Association of growth differentiation factor-15 with coronary atherosclerosis and mortality in a young, multiethnic population: observations from the Dallas Heart Study.

BACKGROUND: Growth differentiation factor 15 (GDF-15) is produced by cardiomyocytes and atherosclerotic lesions under stress conditions. Although higher circulating GDF-15 concentrations are associated with mortality across a spectrum of cardiovascular conditions, the relationship of GDF-15 with atherosclerosis and mortality in the general population remains undefined. METHODS: We measured plasma GDF-15 in 3219 participants of the Dallas Heart Study, a population sample of adults ages 30-65 years (55% women, 49% black). GDF-15 was analyzed in prespecified categories (<1200; 1200-1799; and ≥1800 ng/L) and continuously. End points included prevalent coronary artery calcium (CAC>10 Agatston units), increased CAC (CAC≥100 Agatston units) by electron beam computed tomography, and mortality through a median 7.3 years of follow-up (120 deaths, 48 cardiovascular deaths). RESULTS: Increasing GDF-15 associated with older age, black race, hypertension, diabetes, smoking, left ventricular (LV) mass/body surface area, and worse renal function (P<0.0001 for each). In multivariable models adjusted for traditional risk factors, renal function, and LV mass/body surface area, GDF-15≥1800 ng/L was associated with CAC>10 (odds ratio 2.1; 95% CI 1.2-3.7; P=0.01), CAC≥100 (odds ratio 2.6; 95% CI 1.4-4.9; P=0.002), all-cause mortality (hazard ratio 3.5; 95% CI 2.1-5.9, P<0.0001), and cardiovascular mortality (hazard ratio 2.5; 95% CI 1.1-5.8, P=0.03). Adding log GDF-15 to fully adjusted models modestly improved the c statistic (P=0.025), the integrated discrimination index (0.028; P<0.0001) and the category-less net reclassification index (0.42; P=0.002). These findings remained significant with further adjustment for high-sensitivity C-reactive protein, N-terminal pro-B-type natriuretic peptide, and cardiac troponin T. CONCLUSIONS: GDF-15 is independently associated with subclinical coronary atherosclerosis and mortality, and its potential role for risk stratification in the general population merits further evaluation.

Prospective, comprehensive assessment of cardiac troponin T testing after coronary artery bypass graft surgery.

BACKGROUND: The significance and clinical role of cardiac troponin testing after coronary artery bypass grafting remain unclear. METHODS AND RESULTS: Cardiac troponin T (cTnT) was measured during the first 24 hours after coronary artery bypass graft surgery in 847 consecutive patients. Only 17 patients (2.0%) had new Q waves or left bundle-branch block after surgery; however, cTnT elevation was observed in nearly all subjects, with a median cTnT concentration of 1.08 ng/mL overall. Direct predictors of postoperative cTnT values included preoperative myocardial infarction (P<0.001), preoperative intraaortic balloon pump (P<0.001), intraoperative/postoperative intraaortic balloon pump (P<0.001), number of distal anastomoses (P=0.005), bypass time (P<0.001), and number of intraoperative defibrillations (P=0.009), whereas glomerular filtration rate (P<0.001), off-pump coronary artery bypass grafting (P=0.003), and use of warm cardioplegia (P=0.02) were inversely associated with cTnT values. A linear association was seen between cTnT levels and length of stay and ventilator hours, and in an analysis adjusted for the Society for Thoracic Surgery Risk Model, cTnT remained independently prognostic for death (odds ratio, 3.20; P=0.003), death or heart failure (odds ratio, 2.04; P=0.008), death or need for vasopressors (odds ratio, 2.70; P<0.001), and the composite of all 3 (odds ratio, 2.57; P<0.001). In contrast to consensus-endorsed cTnT cut points for postoperative evaluation, a cTnT <1.60 ng/mL had a negative predictive value of 93% to 99% for excluding various post-coronary artery bypass graft surgery complications. CONCLUSIONS: cTnT concentrations after coronary artery bypass graft surgery are nearly universally elevated, are determined by numerous factors, and are independently prognostic for impending postoperative complications when used at appropriate cut points.

Angiogenesis and expression of estrogen and progesterone receptors as predictive factors for recurrence of meningioma.

Meningiomas are benign tumors, with low rate of recurrence after surgery. The most important factor predicting recurrence is the extent of surgical resection; other factors have been studied with conflicting results. Angiogenesis, an important substratum for growth and spread of neoplasic cells, and the expression of estrogen and progesterone receptors (ER, PR), could play a role in the recurrence of meningioma. We evaluated 42 patients with meningioma diagnosis (confirmed by histopathology) treated exclusively by surgery between January 1995 and December 1999, and compared the recurring and non-recurring groups after a ten-year follow-up period. Recurrence was associated with several factors including vascular density (VD), cell proliferation index (CPI), ER, PR, and cyclin E (CE) tissue expression, as evaluated by immunohistochemistry. Complete surgical resection was achieved in 41% of patients. Recurrence of meningioma was found in 17 patients (40%). Median + or - standard deviation (SD) of recurrence time was 32 + or - 5 months. When recurrence versus no recurrence was compared, mean + or - SD of VD and CPI were 9 + or - 3.6 and 607.6 + or - 233 (40x/10 fields) respectively. Tissue expression was positive for ER, PR, and CE in 28, 62 and 91% of patients, respectively. The sole significant recurrence-associated factors were extent of resection (P = 0.003) and VD (P = 0.004). ER, PR, and CE-tissue expression were not statistically significant. The most important factor associated with meningioma relapse was vascular density, independently of hormonal status and extent of surgical resection. Patients with a high risk of recurrence could benefit from additional treatment.

Relative value of amino-terminal pro-B-type natriuretic peptide testing and radiographic standards for the diagnostic evaluation of heart failure in acutely dyspneic subjects.

To define more clearly the relationship between the information provided by the chest radiograph (CXR) and the natriuretic peptide (NT-proBNP) test as part of the evaluation of dyspneic patients presenting to the emergency department with suspected acute heart failure (HF), we evaluated the PRIDE cohort of 599 patients with and without HF, focusing on blinded NT-proBNP and unblinded CXR information. Clinical characteristics and diagnostic performance for each test were compared. We found that NT-proBNP measurement is superior to routine CXR interpretation for diagnosis or exclusion of acute HF and that normal CXR results should not be used to exclude HF in this population.

Association between anxiety and C-reactive protein levels in stable coronary heart disease patients.

BACKGROUND: Anxiety is highly prevalent among patients with stable coronary heart disease (CHD). However, the biologic effects that may connect these two seemingly unrelated disorders is not well understood. OBJECTIVE: This study aimed for a comprehensive evaluation of anxiety in stable CHD patients, in addition to cardiac biomarkers such as C-reactive protein (CRP), troponin T, and amino-terminal pro-B-type brain natriuretic peptide. METHOD: The study included 43 CHD patients with anxiety disorder and 42 CHD patients without psychiatric disorder given the Structured Clinical Interview for DSM-IV. RESULTS: Regression analyses showed an association between anxiety (anxiety disorder, not otherwise specified) and CRP levels, despite model adjustment for various related demographic and clinical variables. Anxiety was associated with CRP levels. CONCLUSION: There are significant associations between anxiety and CHD risk, with a potential biologic link between anxiety and elevations in a biomarker with powerful prognostic risk, namely CRP. It is not clear whether this association is directly causal or relates to other medical processes among patients with heightened anxiety. The findings suggest that the current focus on depressive disorders with respect to biomarkers and CHD outcomes should be broadened to include anxiety disorders, as well.

Association between major depressive disorder and C-reactive protein levels in stable coronary heart disease patients.

OBJECTIVE: This study aimed for a comprehensive evaluation of major depressive disorder (MDD) in stable coronary heart disease (CHD) patients, excluding all other potential psychiatric comorbidities, and including associations with cardiac biomarkers such as C-reactive protein (CRP), troponin T (TnT), and amino-terminal pro-B-type brain natriuretic peptide (NT-proBNP). METHODS: Cross-sectional study of a consecutive series of 72 stable CHD outpatients (n=30 with MDD, n=42 with no psychiatric disorder). Psychiatric diagnoses were established by using the Structured Clinical Interview for DSM-IV (SCID), and psychiatric assessment was performed on Axis I, Axis III, Axis IV, and Axis V. Regression analyses were performed including CRP, TnT, and NT-proBNP as dependent variables, and MDD, demographics, and comorbid medical conditions as independent variables. RESULTS: Stepwise multiple regression analyses showed a significant association between MDD and CRP (beta=0.262, P=.02), excluding all other demographic and medical variables from the models, except age (beta=0.266, P=.02). In addition, the results described a significant relationship between type II diabetes mellitus and TnT (beta=0.267, P=.02), and age and NT-proBNP levels (beta=0.374, P=.001). CONCLUSION: Major depressive disorder was associated with elevated CRP levels in a consecutive series of stable CHD patients.

Clinical uncertainty, diagnostic accuracy, and outcomes in emergency department patients presenting with dyspnea.

BACKGROUND: Dyspnea is a common complaint in the emergency department (ED) and may be a diagnostic challenge. We hypothesized that diagnostic uncertainty in this setting is associated with adverse outcomes, and amino-terminal pro-B-type natriuretic peptide (NT-proBNP) testing would improve diagnostic accuracy and reduce diagnostic uncertainty. METHODS: A total of 592 dyspneic patients were evaluated from the ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE) study. Managing physicians were asked to provide estimates from 0% to 100%of the likelihood of acutely destabilized heart failure (ADHF). A certainty estimate of either 20% or lower or 80% or higher was classified as clinical certainty, while estimates between 21% and 79% were defined as clinical uncertainty. Associations between clinical uncertainty,hospital length of stay, morbidity, and mortality were examined. The diagnostic value of clinical judgment vs NT-proBNP measurement was compared across categories of clinical certainty. RESULTS: Clinical uncertainty was present in 185 patients (31%), 103 (56%) of whom had ADHF. Patients judged with clinical uncertainty had longer hospital length of stay and increased morbidity and mortality,especially those with ADHF. Receiver operating characteristic analysis of clinical judgment yielded an area under the curve (AUC) of 0.88 in the clinical certainty group and 0.76 in the uncertainty group (P<.001); NT-proBNP testing alone in these same groups had AUCs of 0.96 and 0.91, respectively. The combination of clinical judgment with NT-proBNP testing yielded improvements in AUC. CONCLUSIONS: Among dyspneic patients in the ED, clinical uncertainty is associated with increased morbidity and mortality, especially in those with ADHF.The addition of NT-proBNP testing to clinical judgment may reduce diagnostic uncertainty in this setting.

Association between C-reactive protein and generalized anxiety disorder in stable coronary heart disease patients.

AIMS: Comprehensive evaluation of major depressive disorder (MDD), anxiety disorder, and MDD in conjunction with anxiety disorder in stable coronary heart disease (CHD) patients, including cardiac biomarkers such as C-reactive protein (CRP), troponin T (TnT), and amino-terminal pro-B-type brain natriuretic peptide (NT-proBNP). METHODS AND RESULTS: Cross-sectional study of a consecutive series of 120 stable CHD outpatients (n = 30 with MDD, n = 30 with anxiety disorder, n = 30 with MDD and anxiety disorder, n = 30 with no psychiatric disorder). Psychiatric diagnoses were established by using the structured clinical interview for DSM-IV (Diagnostic and Statistical Manual of Mental Disorders-IV). Binomial logistic regression analyses using cut-off scores of biomarkers as dependent variables showed associations between CRP and generalized anxiety disorder (GAD) (P = 0.04), and education (P = 0.004), whereas MDD, and MDD and anxiety disorder did not reach the significance level. TnT showed relationships with hyperlipidaemia (P = 0.009), history of obesity or overweight (P = 0.04), and education (P = 0.04). NT-proBNP was associated with type II diabetes (P = 0.005). CONCLUSION: After adjusting for relevant demographic, medical, and psychiatric co-variables, CRP was associated with GAD.

Biology of the natriuretic peptides.

The biology of the natriuretic peptide (NP) system is complex, yet highly phylogenetically preserved. It regulates salt and water handling, promotes vasodilatation, and exerts favorable effects on the heart in the context of processes such as heart failure. Prior assumptions about the production of B-type NP (BNP) and its amino-terminal precursor fragment (NT-proBNP) have recently been refuted. It is now recognized that rather than a 1:1 secretion of these 2 NPs, a mixture of cleaved and uncleaved NPs is released by the cardiomyocyte. It is also recognized that BNP is rapidly modified into a mixture of various fragments. Commercial assays for the detection of BNP and NT-proBNP measure a mixture of cleaved and uncleaved NPs as well as varying amounts of degraded BNP. BNP and NT-proBNP are cleared differentially: BNP is actively removed from the bloodstream and also has passive clearance mechanisms, including renal clearance; NT-proBNP is cleared more passively by organs with high rates of blood flow, including the kidney.

Inflammatory markers, amino-terminal pro-brain natriuretic peptide, and mortality risk in dyspneic patients.

Dyspnea is a common emergency department (ED) complaint, and it may be associated with significant mortality risk. We studied 599 dyspneic subjects enrolled in an ED. At 1 year, the role of inflammatory markers (including C-reactive protein [CRP]) and amino-terminal pro-brain natriuretic peptide (NT-proBNP) as independent predictors of mortality was assessed. By 1 year, 91 subjects (15.2%) had died. Among patients who died, the median CRP concentration at admission was significantly higher than in survivors: 47.2 mg/L (449.5 nmol/L; interquartile range [IQR], 10.2-101.9 mg/L [97.1-970.5 nmol/L]) vs 7.25 mg/L (69.5 nmol/L; IQR, 2.2-29.6 mg/L [21.0-281.9 nmol/L]; P < .001). For 1-year mortality, CRP had an area under the receiver operating characteristic curve of 0.76 (95% confidence interval [CI], 0.69-0.80; P < .001). In multivariable analysis, a CRP concentration greater than 14 mg/L was a strong predictor of mortality at 1 year (hazard ratio, 2.47; 95% CI, 1.51-4.02; P < .001). In multivariable models, CRP and NT-proBNP demonstrated independent and additive prognostic value. Among dyspneic patients, CRP levels are significantly associated with mortality at 1 year and show additive value to natriuretic peptide testing for prognosis.

Soluble ST2 plasma concentrations predict 1-year mortality in acutely dyspneic emergency department patients with pulmonary disease.

We evaluated the association between ST2 concentrations and mortality at 1 year in 231 acutely dyspneic patients with pulmonary diseases seen in the emergency department. Blood concentrations of ST2 were ascertained; using 1-year survival as the reference standard, receiver operating characteristic curves with resultant area under the curve (AUC) were measured. Cox proportional hazards models identified independent predictors of 1-year death. Hazard curves compared rates of death as a function of ST2 concentration. Concentrations of ST2 were significantly higher in patients with pulmonary diseases compared with 153 subjects without cardiopulmonary disease (0.23 vs 0.11 ng/mL; P = .01). Among patients with pulmonary diseases, concentrations of ST2 were higher among decedents compared with survivors (1.14 ng/mL vs 0.19 ng/mL; P < .001). ST2 had an AUC of 0.72 as a predictor of death (P < .0001). An ST2 of 0.20 ng/mL had a hazard ratio for death of 6.1 (95% confidence interval, 1.8-21.0; P = .004). Compared with patients with lower ST2 concentrations, mortality rates for patients with an enrollment ST2 of 0.20 ng/mL or more diverged early and rose progressively in 1 year (P < .001). ST2 concentrations are frequently elevated in acute pulmonary diseases and are markedly prognostic for death by 1 year.

Independent and incremental prognostic value of multimarker testing in acute dyspnea: results from the ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE) study.

BACKGROUND: Acute dyspnea is common in the emergency department (ED) and is associated with mortality. Biomarkers may help stratify risk in this setting. METHODS: Among 577 dyspneic subjects we identified 5 candidate biomarkers with prognostic value: amino terminal B-type natriuretic peptide (NT-proBNP), C-reactive protein (CRP), the interleukin family member ST2, hemoglobin and blood urea nitrogen (BUN); these were assessed using both receiver operating characteristic curve and Cox proportional hazards analyses. Results were validated in a population of dyspneic patients from a distinct cohort. RESULTS: At 1 y follow up, 93 (16.1%) patients had died. Independent predictive ability was established in an age-adjusted Cox model containing all markers: NT-proBNP (HR=1.89); CRP (HR=1.95); ST2 (HR=7.17); hemoglobin (HR=1.68); BUN (HR=2.06) (all P<.05). Following categorical assessment based on number of abnormal markers, the 1-y risk of death increased in a monotonic fashion with mortality rates of 0%, 2.0%, 7.8%, 22.3%, 29.3%, and 57.6% respectively; similar results were seen in the validation set. CONCLUSION: Simultaneous assessment of pathophysiologically diverse markers in acute dyspnea provides powerful, independent and incremental prognostic information.

Coexpression of hepatocyte growth factor/scatter factor (HGF/SF) and its receptor cMET predict recurrence of meningiomas.

Hepatocyte growth factor/scatter factor (HGF/SF) and its receptor, the cMET tyrosine kinase participate in cancer invasion, angiogenesis and metastasis in a wide variety of neoplastic cells. Meningioma is a bening tumour, however, it has a high rate of recurrence after surgery; the most important factor to predict relapse is the extent of surgical resection, several other potentially predictive factors have been studied with poor results. We examined by immunohistochemistry the expression of HGF/SF and its cMET receptor in a group of patients with benign meningioma with or without recurrence (n = 17 and n = 25, respectively), after a minimal follow-up of least 6 years. Expression and coexpression of HGF/SF and cMET were compared with cell proliferation index, vascular density and clinical outcome. Coexpression of HGF/SF and cMET in meningiomas had a significant association with cell proliferation index and with recurrence (P < 0.037). Determination of HGF and cMET coexpression in meningiomas could be used as a predictor of recurrence.

Addition of highly sensitive troponin T and N-terminal pro-B-type natriuretic peptide to electrocardiography for detection of left ventricular hypertrophy: results from the Dallas Heart Study.

Left ventricular hypertrophy (LVH) is an independent, modifiable risk factor for cardiovascular disease. However, current screening strategies are limited. In 2478 participants without clinical disease from the Dallas Heart Study, we evaluated a multimarker screening strategy that complements electrocardiographic (ECG) criteria for LVH with 2 biomarkers, amino-terminal pro-B-type natriuretic peptide and highly sensitive cardiac troponin T. An integer LVH risk score from 0 to 3 was determined as the sum of the following: (1) LVH by Sokolow-Lyon ECG; (2) amino-terminal pro-B-type natriuretic peptide in the highest sex-specific quartile; and (3) detectable cardiac troponin T. Cardiac magnetic resonance imaging-determined LVH served as the primary outcome. The probability of LVH increased from 2% with an LVH risk score of 0 to 50% with a score of 3 (P<0.001). Sokolow-Lyon ECG afforded low sensitivity (26% [95% confidence interval {CI}, 17-32%]) and high specificity (96% [95% CI, 95-97%]), whereas a risk score ≥2 offered higher sensitivity (44% [95% CI, 34-51%]) with good specificity (90% [95% CI, 89-93%]) and a score threshold of 1 offered reasonable sensitivity (76% [95% CI, 67-83%]) with lower specificity (55% [95% CI, 53-61%]) and high negative predictive value (98% [95% CI, 97-98%]). Area under the receiver operator characteristic curve improved from 0.760 (95% CI, 0.716-0.804) for ECG alone to 0.798 (95% CI, 0.754-0.842) for the LVH risk score (P=0.0012), consistent with modest improvement in overall discrimination. Better screening for LVH may be achieved by combining simple tests, which collectively provide additional information compared with ECG alone. Further studies are needed to evaluate the impact and cost-effectiveness of a multimarker screening strategy.

Female gender but not cigarette smoking delays the onset of Parkinson's disease.

OBJECTIVE: Cigarette smoking has been proposed as a protective factor against Parkinson's disease (PD); however it is not known whether smoking also delays its onset. METHODS: We conducted a long-term study of 247 patients with idiopathic PD to determine whether smoking and other factors influence its onset and development. RESULTS: The mean age at disease onset was 57+/-9 years. In smokers, the intensity and age at which exposure occurred did not modify the beginning of symptoms. Only female gender (p=0.005) and low educational level (p=0.03) showed a statistical association in the multivariate analysis with a delayed onset of symptoms. CONCLUSION: Our results suggest that females have a delayed onset of symptoms, possibly related to the gonadotropin profile of our population upon the nigrostriatal dopaminergic system. The effect of low educational level may be related to a delayed diagnosis, rather than a true delay of disease onset. This report suggests an influence of gender on the onset of Parkinson's disease.

Non-ST segment elevation acute coronary syndromes: A comprehensive review.

As the non-ST segment elevation acute coronary syndromes (NSTEACS) include unstable angina pectoris (UAP) and the non-ST segment elevation myocardial infarction (NSTEMI), acute diagnosis and risk stratification can often prove challenging. This review will cover guidelines and strategies for risk assessment, contemporary approaches to acute patient management as well as recommendations for timing of specialist referral.