Comprehensive genetic screening of early-onset dementia patients in an Austrian cohort-suggesting new disease-contributing genes.

Early-onset dementia (EOD), with symptom onset before age 65, has a strong genetic burden. Due to genetic and clinical overlaps between different types of dementia, whole-exome sequencing (WES) has emerged as an appropriate screening method for diagnostic testing and novel gene-finding approaches. We performed WES and C9orf72 repeat testing in 60 well-defined Austrian EOD patients. Seven patients (12%) carried likely disease-causing variants in monogenic genes, PSEN1, MAPT, APP, and GRN. Five patients (8%) were APOE4 homozygote carriers. Definite and possible risk variants were detected in the genes TREM2, SORL1, ABCA7 and TBK1. In an explorative approach, we cross-checked rare gene variants in our cohort with a curated neurodegeneration candidate gene list and identified DCTN1, MAPK8IP3, LRRK2, VPS13C and BACE1 as promising candidate genes. Conclusively, 12 cases (20%) carried variants relevant to patient counseling, comparable to previously reported studies, and can thus be considered genetically resolved. Reduced penetrance, oligogenic inheritance and not yet identified high-risk genes might explain the high number of unresolved cases. To address this issue, we provide complete genetic and phenotypic information (uploaded to the European Genome-phenome Archive), enabling other researchers to cross-check variants. Thereby, we hope to increase the chance of independently finding the same gene/variant-hit in other well-defined EOD patient cohorts, thus confirming new genetic risk variants or variant combinations.

Analysis of co-medication in people with dementia.

BACKGROUND AND PURPOSE: Dementia prevalence is increasing, with numbers projected to double by 2050. Risk factors for its development include age and cardiovascular comorbidities, which are found more often in patients with dementia and should be treated properly to improve outcomes. In this case-control study, we analysed a large population-based prescription database to explore the patterns of co-medication in patients with dementia. METHODS: Prescription claims covering >99% of the Austrian population from 2005 to 2016 were obtained. Patients who were treated with an approved antidementia drug (ADD) were included and co-medication exposure was recorded. A group of people not taking ADDs was matched for age, sex and follow-up duration as a control. RESULTS: We included 70,799 patients on ADDs who were exposed to a mean of 5.3 co-medications while control patients were treated with a total of 5.2 co-medications (p < 0.001). We found that patients on ADDs received less somatic (4.1 vs. 4.5) but more psychiatric medication (1.1 vs. 0.6; p < 0.001 for both). Patients on ADDs were less likely to be treated for pain, cardiovascular conditions or hyperlipidemia. More than 50% of patients on ADDs were treated with antidepressants or antipsychotics. Greater number of co-medications was associated with markers of more intensive antidementia treatment. CONCLUSION: Patients on ADDs received more medications overall but were less frequently treated for somatic conditions known to be more prevalent in this group. Together, our data suggest that management of comorbidities in dementia could be improved to optimize outcome and quality of life.

Does [99mTc]-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) soft tissue uptake allow the identification of patients with the diagnosis of cardiac transthyretin-related (ATTR) amyloidosis with higher risk for polyneuropathy?

BACKGROUND: With the introduction of several drugs for the therapy of transthyretin-related amyloidosis (ATTR) which slow down the disease, early detection of polyneuropathy (PNP) is becoming increasingly of interest. [99mTc]-3,3-Diphosphono-1,2-Propanodicarboxylic Acid (DPD) bone scintigraphy, which is used for the diagnosis of cardiac (c)ATTR, can possibly make an important contribution in the identification of patients at risk for PNP. METHODS: Fifty patients with cATTR, who underwent both planar whole-body DPD scintigraphy and nerve conduction studies (NCS) were retrospectively evaluated. A subgroup of 22 patients also underwent quantitative SPECT/CT of the thorax from which Standardized Uptake Values (SUVpeak) in the subcutaneous fat tissue of the left axillar region were evaluated. RESULTS: The Perugini score was significantly increased in patients with cATTR and additional diagnosis of PNP compared to patients without (2.51 ± 0.51 vs 2.13 ± 0.52; P = 0.03). Quantitative SPECT/CT revealed that DPD uptake in the subcutaneous fat of the left axillar region was significantly increased in cATTR patients with compared to patients without (1.36 ± 0.60 vs 0.74 ± 0.52; P = 0.04). CONCLUSION: This study suggests that DPD bone scintigraphy is a useful tool for identification of patients with cATTR and a risk for PNP due to increased DPD soft tissue uptake.

C9orf72 repeat length might influence clinical sub-phenotypes in dementia patients.

BACKGROUND: C9orf72 repeat expansions have been observed in a wide variety of neurodegenerative disorders. The cut-off between normal and pathogenic alleles is not well established as repeat sizing methods are often semi-quantitative. However, intermediate alleles might influence disease prevalence and phenotype, as seen for other repeat expansion disorders. We aimed to further delineate the prevalence of small, intermediate and expanded C9orf72 alleles and elucidate their potential influence on the disease phenotype. METHODS: DNA derived from patients (n = 1804) and healthy individuals (n = 643) was obtained from multiple collectives in Austria. Genotyping was performed using a two-step PCR assay followed by Southern blotting. RESULTS: 3.4% of clinically diagnosed frontotemporal dementia (FTD; n = 5/147) cases and 0.8% of clinically diagnosed Alzheimer's disease (AD; n = 5/602) cases were carriers of a pathological C9orf72 repeat expansion. A significantly earlier disease onset was detected in expansion carriers compared to non-carriers in the FTD and AD cohorts (median 50 years, range 39-64 vs. median 64 years, range 36-92, p = 0.018 and median 63 years, range 54-71 vs. median 74 years, range 45-92, p = 0.006, respectively). C9orf72 intermediate alleles were significantly associated with cerebellar symptoms (p = 0.0004) and sensory deficits in the dementia cohort (p = 0.01). CONCLUSIONS: C9orf72 repeat expansion carriers showed earlier disease onset compared to non-carriers with clinical diagnosis of FTD and AD. Furthermore, C9orf72 intermediate repeats might modify the phenotypic expression in dementia.

Clinical applicability of quantitative atrophy measures on MRI in patients suspected of Alzheimer's disease.

OBJECTIVES: Neurodegeneration in suspected Alzheimer's disease can be determined using visual rating or quantitative volumetric assessments. We examined the feasibility of volumetric measurements of gray matter (GMV) and hippocampal volume (HCV) and compared their diagnostic performance with visual rating scales in academic and non-academic memory clinics. MATERIALS AND METHODS: We included 231 patients attending local memory clinics (LMC) in the Netherlands and 501 of the academic Amsterdam Dementia Cohort (ADC). MRI scans were acquired using local protocols, including a T1-weighted sequence. Quantification of GMV and HCV was performed using FSL and FreeSurfer. Medial temporal atrophy and global atrophy were assessed with visual rating scales. ROC curves were derived to determine which measure discriminated best between cognitively normal (CN), mild cognitive impairment (MCI), and Alzheimer's dementia (AD). RESULTS: Patients attending LMC (age 70.9 ± 8.9 years; 47% females; 19% CN; 34% MCI; 47% AD) were older, had more cerebrovascular pathology, and had lower GMV and HCV compared to those of the ADC (age 64.9 ± 8.2 years; 42% females; 35% CN, 43% MCI, 22% AD). While visual ratings were feasible in > 95% of scans in both cohorts, quantification was achieved in 94-98% of ADC, but only 68-85% of LMC scans, depending on the software. Visual ratings and volumetric outcomes performed similarly in discriminating CN vs AD in both cohorts. CONCLUSION: In clinical settings, quantification of GM and hippocampal atrophy currently fails in up to one-third of scans, probably due to lack of standardized acquisition protocols. Diagnostic accuracy is similar for volumetric measures and visual rating scales, making the latter suited for clinical practice. In a real-life clinical setting, volumetric assessment of MRI scans in dementia patients may require acquisition protocol optimization and does not outperform visual rating scales. KEY POINTS: • In a real-life clinical setting, the diagnostic performance of visual rating scales is similar to that of automatic volumetric quantification and may be sufficient to distinguish Alzheimer's disease groups. • Volumetric assessment of gray matter and hippocampal volumes from MRI scans of patients attending non-academic memory clinics fails in up to 32% of cases. • Clinical MR acquisition protocols should be optimized to improve the output of quantitative software for segmentation of Alzheimer's disease-specific outcomes.

Prediction of Neurological Recovery After Cardiac Arrest Using Neurofilament Light Chain is Improved by a Proteomics-Based Multimarker Panel.

BACKGROUND: Continuous advances in resuscitation care have increased survival, but the rate of favorable neurological outcome remains low. We have shown the usefulness of proteomics in identifying novel biomarkers to predict neurological outcome. Neurofilament light chain (NfL), a marker of axonal damage, has since emerged as a promising single marker. The aim of this study was to assess the predictive value of NfL in comparison with and in addition to our established model. METHODS: NfL was measured in plasma samples drawn at 48 h after cardiac arrest using single-molecule assays. Neurological function was recorded on the cerebral performance category (CPC) scale at discharge from the intensive care unit and after 6 months. The ability to predict a dichotomized outcome (CPC 1-2 vs. 3-5) was assessed with receiver operating characteristic (ROC) curves. RESULTS: Seventy patients were included in this analysis, of whom 21 (30%) showed a favorable outcome (CPC 1-2), compared with 49 (70%) with an unfavorable outcome (CPC 3-5) at discharge. NfL increased from CPC 1 to 5 (16.5 pg/ml to 641 pg/ml, p < 0.001). The addition of NfL to the existing model improved it significantly (Wald test, p < 0.001), and the combination of NfL with a multimarker model showed high areas under the ROC curve (89.7% [95% confidence interval 81.7-97.7] at discharge and 93.7% [88.2-99.2] at 6 months) that were significantly greater than each model alone. CONCLUSIONS: The combination of NfL with other plasma and clinical markers is superior to that of either model alone and achieves high areas under the ROC curve in this relatively small sample.

Performance of the recommended ESC/EASD cardiovascular risk stratification model in comparison to SCORE and NT-proBNP as a single biomarker for risk prediction in type 2 diabetes mellitus.

BACKGROUND: Recently, the European Society of Cardiology (ESC) and European Association for the Society of Diabetes (EASD) introduced a new cardiovascular disease (CVD) risk stratification model to aid further treatment decisions in individuals with diabetes. Our study aimed to investigate the prognostic performance of the ESC/EASD risk model in comparison to the Systematic COronary Risk Evaluation (SCORE) risk model and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in an unselected cohort of type 2 diabetes mellitus (T2DM). METHODS AND RESULTS: A total of 1690 T2DM patients with a 10-year follow up for fatal CVD and all-cause death and a 5-year follow up for CVD and all-cause hospitalizations were analyzed. According to ESC/EASD risk criteria 25 (1.5%) patients were classified as moderate, 252 (14.9%) high, 1125 (66.6%) very high risk and 288 (17.0%) were not classifiable. Both NT-proBNP and SCORE risk model were associated with 10-year CVD and all-cause death and 5-year CVD and all-cause hospitalizations while the ESC/EASD model was only associated with 10-year all-cause death and 5-year all-cause hospitalizations. NT-proBNP and SCORE showed significantly higher C-indices than the ESC/EASD risk model for CVD death [0.80 vs. 0.53, p < 0.001; 0.64 vs. 0.53, p = 0.001] and all-cause death [0.73, 0.66 vs. 0.52, p < 0.001 for both]. The performance of SCORE improved in a subgroup without CVD aged 40-64 years compared to the unselected cohort, while NT-proBNP performance was robust across all groups. CONCLUSION: The new introduced ESC/EASD risk stratification model performed limited compared to SCORE and single NT-proBNP assessment for predicting 10-year CVD and all-cause fatal events in individuals with T2DM.

Proteomics-Enriched Prediction Model for Poor Neurologic Outcome in Cardiac Arrest Survivors.

OBJECTIVES: Neurologic outcome prediction in out-of-hospital cardiac arrest survivors is highly limited due to the lack of consistent predictors of clinically relevant brain damage. The present study aimed to identify novel biomarkers of neurologic recovery to improve early prediction of neurologic outcome. DESIGN: Prospective, single-center study, SETTING:: University-affiliated tertiary care center. PATIENTS: We prospectively enrolled 96 out-of-hospital cardiac arrest survivors into our study. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Neurologic outcome was assessed by the Cerebral Performance Categories score. To identify plasma biomarkers for poor neurologic outcome (Cerebral Performance Categories score ≥ 3), we performed a three-step proteomics strategy of preselection by shotgun analyses, crosschecking in brain tissue samples, and verification by targeted proteomic analyses using a multistep statistical modeling approach. Sixty-three patients (66%) had a poor neurologic outcome. Out of a total of 299 proteins, we identified α-enolase, 14-3-3 protein ζ/δ, cofilin-1, and heat shock cognate 71 kDa protein as novel biomarkers for poor neurologic outcome. The implementation of these biomarkers into a clinical multimarker model, consisting of previously identified covariates associated to outcome, resulted in a significant improvement of neurologic outcome prediction (C-index, 0.70; explained variation, 11.9%; p for added value, 0.019). CONCLUSIONS: This study identified four novel biomarkers for the prediction of poor neurologic outcome in out-of-hospital cardiac arrest survivors. The implementation of α-enolase, 14-3-3 protein ζ/δ, cofilin-1, and heat shock cognate 71 kDa protein into a multimarker predictive model along with previously identified risk factors significantly improved neurologic outcome prediction. Each of the proteomically identified biomarkers did not only outperform current risk stratification models but may also reflect important pathophysiologic pathways undergoing during cerebral ischemia.

Efficacy, immunogenicity, and safety of IC43 recombinant Pseudomonas aeruginosa vaccine in mechanically ventilated intensive care patients-a randomized clinical trial.

BACKGROUND: Pseudomonas aeruginosa infections are a serious threat in intensive care units (ICUs). The aim of this confirmatory, randomized, multicenter, placebo-controlled, double-blind, phase 2/3 study was to assess the efficacy, immunogenicity, and safety of IC43 recombinant Pseudomonas aeruginosa vaccine in non-surgical ICU patients. METHODS: Eight hundred patients aged 18 to 80 years admitted to the ICU with expected need for mechanical ventilation for ≥ 48 h were randomized 1:1 to either IC43 100 µg or saline placebo, given in two vaccinations 7 days apart. The primary efficacy endpoint was all-cause mortality in patients 28 days after the first vaccination. Immunogenicity and safety were also evaluated. FINDINGS: All-cause mortality rates at day 28 were 29.2% vs 27.7% in the IC43 and placebo groups, respectively (P = .67). Overall survival (Kaplan-Meier survival estimates, P = .46) and proportion of patients with ≥ one confirmed P. aeruginosa invasive infection or respiratory tract infection also did not differ significantly between both groups. The geometric mean fold increase in OprF/I titers was 1.5 after the first vaccination, 20 at day 28, after the second vaccination, and 2.9 at day 180. Significantly more patients in the placebo group (96.5%) had ≥ one adverse event (AE) versus the IC43 100 µg group (93.1%) (P = .04). The most frequently reported severe AEs in the IC43 and placebo groups were respiratory failure (6.9% vs 5.7%, respectively), septic shock (4.1% vs 6.5%), cardiac arrest (4.3% vs 5.7%), multiorgan failure (4.6% vs 5.5%), and sepsis (4.6% vs 4.2%). No related serious AEs were reported in the IC43 group. INTERPRETATION: The IC43 100 µg vaccine was well tolerated in this large population of medically ill, mechanically ventilated patients. The vaccine achieved high immunogenicity but provided no clinical benefit over placebo in terms of overall mortality. TRIAL REGISTRATION: https://clinicaltrials.gov (NCT01563263). Registration was sent to ClinicalTrials.gov on March 14, 2012, but posted by ClinicalTrials.gov on March 26, 2012. The first subject was included in the trial on March 22, 2012.

GDF-15 in solid vs non-solid treatment-naïve malignancies.

AIM: GDF-15 is an established cardiovascular risk marker but is equally implicated in tumour biology. Elevated levels of GDF-15 have indeed been observed in distinct tumour entities. This study aimed to explore the relation of GDF-15 to other cardiac biomarkers and the general association of GDF-15 on prognosis in an unselected cohort of treatment-naïve cancer patients. METHODS: We prospectively enrolled 555 consecutive patients at time of diagnosis of malignant disease prior receiving anticancer therapy. Plasma GDF-15 concentrations were determined alongside other cardiac and routine laboratory markers. All-cause mortality was defined as primary endpoint. RESULTS: GDF-15 levels were 338 ng/L (IQR:205-534) for the total cohort, and values were comparable for different tumour entities except breast cancer. Metastatic disease was characterized by higher plasma GDF-15 [435 ng/L (IQR:279-614) vs 266 ng/L (IQR:175-427), P < .001]. GDF-15 correlated positively with inflammatory status reflected by CRP, SAA and IL-6 [r = .31, P < .001, r = .23, P < .001 and r = .14, P = .002] and cardiac biomarkers as NT-proBNP, hsTnT, MR-proADM and CT-proET-1 [r = .46; r = .46; r = .59 and r = .50; P < .001 for all]. GDF-15 was significantly associated with all-cause mortality after multivariate adjustment [adj.HR for ln(GDF-15) 1.78, 95%CI:1.47-2.16, P < .001]. There was a significant interaction between solid and haematological malignancies with loss of association of GDF-15 with outcome in myelodysplastic and myeloproliferative disease. CONCLUSIONS: Elevated plasma GDF-15 is associated with progressing disease severity and poor prognosis in solid tumours of treatment-naïve cancer patients. GDF-15 increase is accompanied by worsening systemic inflammation and a subclinical functional impairment of different organs including the heart. GDF-15 represents a promising target for our pathophysiologic understanding in cardio-oncology linking conditions of both cardiac and neoplastic disease.

Refining the prognostic impact of functional mitral regurgitation in chronic heart failure.

Aims: Significant efforts are currently undertaken to reduce functional mitral regurgitation (FMR) in patients with chronic heart failure in the hope to improve prognosis. We aimed to assess the prognostic impact of FMR in heart failure with reduced ejection fraction (HFrEF) under optimal medical therapy (OMT) and various conditions of HFrEF. We further intended to identify a heart failure phenotype, where FMR is most likely a driving force and not a mere bystander of the disease. Methods and results: We prospectively included 576 consecutive HFrEF patients into our long-term observational study. Functional [i.e. New York Heart Association (NYHA) class], echocardiographic, invasive haemodynamic, and biochemical (i.e. NT-proBNP, MR-proANP, MR-proADM, CT-proET-1, copeptin) measurements were performed at baseline. During a median follow-up of 62 months (interquartile range 52-76), 47% of patients died. Severe FMR was a significant predictor of mortality [hazard ratio (HR) 1.76, 95% confidence interval (CI) 1.34-2.30; P < 0.001], independent of clinical (adjusted HR 1.61, 95% CI 1.22-2.12; P = 0.001), and echocardiographic (adjusted HR 1.46, 95% CI 1.09-1.94; P = 0.01) confounders, OMT (adjusted HR 1.81, 95% CI 1.25-2.63; P = 0.002), and neurohumoral activation (adjusted HR 1.38, 95% CI 1.03-1.84; P = 0.03). Subanalysis revealed that severe FMR was associated with poor outcome in an intermediate-failure phenotype of HFrEF i.e. patients with NYHA class II (adjusted HR 2.17, 95% CI 1.07-4.44; P = 0.03) and III (adjusted HR 1.80, 95% CI 1.17-2.77; P = 0.008), moderately reduced left ventricular function (adjusted HR 2.37, 95% CI 1.36-4.12; P = 0.002), and within the second quartile (871-2360 pg/mL) of NT-proBNP (adjusted HR 2.16, 95% CI 1.22-3.86; P = 0.009). Conclusion: In a patient cohort under OMT, the adverse prognostic impact of FMR is given predominantly in a sub-cohort of a specific intermediate-failure phenotype-well-defined functionally, haemodynamically, biochemically, and morphologically.

Low- and High-renin Heart Failure Phenotypes with Clinical Implications.

BACKGROUND: Blockade of the renin-angiotensin system (RAS) represents a main strategy in the therapy of heart failure with reduced ejection fraction (HFrEF), but the role of active renin concentration (ARC) for guiding therapy in the presence of an RAS blockade remains to be established. This study assessed angiotensin profiles of HFrEF patients with distinct RAS activations as reflected by ARC. METHODS: Two cohorts of stable chronic HFrEF patients on optimal medical treatment (OMT) were enrolled. We assessed ARC and all known circulating angiotensin metabolites, including AngI and AngII, by mass spectrometry to investigate the effect of different therapy modalities. Low- and high-renin HFrEF patients were identified by ARC screening and subsequently characterized by their angiotensin profiles. RESULTS: Although different modes of RAS blockade resulted in typical AngII/AngI ratios, concentrations of (AngI+AngII) strongly correlated with ARC [r = 0.95, P < 0.001] independent of therapy mode. Despite RAS blocker treatment with angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin II type 1 receptor blockers (ARB), which anticipated ARC upregulation, about 30% of patients showed lower/normal range ARC values. ARC did not correlate with N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations and New York Heart Association (NYHA) stages. Angiotensin concentrations were profoundly diminished for the low-ARC group compared with the high-ARC group: AngI [6.4 ng/L (IQR: 2.1-12.5) vs 537.9 ng/L (IQR: 423.1-728.4), P < 0.001 for ACE-I; and 4.5 ng/L (IQR: 1.4-11.2) vs 203.0 ng/L (IQR: 130.2-247.9), P = 0.003 for ARB] and AngII [<1.4 ng/L (IQR: <1.4-1.5) vs 6.1 ng/L (IQR: 2.0-11.1), P = 0.002 for ACE-I and 4.7 ng/L (IQR: <1.4-12.3) vs 206.4 ng/L (IQR: 142.2-234.4), P < 0.001 for ARB]. CONCLUSIONS: In addition to NT-proBNP and NYHA stages, ARC enables classification of HFrEF patients receiving OMT into more distinguished neurohumoral HFrEF phenotypes, offering a rationale for adaptive therapeutic interventions.

N-terminal B-type natriuretic peptide (NT-proBNP) is associated with disease severity in multiple myeloma.

BACKGROUND: Elevated levels of cardiovascular markers including N-terminal B-type natriuretic peptide (NT-proBNP) have been shown to be associated with disease severity and mortality in an unselected population of cancer patients without cardiac disease. The aim of this study was to investigate whether NT-proBNP levels are related to disease severity in multiple myeloma (MM) and to assess the natural course of NT-proBNP levels throughout disease progression. MATERIALS AND METHODS: We retrospectively analysed a total of 118 patients with MM, who were followed up routinely. NT-proBNP, beta-2-microglobulin (B2M) and levels of plasma cell-derived light chains were measured at baseline and follow-up (FUP) visits. All-cause mortality was defined as primary study endpoint, and the correlation between NT-proBNP and disease severity reflected by B2M and the International Staging System (ISS) was assessed. RESULTS: During a median FUP of 845 (IQR:683-978) days, 31 patients (26%) died. NT-proBNP showed a highly significant positive correlation with B2M at first presentation [r = .65, P < .001] and increased significantly with progressing MM disease stage [133.3 pg/mL (IQR:51.5-282.0) for ISS stage 1, 487.4 pg/mL (IQR:123.8-738.3) for ISS stage 2 and 969.1 pg/mL (IQR:472.8-3748.0) for ISS stage 3, P < .001 between all groups]. During FUP, NT-proBNP levels rose significantly alongside other MM disease severity markers for patients experiencing the primary outcome [356.6 pg/mL (IQR:142.9-782.3) vs 862.9 pg/mL (IQR:338.8-4215.0), P < .001], whereas no significant changes in laboratory parameters could be detected for survivors. CONCLUSIONS: Elevated levels of the cardiovascular marker NT-proBNP are associated with disease severity in patients with MM.

Polyunsaturated fatty acids supplementation impairs anti-oxidant high-density lipoprotein function in heart failure.

BACKGROUND: The underlying reasons for the highly inconsistent clinical outcome data for omega-3-polyunsaturated fatty acids (n3-PUFAs) supplementation in patients with cardiac disease have not been understood yet. The aim of this prospective, randomized, double-blind, placebo controlled study was to determine the effects of oral treatment with n3-PUFAs on the anti-oxidant capacity of HDL in heart failure (HF) patients. METHODS: A total of 40 patients with advanced HF of nonischaemic origin, defined by NT-proBNP levels of >2000 pg/mL, NYHA class III or IV and a LVEF <35% who were on stable optimized medical therapy for ≥3 months, were consecutively enrolled into this prospective, double-blind, placebo-controlled trial and randomized in a 1:1:1 fashion to receive 1 g/day or 4 g/day of n3-PUFA, or placebo, respectively, for 12 weeks. RESULTS: After 12 weeks of treatment, the anti-oxidant function of HDL, measured by the HDL inflammatory index, was found significantly impaired in the treatment group in a dose-dependent fashion with 0.67 [IQR 0.49-1.04] for placebo vs 0.71 [IQR 0.55-1.01] for 1 g/day n3-PUFA vs 0.98 [IQR 0.73-1.16] for 4 g/day n3-PUFA (P for trend = 0.018). CONCLUSION: We provide evidence for an adverse effect of n3-PUFA supplementation on anti-oxidant function of HDL in nonischaemic heart failure patients, establishing a potential mechanistic link for the controversial outcome data on n3-PUFA supplementation.

Sublingual functional capillary rarefaction in chronic heart failure.

BACKGROUND AND OBJECTIVE: Microcirculatory changes contribute to clinical symptoms and disease progression in chronic heart failure (CHF). A depression of coronary flow reserve is associated with a lower myocardial capillary density in biopsies. We hypothesized that changes in cardiac microcirculation might also be reflected by a systemic reduction in capillaries and visualized by sublingual videomicroscopy. The aim was to study in vivo capillary density and glycocalyx dimensions in patients with CHF vs healthy controls. METHODS: Fifty patients with ischaemic and nonischaemic CHF and standard treatment were compared to 35 healthy age-matched subjects in a prospective cross-sectional study. Sublingual microcirculation was visualized using a sidestream darkfield videomicroscope. Functional and perfused total capillary densities were compared between patients and controls. A reduced glycocalyx thickness was measured by an increased perfused boundary region (PBR). RESULTS: Median functional and total perfused capillary densities were 30% and 45% lower in patients with CHF (both P < .001). Intake of oral vitamin K antagonists was associated with significantly lower capillary densities (P < .05), but not independent of NT-proBNP. Dimensions of the glycocalyx were marginally lower in CHF patients than in healthy controls (<7% difference). However, PBR correlated significantly with inflammation markers (fibrinogen: r = .58; C-reactive protein: r = .42), platelet counts (r = .36) and inversely with measures of liver/renal function such as bilirubin (r = -.38) or estimated glomerular filtration rate (r = -.34) in CHF patients. CONCLUSION: CHF patients have got a markedly lower functional and total perfused capillary density in sublingual microvasculature when compared to controls, indicating a systemic decrease in microcirculation.

GDF-15 Is Associated with Cancer Incidence in Patients with Type 2 Diabetes.

BACKGROUND: Diabetes has been linked epidemiologically to increased cancer incidence and mortality. Growth differentiation factor 15 (GDF-15) is increased in patients with diabetes and has recently been linked to the occurrence of cancer. We investigated whether circulating GDF-15 concentrations can predict the incidence of malignant diseases in a diabetic patient cohort already facing increased risk for cancer. METHODS: We prospectively enrolled a total of 919 patients with type 2 diabetes and no history of malignant disease, who were clinically followed up for 60 months. GDF-15, N-terminal pro-B-type natriuretic peptide and troponin T were measured at baseline; an additional 4 cardiovascular biomarkers were determined for a subpopulation (n = 259). Study end point was defined as the first diagnosis of any type of cancer during the follow-up period. RESULTS: During a median follow-up of 60 months, 66 patients (7.2%) were diagnosed with cancer. Baseline circulating GDF-15 concentrations were higher in patients that developed cancer over the follow-up period when compared to cancer-free patients. Increased GDF-15 concentrations were significantly associated with cancer incidence [crude hazard ratio (HR) per 1-IQR (interquartile range) increase 2.13, 95% CI 1.53-2.97, P < 0.001]. This effect persisted after multivariate adjustment with an adjusted HR of 1.86 (95% CI 1.22-2.84; P = 0.004). Among the 4 additionally tested cardiovascular markers in the subpopulation, only troponin T and C-terminal proendothelin-1 showed a significant association with future cancer incidence with unadjusted HRs of 1.71 (95% CI 1.28-2.28, P < 0.001) and 1.68 (95% CI 1.02-2.76, P = 0.042), respectively. CONCLUSIONS: Increased circulating concentrations of GDF-15 are associated with increased cancer incidence in patients with type 2 diabetes.

Outcome of conservative management vs. assist device implantation in patients with advanced refractory heart failure.

BACKGROUND: In patients with advanced refractory heart failure (HF) cardiac transplantation (HTX), conservative medical management and the implantation of a ventricular assist device (VAD) represent valuable options. The determination of the best therapeutic destination strategy for the individual patient remains a challenge. The aim of this study was to assess the clinical outcome in advanced refractory HF patients either managed conservatively receiving optimal contemporary medical therapy ('conservative'), or who who underwent pulsatile flow VAD ('pVAD') or continuous-flow VAD ('contVAD') implantation. MATERIALS AND METHODS: A total of 118 patients with INTERMACS profile >1 at baseline, who died, or fully completed a 24-month follow-up free from HTX were included into this retrospective analysis. All-cause mortality at 24 months was assessed and compared between the three groups. RESULTS: Fifty (42%) patients were managed conservatively, 25 (21%) received a pVAD and 43 (36%) a contVAD. NT-proBNP values were comparable between the three groups (median 4402 (IQR 2730-13390) pg/mL, 3580 (1602-6312) pg/mL and 3693 (2679-8065) pg/mL, P = 0·256). Mean survival was 18·6 (95% CI 16·2-21·0) months for patients managed conservatively, 7·0 (3·9-10·0) for pVAD and 20·5 (18·2-22·8) for contVAD (overall log-rank test P < 0·001). Conservatively managed patients spent a mean of 22·4 (95% CI 22·1-22·8), pVAD 17·7 (15·4-20·1) and contVAD 21·6 (21·2-22·1) months out of hospital (conservative vs. pVAD P < 0·001; conservative vs. contVAD P = 0·015; pVAD vs. contVAD P < 0·001). CONCLUSIONS: In accordance with the literature, contVAD resulted in a significantly better clinical outcome than pVAD implantation. However, conservative management with current optimal medical therapy appears to remain a valuable option for patients with advanced HF.

Real-world performance of plasma p-tau181 in a heterogeneous memory clinic cohort.

OBJECTIVE: In light of clinical trials and disease-modifying therapies, an early identification of patients at-risk of developing Alzheimer's disease (AD) is crucial. Blood-based biomarkers have shown promising results regarding the in vivo detection of the earliest neuropathological changes in AD. Herein, we investigated the ability of plasma p-tau181 to act as a prescreening marker for amyloid positivity in a heterogeneous memory clinic-based cohort. METHODS: In this retrospective cross-sectional study, we included a total of 115 patients along the clinical AD continuum (mild cognitive impairment [MCI] due to AD, n = 62, probable AD dementia, n = 53). Based on their biomarker status, they were stratified into an amyloid-positive (Aß+, n = 88) or amyloid-negative cohort (Aß-, n = 27). Plasma and CSF p-tau181 concentrations were quantified using an ultrasensitive single-molecule array (SIMOA©). Furthermore, age- and sex-adjusted receiver operating characteristic (ROC) curves were calculated and the area under the curve (AUC) of each model was compared using DeLong's test for correlated AUC curves. RESULTS: The median (interquartile range [IQR]) concentration of plasma p-tau181 was significantly higher in Aß+ patients (3.6 pg/mL [2.5-4.6]), compared with Aß- patients (1.7 pg/mL [1.2-1.9], p < 0.001). Regarding the distinction between Aß+ and Aß- patients and the prediction of amyloid positivity, a high diagnostic accuracy for plasma p-tau181 with an AUC of 0.89 (95% CI = 0.82-0.95) was calculated. Adding the risk factors, age and APOE4, to the model did not significantly improve its performance. INTERPRETATION: Our findings demonstrate that plasma p-tau181 could be a noninvasive and feasible prescreening marker for amyloid positivity in a heterogeneous clinical AD cohort and therefore help in identifying those who would benefit from more invasive assessment of amyloid pathology.