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The complement system plays an important role in the inflammatory response subsequent to acute myocardial infarction (AMI). The aim of this study is to create a systematic overview of studies that have investigated therapeutic administration of complement inhibitors in both AMI animal models and human clinical trials. To enable extrapolation of observations from included animal studies toward post-AMI clinical trials, ex vivo studies on isolated hearts and proof-of-principle studies on inhibitor administration before experimental AMI induction were excluded. Positive therapeutic effects in AMI animal models have been described for cobra venom factor, soluble complement receptor 1, C1-esterase inhibitor (C1-inh), FUT-175, C1s-inhibitor, anti-C5, ADC-1004, clusterin, and glycosaminoglycans. Two types of complement inhibitors have been tested in clinical trials, being C1-inh and anti-C5. Pexelizumab (anti-C5) did not result in reproducible beneficial effects for AMI patients. Beneficial effects were reported in AMI patients for C1-inhibitor, albeit in small patient groups. In general, despite the absence of consistent positive effects in clinical trials thus far, the complement system remains a potentially interesting target for therapy in AMI patients. Based on the study designs of previous animal studies and clinical trials, we discuss several issues which require attention in the design of future studies: adjustment of clinical trial design to precise mechanism of action of administered inhibitor, optimizing the duration of therapy, and optimization of time point(s) on which therapeutic effects will be evaluated.

Introduction: Congenital atrioventricular block (CAVB) is a rare disorder with a significant morbidity and mortality. Consensus regarding the prescription and efficacy of prenatal corticosteroids is lacking. This nationwide study was initiated to evaluate the effects of prenatal treatment with corticosteroids on the outcome of CAVB in The Netherlands.Methods: All fetuses identified with isolated congenital AVB-II degrees or AVB-III degrees in any of the eight academic fetal heart centers of The Netherlands between 2003 and 2013 were included and reviewed.Results: Fifty-six fetuses were included. Fourteen (25%) fetuses were treated with dexamethasone. We found no differences between the steroid-treated and untreated cases regarding in utero progression of the AVB (63% vs 67% respectively), survival to birth (86% vs 84%), pacemaker implantations (74% vs 58%) or long-term dilated cardiomyopathy (13% vs 17%). Steroid treated fetuses demonstrated more in utero growth restriction (38% vs 11%).Conclusion: No benefit from prenatal corticosteroid treatment was demonstrated for fetuses with isolated CAVB in this study. However, we found negative side effects. Our data provide no evidence to support the routine administration of corticosteroids for the treatment of fetal CAVB. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

Purpose To investigate whether multivariate pattern recognition analysis of arterial spin labeling (ASL) perfusion maps can be used for classification and single-subject prediction of patients with Alzheimer disease (AD) and mild cognitive impairment (MCI) and subjects with subjective cognitive decline (SCD) after using the W score method to remove confounding effects of sex and age. Materials and Methods Pseudocontinuous 3.0-T ASL images were acquired in 100 patients with probable AD; 60 patients with MCI, of whom 12 remained stable, 12 were converted to a diagnosis of AD, and 36 had no follow-up; 100 subjects with SCD; and 26 healthy control subjects. The AD, MCI, and SCD groups were divided into a sex- and age-matched training set (n = 130) and an independent prediction set (n = 130). Standardized perfusion scores adjusted for age and sex (W scores) were computed per voxel for each participant. Training of a support vector machine classifier was performed with diagnostic status and perfusion maps. Discrimination maps were extracted and used for single-subject classification in the prediction set. Prediction performance was assessed with receiver operating characteristic (ROC) analysis to generate an area under the ROC curve (AUC) and sensitivity and specificity distribution. Results Single-subject diagnosis in the prediction set by using the discrimination maps yielded excellent performance for AD versus SCD (AUC, 0.96; P < .01), good performance for AD versus MCI (AUC, 0.89; P < .01), and poor performance for MCI versus SCD (AUC, 0.63; P = .06). Application of the AD versus SCD discrimination map for prediction of MCI subgroups resulted in good performance for patients with MCI diagnosis converted to AD versus subjects with SCD (AUC, 0.84; P < .01) and fair performance for patients with MCI diagnosis converted to AD versus those with stable MCI (AUC, 0.71; P > .05). Conclusion With automated methods, age- and sex-adjusted ASL perfusion maps can be used to classify and predict diagnosis of AD, conversion of MCI to AD, stable MCI, and SCD with good to excellent accuracy and AUC values. (©) RSNA, 2016.

Coronary intervention for myocardial infarction often results in microvascular embolization of thrombus. Sonoreperfusion therapy (SRP) using ultrasound and microbubbles restored perfusion in our in vitro flow model of microvascular obstruction. In this study, we assessed SRP efficacy using whole blood as the perfusate with and without tissue plasminogen activator (tPA). In a phantom vessel bearing a 40-μm pore mesh to simulate the microvasculature, microthrombi were injected to cause microvascular obstruction and were treated using SRP. Without tPA, the lytic rate increased from 2.6±1.5 mmHg/min with 1000 cycles to 7.3±3.2 mmHg/min with 5000 cycles ultrasound pulses (p

Netherlands heart journal 24(12), 722-729 (2016). doi:10.1007/s12471-016-0884-9, Published by PubMed Central, [S.l.]

IntroductionTyrosine kinase inhibitors (TKIs) are very attractive targeted drugs, although a large portion of patients remains unresponsive. PET imaging with EGFR targeting TKIs ([11C]erlotinib and [18F]afatinib) showed promise in identifying treatment sensitive tumors. The aim of this study was to synthesize two anti-angiogenic TKI tracers, [11C]axitinib and [11C]nintedanib, and to evaluate their potential for PET.MethodsFollowing successful tracer synthesis, biodistribution studies in VU-SCC-OE and FaDu xenograft bearing mice were performed. Furthermore, tracer stability studies in mice were performed employing (radio-)HPLC and LC–MS/MS techniques. For [11C]nintedanib an LC–MS/MS method was developed to detect the primary carboxylic acid metabolite, resulting from methylester cleavage, in plasma and tumors, because this metabolite is postulated to be important for nintedanib efficacy. LC–MS/MS was also explored to assess the metabolic fate of [11C]axitinib in vivo, since axitinib has an isomerizable double bond.Results[11C]axitinib and [11C]nintedanib were successfully synthesized with 10.5 ± 2.6% and 25.6 ± 3.3% radiochemical yield (corrected for decay), respectively. Biodistribution studies only demonstrated tumor uptake of [11C]nintedanib in FaDu xenografts of 1.66 ± 0.02% ID/g at 60 min p.i. In vivo stability analysis of [11C]axitinib at 45 min p.i. revealed the formation of predominantly non-polar metabolites (36.6 ± 6.8% vs 47.1 ± 8.4% of parent tracer and 16.3 ± 2.1% of polar metabolites), while for [11C]nintedanib mostly polar metabolites were found (70.9 ± 4.1 vs 26.7 ± 3.9% of parent tracer and only 2.4 ± 1.6 of a non-polar metabolites). No isomerization of [11C]axtinib was observed in vivo; however, a sulfoxide metabolite could be detected using LC–MS/MS. For [11C]nintedanib, LC–MS/MS revealed formation of the reported primary carboxylic acid metabolite when in vitro plasma incubations were performed, with large differences in plasmas from different species. In vivo metabolite analysis, however, did not demonstrate the presence of the carboxylic acid in plasma or tumor tissue.ConclusionsReliable syntheses of [11C]axitinib and [11C]nintedanib were successfully developed. Tumor uptake was observed for [11C]nintedanib, albeit modest. The metabolic profiles of the tracers suggest that rapid metabolism is partly responsible for the modest tumor targeting observed.

Pathogenic gene mutations are found in about 50% of patients with hypertrophic cardiomyopathy (HC). Previous studies have shown an association between sarcomere mutations and medium-term outcome. The association with long-term outcome has not been described. The aim of this cohort study was to assess the long-term outcomes of patients with genotype positive (G+) and genotype negative (G-) HC. The study population consisted of 626 patients with HC (512 probands and 114 relatives) who underwent phenotyping and genetic testing from 1985 to 2014. End points were all-cause mortality, cardiovascular (CV) mortality, heart failure (HF)-related mortality, and sudden cardiac death/aborted sudden cardiac death (SCD/aborted SCD). Kaplan-Meier and multivariate Cox regression analyses were performed. A pathogenic mutation was detected in 327 patients (52%). G+ probands were younger than G- probands (46 ± 15 vs 55 ± 15 years, p0.001), had more non sustained ventricular tachycardia (34% vs 13%; p0.001), more often a history of syncope (14% vs 7%; p = 0.016), and more extreme hypertrophy (maximal wall thickness ≥30 mm, 7% vs 1%; p0.001). G- probands were more symptomatic (New York Heart Association ≥II, 73% vs 53%, p0.001) and had higher left ventricular outflow tract gradients (42 ± 39 vs 29 ± 33 mm Hg, p = 0.001). During 12 ± 9 years of follow-up, G+ status was an independent risk factor for all-cause mortality (hazard ratio [HR] 1.90, 95% CI 1.14 to 3.15; p = 0.014), CV mortality (HR 2.82, 95% CI 1.49 to 5.36; p = 0.002), HF-related mortality (HR 6.33, 95% CI 1.79 to 22.41; p = 0.004), and SCD/aborted SCD (HR 2.88, 95% CI 1.23 to 6.71; p = 0.015). In conclusion, during long-term follow-up, patients with G+ HC are at increased risk of all-cause death, CV death, HF-related death, and SCD/aborted SCD.

11C-meta-hydroxyephedrine (11C-HED) kinetics in the myocardium can be quantified using a single-tissue-compartment model together with a metabolite-corrected arterial blood sampler input function (BSIF). The need for arterial blood sampling, however, limits clinical applicability. The purpose of this study was to investigate the feasibility of replacing arterial sampling with imaging-derived input function (IDIF) and venous blood samples. Methods: Twenty patients underwent 60-min dynamic 11C-HED PET/CT scans with online arterial blood sampling. Thirteen of these patients also underwent venous blood sampling. Data were reconstructed using both 3-dimensional row-action maximum-likelihood algorithm (3DR) and a time-of-flight (TF) list-mode reconstruction algorithm. For each reconstruction, IDIF results were compared with BSIF results. In addition, IDIF results obtained with venous blood samples and with a transformed venous-to-arterial metabolite correction were compared with results obtained with arterial metabolite corrections. Results: Correlations between IDIF- and BSIF-derived K1 and VT were high (r2 > =0.89 for 3DR and TF). Slopes of the linear fits were significantly different from 1 for K1, for both 3DR (slope = 0.94) and TF (slope = 1.06). For VT, the slope of the linear fit was different from 1 for TF (slope = 0.93) but not for 3DR (slope = 0.98). Use of venous blood data introduced a large bias in VT (r2 = 0.96, slope = 0.84) and a small bias in K1 (r2 = 0.99, slope = 0.98). Use of a second-order polynomial venous-to-arterial transformation was robust and greatly reduced bias in VT (r2 = 0.97, slope = 0.99) with no effect on K1. Conclusion: IDIF yielded precise results for both 3DR and TF. Venous blood samples can be used for absolute quantification of 11C-HED studies, provided a venous-to-arterial transformation is applied. A venous-to-arterial transformation enables noninvasive, absolute quantification of 11C-HED studies.

BIBF1000 is a small molecule tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), and platelet-derived growth factor receptor (PDGFR) and is a powerful inhibitor of fibrogenesis. BIBF1000 is very similar to BIBF1120 (nintedanib), a drug recently approved for the treatment of idiopathic pulmonary fibrosis (IPF). A safety concern pertaining to VEGFR, FGFR, and PDGFR inhibition is the possible interference with right ventricular (RV) responses to an increased afterload, which could adversely affect clinical outcome in patients with IPF who developed pulmonary hypertension. We tested the effect of BIBF1000 on the adaptation of the RV in rats subjected to mechanical pressure overload. BIBF1000 was administered for 35 days in pulmonary artery-banded (PAB) rats. RV adaptation was assessed by echocardiography, pressure volume loop analysis, histology, and determination of atrial natriuretic peptide (ANP) expression. BIBF1000 treatment resulted in growth attenuation but had no effects on RV function after PAB, given absence of changes in cardiac index, end-systolic elastance, connective tissue disposition, and capillary density. We conclude that, in this experimental model of increased afterload, combined VEGFR, FGFR, and PDGFR inhibition does not hamper RV adaptation to pressure overload.

Contains fulltext : 171478.pdf (Publisher’s version ) (Open Access) The textural patterns in the lung parenchyma, as visible on computed tomography (CT) scans, are essential to make a correct diagnosis in interstitial lung disease. We developed one automatic and two interactive protocols for classification of normal and seven types of abnormal lung textures. Lungs were segmented and subdivided into volumes of interest (VOIs) with homogeneous texture using a clustering approach. In the automatic protocol, VOIs were classified automatically by an extra-trees classifier that was trained using annotations of VOIs from other CT scans. In the interactive protocols, an observer iteratively trained an extra-trees classifier to distinguish the different textures, by correcting mistakes the classifier makes in a slice-by-slice manner. The difference between the two interactive methods was whether or not training data from previously annotated scans was used in classification of the first slice. The protocols were compared in terms of the percentages of VOIs that observers needed to relabel. Validation experiments were carried out using software that simulated observer behavior. In the automatic classification protocol, observers needed to relabel on average 58\% of the VOIs. During interactive annotation without the use of previous training data, the average percentage of relabeled VOIs decreased from 64\% for the first slice to 13\% for the second half of the scan. Overall, 21\% of the VOIs were relabeled. When previous training data was available, the average overall percentage of VOIs requiring relabeling was 20\%, decreasing from 56\% in the first slice to 13\% in the second half of the scan.

The excimer laser assisted non-occlusive anastomosis (ELANA) technique is used to make anastomoses on intracerebral arteries. This end-to-side anastomosis is created without temporary occlusion of the recipient artery using a 308-nm excimer laser with a ring-shaped multi-fiber catheter to punch an opening in the arterial wall. Over 500 patients have received an ELANA bypass. However, the vessel wall perforation mechanism of the laser catheter is not known exactly and not 100 % successful. In this study, we aimed to understand the mechanism of ELANA vessel perforation using specialized imaging techniques to ultimately improve its effectiveness. High-speed imaging, high-contrast imaging, and high-sensitivity thermal imaging were used to study the laser wall perforation mechanism and reveal the mechanical and thermal effects involved. In vitro, rabbit arteries were exposed with the special designed laser catheter in a setup representative for the clinical setting, in which blood was replaced with a transparent UV absorbing liquid for visualization. We observed that laser vessel wall perforation was caused by explosive vapor bubbles tearing through the vessel wall, mostly within the first 20 of the total 200 pulses. Thermal effects were minimal. Unsymmetrical tension in the vessel wall inducing migration of the flap during laser exposure was observed in case of unsuccessful wall perforations. The laser wall perforation mechanism in the ELANA technique is primarily mechanical. Symmetric tension in the recipient vessel wall is essential and should be trained by neurosurgeons.

Background We compared three-dimensional speckle tracking echocardiography (3DSTE) and its strain to cardiac magnetic resonance (CMR) with delayed contrast enhancement for left ventricular (LV) chamber quantification and transmurality of myocardial scar. Furthermore, we examined the ability of 3DSTE strain to differentiate between ischaemic and non-ischaemic LV dysfunction. Methods In 80 consecutive patients with ischaemic and 40 patients with non-ischaemic LV dysfunction, the correlations between LV volumes and ejection fraction were measured using 3DSTE and CMR. Global and regional 3DSTE strains and total or percentage enhanced LV mass were evaluated. Results LV end-diastolic and end-systolic volumes and ejection fraction correlated well between 3DSTE and CMR (r: 0.83, 0.88 and 0.89, respectively). However, 3DSTE significantly underestimated volumes. Correlation for LV mass was modest (r = 0.59). All 3DSTE regional strain values except for radial strain were lower in segments with versus segments without transmural enhancement. However, strain parameters could not identify the transmurality of scar. No significant difference between ischaemic and non-ischaemic LV dysfunction was observed in either global or regional 3DSTE strain except for twist, which was lower in the non-ischaemic group (4.9 ± 3.3 vs. 6.4 ± 3.2°, p = 0.03). Conclusion 3DSTE LV volumes are underestimated compared with CMR, while LV ejection fraction revealed excellent accuracy. Functional impairment by 3DSTE strain does not correlate well with scar localisation or extent by CMR. 3DSTE strain could not differentiate between ischaemic and non-ischaemic LV dysfunction. Future studies will need to clarify if 3DSTE strain and CMR delayed contrast enhancement can provide incremental value to the prediction of future cardiovascular events.

The N-Methyl-d-Aspartate receptor (NMDAR) is involved in many neurological and psychiatric disorders including Alzheimer's disease and schizophrenia. The aim of this study was to develop a positron emission tomography (PET) ligand to assess the bio-availability of the NMDAR ion channel in vivo. A series of tri-N-substituted diarylguanidines was synthesized and their in vitro binding affinities for the NMDAR ion channel assessed in rat forebrain membrane fractions. Compounds 21, 23 and 26 were radiolabeled with either carbon-11 or fluorine-18 and ex vivo biodistribution and metabolite studies were performed in Wistar rats. Biodistribution studies showed high uptake especially in prefrontal cortex and lowest uptake in cerebellum. Pre-treatment with MK-801, however, did not decrease uptake of the radiolabeled ligands. In addition, all three ligands showed fast metabolism.

AIMS: ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13, is a metalloprotease that cleaves von Willebrand factor (VWF). There is considerable evidence that VWF levels increase and ADAMTS13 levels decrease in ST-elevation myocardial infarction (STEMI) patients. It is unclear whether this contributes to no reflow, infarct size, and intramyocardial haemorrhage (IMH). We aimed to determine the role of ADAMTS13 in STEMI patients and to investigate the benefits of recombinant ADAMTS13 (rADAMTS13) in a porcine model of myocardial ischaemia-reperfusion.METHODS AND RESULTS: In 49 consecutive percutaneous coronary intervention (PCI)-treated STEMI patients, blood samples were collected directly after through 7 days following PCI. Cardiac magnetic resonance was performed 4-6 days after PCI to determine infarct size and IMH. In 23 Yorkshire swine, the circumflex coronary artery was occluded for 75 min. rADAMTS13 or vehicle was administered intracoronary following reperfusion. Myocardial injury and infarct characteristics were assessed using cardiac enzymes, ECG, and histopathology. In patients with IMH, VWF activity and VWF antigen were significantly elevated directly after PCI and for all subsequent measurements, and ADAMTS13 activity significantly decreased at 4 and 7 days following PCI, in comparison with patients without IMH. VWF activity and ADAMTS13 activity were not related to infarct size. In rADAMTS13-treated animals, no differences in infarct size, IMH, or formation of microthrombi were witnessed compared with controls.CONCLUSIONS: No correlation was found between VWF/ADAMTS13 and infarct size in patients. However, patients suffering from IMH had significantly higher VWF activity and lower ADAMTS13 activity. Intracoronary administration of rADAMTS13 did not decrease infarct size or IMH in a porcine model of myocardial ischaemia-reperfusion. These data dispute the imbalance in ADAMTS13 and VWF as the cause of no reflow.

BACKGROUND: There is a clinical need for immunosuppressive therapy that can treat myocarditis patients in the presence of an active viral infection. In this study we therefore investigated the effects of colchicine, an immunosuppressive drug which has been used successfully as treatment for pericarditis patients, in a mouse model of coxsackievirus B3(CVB3)-induced myocarditis.METHODS: Four groups of C3H mice were included: control mice (n=8), mice infected with CVB3 (1×10(5) PFU, n=10), mice with colchicine administration (2mg/kg i.p, n=5) and mice with combined CVB3 infection and colchicine administration (n=10). After three days, the heart, pancreas and spleen were harvested and evaluated using (immuno)histochemical analysis and CVB3 qPCR.RESULTS: Mice were terminated at day 3 post-virus infection as colchicine treatment rapidly resulted in severe illness and mortality in CVB3-infected mice. Colchicine significantly decreased the number of macrophages in the heart in CVB3-infected mice (pCONCLUSIONS: Colchicine treatment in CVB3-induced myocarditis has a detrimental effect as it causes complete destruction of the exocrine pancreas and enhances viral load in both heart and pancreas.

Item does not contain fulltext AIMS: In cardiac hypertrophy (CH) and heart failure (HF), alterations occur in mitochondrial enzyme content and activities but the origin and implications of these changes for mitochondrial function need to be resolved. METHODS AND RESULTS: Right ventricular CH or HF was induced by monocrotaline injection, which causes pulmonary artery hypertension, in rats. Results were compared with saline injection (CON). NAD(P)H and FAD autofluorescence were recorded in thin intact cardiac trabeculae during transitions in stimulation frequency, to assess mitochondrial complex I and complex II function, respectively. Oxygen consumption, mitochondrial morphology, protein content, and enzymatic activity were assessed. NAD(P)H autofluorescence upon an increase in stimulation frequency showed a rapid decline followed by a slow recovery. FAD autofluorescence followed a similar time course, but in opposite direction. The amplitude of the early rapid change in NAD(P)H autofluorescence was severely depressed in CH and HF compared with CON. The rapid changes in FAD autofluorescence in CH and HF were reduced to a lesser extent. Complex I-coupled respiration showed an approximately 3.5-fold reduction in CH and HF; complex II-coupled respiration was depressed two-fold in HF. Western blot analyses revealed modest reductions in complex I protein content in CH and HF and in complex I activity in supercomplexes in HF. Mitochondrial volume density was similar, but mitochondrial remodelling was evident from changes in ultrastructure and fusion/fission indices in CH and HF. CONCLUSION: These results suggest that the alterations in mitochondrial function observed in right ventricular CH and HF can be mainly attributed to complex I dysfunction.

While beta-blockers are considered contraindicated in pulmonary arterial hypertension (PAH), the prognostic significance of sympathetic nervous system over-activity suggests a potential benefit of beta-blocker therapy. The aim of this randomised, placebo-controlled, crossover, single centre study was to determine the effects of bisoprolol on right ventricular ejection fraction (RVEF) in idiopathic PAH (iPAH) patients. Additional efficacy and safety parameters were explored.Patients with optimally treated, stable iPAH (New York Heart Association functional class II/III) were randomised to placebo or bisoprolol. Imaging and functional measurements were performed at baseline, crossover and end of study.18 iPAH patients were included, because inclusion faltered before enrolment of the targeted 25 patients. 17 patients completed 6 months of bisoprolol, 15 tolerated bisoprolol, one patient required intravenous diuretics. Bisoprolol was associated with a lower heart rate (17 beats per minute, p=0.0001) but RVEF remained unchanged. A drop in cardiac index (0.5 L·min−1·m−2, p=0.015) was observed, along with a trend towards a decreased 6-min walking distance (6MWD).Although careful up-titration of bisoprolol was tolerated by most patients and resulted in a decreased heart rate, no benefit of bisoprolol in iPAH was demonstrated. Decreases in cardiac index and 6MWD suggest a deteriorated cardiac function. The results do not favour the use of bisoprolol in iPAH patients.

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

Chronic thromboembolic pulmonary hypertension (CTEPH) is a late sequel of venous thromboembolism that cannot be completely reproduced in animal models. The prevalence of CTEPH in humans is estimated at roughly 17-20 per million; however, partly because up to 50% of patients with CTEPH never experience symptomatic pulmonary embolism, precise numbers on the incidence and prevalence are not known. Because CTEPH is diagnosed at a median age of 63 years in patients who often have other concomitant cardiovascular disease or lung disease, assessment of pathophysiology in patients can be challenging, We do know that CTEPH is a dual vascular disorder. Stenoses, webs, and occlusions predominate in large and medium-sized pulmonary arteries at the sites of previous pulmonary emboli. A "secondary vasculopathy" resembling the pulmonary arteriopathy encountered in other forms of pulmonary hypertension predominates in low-resistance vessels. Anastomoses between bronchial artery branches and precapillary pulmonary arterioles appear during evolution of the disease. Other acquired vascular connections between bronchial arteries and pulmonary veins may trigger venous remodeling. Current concepts regarding the pathophysiology of CTEPH include contributions of hyperactive coagulation (e.g., high coagulation factor VIII, combined coagulation defects, dysfibrinogenemias), insufficient anticoagulation, non-O blood groups, and misguided thrombus resolution (e.g., infection, inflammation, dysfunctional innate immunity, abnormal circulating phospholipids). Current research focuses on the question as to whether a genetic predisposition leads to misguided vascular healing after pulmonary thromboembolism in susceptible individuals.

The Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) is the first disease-specific instrument for pulmonary arterial hypertension (PAH) to assess patient-perceived symptoms, activity limitations and quality of life. To be able to use this questionnaire in the Netherlands, the aim of the study was to translate and validate this instrument for the Dutch-speaking population.First the CAMPHOR was translated into Dutch (by means of a bilingual and a lay panel) and field-tested by means of cognitive debriefing interviews with ten PAH patients. For psychometric evaluation, 80 patients with PAH or chronic thromboembolic pulmonary hypertension (CTEPH) were asked to complete the CAMPHOR twice over a two-week period. To test for construct validity, participants also completed the Nottingham Health Profile (NHP).The Dutch version of the CAMPHOR showed high internal consistency for all scales (Cronbach's alpha 0.89-0.91) and excellent reproducibility over two weeks (reliability coefficients 0.87-0.91). Concurrent validity showed that the CAMPHOR scales correlated as expected with the NHP scales. The CAMPHOR was able to distinguish between patient groups based on self-reported general health status, disease severity and NYHA classification demonstrating evidence of known group validity. The CAMPHOR activity limitations scale correlated moderately with the distance walked during the 6‑minute walk test (r = -0.47, p 0.01) and the symptoms scale with the Borg dyspnoea score (r = 0.51, p 0.01).The Dutch version of the CAMPHOR is a reliable and valid measure of quality of life and health status in patients with PAH and CTEPH is recommended for use in routine care and in clinical research.

Renal dysfunction in heart failure with preserved ejection fraction (HFpEF) is common and is associated with increased mortality. Impaired renal function is also a risk factor for developing HFpEF. A new paradigm for HFpEF, proposing a sequence of events leading to myocardial remodelling and dysfunction in HFpEF, was recently introduced, involving inflammatory, microvascular, and cardiac components. The kidney might play a key role in this systemic process. Renal impairment causes metabolic and systemic derangements in circulating factors, causing an activated systemic inflammatory state and endothelial dysfunction, which may lead to cardiomyocyte stiffening, hypertrophy, and interstitial fibrosis via cross-talk between the endothelium and cardiomyocyte compartments. Here, we review the role of endothelial dysfunction and inflammation to explain the link between renal dysfunction and HFpEF, which allows for identification of new early risk markers, prognostic factors, and unique targets for intervention.

Pulmonary hypertension (PH) is a condition that refers to a mean pulmonary artery pressure of at least 25 mmHg measured by right heart catheterisation at rest. PH is classified in five groups based on the underlying clinical condition [1]. Some of these conditions are orphan diseases and managed in designed tertiary PH centres with dedicated multidisciplinary teams. During the last decades great progress has been made on the epidemiology, aetiology, pathophysiology and treatment of PH. Some of these efforts were mainly based on national PH registries, first published in the early 1980 s [2]. The primary goal of these clinical observational PH registries is to describe patients with PH and the impact of this disease [3]. Until recently, no such a national PH registry was available in the Netherlands. In 2012, the Dutch multidisciplinary multicentre registry for PH (PulmoCor) was initiated by three tertiary PH centres and supported by the Interuniversity Cardiology Institute of the Netherlands (ICIN). Nowadays, six tertiary PH centres participate in this program (5 university medical centres and 1 non-university hospital). A working group including PH specialists (both cardiologists and pulmonologists) of all participating centres was established and regulations for this project have been drawn up. Several privacy-enhancing technologies have been used in accordance with the Dutch Privacy protections laws for data collection. The aims of the PulmoCor registry are to further optimise patient care and research in the field of PH, and the joint collaboration between the national and international PH centres. Interestingly, the same structured web-based PH database, specially developed for the management of PH patients (PAHtool, Inovolutus, Portugal), is used in other international PH centres as well, both European and non-European [4]. The PulmoCor registry will facilitate investigation of the epidemiology of specific subtypes of PH, the treatment and long-term outcome. It will increase the awareness of this rare disease throughout the Netherlands. Furthermore, the registry can be used as clinical database as well. Based on the current international guidelines, all PH centres used a standardised diagnostic approach for PH analysis [1]. Different data regarding the initial work-up and follow-up could be included in the PulmoCor registry. Each participating PH centre is using the secured uniformly structured database for the registration of their patients and these data are only accessible by this centre. To date, a total of 1493 patients with pulmonary hypertension (both prevalent and incident cases) have been included in the PulmoCor registry. In Fig. 1, this total group is shown according to the clinical classification (a) and the subgroup of patients with pulmonary arterial hypertension (PAH), group 1 (b). Fig. 1 Total number of patients with pulmonary hypertension included in the PulmoCor registry divided by clinical classification (a) and the subgroup of pulmonary arterial hypertension (b). Group 1 Pulmonary arterial hypertension; Group 2 ... The uniformly designed PulmoCor registry data acquisition will increase the value of national collaboration both clinically and scientifically.

Contains fulltext : 172088.pdf (Publisher’s version ) (Open Access) With around 500 cases published worldwide, pulmonary alveolar microlithiasis is a rare disorder with an autosomal recessive pattern of inheritance. We show for the first time that homozygous deletions encompassing the entire SCL34A2 can be associated with this rare genetic pulmonary disease.

Heart failure with preserved ejection fraction (HFpEF) is characterised by a high incidence of metabolic comorbidities that share the potential to induce both systemic and coronary microvascular inflammation and oxidative stress. These pathophysiological alterations contribute to increased passive stiffness of the myocardium and to diastolic dysfunction, both hallmarks of HFpEF. Passive myocardial stiffness depends mainly on two components: the extracellular matrix (ECM) and the cardiomyocytes. Quantitative and qualitative changes in collagen metabolism leading to myocardial fibrosis determine the ECM-based stiffness of the myocardium. Different noninvasive diagnostic tools to assess myocardial fibrosis are being developed, some of which have demonstrated to correlate with clinical status and prognosis. Cardiomyocytes mainly alter the passive stiffness through alterations in the giant myofilament titin, which serves as a spring. By modifying its phosphorylation state or by direct oxidative effects, titin determines cardiomyocyte-based passive stiffness. Probably the relative importance of cardiomyocyte-based changes is more important in the beginning of the disease, whereas ECM-based changes become more prominent in the more advanced stages. The present review focuses on these changes in ECM and cardiomyocytes in HFpEF and their potential prognostic and therapeutic implications.

Background To maintain the balance between the demand of the body and supply (cardiac output), cardiac performance is tightly regulated via the parasympathetic and sympathetic nervous systems. In heart failure, cardiac output (supply) is decreased due to pathologic remodelling of the heart. To meet the demands of the body, the sympathetic system is activated and catecholamines stimulate β-adrenergic receptors (β-ARs) to increase contractile performance and cardiac output. Although this is beneficial in the acute phase, chronic β-ARs stimulation initiates a cascade of alterations at the cellular level, resulting in a diminished contractile performance of the heart. Materials and methods This narrative review includes results from previously published systematic reviews and clinical and basic research publications obtained via PubMed up to May 2015. Results We discuss the alterations that occur during sustained β-AR stimulation in diseased myocardium and emphasize the consequences of β-AR overstimulation for cardiac function. In addition, current treatment options as well as future therapeutic strategies to treat patients with heart failure to normalize consequences of β-AR overstimulation are discussed. Conclusions The heart is able to protect itself from chronic stimulation of the β-ARs via desensitization and reduced membrane availability of the β-ARs. However, ultimately this leads to an impaired downstream signalling and decreased protein kinase A (PKA)-mediated protein phosphorylation. β-blockers are widely used to prevent β-AR overstimulation and restore β-ARs in the failing hearts. However, novel and more specific therapeutic treatments are needed to improve treatment of HF in the future.

The power in the myocardium sarcomere is generated by two bipolar arrays of the motor protein cardiac myosin II extending from the thick filament and pulling the thin, actin-containing filaments from the opposite sides of the sarcomere. Despite the interest in the definition of myosin-based cardiomyopathies, no study has yet been able to determine the mechanokinetic properties of this motor protein in situ. Sarcomere-level mechanics recorded by a striation follower is used in electrically stimulated intact ventricular trabeculae from the rat heart to determine the isotonic velocity transient following a stepwise reduction in force from the isometric peak force TP to a value T(0.8-0.2 TP). The size and the speed of the early rapid shortening (the isotonic working stroke) increase by reducing T from ∼3 nm per half-sarcomere (hs) and 1,000 s(-1) at high load to ∼8 nm⋅hs(-1) and 6,000 s(-1) at low load. Increases in sarcomere length (1.9-2.2 μm) and external [Ca(2+)]o (1-2.5 mM), which produce an increase of TP, do not affect the dependence on T, normalized for TP, of the size and speed of the working stroke. Thus, length- and Ca(2+)-dependent increase of TP and power in the heart can solely be explained by modulation of the number of myosin motors, an emergent property of their array arrangement. The motor working stroke is similar to that of skeletal muscle myosin, whereas its speed is about three times slower. A new powerful tool for investigations and therapies of myosin-based cardiomyopathies is now within our reach.

Neuroinflammation is thought to play a pivotal role in many diseases affecting the brain, including Alzheimer's disease, multiple sclerosis and stroke. Neuroinflammation is characterised predominantly by microglial activation, which can be visualised using positron emission tomography (PET). Traditionally, translocator protein 18kDa (TSPO) is the target for imaging of neuroinflammation using PET. In this review, recent preclinical and clinical research using PET in Alzheimer's disease, multiple sclerosis and stroke is summarised. In addition, new molecular targets for imaging of neuroinflammation, such as monoamine oxidases, adenosine receptors and cannabinoid receptor type 2, are discussed. This article is part of a Special Issue entitled: Neuro Inflammation edited by Helga E. de Vries and Markus Schwaninger.

Objectives When evaluating anti-tumor treatment response by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) it is necessary to assure its validity and reproducibility. This has not been well addressed in lung tumors. Therefore we have evaluated the inter-reader reproducibility of response classification by DCE-MRI in patients with non-small cell lung cancer (NSCLC) treated with bevacizumab and erlotinib enrolled in a multicenter trial.Materials and methods: Twenty-one patients were scanned before and 3 weeks after start of treatment with DCE-MRI in a multicenter trial. The scans were evaluated by two independent readers. The primary lung tumor was used for response assessment. Responses were assessed in terms of relative changes in tumor mean trans endothelial transfer rate (K-trans) and its heterogeneity in terms of the spatial standard deviation. Reproducibility was expressed by the inter-reader variability, intra-class correlation coefficient (ICC) and dichotomous response classification.Results: The inter-reader variability and ICC for the relative K-trans were 5.8% and 0.930, respectively. For tumor heterogeneity the inter-reader variability and ICC were 0.017 and 0.656, respectively. For the two readers the response classification for relative K-trans was concordant in 20 of 21 patients (k = 0.90, p Conclusions: Strong agreement was seen with regard to the inter-reader variability and reproducibility of response classification by the two readers of lung cancer DCE-MRI scans. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

Cardiac magnetic resonance imaging of the pressure overloaded right ventricle (RV) of precapillary pulmonary hypertension (PH) patients, exhibits late gadolinium enhancement at the interventricular insertion regions, a phenomenon which has been linked to focal fibrosis. Native T1-mapping is an alternative technique to characterize myocardium and has the advantage of not requiring the use of contrast agents. The aim of this study was to characterize the myocardium of idiopathic pulmonary arterial hypertension (IPAH), systemic scleroderma related PH (PAH-Ssc) and chronic thromboembolic PH (CTEPH) patients using native T1-mapping and to see whether native T1-values were related to disease severity. Furthermore, we compared native T1-values between the different precapillary PH categories. Native T1-mapping was performed in 46 IPAH, 14 PAH-SSc and 10 CTEPH patients and 10 control subjects. Native T1-values were assessed using regions of interest at the RV and LV free wall, interventricular septum and interventricular insertion regions. In PH patients, native T1-values of the interventricular insertion regions were significantly higher than the native T1-values of the RV free wall, LV free wall and interventricular septum. Native T1-values at the insertion regions were significantly related to disease severity. Native T1-values were not different between IPAH, PAH-Ssc and CTEPH patients. Native T1-values of the interventricular insertion regions are significantly increased in precapillary PH and are related to disease severity. Native T1-mapping can be developed as an alternative technique for the characterization of the interventricular insertion regions and has the advantage of not requiring the use of contrast agents.

UNLABELLED Quantitative assessment of (11)C-erlotinib uptake may be useful in selecting non-small cell lung cancer (NSCLC) patients for erlotinib therapy. The purpose of this study was to find the optimal pharmacokinetic model for quantification of uptake and to evaluate various simplified methods for routine analysis of (11)C-erlotinib uptake in NSCLC patients. METHODS Dynamic (15)O-H2O and (11)C-erlotinib scans were obtained in 17 NSCLC patients, 8 with and 9 without an activating epidermal growth factor receptor mutation (exon 19 deletion or exon 21-point mutation). Ten of these subjects also underwent a retest scan on the same day. (11)C-erlotinib data were analyzed using single-tissue and 2-tissue-irreversible and -reversible (2T4k) plasma input models. In addition, several advanced models that account for uptake of radiolabeled metabolites were evaluated, including a variation of the 2T4k model without correcting for metabolite fractions in plasma (2T4k-WP). Finally, simplified methods were evaluated-that is, SUVs and tumor-to-blood ratios (TBR)-for several scan intervals. RESULTS Tumor kinetics were best described using the 2T4k-WP model yielding optimal fits to the data (Akaike preference, 43.6%), acceptable test-retest variability (12%), no dependence on perfusion changes, and the expected clinical group separation (P

Cardiac myosin-binding protein C (cMyBP-C) regulates actin-myosin interaction and thereby cardiac myocyte contraction and relaxation. This physiologic function is regulated by cMyBP-C phosphorylation. In our study, reduced site-specific cMyBP-C phosphorylation coincided with increased S-glutathiolation in ventricular tissue from patients with dilated or ischemic cardiomyopathy compared to nonfailing donors. We used redox proteomics, to identify constitutive and disease-specific S-glutathiolation sites in cMyBP-C in donor and patient samples, respectively. Among those, a cysteine cluster in the vicinity of the regulatory phosphorylation sites within the myosin S2 interaction domain C1-M-C2 was identified and showed enhanced S-glutathiolation in patients. In vitro S-glutathiolation of recombinant cMyBP-C C1-M-C2 occurred predominantly at Cys(249), which attenuated phosphorylation by protein kinases. Exposure to glutathione disulfide induced cMyBP-C S-glutathiolation, which functionally decelerated the kinetics of Ca(2+)-activated force development in ventricular myocytes from wild-type, but not those from Mybpc3-targeted knockout mice. These oxidation events abrogate protein kinase-mediated phosphorylation of cMyBP-C and therefore potentially contribute to the reduction of its phosphorylation and the contractile dysfunction observed in human heart failure.-Stathopoulou, K., Wittig, I., Heidler, J., Piasecki, A., Richter, F., Diering, S., van der Velden, J., Buck, F., Donzelli, S., Schröder, E., Wijnker, P. J. M., Voigt, N., Dobrev, D., Sadayappan, S., Eschenhagen, T., Carrier, L., Eaton, P., Cuello, F. S-glutathiolation impairs phosphoregulation and function of cardiac myosin-binding protein C in human heart failure.

Background Patients with left ventricular (LV) dyssynchrony have a marked misbalance in LV myocardial work distribution, with wasted work in the septum and increased work in the lateral wall. We hypothesized that a low septum-to-lateral wall (SL) myocardial work ratio at baseline predicts acute LV pump function improvement during cardiac resynchronization therapy (CRT). Methods and Results Twenty patients (age 65 ± 10 y, 15 men) underwent cardiac magnetic resonance (CMR) tagging for regional LV circumferential strain assessment and invasive pressure-volume loop assessment at baseline and during biventricular pacing. Segmental work at baseline was calculated from regional strain rate and LV pressure. Subsequently, the SL work ratio was calculated and related to acute pump function (stroke work [SW]) improvement during CRT. During biventricular pacing, SW increased by 33% ( P .001). SL work ratio at baseline was found to be significantly related to SW improvement by means of CRT ( R = −0.54; P = .015). Moreover, it proved to be the only marker that was significantly related to acute response to CRT, whereas QRS duration and other measures of dyssynchrony or dyscoordination were not. Conclusions The contribution of the septum to LV work varies widely in CRT candidates with left bundle branch block. The lower the septal contribution to myocardial work at baseline, the higher the acute pump function improvement that can be achieved during CRT.

V̇o2 maxduring whole body exercise is presumably constrained by oxygen delivery to mitochondria rather than by mitochondria's ability to consume oxygen. Humans and animals have been reported to exploit only 60-80% of their mitochondrial oxidative capacity at maximal oxygen uptake (V̇o2 max). However, ex vivo quantification of mitochondrial overcapacity is complicated by isolation or permeabilization procedures. An alternative method for estimating mitochondrial oxidative capacity is via enzyme histochemical quantification of succinate dehydrogenase (SDH) activity. We determined to what extent V̇o2 maxattained during cycling exercise differs from mitochondrial oxidative capacity predicted from SDH activity of vastus lateralis muscle in chronic heart failure patients, healthy controls, and cyclists. V̇o2 maxwas assessed in 20 healthy subjects and 28 cyclists, and SDH activity was determined from biopsy cryosections of vastus lateralis using quantitative histochemistry. Similar data from our laboratory of 14 chronic heart failure patients and 6 controls were included. Mitochondrial oxidative capacity was predicted from SDH activity using estimated skeletal muscle mass and the relationship between ex vivo fiber V̇o2 maxand SDH activity of isolated single muscle fibers and myocardial trabecula under hyperoxic conditions. Mitochondrial oxidative capacity predicted from SDH activity was related ( r2= 0.89, P < 0.001) to V̇o2 maxmeasured during cycling in subjects with V̇o2 maxranging from 9.8 to 79.0 ml·kg−1·min−1. V̇o2 maxmeasured during cycling was on average 90 ± 14% of mitochondrial oxidative capacity. We conclude that human V̇o2 maxis related to mitochondrial oxidative capacity predicted from skeletal muscle SDH activity. Mitochondrial oxidative capacity is likely marginally limited by oxygen supply to mitochondria.

Aim Mutations in the RS-domain of RNA-binding motif protein 20 (RBM20) have recently been identified to segregate with aggressive forms of familial dilated cardiomyopathy (DCM). Loss of RBM20 in rats results in missplicing of the sarcomeric gene titin (TTN). The functional and physiological consequences of RBM20 mutations outside the mutational hotspot of RBM20 have not been explored to date. In this study, we investigated the pathomechanism of DCM caused by a novel RBM20 mutation in human cardiomyocytes. Methods and results We identified a family with DCM carrying a mutation (RBM20 E913K/+) in a glutamate-rich region of RBM20. Western blot analysis of endogenous RBM20 protein revealed strongly reduced protein levels in the heart of an RBM20 E913K/+ carrier. RNA deep-sequencing demonstrated massive inclusion of exons coding for the spring region of titin in the RBM20 E913K/+ carrier. Titin isoform analysis revealed a dramatic shift from the less compliant N2B towards the highly compliant N2BA isoforms in RBM20 E913K/+ heart. Moreover, an increased sarcomere resting-length was observed in single cardiomyocytes and isometric force measurements revealed an attenuated Frank-Starling mechanism (FSM), which was rescued by protein kinase A treatment. Conclusion A mutation outside the mutational hotspot of RBM20 results in haploinsufficiency of RBM20. This leads to disturbed alternative splicing of TTN, resulting in a dramatic shift to highly compliant titin isoforms and an impaired FSM. These effects may contribute to the early onset, and malignant course of DCM caused by RBM20 mutations. Altogether, our results demonstrate that heterozygous loss of RBM20 suffices to profoundly impair myocyte biomechanics by its disturbance of TTN splicing.

Item does not contain fulltext BACKGROUND: Glioma imaging, used for diagnostics, treatment planning, and follow-up, is currently based on standard magnetic resonance imaging (MRI) modalities (T1 contrast-enhancement for gadolinium-enhancing gliomas and T2 fluid-attenuated inversion recovery hyperintensity for nonenhancing gliomas). The diagnostic accuracy of these techniques for the delineation of gliomas is suboptimal. OBJECTIVE: To assess the diagnostic accuracy of advanced neuroimaging compared with standard MRI modalities for the detection of diffuse glioma infiltration within the brain. METHODS: A monocenter, prospective, diagnostic observational study in adult patients with a newly diagnosed, diffuse infiltrative glioma undergoing resective glioma surgery. Forty patients will be recruited in 3 years. Advanced neuroimaging will be added to the standard preoperative MRI. Serial neuronavigated biopsies in and around the glioma boundaries, obtained immediately preceding resective surgery, will provide histopathologic and molecular characteristics of the regions of interest, enabling comparison with quantitative measurements in the imaging modalities at the same biopsy sites. DISCUSSION: In this clinical study, we determine the diagnostic accuracy of advanced imaging in addition to standard MRI to delineate glioma. The results of our study can be valuable for the development of an improved standard imaging protocol for glioma treatment. EXPECTED OUTCOME: We hypothesize that a combination of positron emission tomography, MR spectroscopy, and standard MRI will have a superior accuracy for glioma delineation compared with standard MRI alone. In addition, we anticipate that advanced imaging will correlate with the histopathologic and molecular characteristics of glioma. ABBREVIATIONS: CHO, [11C-]CholineCRF, case report formsFET, [18F-]Fluoroethyl-tyrosineFLAIR, fluid-attenuated inversion recoveryMETC, Medical Ethical CommitteeMRS, magnetic resonance spectroscopyPET, positron emission tomographyVUmc, VU University Medical Center.

INTRODUCTION: Atrial fibrillation (AF) is a common complication in myocarditis. Atrial inflammation has been suggested to play an important role in the pathophysiology of AF. However, little is known about the occurrence of atrial inflammation in myocarditis patients. Here, we analyzed inflammatory cell numbers in the atria of myocarditis patients without symptomatic AF.METHODS: Cardiac tissue was obtained postmortem from lymphocytic myocarditis patients (n=6), catecholamine-induced myocarditis patients (n=5), and control patients without pathological evidence of heart disease (n=5). Tissue sections of left and right ventricle and left and right atrium were stained for myeloperoxidase (neutrophilic granulocytes), CD45 (lymphocytes), and CD68 (macrophages). These cells were subsequently quantified in atrial and ventricular myocardium and atrial adipose tissue.RESULTS: In lymphocytic myocarditis patients, a significant increase was observed for lymphocytes in the left atrial adipose tissue. In catecholamine-induced myocarditis patients, significant increases were found in the atria for all three inflammatory cell types. Infiltrating inflammatory cell numbers in the atrial myocardium correlated positively with those in the ventricles, especially in catecholamine-induced myocarditis patients.CONCLUSIONS: To a varying extent, atrial myocarditis occurs concurrently with ventricular myocarditis in patients diagnosed with myocarditis of different etiology. This provides a substrate that potentially predisposes myocarditis patients to the development of AF and subsequent complications such as sudden cardiac death and heart failure.

AIMS: Inflammation plays an important role in the pathogenesis of myocardial infarction (MI). Whether MI induces atrial inflammation is unknown however. Here, we analysed atrial inflammation in patients with MI and in rats with experimentally induced MI. The effect of the anti-inflammatory agent C1-esterase inhibitor (C1inh) on atrial inflammation in rats was also analysed.METHODS: In the hearts of patients who died at different time points after MI (total n=24, mean age=60), neutrophils (myeloperoxidase-positive cells), lymphocytes (CD45-positive cells) and macrophages (CD68-positive cells) were quantified in the myocardium of the left and right atria and the infarcted left and non-infarcted right ventricles and compared with control patients (n=5, mean age=59). For the left and right atria, inflammatory cells were also quantified in the atrial adipose tissue. MI was induced in 17 rats, of which 10 were subsequently treated with C1inh for 6 days. Forty-two days post-MI, lymphocytes, macrophages and the endothelial inflammation marker Nε-(carboxymethyl)lysine (CML) were analysed in the myocardium of both the atria and ventricles.RESULTS: In all investigated areas of the human hearts increased lymphocytes and macrophages were observed to a varying extent, especially between 6 h and 5 days following MI. Similarly, in rats MI resulted in an increase of inflammatory cells and CML in the atria. C1inh treatment decreased atrial inflammation.CONCLUSIONS: MI induces atrial inflammation in patients and in rats. C1inh treatment could counteract this MI-induced atrial inflammation in rats.

Contains fulltext : 171611.pdf (Publisher’s version ) (Open Access) The prevalence of patients with congenital heart disease (CHD) has increased over the last century. As a result, the number of CHD patients presenting with late, postoperative tachyarrhythmias has increased as well. The aim of this review is to discuss the present knowledge on the mechanisms underlying both atrial and ventricular tachyarrhythmia in patients with CHD and the advantages and disadvantages of the currently available invasive treatment modalities.

Survival of patients after resection of colorectal cancer liver metastasis (CRCLM) is 36%-58%. Positron emission tomography (PET) tracers, imaging the expression of prognostic biomarkers, may contribute to assign appropriate management to individual patients. Aurora kinase A (AURKA) expression is associated with survival of patients after CRCLM resection.We synthesized [(3)H]alisertib and [(11)C]alisertib, starting from [(3)H]methyl nosylate and [(11)C]methyl iodide, respectively. We measured in vitro uptake of [(3)H]alisertib in cancer cells with high (Caco2), moderate (A431, HCT116, SW480) and low (MKN45) AURKA expression, before and after siRNA-mediated AURKA downmodulation, as well as after inhibition of P-glycoprotein (P-gp) activity. We measured in vivo uptake and biodistribution of [(11)C]alisertib in nude mice, xenografted with A431, HCT116 or MKN45 cells, or P-gp knockout mice.[(3)H]Alisertib was synthesized with an overall yield of 42% and [(11)C]alisertib with an overall yield of 23%±9% (radiochemical purity ≥99%). Uptake of [(3)H]alisertib in Caco2 cells was higher than in A431 cells (P=.02) and higher than in SW480, HCT116 and MKN45 cells (P.01). Uptake in A431 cells was higher than in SW480, HCT116 and MKN45 cells (P.01). Downmodulation of AURKA expression reduced [(3)H]alisertib uptake in Caco2 cells (P.01). P-gp inhibition increased [(3)H]alisertib uptake in Caco2 (P.01) and MKN45 (P.01) cells. In vivo stability of [(11)C]alisertib 90min post-injection was 94.7%±1.3% and tumor-to-background ratios were 2.3±0.8 (A431), 1.6±0.5 (HCT116) and 1.9±0.5 (MKN45). In brains of P-gp knockout mice [(11)C]alisertib uptake was increased compared to uptake in wild-type mice (P.01) CONCLUSIONS: Radiolabeled alisertib can be synthesized and may have potential for the imaging of AURKA, particularly when AURKA expression is high. However, the exact mechanisms underlying alisertib accumulation need further investigation.Radiolabeled alisertib may be used for non-invasively measuring AURKA protein expression and to stratify patients for treatment accordingly.

BACKGROUND: Natriuretic peptides are currently used to predict mortality in patients with heart failure (HF). However, novel independent biomarkers are needed to improve risk stratification in these patients. We hypothesized that annexin A5 (anxA5) would be highly expressed by organs which are generally affected by HF and that circulating anxA5 levels would predict mortality in HF patients.METHODS: We prospectively determined the diagnostic value of anxA5, N-terminal pro-B-type natriuretic peptide (NT-proBNP), C-reactive protein (CRP) and estimated glomerular filtration rate (eGFR) to predict mortality in 180 HF patients during a median follow-up of 3.6 years. Studies were conducted with anxA5(-/-) mice to investigate the underlying mechanisms.RESULTS: AnxA5 levels were significantly elevated in HF patients compared to healthy control subjects. Cox regression analysis demonstrated that anxA5, NT-proBNP and eGFR all predict mortality independently. AnxA5 significantly improved the diagnostic efficiency of NT-proBNP alone (improvement of c-statistic from 0.662 to 0.705, P < 0.001) and also combined with eGFR and CRP (improvement of c-statistic from 0.675 to 0.738, P < 0.001) to predict mortality in the Cox regression model. Receiver operating characteristic curve analysis showed that anxA5 predicted 3-year survival (area under curve 0.708) with an optimal cut-off value of 2.24 ng mL(-1) . Using anxA5(-/-) mice, we demonstrated that anxA5 is highly expressed in organs that are often affected by HF including lung, kidney, liver and spleen. Lysis of these organs in vitro resulted in a marked and significant increase in anxA5 concentrations.CONCLUSION: AnxA5 improves the diagnostic efficiency of conventional biomarkers to predict mortality in HF patients. Whereas natriuretic peptides originate from the myocardium, high circulating anxA5 levels in patients with HF are likely to reflect peripheral organ damage secondary to HF.

ABC transporters at the human blood-brain barrier protect the brain against the entry of harmful compounds but may also limit (or prevent) the cerebral entry of therapeutic drugs (e.g. anti-epileptics, antidepressants and antipsychotics). The efflux function of these transporters may be impaired in neurodegenerative disorders like Alzheimer and Parkinson disease. For such reasons, there is much interest in modulation of the efflux function of ABC transporters and in the monitoring of this function with positron emission tomography (PET). The efflux function of P-glycoprotein, an important member of the ABC transporter family, can be quantified with the PET tracer (R)-[ 11 C]verapamil, but the lipophilicity of this probe and the formation of radioactive metabolites which enter the brain complicate such measurements considerably. (R)-[ 11 C]verapamil is also not very suitable for the detection of P-gp upregulation, as may occur in epilepsy or drug resistance. Current radiochemical efforts are therefore focused on the development of PET probes with improved characteristics, for example; capability to detect both up- and down regulation of transporter function and expression, a better metabolic profile (no brain-entering metabolites), reduced lipophilicity and a longer physical half-life (labeling with 18 F instead of 11 C).

Objective. In 2008 GROINSS-V-I, the largest validation trial on the sentinel node (SN) procedure in vulvar cancer, showed that application of the SN-procedure in patients with early-stage vulvar cancer is safe. The current study aimed to evaluate long-term follow-up of these patients regarding recurrences and survival. Methods. From2000 until 2006 GROINSS-V-I included 377 patientswith unifocal squamous cell carcinoma of the vulva (T1

Background Complement activation contributes significantly to inflammation-related damage in the heart after acute myocardial infarction. Knowledge on factors that regulate postinfraction complement activation is incomplete however. In this study, we investigated whether endogenous C1-inhibitor, a well-known inhibitor of complement activation, is expressed in the heart after acute myocardial infarction. Materials and methods C1-inhibitor and complement activation products C3d and C4d were analyzed immunohistochemically in the hearts of patients who died at different time intervals after acute myocardial infarction ( n = 28) and of control patients ( n = 8). To determine putative local C1-inhibitor production, cardiac transcript levels of the C1-inhibitor-encoding gene serping1 were determined in rats after induction of acute myocardial infarction (microarray). Additionally, C1-inhibitor expression was analyzed (fluorescence microscopy) in human endothelial cells and rat cardiomyoblasts in vitro. Results C1-inhibitor was found predominantly in and on jeopardized cardiomyocytes in necrotic infarct cores between 12 h and 5 days old. C1-inhibitor protein expression coincided in time and colocalized with C3d and C4d. In the rat heart, serping1 transcript levels were increased from 2 h up until 7 days after acute myocardial infarction. Both endothelial cells and cardiomyoblasts showed increased intracellular expression of C1-inhibitor in response to ischemia in vitro ( n = 4). Conclusions These observations suggest that endogenous C1-inhibitor is likely involved in the regulation of complement activity in the myocardium following acute myocardial infarction. Observations in rat and in vitro suggest that C1-inhibitor is produced locally in the heart after acute myocardial infarction.

Fluorine-18 labelled N,N-diethyl-2-(2-[4-(2-fluoroethoxy)phenyl]-5,7-dimethylpyrazolo[1,5-α]pyrimidine-3-yl)acetamide (18F-DPA-714) is a radioligand for the 18-kDa translocator protein. The purpose of the present study was to identify the best method for generating quantitative parametric images of 18F-DPA-714 binding. METHODS: Ninety minutes dynamic 18F-DPA-714 positron emission tomography scans with full arterial sampling from 6 healthy subjects and 9 Alzheimer's disease (AD) patients were used. Plasma input based Logan graphical and spectral (SA) analyses were used to generate parametric volume of distribution (VT) images. Five versions of Ichise, reference Logan (RLogan) and two basis function implementations (Receptor Parametric Mapping, RPM; Simplified Reference Tissue Model2, SRTM2) of SRTM, all using grey matter cerebellum as reference region, were used to generate binding potential (BPND) images. RESULTS: Plasma input Logan (r2 = 0.99, slope = 0.88) and SA (r2 = 0.99, slope = 0.93) generated estimates of VT that correlated well with values obtained using non-linear regression. BPND values generated using SRTM2 (r2 = 0.83, slope = 0.95) and RLogan (r2 = 0.88, slope = 1.01) correlated well with non-linear regression based estimates. CONCLUSION: Both Logan and SA can be used to obtain quantitatively accurate VT images of 18F-DPA-714. In addition, SRTM2 and RLogan can provide accurate BPND images. These parametric images could be used for voxel based comparisons.

Background— The predictive performance of static risk prediction models such as EuroSCORE deteriorates over time. We aimed to explore different methods for continuous updating of EuroSCORE (dynamic modeling) to improve risk prediction. Methods and Results— Data on adult cardiac surgery from 2007 to 2012 (n=95 240) were extracted from the Netherlands Association for Cardio-Thoracic Surgery database. The logistic EuroSCORE predicting in-hospital death was updated using 6 methods: recalibrating the intercept of the logistic regression model; recalibrating the intercept and joint effects of the prognostic factors; re-estimating all prognostic factor effects, re-estimating all prognostic factor effects, and applying shrinkage of the estimates; applying a test procedure to select either of these; and a Bayesian learning strategy. Models were updated with 1 or 3 years of data, in all cardiac surgery or within operation subgroups. Performance was tested in the subsequent year according to discrimination (area under the receiver operating curve, area under the curve) and calibration (calibration slope and calibration-in-the-large). Compared with the original EuroSCORE, all updating methods resulted in improved calibration-in-the-large (range −0.17 to 0.04 versus −1.13 to −0.97, ideally 0.0). Calibration slope (range 0.92–1.15) and discrimination (area under the curve range 0.83–0.87) were similar across methods. In small subgroups, such as aortic valve replacement and aortic valve replacement+coronary artery bypass grafting, extensive updating using 1 year of data led to poorer performance than using the original EuroSCORE. The choice of updating method had little effect on benchmarking results of all cardiac surgery. Conclusions— Several methods for dynamic modeling may result in good discrimination and superior calibration compared with the original EuroSCORE. For large populations, all methods are appropriate. For smaller subgroups, it is recommended to use data from multiple years or a Bayesian approach.

A new (18)F-labeled tetrazine derivative was developed aiming at optimal radiochemistry, fast reaction kinetics in inverse electron-demand Diels-Alder cycloaddition (IEDDA), and favorable pharmacokinetics for in vivo bioorthogonal chemistry. The radiolabeling of the tetrazine was achieved in high yield, purity, and specific activity under mild reaction conditions via conjugation with 5-[(18)F]fluoro-5-deoxyribose, providing a glycosylated tetrazine derivative with low lipophilicity. The (18)F-tetrazine showed fast reaction kinetics toward the most commonly used dienophiles in IEDDA reactions. It exhibited excellent chemical and enzymatic stability in mouse plasma and in phosphate-buffered saline (pH 7.41). Biodistribution in mice revealed favorable pharmacokinetics with major elimination via urinary excretion. The results indicate that the glycosylated (18)F-labeled tetrazine is an excellent candidate for in vivo bioorthogonal chemistry applications in pretargeted PET imaging approaches.

More than a century of research on the Frank–Starling Law has significantly advanced our knowledge about the working heart. The Frank–Starling Law mandates that the heart is able to match cardiac ejection to the dynamic changes occurring in ventricular filling and thereby regulates ventricular contraction and ejection. Significant efforts have been attempted to identify a common fundamental basis for the Frank–Starling heart and, although a unifying idea has still to come forth, there is mounting evidence of a direct relationship between length changes in individual constituents (cardiomyocytes) and their sensitivity to Ca2+ ions. As the Frank–Starling Law is a vital event for the healthy heart, it is of utmost importance to understand its mechanical basis in order to optimize and organize therapeutic strategies to rescue the failing human heart. The present review is a historic perspective on cardiac muscle function. We “revive” a century of scientific research on the heart’s fundamental protein constituents (contractile proteins), to their assemblies in the muscle (the sarcomeres), culminating in a thorough overview of the several synergistically events that compose the Frank–Starling mechanism. It is the authors’ personal beliefs that much can be gained by understanding the Frank–Starling relationship at the cellular and whole organ level, so that we can finally, in this century, tackle the pathophysiologic mechanisms underlying heart failure.

Item does not contain fulltext Increased serotonin serum levels have been proposed to play a key role in pulmonary arterial hypertension (PAH) by regulating vessel tone and vascular smooth muscle cell proliferation. An intact serotonin system, which critically depends on a normal function of the serotonin transporter (SERT), is required for the development of experimental pulmonary hypertension in rodents exposed to hypoxia or monocrotaline. While these animal models resemble human PAH only with respect to vascular media remodeling, we hypothesized that SERT is likewise required for the presence of lumen-obliterating intima remodeling, a hallmark of human PAH reproduced in the Sugen hypoxia (SuHx) rat model of severe angioproliferative pulmonary hypertension. Therefore, SERT wild-type (WT) and knockout (KO) rats were exposed to the SuHx protocol. SERT KO rats, while completely lacking SERT, were hemodynamically indistinguishable from WT rats. After exposure to SuHx, similar degrees of severe angioproliferative pulmonary hypertension and right ventricular hypertrophy developed in WT and KO rats (right ventricular systolic pressure 60 vs. 55 mmHg, intima thickness 38 vs. 30%, respectively). In conclusion, despite its implicated importance in PAH, SERT does not play an essential role in the pathogenesis of severe angioobliterative pulmonary hypertension in rats exposed to SuHx.