Brand first? The effect of hotel online word-of-mouth on consumer brand sensitivity.

With the e-commerce development and changing of hotels' booking channels, the online word-of-mouth, as a new signal of quality, is becoming to attract more attention of consumers. Using the scenario experiment, this study explores the effect of online word-of-mouth on brand sensitivity of consumers during the decision making for hotel booking. The results show that if the information about hotels obtained is limited in the decision-making process, consumers would have a higher sensitivity to the hotel brand. Increasing information about the online word-of-mouth can effectively reduce consumers' brand sensitivity to hotels. Besides, the moderating effect of the hotel grade on the relationship between the online word-of-mouth and brand sensitivity is affected by the scale of the negative differences of word-of-mouth.

Increased Trimethylamine N-Oxide Portends High Mortality Risk Independent of Glycemic Control in Patients with Type 2 Diabetes Mellitus.

BACKGROUND: Recent studies show a mechanistic link between intestinal microbial metabolism of dietary phosphatidylcholine and coronary artery disease pathogenesis. Concentrations of a proatherogenic gut microbe-generated metabolite, trimethylamine N-oxide (TMAO), predict increased incident cardiovascular disease risks in multiple cohorts. TMAO concentrations are increased in patients with type 2 diabetes mellitus (T2DM), but their prognostic value and relation to glycemic control are unclear. METHODS: We examined the relationship between fasting TMAO and 2 of its nutrient precursors, choline and betaine, vs 3-year major adverse cardiac events and 5-year mortality in 1216 stable patients with T2DM who underwent elective diagnostic coronary angiography. RESULTS: TMAO [4.4 µmol/L (interquartile range 2.8-7.7 µmol/L) vs 3.6 (2.3-5.7 µmol/L); P < 0.001] and choline concentrations were higher in individuals with T2DM vs healthy controls. Within T2DM patients, higher plasma TMAO was associated with a significant 3.0-fold increased 3-year major adverse cardiac event risk (P < 0.001) and a 3.6-fold increased 5-year mortality risk (P < 0.001). Following adjustments for traditional risk factors and high-sensitivity C-reactive protein, glycohemoglobin, and estimated glomerular filtration rate, increased TMAO concentrations remained predictive of both major adverse cardiac events and mortality risks in T2DM patients [e.g., quartiles 4 vs 1, hazard ratio 2.05 (95% CI, 1.31-3.20), P < 0.001; and 2.07 (95% CI, 1.37-3.14), P < 0.001, respectively]. CONCLUSIONS: Fasting plasma concentrations of the proatherogenic gut microbe-generated metabolite TMAO are higher in diabetic patients and portend higher major adverse cardiac events and mortality risks independent of traditional risk factors, renal function, and relationship to glycemic control.

Trimethylamine N-Oxide and Mortality Risk in Patients With Peripheral Artery Disease.

BACKGROUND: Production of the proatherogenic metabolite, trimethylamine N-oxide (TMAO), from dietary nutrients by intestinal microbiota enhances atherosclerosis development in animal models and is associated with atherosclerotic coronary artery disease in humans. The utility of studying plasma levels of TMAO to risk stratify in patients with peripheral artery disease (PAD) has not been reported. METHODS AND RESULTS: We examined the relationship between fasting plasma TMAO and all-cause mortality (5-year), stratified by subtypes of PAD and presence of coronary artery disease in 935 patients with PAD who underwent elective angiography for cardiac evaluation at a tertiary care hospital. Median plasma TMAO was 4.8 µmol/L (interquartile range, 2.9-8.0 µmol/L). Elevated TMAO levels were associated with 2.7-fold increased mortality risk (fourth versus first quartiles, hazard ratio 2.86, 95% CI 1.82-3.97, P<0.001). Following adjustments for traditional risk factors, inflammatory biomarkers, and history of coronary artery disease, the highest TMAO quartile remained predictive of 5-year mortality (adjusted hazard ratio 2.06, 95% CI 1.36-3.11, P<0.001). Similar prognostic value for elevated TMAO was seen for subjects with carotid artery, non-carotid artery, or lower extremity PAD. TMAO provided incremental prognostic value for all-cause mortality (net reclassification index, 40.22%; P<0.001) and improvement in area under receiver operator characteristic curve (65.7% versus 69.4%; P=0.013). CONCLUSIONS: TMAO, a pro-atherogenic metabolite formed by gut microbes, predicts long-term adverse event risk and incremental prognostic value in patients with PAD. These findings point to the potential for TMAO to help improve selection of high-risk PAD patients with or without significant coronary artery disease, who likely need more aggressive and specific dietary and pharmacologic therapy.

Intestinal Microbiota-Generated Metabolite Trimethylamine-N-Oxide and 5-Year Mortality Risk in Stable Coronary Artery Disease: The Contributory Role of Intestinal Microbiota in a COURAGE-Like Patient Cohort.

BACKGROUND: Trimethylamine-N-oxide (TMAO), a metabolite derived from gut microbes and dietary phosphatidylcholine, is linked to both coronary artery disease pathogenesis and increased cardiovascular risks. The ability of plasma TMAO to predict 5-year mortality risk in patients with stable coronary artery disease has not been reported. This study examined the clinical prognostic value of TMAO in patients with stable coronary artery disease who met eligibility criteria for a patient cohort similar to that of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial. METHODS AND RESULTS: We examined the relationship between fasting plasma TMAO and all-cause mortality over 5-year follow-up in sequential patients with stable coronary artery disease (n=2235) who underwent elective coronary angiography. We identified the COURAGE-like patient cohort as patients who had evidence of significant coronary artery stenosis and who were managed with optimal medical treatment. Higher plasma TMAO levels were associated with a 4-fold increased mortality risk. Following adjustments for traditional risk factors, high-sensitivity C-reactive protein, and estimated glomerular filtration rate, elevated TMAO levels remained predictive of 5-year all-cause mortality risk (quartile 4 versus 1, adjusted hazard ratio 1.95, 95% CI 1.33-2.86; P=0.003). TMAO remained predictive of incident mortality risk following cardiorenal and inflammatory biomarker adjustments to the model (adjusted hazard ratio 1.71, 95% CI 1.11-2.61; P=0.0138) and provided significant incremental prognostic value for all-cause mortality (net reclassification index 42.37%, P<0.001; improvement in area under receiver operator characteristic curve 70.6-73.76%, P<0.001). CONCLUSIONS: Elevated plasma TMAO levels portended higher long-term mortality risk among patients with stable coronary artery disease managed with optimal medical treatment.

Prognostic value of estimating functional capacity with the use of the duke activity status index in stable patients with chronic heart failure.

BACKGROUND: Over the years, several methods have been developed to reliably quantify functional capacity in patients with heart failure. Few studies have investigated the prognostic value of these assessment tools beyond cardiorenal prognostic biomarkers in stable patients with chronic heart failure. METHODS AND RESULTS: We administered the Duke Activity Status Index (DASI) questionnaire, a self-assessment tool comprising 12 questions for estimating functional capacity, to 1,700 stable nonacute coronary syndrome patients with history of heart failure who underwent elective diagnostic coronary angiography with 5-year follow-up of all-cause mortality. In a subset of patients (n = 800), B-type natriuretic peptide (BNP) was measured. In our study cohort, the median DASI score was 26.2 (interquartile range [IQR] 15.5-42.7). Low DASI score provided independent prediction of a 3.3-fold increase in 5-year mortality risk (quartile 1 vs quartile 4: hazard ratio [HR] 3.33, 95% confidence interval [CI] 2.57-4.36; P < .0001). After adjusting for traditional risk factors, BNP, and estimated glomerular filtration rate, low DASI score still conferred a 2.6-fold increase in mortality risk (HR 2.57, 95% CI 1.64-4.15; P < .0001). CONCLUSIONS: A simple self-assessment tool of functional capacity provides independent and incremental prognostic value for mortality prediction in stable patients with chronic heart failure beyond cardiorenal biomarkers.

Prognostic value of elevated levels of intestinal microbe-generated metabolite trimethylamine-N-oxide in patients with heart failure: refining the gut hypothesis.

BACKGROUND: Altered intestinal function is prevalent in patients with heart failure (HF), but its role in adverse outcomes is unclear. OBJECTIVES: This study investigated the potential pathophysiological contributions of intestinal microbiota in HF. METHODS: We examined the relationship between fasting plasma trimethylamine-N-oxide (TMAO) and all-cause mortality over a 5-year follow-up in 720 patients with stable HF. RESULTS: The median TMAO level was 5.0 µM, which was higher than in subjects without HF (3.5 µM; p < 0.001). There was modest but significant correlation between TMAO concentrations and B-type natriuretic peptide (BNP) levels (r = 0.23; p < 0.001). Higher plasma TMAO levels were associated with a 3.4-fold increased mortality risk. Following adjustments for traditional risk factors and BNP levels, elevated TMAO levels remained predictive of 5-year mortality risk (hazard ratio [HR]: 2.2; 95% CI: 1.42 to 3.43; p < 0.001), as well as following the addition of estimated glomerular filtration rate to the model (HR: 1.75; 95% CI: 1.07 to 2.86; p < 0.001). CONCLUSIONS: High TMAO levels were observed in patients with HF, and elevated TMAO levels portended higher long-term mortality risk independent of traditional risk factors and cardiorenal indexes.

Prognostic value of estimated functional capacity incremental to cardiac biomarkers in stable cardiac patients.

BACKGROUND: Few studies have investigated functional capacity self-assessment tools in either prediction of future major adverse cardiac outcomes beyond all-cause mortality or direct comparisons with clinically available biomarkers. METHODS AND RESULTS: We estimated functional capacity using the Duke Activity Status Index (DASI) questionnaire in 8987 sequential stable patients without acute coronary syndrome who were undergoing elective diagnostic coronary angiography with 3-year follow-up of major adverse cardiac events (death, nonfatal myocardial infarction, or stroke). A low DASI score provided independent prediction of a 4.8-fold increase in future risk of incident major adverse cardiac events at 3 years (quartiles 1 versus 4 hazard ratio [95% CI] 4.76 [4.03 to 5.61], P<0.001), and a 3.8-fold increased risk after adjusting for traditional risk factors (3.77 [3.15 to 4.51], P<0.001). The prognostic value of the DASI score was evident in both primary and secondary prevention cohorts, with and without heart failure, as well as high and low C-reactive protein and B-type natriuretic peptide levels. The DASI score reclassified 15% of patients (P<0.001) beyond traditional risk factors in predicting future MACE. CONCLUSION: A simple self-assessment tool of functional capacity in stable patients undergoing elective diagnostic cardiac evaluation provides independent and incremental prognostic value for prediction of both significant coronary angiographic disease and long-term adverse clinical events.

Prognostic value of elevated serum ceruloplasmin levels in patients with heart failure.

BACKGROUND: Ceruloplasmin (Cp) is a copper-binding acute-phase protein that is increased in inflammatory states and deficient in Wilson's disease. Recent studies demonstrate that increased levels of Cp are associated with increased risk of developing heart failure. Our objective was to test the hypothesis that serum Cp provides incremental and independent prediction of survival in stable patients with heart failure. METHODS AND RESULTS: We measured serum Cp levels in 890 patients with stable heart failure undergoing elective cardiac evaluation that included coronary angiography. We examined the role of Cp levels in predicting survival over 5 years of follow-up. Mean Cp level was 26.6 ± 6.9 mg/dL and demonstrated relatively weak correlation with B-type natriuretic peptide (BNP; r = 0.187; P < .001). Increased Cp levels were associated with increased 5-year all-cause mortality (quartile [Q] 4 vs Q1 hazard ratio [HR] 1.9, 95% confidence interval [CI] 1.4-2.8; P < .001). When controlled for coronary disease traditional risk factors, creatinine clearance, dialysis, body mass index, medications, history of myocardial infarction, BNP, left ventricular ejection fraction (LVEF), heart rate, QRS duration, left bundle branch blockage, and implantable cardioverter-defibrillator placement, higher Cp remained an independent predictor of increased mortality (Q4 vs Q1 HR 1.7, 95% CI 1.1-2.6; P < .05). Model quality was improved with addition of Cp to the aforementioned covariables (net reclassification improvement of 9.3%; P < .001). CONCLUSIONS: Ceruloplasmin is an independent predictor of all-cause mortality in patients with heart failure. Measurement of Cp may help to identify patients at heightened mortality risk.

Prognostic value of choline and betaine depends on intestinal microbiota-generated metabolite trimethylamine-N-oxide.

AIMS: Recent metabolomics and animal model studies show trimethylamine-N-oxide (TMAO), an intestinal microbiota-dependent metabolite formed from dietary trimethylamine-containing nutrients such as phosphatidylcholine (PC), choline, and carnitine, is linked to coronary artery disease pathogenesis. Our aim was to examine the prognostic value of systemic choline and betaine levels in stable cardiac patients. METHODS AND RESULTS: We examined the relationship between fasting plasma choline and betaine levels and risk of major adverse cardiac events (MACE = death, myocardial infraction, stroke) in relation to TMAO over 3 years of follow-up in 3903 sequential stable subjects undergoing elective diagnostic coronary angiography. In our study cohort, median (IQR) TMAO, choline, and betaine levels were 3.7 (2.4-6.2)µM, 9.8 (7.9-12.2)µM, and 41.1 (32.5-52.1)µM, respectively. Modest but statistically significant correlations were noted between TMAO and choline (r = 0.33, P < 0.001) and less between TMAO and betaine (r = 0.09, P < 0.001). Higher plasma choline and betaine levels were associated with a 1.9-fold and 1.4-fold increased risk of MACE, respectively (Quartiles 4 vs. 1; P < 0.01, each). Following adjustments for traditional cardiovascular risk factors and high-sensitivity C-reactive protein, elevated choline [1.34 (1.03-1.74), P < 0.05], and betaine levels [1.33 (1.03-1.73), P < 0.05] each predicted increased MACE risk. Neither choline nor betaine predicted MACE risk when TMAO was added to the adjustment model, and choline and betaine predicted future risk for MACE only when TMAO was elevated. CONCLUSION: Elevated plasma levels of choline and betaine are each associated with incident MACE risk independent of traditional risk factors. However, high choline and betaine levels are only associated with higher risk of future MACE with concomitant increase in TMAO.

Plasma ceruloplasmin, a regulator of nitric oxide activity, and incident cardiovascular risk in patients with CKD.

BACKGROUND AND OBJECTIVES: Increased serum levels of the acute-phase reactant ceruloplasmin predict adverse clinical outcomes in the setting of acute coronary syndromes and heart failure, but their role in patients with CKD is unclear. This study investigated the relationship of ceruloplasmin with clinical outcomes in CKD, especially with regard to traditional cardiac biomarkers. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Serum ceruloplasmin levels in consecutive study participants with CKD (n=654; estimated GFR<60 ml/min per 1.73 m(2)) as well as a control group of non-CKD participants matched for age and sex (n=250) were measured. Study participants were enrolled during 2001-2006 from a population of patients presenting for elective diagnostic coronary angiography and prospectively followed for 3 years (median follow-up=1095 days) to determine incident major adverse cardiac events (defined as a composite of death, nonfatal myocardial infarction, and stroke). RESULTS: Serum ceruloplasmin levels in CKD patients were elevated versus controls (median [interquartile range]; 25.5 [21.8-29.6] versus 22.7 [19.7-26.5] mg/dl; P<0.001) and associated with increased risk of future major adverse cardiac events (hazard ratio, 1.35; 95% confidence interval, 1.0 to 1.82; P=0.04). After adjusting for traditional risk factors, higher serum ceruloplasmin was still associated with higher risk of major adverse cardiac events at 3 years (hazard ratio, 1.61; 95% confidence interval, 1.15 to 2.25; P=0.01). CONCLUSION: In CKD patients, increased serum ceruloplasmin, a regulator of nitric oxide activity, is associated with increased risk of long-term adverse cardiovascular events, even after multivariable model adjustment for traditional clinical and biologic risk factors.

Diminished antioxidant activity of high-density lipoprotein-associated proteins in chronic kidney disease.

BACKGROUND: Decreased serum arylesterase activity, catalyzed by the high-density lipoprotein-associated paraoxonase (PON)-1, is associated with increased oxidant stress and atherosclerosis risk. We sought to determine the prognostic value of serum PON-1 activity, as monitored by PON or arylesterase activities, in subjects with chronic kidney disease (CKD), particularly in relation to established cardiac biomarkers. METHODS AND RESULTS: Serum arylesterase and PON activities were measured in sequential subjects with CKD (n=630; estimated glomerular filtration rate [eGFR] <60 mL/min per 1.73 m(2)) and an age- and sex-matched control group of non-CKD subjects (n=315) presenting for cardiac evaluations and prospectively followed for incident (3-year) major adverse cardiac events (composite of death, nonfatal myocardial infarction, and stroke). Serum arylesterase activity in CKD subjects was lower compared with that in non-CKD control subjects [median (interquartile range) 94 (77 to 112) versus 103 (85 to 121) µmol(L·min) per mL, P<0.001]; similarly, PON activity in CKD subjects was lower compared with that in non-CKD control subjects [median (interquartile range) 474 (275 to 936) versus 586 (301 to 1118) nmol(L·min) per mL, P<0.001]. Lower serum arylesterase (hazard ratio 1.8, 95% CI 1.26 to 2.57, P<0.01) was a predictor of poorer outcomes. After adjusting for traditional risk factors and medication use, lower serum arylesterase (hazard ratio 1.55, 95% CI 1.08 to 2.23, P<0.05) still conferred an increased risk of major adverse cardiac events at 3 years. CONCLUSIONS: In patients with CKD, decreased serum arylesterase activity, a measure of diminished antioxidant properties of PON-1, predicts higher risk of incident long-term adverse cardiovascular events (heart attack, stroke, or death) in multivariable models adjusting for established clinical and biochemical risk factors.

Clinical and genetic association of serum paraoxonase and arylesterase activities with cardiovascular risk.

OBJECTIVE: Diminished serum paraoxonase and arylesterase activities (measures of paraoxonase-1 [PON-1] function) in humans have been linked to heightened systemic oxidative stress and atherosclerosis risk. The clinical prognostic use of measuring distinct PON-1 activities has not been established, and the genetic determinants of PON-1 activities are not known. METHODS AND RESULTS: We established analytically robust high-throughput assays for serum paraoxonase and arylesterase activities and measured these in 3668 stable subjects undergoing elective coronary angiography without acute coronary syndrome and were prospectively followed for major adverse cardiovascular events (MACE= death, myocardial infarction, stroke) over 3 years. Low serum arylesterase and paraoxonase activities were both associated with increased risk for MACE, with arylesterase activity showing greatest prognostic value (quartile 4 versus quartile 1; hazard ratio 2.63; 95% CI, 1.97-3.50; P<0.01). Arylesterase remained significant after adjusting for traditional risk factors, C-reactive protein, and creatinine clearance (hazard ratio, 2.20; 95% CI, 1.60-3.02; P<0.01), predicted future development of MACE in both primary and secondary prevention populations, and reclassified risk categories incrementally to traditional clinical variables. A genome-wide association study identified distinct single nucleotide polymorphisms within the PON-1 gene that were highly significantly associated with serum paraoxonase (1.18×10(-303)) or arylesterase (4.99×10(-116)) activity but these variants were not associated with either 3-year MACE risk in an angiographic cohort (n=2136) or history of either coronary artery disease or myocardial infarction in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis consortium (n≈80 000 subjects). CONCLUSIONS: Diminished serum arylesterase activity, but not the genetic determinants of PON-1 functional measures, provides incremental prognostic value and clinical reclassification of stable subjects at risk of developing MACE.

Nitrated fibrinogen is a biomarker of oxidative stress in venous thromboembolism.

The pathogenesis of venous thromboembolism (VTE) is linked to inflammation and oxidant production, although specific markers for these pathways with pathological relevance to VTE have not been explored. The coagulant protein fibrinogen is posttranslationally modified by nitric oxide-derived oxidants to nitrated fibrinogen in both acute and chronic inflammatory states. Therefore, nitrated fibrinogen may serve as a marker of inflammation and oxidative stress in VTE. To test this hypothesis we enrolled subjects (n=251) presenting with suspected VTE at the University of Pennsylvania Hospital emergency department, 50 (19.9%) of whom were positive by imaging or 90-day follow-up. Mean nitrated fibrinogen was elevated in VTE-positive (62.7 nM, 95% CI 56.6-68.8) compared to VTE-negative patients (54.2 nM, 95% CI 51.4-57.1; P<0.01). Patients in the highest quartile of nitrated fibrinogen had an increased risk of VTE compared with patients in the lowest quartile (OR 3.30; 95% CI 1.25-8.68; P<0.05). This risk persisted after univariate adjustment for age, active cancer, and recent surgery, but not after multivariate adjustment. Mean fibrinogen levels measured either by the Clauss assay or by ELISA were not different between VTE-negative and VTE-positive patients. These data indicate that nitrated fibrinogen is an oxidative risk marker in VTE, providing a novel mechanistic link between oxidant production, inflammation, and VTE.

Clinical and genetic association of serum ceruloplasmin with cardiovascular risk.

OBJECTIVE: Ceruloplasmin (Cp) is an acute-phase reactant that is increased in inflammatory diseases and in acute coronary syndromes. Cp has recently been shown to possess nitric oxide (NO) oxidase catalytic activity, but its impact on long-term cardiovascular outcomes in stable cardiac patients has not been explored. METHODS AND RESULTS: We examined serum Cp levels and their relationship with incident major adverse cardiovascular events (MACE; death, myocardial infarction [MI], stroke) over 3-year follow-up in 4177 patients undergoing elective coronary angiography. We also carried out a genome-wide association study to identify the genetic determinants of serum Cp levels and evaluate their relationship to prevalent and incident cardiovascular risk. In our cohort (age 63±11 years, 66% male, 32% history of MI, 31% diabetes mellitus), mean Cp level was 24±6 mg/dL. Serum Cp level was associated with greater risk of MI at 3 years (hazard ratio [quartile 4 versus 1] 2.35, 95% confidence interval [CI] 1.79-3.09, P<0.001). After adjustment for traditional risk factors, high-sensitivity C-reactive protein, and creatinine clearance, Cp remained independently predictive of MACE (hazard ratio 1.55, 95% CI 1.10-2.17, P=0.012). A 2-stage genome-wide association study identified a locus on chromosome 3 over the CP gene that was significantly associated with Cp levels (lead single-nucleotide polymorphism rs13072552; P=1.90×10(-11)). However, this variant, which leads to modestly increased serum Cp levels (≈1.5-2 mg/dL per minor allele copy), was not associated with coronary artery disease or future risk of MACE. CONCLUSIONS: In stable cardiac patients, serum Cp provides independent risk prediction of long-term adverse cardiac events. Genetic variants at the CP locus that modestly affect serum Cp levels are not associated with prevalent or incident risk of coronary artery disease in this study population.