Increased serum levels of adhesion molecules ICAM-1 and VCAM-1 in systemic sclerosis are not specific for pulmonary manifestations

Studies suggest elevated serum intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) levels may be markers of pulmonary arterial hypertension in systemic sclerosis (SSc-PAH). We sought to evaluate whether ICAM-1 and VCAM-1 levels are useful screening biomarkers for incident SSc-PAH. In this cross-sectional study, four groups were selected from the Australian Scleroderma Cohort Study: group 1 (n?=?15) had definite PAH; group 2 (n?=?19) had interstitial lung disease (ILD); group 3 (n?=?30) were SSc-controls; and group 4 (n?=?34) were healthy controls. Serum ICAM-1 and VCAM-1 levels were measured using the Millipore Milliplex MAP Human 2-Plex Panel. There were no differences in ICAM-1 levels in the PAH versus ILD group (263.0?±?85.4 vs 380.4?±?168.3 ng/mL, p?=?0.136), SSc-controls (263.0?±?85.4 vs 253.1?±?98.0 ng/mL, p?=?1.00), or healthy controls (263.0?±?85.4 vs 201.8?±?57.2 ng/mL, p?=?0.093). Similarly, there were no differences in VCAM-1 level in PAH versus ILD groups (1476.2?±?434.9 vs 1424.8?±?527.6 ng/mL, p?=?1.00) and SSc-controls (1476.2?±?434.9 vs 1409.5?±?341.1 ng/mL, p?=?1.00). SSc subjects had significantly higher levels of ICAM-1 (297.4?±?134.0 vs 201.8?±?57.2 ng/mL, p?<?0.0001) and VCAM-1 compared to healthy controls (1432.7?±?427.4 vs 1125.6?±?273.4 ng/mL, p?<?0.0001). Neither ICAM-1 nor VCAM-1 is a specific screening biomarker of SSc-PAH. Instead, increased levels of these adhesion molecules in SSc, irrespective of pulmonary complications, suggest that they may play a role in SSc pathogenesis.     

Effects of <Emphasis Type="Italic">S</Emphasis>-Nitrosoglutathione on Electrophysiological Manifestations of Mechanoelectric Feedback

Electromechanical coupling studies have described the intervention of nitric oxide and S-nitrosylation processes in Ca²⁺ release induced by stretch, with heterogeneous findings. On the other hand, ion channel function activated by stretch is influenced by nitric oxide, and concentration-dependent biphasic effects upon several cellular functions have been described. The present study uses isolated and perfused rabbit hearts to investigate the changes in mechanoelectric feedback produced by two different concentrations of the nitric oxide carrier S-nitrosoglutathione. Epicardial multielectrodes were used to record myocardial activation at baseline and during and after left ventricular free wall stretch using an intraventricular device. Three experimental series were studied: (a) control (n?=?10); (b) S-nitrosoglutathione 10 µM (n?=?11); and (c) S-nitrosoglutathione 50 µM (n?=?11). The changes in ventricular fibrillation (VF) pattern induced by stretch were analyzed and compared. S-nitrosoglutathione 10 µM did not modify VF at baseline, but attenuated acceleration of the arrhythmia (15.6?±?1.7 vs. 21.3?±?3.8 Hz; p?<?0.0001) and reduction of percentile 5 of the activation intervals (42?±?3 vs. 38?±?4 ms; p?<?0.05) induced by stretch. In contrast, at baseline using the 50 µM concentration, percentile 5 was shortened (38?±?6 vs. 52?±?10 ms; p?<?0.005) and the complexity index increased (1.77?±?0.18 vs. 1.27?±?0.13; p?<?0.0001). The greatest complexity indices (1.84?±?0.17; p?<?0.05) were obtained during stretch in this series. S-nitrosoglutathione 10 µM attenuates the effects of mechanoelectric feedback, while at a concentration of 50 µM the drug alters the baseline VF pattern and accentuates the increase in complexity of the arrhythmia induced by myocardial stretch.     

Beta-blocker therapy is associated with a lower incidence of syncope due to fast ventricular tachycardias among implantable cardioverter-defibrillator patients with left ventricular dysfunction: results from a multicenter study

Introduction

Among implantable cardioverter-defibrillator (ICD) patients, a substantial proportion of syncopes are due to fast ventricular tachycardias (FVTs). In the experimental models of ventricular tachycardias, the arterial vasoconstriction plays an important role in recovering the arterial pressure. Since beta-blockers increase vascular resistance, we hypothesized that beta-blockers could reduce the occurrence of syncope due to FVTs. Our objective was to determine the relationship between the beta-blocker therapy and the incidence of syncope in FVT (cycle length [CL] 250–320 ms) occurring in ICD patients. Slow VTs were excluded because of the lack of symptoms and VF episodes because of the small number.

Methods and results

In this multicenter study, 226 patients (LVEF 31?±?10%) with single-chamber ICDs were followed. FVT programming was standardized, including antitachycardia pacing (ATP) as initial therapy. Symptoms were correlated with ICD-stored episode data of FVTs. The beta-blocker therapy was determined at each FVT presentation. We analyzed 289 FVTs (CL 291?±?21 ms; 77% under beta-blockers; median of the duration:8 s) occurring consecutively in 52 ICD patients. The frequency of FVT-related syncope was 22 (7.6%). Beta-blockers were associated with a lower heart rate preceding FVT (85?±?22 vs. 94?±?23 bpm; p?=?0.009), a higher ATP effectiveness (86 vs. 57%; p?<?0.001), a lower duration of episodes (8 [2] vs. 10 [14] s; p?<?0.001), and a lower incidence of FVT-related syncope (4.5 vs. 18%; p?<?0.001). By logistic regression, a FVT >?8 s (OR?=?21; p?=?0.003) and the beta-blocker therapy (OR?=?0.3; p?=?0.012) were found as independent predictors of syncope.

Conclusion

Among ICD patients with left ventricular dysfunction, beta-blockers are associated with a lower incidence of FVT-related syncope.

     

Arterial stiffness is associated with left ventricular dysfunction in patients with rheumatoid arthritis

Arterial stiffness (AS) has a detrimental effect on cardiovascular system particularly on left ventricle (LV). The aim of the study was to evaluate the impact of AS on LV functions in patients with rheumatoid arthritis (RA). Forty patients with RA and 25 age-sex matched control subjects (mean age 48.5?±?6.3 vs. 45.1?±?6.9 years, respectively, p?=?0.06) were enrolled in study. AS was assessed by carotid-femoral pulse wave velocity (CF-PWV) and heart rate corrected augmentation index (AIx@75) measured by applanation tonometry (SphygmoCor). LV function was evaluated using tissue Doppler-derived myocardial performance index (MPI) from lateral mitral annulus. CF-PWV (28.3?±?10.3 vs. 21.8?±?9.3 m/s, p?=?0.03), AIx@75 (10.2?±?2.3 vs. 9.2?±?1, %, p?=?0.01) and MPI (0.46?±?0.12 vs. 0.36?±?0.1, p?<?0.001) were significantly higher in patients with RA than in controls. LV MPI was found to be significantly positive correlated with CF-PWV, AIx@75, and ESR (r?=?0.360, p?=?0.005; r?=?0.334, p?=?0.009; r?=?0.293, p?=?0.023, respectively). Arterial stiffness parameters including CF-PWV and AIx@75 are associated with subclinical left ventricular dysfunction in patients with RA.     

Use of the PET ligand florbetapir for in vivo imaging of pancreatic islet amyloid deposits in h<Emphasis Type="Italic">IAPP</Emphasis> transgenic mice

Aims/hypothesis

Islet amyloid deposits contribute to beta cell dysfunction and death in most individuals with type 2 diabetes but non-invasive methods to determine the presence of these pathological protein aggregates are currently not available. Therefore, we examined whether florbetapir, a radiopharmaceutical agent used for detection of amyloid-β deposits in the brain, also allows identification of islet amyloid in the pancreas.

Methods

Saturation binding assays were used to determine the affinity of florbetapir for human islet amyloid polypeptide (hIAPP) aggregates in vitro. Islet amyloid-prone transgenic mice that express hIAPP in their beta cells and amyloid-free non-transgenic control mice were used to examine the ability of florbetapir to detect islet amyloid deposits in vitro, in vivo and ex vivo. Mice or mouse pancreases were subjected to autoradiographic, histochemical and/or positron emission tomography (PET) analyses to assess the utility of florbetapir in identifying islet amyloid.

Results

In vitro, florbetapir bound synthetic hIAPP fibrils with a dissociation constant of 7.9 nmol/l. Additionally, florbetapir bound preferentially to amyloid-containing hIAPP transgenic vs amyloid-free non-transgenic mouse pancreas sections in vitro, as determined by autoradiography (16,475?±?5581 vs 5762?±?575 density/unit area, p?<?0.05). In hIAPP transgenic and non-transgenic mice fed a high-fat diet for 1 year, intravenous administration of florbetapir followed by PET scanning showed that the florbetapir signal was significantly higher in amyloid-laden hIAPP transgenic vs amyloid-free non-transgenic pancreases in vivo during the first 5 min of the scan (36.83?±?2.22 vs 29.34?±?2.03 standardised uptake value × min, p?<?0.05). Following PET, pancreases were excised and florbetapir uptake was determined ex vivo by γ counting. Pancreatic uptake of florbetapir was significantly correlated with the degree of islet amyloid deposition, the latter assessed by histochemistry (r?=?0.74, p?<?0.001).

Conclusions/interpretation

Florbetapir binds to islet amyloid deposits in a specific and quantitative manner. In the future, florbetapir may be useful as a non-invasive tool to identify islet amyloid deposits in humans.

     

Electrophysiologic features of protected channels in late postinfarction patients with and without spontaneous ventricular tachycardia

Purpose

Protected channels of surviving myocytes in late postinfarction ventricular scar predispose to ventricular tachycardia (VT). However, only a few patients develop VT spontaneously. We studied differences in electric remodeling and protected channels in late postinfarction patients with and without spontaneous VT.

Methods

Patients with ischemic cardiomyopathy (ICM) with recurrent sustained monomorphic VT (n?=?22) were compared with stable ICM patients without spontaneous VT (control group; n?=?5). Left ventricular mapping was performed with a 20-pole catheter. Detailed pace mapping was used to identify channels of protected conduction, and confirmed, when feasible, by entrainment. Anatomical and electrophysiological properties of VT channels and non-VT channels in VT patients and channels in controls were evaluated.

Results

Seventy-three (median 3) VTs were inducible in VT patients compared to two (median 0) in controls. The VT channels in VT patients (n?=?57, 3?±?1 per patient) were lengthier (mean?±?SEM 53?±?5 vs. 33?±?4 vs. 24?±?8 mm), had longer S-QRS (73?±?4 vs. 63?±?3 vs. 44?±?8 ms), longer conduction time (103?±?13 vs. 33?±?4 vs. 24?±?8 ms), and slower conduction velocity (CV) (0.85?±?0.21 vs. 1.39?±?0.20 vs. 1.31?±?0.41 m/s) than non-VT channels in VT patients (n?=?183, 8?±?6 per patient) (p?≤?0.01) and channels in controls (n?=?46, 9?±?8 per patient) (p?≤?0.01). Additionally, non-VT channels in VT patients had longer S-QRS (p?=?0.02); however, they were similar in length, conduction time, and CV compared to channels in controls.

Conclusions

Channels supporting VT are lengthier, with longer conduction times and slower CV compared to channels in patients without spontaneous VT. These observations may explain why some ICM patients have spontaneous VT and others do not.

     

Serum uric acid levels are associated with lupus nephritis in patients with normal renal function

Uric acid has been recognised as a potential marker of endothelial dysfunction and kidney disease but there are scarce data about its importance in systemic lupus erythematosus (SLE) nephritis. This study aimed to evaluate serum uric acid (UA) levels in lupus nephritis (LN), by comparing SLE patients with normal renal function, with and without nephritis. Forty-six female SLE patients were consecutively selected and divided in two groups according to renal activity at the evaluation: presence of a recently diagnosed lupus nephritis (LN+, n?=?18) and absence of lupus nephritis (LN?, n?=?28). Age-matched healthy women were selected (CONTROL, n?=?28). Patients with gout, creatinine clearance lower than 80 ml/min and use of drugs that interfere in UA were excluded. Laboratory and clinical data were analysed by appropriate tests. A multivariate analysis was performed, and a receiver operating characteristic (ROC) curve was plotted, and the area under the curve was calculated to assess the diagnostic strength of UA in LN. The mean age was similar among LN+, LN? and CONTROL groups (32.44?±?6.09 vs. 30.68?±?5.36 vs. 30.86?±?5.00 years, p?=?0.52). UA was significantly higher in LN+ compared to LN? (5.54?±?1.67 vs. 3.65?±?1.090 mg/dL, p?<?0.001) and CONTROL (5.54?±?1.67 vs. 3.92?±?0.95 mg/dL p?<?0.001). Multivariate analysis confirmed that high UA was an independent variable related to LN (p?<?0.001). The cut-off value for UA using the ROC curve was 4.47 mg/dL (AUC 0.86, p?=?0.00004, CI 95% 0.75–0.96). Lupus nephritis was associated with higher UA. Hyperuricemia as a predictor of renal damage in SLE needs to be evaluated in further studies.     

Value of whole-body contrast-enhanced magnetic resonance angiography with vessel wall imaging in quantitative assessment of disease activity and follow-up examination in Takayasu’s arteritis

The aim of this study is to determine the value of whole-body contrast-enhanced magnetic resonance angiography(CE-MRI) with vessel wall imaging in quantitative assessments of Takayasu’s arteritis (TA) disease activity and follow-up examinations. Whole-body CE-MRI with vessel wall imaging (dark blood sequences) was performed in 52 TA patients and repeated in 15 patients after 6 months. Images were analyzed using quantitative scores. The distribution of Lupi-Herrera types (type III, 48.1 %; I, 40.4 %; II, 9.6 %; IV, 1.9 %) did not differ between active and inactive TA. Active vessel inflammation was found in seven patients diagnosed with inactive disease as Kerr scores and mainly involved the aortic arch, abdominal aorta, and ascending aorta. Quantitative MR scores were significantly higher in active TA (luminal stenosis 16.7?±?5.3 vs. 4.2?±?3.7, p?<?0.01; wall thickening 7.2?±?3.4 vs. 2.9?±?2.3, p?=?0.02; wall enhancement 8.7?±?4.1 vs. 3.6?±?2.4, p?=?0.04) and positively correlated with Kerr scores, ITAS 2010, erythrocyte-sedimentation rate (ESR), and C-reactive protein (CRP) and pentraxin-3 (PTX-3) levels. At 6 months, the clinical symptoms, CRP level, and ESR improved significantly (p?<?0.05) and wall enhancement decreased (6.7?±?3.1 vs. 4.1?±?2.1; p?=?0.04), but the luminal stenosis (10.2?±?4.3 vs. 8.8?±?5.2; p?=?0.12) and wall thickening (6.3?±?3.8 vs. 5.8?±?4.2; p?=?0.27) remained unchanged. Whole-body CE-MRI with vessel wall imaging detected luminal changes and vessel wall inflammation in TA. Our MR scoring system enabled quantitative assessment of TA activity.     

Early deficits in insulin secretion,beta cell mass and islet blood perfusion precede onset of autoimmune type 1 diabetes in BioBreeding rats

Aims/hypothesis

Genetic studies show coupling of genes affecting beta cell function to type 1 diabetes, but hitherto no studies on whether beta cell dysfunction could precede insulitis and clinical onset of type 1 diabetes are available.

Methods

We used 40-day-old BioBreeding (BB) DRLyp/Lyp rats (a model of spontaneous autoimmune type 1 diabetes) and diabetes-resistant DRLyp/+ and DR+/+ littermates (controls) to investigate beta cell function in vivo, and insulin and glucagon secretion in vitro. Beta cell mass was assessed by optical projection tomography (OPT) and morphometry. Additionally, measurements of intra-islet blood flow were performed using microsphere injections. We also assessed immune cell infiltration, cytokine expression in islets (by immunohistochemistry and qPCR), as well as islet Glut2 expression and ATP/ADP ratio to determine effects on glucose uptake and metabolism in beta cells.

Results

DRLyp/Lyp rats were normoglycaemic and without traces of immune cell infiltrates. However, IVGTTs revealed a significant decrease in the acute insulin response to glucose compared with control rats (1685.3?±?121.3 vs 633.3?±?148.7; p?<?0.0001). In agreement, insulin secretion was severely perturbed in isolated islets, and both first- and second-phase insulin release were lowered compared with control rats, while glucagon secretion was similar in both groups. Interestingly, after 5–7 days of culture of islets from DRLyp/Lyp rats in normal media, glucose-stimulated insulin secretion (GSIS) was improved; although, a significant decrease in GSIS was still evident compared with islets from control rats at this time (7393.9?±?1593.7 vs 4416.8?±?1230.5 pg islet^?1 h^?1; p?<?0.0001). Compared with controls, OPT of whole pancreas from DRLyp/Lyp rats revealed significant reductions in medium (4.1?×?10⁹?±?9.5?×?10⁷ vs 3.8?×?10⁹?±?5.8?×?10⁷ μm³; p?=?0.044) and small sized islets (1.6?×?10⁹?±?5.1?×?10⁷ vs 1.4?×?10⁹?±?4.5?×?10⁷ μm³; p?=?0.035). Finally, we found lower intra-islet blood perfusion in vivo (113.1?±?16.8 vs 76.9?±?11.8 μl min^?1 [g pancreas]^?1; p?=?0.023) and alterations in the beta cell ATP/ADP ratio in DRLyp/Lyp rats vs control rats.

Conclusions/interpretation

The present study identifies a deterioration of beta cell function and mass, and intra-islet blood flow that precedes insulitis and diabetes development in animals prone to autoimmune type 1 diabetes. These underlying changes in islet function may be previously unrecognised factors of importance in type 1 diabetes development.

     

Atrial mapping during pulmonary vein pacing to detect conduction gaps in a second pulmonary vein isolation procedure

Background

Finding the conduction gaps in redo PV isolation procedures is challenging, and several maneuvers have been described. In the present study, we analyze the pace and map (P&M) maneuver [atrial mapping during pulmonary vein (PV) pacing] to locate the gaps in redo PV isolation procedures.

Methods

Consecutive patients undergoing a second PV isolation procedure at a single institution over a 4-year period were included. For the last 2 years, all the patients (n?=?38) studied underwent PV isolation based on the P&M maneuver and were compared to the previous patients (n?=?45). The atrial side of the ablation line was mapped with the ablation catheter during PV pacing, and the earliest site was considered a gap site.

Results

Shorter radiofrequency time was required to obtain PV isolation in the P&M group (485?±?374 vs. 864?±?544 s; p?<?0.001), which remained significant after adjusting for the number of reconnected PVs (p?=?0.01). We did not find significant differences in the procedure duration (106?±?46 vs. 112?±?53 min; p?=?0.57) and arrhythmia recurrence during 1-year follow-up (26.6 vs. 28.9%; p?=?0.82) after adjusting for several confounding factors (HR 1.32; 95% CI 0.5–3.4; p?=?0.57).

Conclusions

P&M is a simple maneuver to identify the gaps in ablation lines around the PV. It remains efficacious in redo procedures despite the difficulties in localizing the ablation lines performed in the first procedure. The P&M maneuver reduced the radiofrequency time required to isolate the PV without compromising the efficacy.

     

Impaired arterial responsiveness in untreated gout patients compared with healthy non-gout controls: association with serum urate and C-reactive protein

To determine whether arterial responsiveness is impaired among patients with gout, and whether arterial responsiveness inversely correlates with serum urate and inflammatory measures. This is a cross-sectional study of untreated gout subjects (n?=?34) and non-gout healthy controls (n?=?64). High-resolution dynamic ultrasound-measured flow-mediated dilation (FMD) and nitroglycerin-mediated dilation (NMD) assessed endothelium-dependent and endothelium-independent arterial responsiveness respectively. Serum urate (sUA) and high-sensitivity C-reactive protein (hsCRP) were measured in the gout group, and correlated with FMD and NMD responses. Both FMD (2.20?±?0.53 vs 3.56?±?0.31, p?=?0.021) and NMD (16.69?±?1.54 vs 24.51?±?0.90, p?=?0.00002) were impaired in the gout versus control group. Stratification for individual comorbidities suggested that no single risk factor accounted for impaired FMD/NMD in the gout subjects. However, the degree of association between gout and FMD, but not NMD impairment, was dampened after multivariable adjustment (FMD unadjusted beta?=???1.36 (SE 0.58), p?=?0.02; adjusted beta?=???1.16 (SE 0.78), p?=?0.14 and NMD unadjusted beta?=???7.68 (SE 1.78), p?<?0.0001; adjusted beta?=???5.33 (SE 2.46), p?=?0.03). Within the gout group, there was an inverse correlation between FMD and sUA (R?=???0.5, p?=?0.003), and between FMD and hsCRP (R?=???0.42, p?=?0.017), but not between NMD and sUA or hsCRP. Compared with healthy controls, subjects with gout have reduced arterial function. Individual comorbidities are insufficient to account for differences between gout and control groups, but multiple comorbidities may collectively contribute to impairment in endothelium-dependent arterial responsiveness. Endothelial impairment is also related to sUA and hsCRP, markers of gout severity and inflammation respectively. Studies to determine whether gout therapy may improve arterial responsiveness are warranted.     

ADAM-17 is expressed in the inflammatory myopathy and is involved with interstitial lung disease

The “A disintegrin and metalloprotease” (ADAM) family is thought to play an important role in tissue destruction and inflammatory reactions. ADAM-17 was first described as the protease responsible for tumor necrosis factor (TNF)-α shedding. Here, we have shown the expression of ADAM-17 in inflammatory myopathy and demonstrated the role of inflammation in interstitial lung diseases (ILD). ADAM-17 in inflammatory myopathy serum [polymyositis (n?=?26), dermatomyositis (n?=?34), and clinically amyopathic dermatomyositis (n?=?10)] and healthy control (n?=?19) was measured using enzyme-linked immunosorbent assay. The relationship between ADAM-17 and clinical data was examined. Finally, we performed immunohistological analysis to investigate the expression of ADAM-17 on the muscles of the inflammatory myopathy patients. ADAM-17 in inflammatory myopathy was significantly higher than that in healthy control (mean ± SEM, 1048?±?312 and 36?±?18 pg/ml, respectively; p?<?0.05). ADAM-17 in post-treatment with corticosteroid and/or immunosuppressant serum was significantly decreased compared with that in pre-treatment serum (1465?±?562 and 1059?±?503 pg/ml, respectively; p?<?0.01). ADAM-17 was significantly positively correlated with fractalkine/CX3CL1 and CXCL16. In addition, ADAM-17 in inflammatory myopathy with ILD patients (n?=?46) was significantly higher than that in non-ILD patients (n?=?24) (1379?±?454 and 413?±?226 pg/ml, respectively; p?<?0.05). We found the expression of ADAM-17 on muscle biopsy tissue. ADAM-17 is expressed in inflammatory myopathies especially ILD, suggesting that ADAM-17 plays a role in lung fibrosis. ADAM-17 may be a potential target in inflammatory myopathies with ILD.     

Validation of [<Superscript>18</Superscript>F]fluorodeoxyglucose and positron emission tomography (PET) for the measurement of intestinal metabolism in pigs,and evidence of intestinal insulin resistance in patients with morbid obesity

Aims/hypothesis

The role of the intestine in the pathogenesis of metabolic diseases is gaining much attention. We therefore sought to validate, using an animal model, the use of positron emission tomography (PET) in the estimation of intestinal glucose uptake (GU), and thereafter to test whether intestinal insulin-stimulated GU is altered in morbidly obese compared with healthy human participants.

Methods

In the validation study, pigs were imaged using [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG) and the image-derived data were compared with corresponding ex vivo measurements in tissue samples and with arterial–venous differences in glucose and [¹⁸F]FDG levels. In the clinical study, GU was measured in different regions of the intestine in lean (n?=?8) and morbidly obese (n?=?8) humans at baseline and during euglycaemic hyperinsulinaemia.

Results

PET- and ex vivo-derived intestinal values were strongly correlated and most of the fluorine-18-derived radioactivity was accumulated in the mucosal layer of the gut wall. In the gut wall of pigs, insulin promoted GU as determined by PET, the arterial–venous balance or autoradiography. In lean human participants, insulin increased GU from the circulation in the duodenum (from 1.3?±?0.6 to 3.1?±?1.1 μmol [100 g]^?1?min^?1, p?<?0.05) and in the jejunum (from 1.1?±?0.7 to 3.0?±?1.5 μmol [100 g]^?1?min^?1, p?<?0.05). Obese participants failed to show any increase in insulin-stimulated GU compared with fasting values (NS).

Conclusions/interpretation

Intestinal GU can be quantified in vivo by [¹⁸F]FDG PET. Intestinal insulin resistance occurs in obesity before the deterioration of systemic glucose tolerance.

     

The influence of tumour site on prognosis in metastatic colorectal carcinomas with primary tumour resection

Purpose

The aim of our study was to compare the characteristics and prognosis between right- and left-sided metastatic colorectal carcinomas.

Methods

Data from 937 patients with stage IV colorectal carcinomas (synchronous distant metastasis) who had a resection of the primary tumour between 1985 and 2014 were analysed. Carcinomas in the caecum to transverse colon were defined as right-sided (n?=?250; 26.7%). They were compared to tumours located from the splenic flexure to the rectum categorised as left-sided (n?=?687; 73.3%).

Results

In right-sided carcinomas, we observed significantly more female patients (50.8 vs 36.2%; p?<?0.001), more unfavourable histological types (24.0 vs 8.6%; p?<?0.001), more M1c carcinomas (metastases to the peritoneum?±?others; 32.0 vs 14.4%; p?<?0.001) and more emergencies (11.6 vs 7.1%; p?=?0.029), while multimodal treatment was utilised in fewer patients (51.6 vs 63.8%; p?=?0.001) and curative resections were less frequently (24.1 vs 35.4%; p?=?0.002). Prognosis was significantly worse in patients with right-sided carcinomas (2-year-survival 27.2 vs 44.6%, p?<?0.01). This difference was more pronounced after R2 resection (15.3 vs 29.7%; p?<?0.001), than after macroscopic curative resection (2-year-survival 63.9 vs 71.9%; p?=?0.106). In multivariate Cox regression analysis, tumour site was found to be an independent prognostic factor for overall survival (HR 1.2; 95% CI 1.0–1.5; p?=?0.012). During the three 10-year periods, the prognosis improved equally in patients with right- and left-sided carcinomas, while the differences in survival remained identical.

Conclusions

In a surgical patient cohort undergoing primary tumour resection, significant differences in prognosis were observed between patients with metastatic right- and left-sided colorectal carcinomas.

     

Type 1 diabetic patients with peripheral neuropathy have pan-enteric prolongation of gastrointestinal transit times and an altered caecal pH profile

Aims/hypothesis

We hypothesised that type 1 diabetic patients with established diabetic sensorimotor polyneuropathy (DSPN) would have segmental and/or pan-enteric dysmotility in comparison to healthy age-matched controls. We aimed to investigate the co-relationships between gastrointestinal function, degree of DSPN and clinical symptoms.

Methods

An observational comparison was made between 48 patients with DSPN (39 men, mean age 50 years, range 29–71 years), representing the baseline data of an ongoing clinical trial (representing a secondary analysis of baseline data collected from an ongoing double-blind randomised controlled trial investigating the neuroprotective effects of liraglutide) and 41 healthy participants (16 men, mean age 49 years, range 30–78) who underwent a standardised wireless motility capsule test to assess gastrointestinal transit. In patients, vibration thresholds, the Michigan Neuropathy Screening Instrument and Patient Assessment of Upper Gastrointestinal Symptom questionnaires were recorded.

Results

Compared with healthy controls, patients showed prolonged gastric emptying (299?±?289 vs 179?±?49 min; p?=?0.01), small bowel transit (289?±?107 vs 224?±?63 min; p?=?0.001), colonic transit (2140, interquartile range [IQR] 1149–2799 min vs 1087, IQR 882–1650 min; p?=?0.0001) and whole-gut transit time (2721, IQR 1196–3541 min vs 1475 (IQR 1278–2214) min; p?<?0.0001). Patients also showed an increased fall in pH across the ileocaecal junction (?1.8?±?0.4 vs ?1.3?±?0.4 pH; p?<?0.0001), which was associated with prolonged colonic transit (r?=?0.3, p?=?0.001). Multivariable regression, controlling for sex, disease duration and glycaemic control, demonstrated an association between whole-gut transit time and total GCSI (p?=?0.02).

Conclusions/interpretation

Pan-enteric prolongation of gastrointestinal transit times and a more acidic caecal pH, which may represent heightened caecal fermentation, are present in patients with type 1 diabetes. The potential implication of delayed gastrointestinal transit on the bioavailability of nutrition and on pharmacotherapeutic and glycaemic control warrants further investigation.

Trial registration

EUDRA CT: 2013-004375-12

     

Hemodynamic impact of percutaneous left atrial appendage closure in patients with paroxysmal atrial fibrillation

Purpose

Percutaneous left atrial appendage (LAA) closure has become a valid alternative to anticoagulation therapy for the prevention of thromboembolic events in patients with atrial fibrillation (AF). However, scarce data exist on the impact of LAA closure on left atrial and ventricular function. We sought to assess the acute hemodynamic changes associated with percutaneous LAA closure in patients with paroxysmal AF.

Methods

The study population consisted of 31 patients (mean age 73?±?10 years; 49% women) with paroxysmal AF who underwent successful percutaneous LAA closure. All patients were in sinus rhythm and underwent 2D transthoracic echocardiography at baseline and the day after the procedure. A subset of 14 patients underwent preprocedural cardiac computed tomography (CT) with 3D LA and LAA reconstruction.

Results

Left ventricular systolic function parameters and LA volumetric indexes remained unchanged after the procedure. No significant changes in left ventricular stroke volume (72.4?±?16.0 vs. 73.3?±?15.7 mL, p?=?0.55) or LA stroke volume (total 15.6?±?4.2 vs. 14.6?±?4.2 mL, p?=?0.21; passive 9.0?±?2.8 vs. 8.3?±?2.6 mL, p?=?0.31; active 10.3?±?5.6 vs. 10.0?±?6.4 mL, p?=?0.72) occurred following LAA closure. Mean ratio of LAA to LA volume by 3D CT was 10.2?±?2.3%. No correlation was found between LAA/LA ratio and changes in LA stroke volume (r?=?0.35, p?=?0.22) or left ventricular stroke volume (r?=?0.28, p?=?0.33).

Conclusions

The LAA accounts for about 10% of the total LA volume, but percutaneous LAA closure did not translate into any significant changes in LA and left ventricular function.

     

Long-term quality of life after conservative treatment versus surgery for different stages of acute sigmoid diverticulitis

Purpose

It is controversial whether patients fare better with conservative or surgical treatment in certain stages of acute diverticulitis (AD), in particular when phlegmonous inflammation or covered micro- or macro-perforation are present. The aim of this study was to determine long-term quality of life (QoL) for AD patients who received either surgery or conservative treatment in different stages.

Methods

We included patients treated for AD at the University Hospital Grosshadern, Munich, Germany, between January 1, 2000, and December 31, 2010. Patients were classified by the Hansen and Stock (HS) classification, the modified Hinchey classification, and the German classification of diverticular disease (CDD). Pre-therapeutic staging was based on multidetector computed tomography. Long-term QoL was assessed by the Cleveland Global Quality of Life (CGQL) questionnaire, the Short Form 36 (SF-36), and the Gastrointestinal Quality of Life Index (GIQLI). Data are mean?±?SEM.

Results

Patients with phlegmonous AD (HS type 2a, Hinchey Ia and CDD 1b, respectively) had a better long-term QoL on the GIQLI when they were operated (78.5?±?2.5 vs. 70.7?±?2.1; p?<?0.05). Patients with micro-abscess (CDD 2a) had a better long-term QoL on the GIQLI, CGQL, and the “Role Physical” scale of the SF-36 when they were not operated (GIQLI 86.9?±?2.1 vs. 76.8?±?1.0; p?=?0.10; CGQL 82.8?±?5.1 vs. 65.3?±?11.0; p?=?0.08; SF-36/Role Physical 100?±?0.0 vs. 41.7?±?13.9; p?<?0.001). Patients with macro-abscess (CDD 2b) had a better long-term QoL when they were operated (GIQLI 89.3?±?1.4 vs. 69.5?±?4.5; p?<?0.01; CGQL 80.3?±?7.6 vs. 60.5?±?5.8; p?<?0.05; SF-36/Role Physical 95.8?±?4.2 vs. 47.9?±?13.6; p?<?0.001).

Conclusion

Considering long-term QoL, phlegmonous AD (HS type 2a, Hinchey Ia and CDD 1b, respectively) should be treated conservatively. In patients with covered perforation, abscess size should guide the decision on whether to perform surgery later on or not. In the light of long-term quality of life, patients fare better after elective sigmoid colectomy when abscess size exceeds 1 cm.

     

Recent-onset dilated cardiomyopathy associated with <Emphasis Type="Italic">Borrelia burgdorferi</Emphasis> infection

Background

Several recent small studies have suggested a causal link between Lyme disease and dilated cardiomyopathy (DCM) by demonstrating the presence of the Borrelia burgdorferi (Bb) genome in the myocardium of patients with recent-onset DCM. The aim of this study was to further investigate the effect of targeted antibiotic treatment of Bb-related recent-onset DCM in a larger cohort of patients.

Patients and methods

We performed endomyocardial biopsy (EMB) in 110 individuals (53?±?11 years, 34 women) with recent-onset unexplained DCM, and detected the Bb genome in 22 (20?%) subjects. Bb-positive patients were subsequently treated with intravenous ceftriaxone for 21 days in addition to conventional heart failure medication.

Results

At the 1-year follow-up, a significant improvement in left ventricular (LV) ejection fraction (26?±?6? vs. 44?±?12?%; p?<?0.01) and a decrease in LV end-diastolic (69?±?7 vs. 63?±?11 mm; p?<?0.01) and end-systolic (61?±?9 vs. 52?±?4 mm; p?<?0.01) diameters were documented. Moreover, a significant improvement in heart failure symptoms (NYHA class 3.4?±?0.6 vs. 1.5?±?0.7; p?<?0.01) was also observed.

Conclusion

Targeted antibiotic treatment of Bb-related recent-onset DCM in addition to conventional heart failure therapy is associated with favorable cardiac remodeling and improvement of heart failure symptoms.

     

Amiodarone plus Ranolazine for Conversion of Post-Cardiac Surgery Atrial Fibrillation: Enhanced Effectiveness in Reduced Versus Preserved Ejection Fraction Patients

Purpose

Ranolazine (RAN) added to amiodarone (AMIO) has been shown to accelerate termination of postoperative atrial fibrillation (POAF) following coronary artery bypass surgery in patients without heart failure (HF). This study aimed to investigate if treatment efficacy with AMIO or AMIO + RAN differs between patients with concomitant HF with reduced or preserved ejection fraction (HFrEF or HFpEF).

Methods

Patients with POAF and HFrEF (n?=?511, 446 males; 65?±?9 years) and with HFpEF (n?=?301, 257 males; 66?±?10 years) were enrolled. Onset of AF occurred 2.15?±?1.0 days after cardiac surgery, and patients within each group were randomly assigned to receive either AMIO monotherapy (300 mg in 30 min?+?1125 mg in 36 h iv) or AMIO+RAN combination (500 mg po?+?375 mg, after 6 h and 375 mg twice daily thereafter). Primary endpoint was the time to conversion of POAF within 36 h after initiation of treatment.

Results

AMIO restored sinus rhythm earlier in HFrEF vs. in HFpEF patients (24.3?±?4.6 vs. 26.8?±?2.8 h, p?<?0.0001). AMIO + RAN converted POAF faster than AMIO alone in both HFrEF and HFpEF groups, with conversion times 10.4?±?4.5 h in HFrEF and 12.2?±?1.1 h in HFpEF patients (p?<?0.0001). Left atrial diameter was significantly greater in HFrEF vs. HFpEF patients (48.2?±?2.6 vs. 35.2?±?2.9 mm, p?<?0.0001). No serious adverse drug effects were observed during AF or after restoration to sinus rhythm in any of the patients enrolled.

Conclusion

AMIO alone or in combination with RAN converted POAF faster in patients with reduced EF than in those with preserved EF. Thus, AMIO + RAN seems to be a valuable alternative treatment for terminating POAF in HFrEF patients.