.5 vs 26.7±4.6, p = 0.027) and poorer coronary collateral (58.2% vs 71.2%, p = 0.040). Patients with poor collateral (n = 331) had a higher incidence of CE (15.7% vs 9.5%, p = 0.040) and fewer diseased vessels numbers (1.96±0.84 vs 2.48±0.69, p<0.001). Multivariate analysis showed diabetes (odd ratio (OR) 0.630, p = 0.026), CE (OR = 0.544, p = 0.048), and number of diseased vessels (OR = 2.488, p<0.001) were significant predictors of coronary collaterals development.

Conclusion

The presence of CE was associated with poorer coronary collateral development in patients with SCAD.     

Mitral Tissue Inhibitor of Metalloproteinase 2 Is Associated with Mitral Valve Surgery Outcome

Background

Matrix metalloproteinases play a role in regulating cardiac remodeling. We previously reported an association between tissue inhibitor of metalloproteinase 2 (TIMP-2) expression and mitral valve (MV) disease. However, the determinants and prognostic value of mitral TIMP2 after MV surgery are unknown.

Methods

This retrospective study of 164 patients after MV surgery in a tertiary medical center in Taiwan assessed mitral TIMP2 on a semiquantitative scale (0–2) by immunohistochemical staining. The primary endpoints were the composite of cardiovascular death and heart failure admission.

Results

Mean age was 50.4±13.7 years. After a mean follow-up period of 101±59 months, primary endpoints had occurred in 25 (15.2%) subjects. Patients with and without primary endpoint events significantly differed in terms of age (56.6±14.4 vs. 49.2±13.4 years, respectively; p = 0.013) and left ventricular end-systolic diameter (LVESD) (39.7±8.2 vs. 35.5±7.5 mm, p = 0.010) at surgery. The TIMP2 had a significant dose-dependent association with development of a primary endpoint (p = 0.002). Kaplan–Meier analysis showed that TIMP2 expression has a significant positive association with primary endpoint-free survival (log-rank test; p = 0.004). Cox regression analysis showed that independent predictors of primary endpoints were TIMP2 (hazard ratio [HR] 0.28; 95% confidence interval [CI] 0.12–0.65; p = 0.003), age (HR 1.05; 95% CI 1.02–1.09; p = 0.003) and LVESD (HR 1.05; 95% CI 1.01–1.10; p = 0.020).

Conclusions

The lack of mitral TIMP2 expression is associated with increases in cardiovascular death and heart failure following MV surgery.     

Dynamic Changes of Lipopolysaccharide Levels in Different Phases of Acute on Chronic Hepatitis B Liver Failure

Background

High serum levels of lipopolysaccharide (LPS) with LPS-MD-2/TLR4 complex activated NF-kb and cytokine cause hepatic necrosis in animal models. We investigated the dynamic changes of LPS levels in patients with acute on chronic hepatitis B liver failure (ACHBLF).

Methods

We enrolled ACHBLF patients for a 12-week study. Patients’ LPS levels were measured along with 10 healthy controls. Patients on supportive care and recovered without intervention(s) were analyzed. Patients’ LPS levels during the disease progression phase, peak phase, and remission phase were compared with healthy controls.

Results

Among 30 patients enrolled, 25 who received interventions or expired during the study period were excluded from the analysis, five patients on supportive care who completed the study were analyzed. Significant abnormal distributions of LPS levels were observed in patients in different phases (0.0168±0.0101 in progression phase; 0.0960±0.0680 in peak phase; 0.0249±0.0365 in remission phase; and 0.0201±0.0146 in controls; respectively, p<0.05). The highest level of LPS was in the peak phase and significantly elevated when compared to controls (0.0201±0.0146 vs. 0.0960±0.0680, p = 0.007). There were no statistically significant differences in LPS levels between healthy controls and subjects in the progression phase or remission phase. Dynamic changes of LPS were correlated with MELD-Na in the progression phase (p = 0.01, R = 0.876) and in the peak phase (p = 0.000, R = −1.00).

Conclusions

Significant abnormal distributions of LPS levels were observed in ACHBLF with the highest level in the peak phase. The dynamic changes of LPS were correlated with disease severity and suggested LPS causing secondary hepatic injury.