The integration of BNP and NT-proBNP into clinical medicine.

B-type natriuretic peptide (BNP) and NTproBNP have been shown to be extremely helpful in the diagnosis and management of patients with heart failure (HF). These neurohormones are predominately secreted from the left and the right cardiac ventricle in response to volume and pressure overload. BNP and NT-proBNP can be seen as quantitative markers of HF summarizing the extent of systolic and diastolic left ventricular dysfunction. Research data from clinical studies and six years of clinical experience with BNP allow us to provide clear recommendations regarding the integration of BNP/NT-proBNP into clinical medicine. With multiple additional indications in prospect, current evidence clearly supports the use of BNP and NT-proBNP in three clinical settings: patients with acute dyspnoea, prior to discharge in patients hospitalised with acute HF, and the longterm management of patients with HF.

Neurohormonal activation and left ventricular ejection fraction in patients with suspected myocardial ischemia.

BACKGROUND: B-type natriuretic peptide (BNP) and left ventricular ejection fraction (LVEF) are both increasingly used in the clinical management of patients with suspected coronary artery disease (CAD). Unfortunately, there is very limited data regarding the association between BNP and LVEF. METHODS: BNP and LVEF were measured in 260 consecutive patients with suspected myocardial ischemia referred for rest/ergometry myocardial perfusion single-photon emission computed tomography (SPECT). The correlation between BNP and LVEF was studied using Spearman's correlation test. RESULTS: Median LVEF was 57% (IQR, 50 to 64), and median BNP level was 53 pg/ml (IQR, 24 to 109). LVEF and BNP levels showed a statistically significant, but overall weak correlation (r=0.274, p<0.001). The correlation seemed to depend on the presence of a myocardial scar, which was detected in 104 patients (40%), including 89 men (49% of men) and 15 women (20% of women). The correlation between BNP and LVEF was moderate in patients with a myocardial scar (r=-0.540, p<0.001), but very weak in patients without a scar (r=0.185, p=0.025). Moreover, the correlation between BNP and LVEF was moderate in men (r=-0.503, p<0.001), but not existent at all in women. In the overall cohort, BNP was not an accurate test to detect left ventricular systolic dysfunction. The area under the ROC curve was 0.643 (95% CI, 0.563-0.723). CONCLUSIONS: The BNP level and LVEF show only a weak correlation in patients with suspected myocardial ischemia. Neurohormonal and morphologic assessments provide different windows to the heart.

Gender-specific risk stratification with B-type natriuretic peptide levels in patients with acute dyspnea: insights from the B-type natriuretic peptide for acute shortness of breath evaluation study.

OBJECTIVES: We examined whether B-type natriuretic peptide (BNP) levels allow gender-specific risk stratification in patients with acute dyspnea. BACKGROUND: B-type natriuretic peptide levels determined in patients with heart failure correlate with the severity of disease and prognosis. Gender differences in risk prediction are poorly examined. METHODS: The BASEL (B-type natriuretic peptide for Acute Shortness of Breath Evaluation) Study enrolled 190 female and 262 male patients presenting with acute dyspnea. RESULTS: At 24 months, cumulative mortality was comparable in women and men (38% vs. 35%, p = 0.66). Cox regression analyses revealed that BNP levels >500 pg/ml indicated a 5.1-fold increase in mortality for women (95% confidence interval [CI] 3.0 to 8.5, p < 0.001) versus a 1.8-fold increase in men (95% CI 1.2 to 2.6; p = 0.007). The area under the receiver-operating characteristic curve (AUC) for BNP to predict death was significantly higher in female (AUC: 0.80, 95% CI 0.73 to 0.86) than in male patients (AUC: 0.64, 95% CI 0.57 to 0.71; p = 0.001 for the comparison of AUC(women) versus AUC(men)). Women with BNP >500 pg/ml displayed a higher mortality as compared with men with BNP >500 pg/ml (68% vs. 46%, p = 0.015). Interaction analysis showed that BNP is a stronger predictor of death in women than in men (p = 0.008). CONCLUSIONS: B-type natriuretic peptide plasma levels seem to be stronger predictors of death in women than in men.

Progressive pulmonary sarcoidosis--a fibroproliferative process potentially triggered by EGR-1 and IL-6.

BACKGROUND AND AIM OF THE WORK: Sarcoidosis is a chronic granulomatous disorder of unknown etiology. In most patients the disease is self-limited, although for reasons unclear, others progress or die from progressive organ fibrosis. Growth factors have been implicated in the pathogenesis of other fibrotic lung conditions. We have, therefore, examined the relationship between growth factor expression and disease phenotype in sarcoidosis. METHODS: Adopting a target gene approach utilizing gene expression arrays, growth factor gene expression profile was analyzed in the peripheral blood of 12 patients and 12 healthy controls. Expression, functional activity and the effect of oligonucleotide antisense treatment on selected proteins differentially expressed in progressive sarcoidosis were then tested in vitro on primary human lung fibroblasts. RESULTS: Genes regulating angiogenesis were preferentially upregulated in the self-limited form of disease, while early growth response-1 and interleukin-6 were predominantly activated in progressive sarcoidosis. Increased expression of early growth response-1 in sarcoid lung was confirmed by immunohistochemistry. Stimulated human fibroblasts also rapidly expressed interleukin-6 and early growth response-1 and these proteins were found to mediate serum-induced fibroblast proliferation as proliferation could be significantly abrogated with interleukin-6 and early growth response-1 antisense oligonucelotides. CONCLUSION: We conclude that progressive pulmonary sarcoidosis is characterized by a fibroproliferative dysregulation potentially triggered by early growth response-1 and interleukin-6. Our disease model underlines the inability of steroids to prevent ongoing fibroproliferation in the lung.

Gender differences in acute congestive heart failure.

BACKGROUND: Little is known about sex differences in baseline characteristics and outcomes in patients with acute congestive heart failure (CHF). METHODS AND RESULTS: This prospective observational study evaluated gender differences among 217 consecutive patients (124 men and 93 women) presenting with acute CHF to the emergency department. The primary endpoint was all-cause mortality. Women were older, and had less pulmonary comorbidity, but more noticeable jugular venous distension, as well as higher diastolic blood pressure and troponin level at presentation. Among contributing causes of acute CHF, myocardial ischaemia and anaemia were more frequent in women. Adequate medical CHF therapy was initiated more rapidly in women. Initial resource utilisation, time to discharge, and mortality were similar. Important differences to the disadvantage of women were noted during long-term follow-up. Mean cumulative survival was 619 (95% CI, 533-705) days in women as compared with 669 (95% CI, 601-737; p = 0.0663) in men. However, after multivariate adjustment female sex was not an independent predictor of long-term mortality (hazard ratio 1.14, 95% CI, 0.68-1.90; p = 0.619). Total spending for treatment cost was 11,858 US dollars University of Basel, University Hospital, Department of Internal Medicine, Switzerland (95% CI, 8921-14794) in women compared to 15,965 US dollars (95% CI, 12328-18003; p = 0.115) in men after 1 year. Functional status was similar in women and men at 6 and 12 months. CONCLUSIONS: The trend towards lower survival in women seems primarily related to higher age and other factors rather than gender itself. Female sex is not an independent predictor of long-term mortality in acute CHF.

Cost-effectiveness of B-type natriuretic peptide testing in patients with acute dyspnea.

BACKGROUND: B-type natriuretic peptide (BNP) is a quantitative marker of heart failure that seems to be helpful in its diagnosis. METHODS: We performed a prospective randomized study (B-Type Natriuretic Peptide for Acute Shortness of Breath Evaluation) including 452 patients who presented to the emergency department with acute dyspnea to estimate the long-term cost-effectiveness of BNP guidance. Participants were randomly assigned to a diagnostic strategy involving the measurement of BNP levels (n = 225) or assessment in a standard manner (n = 227). Nonparametric bootstrapping was used to estimate the distribution of incremental costs and effects on the cost-effectiveness plane during 180 days of follow-up. RESULTS: Testing of BNP induced several important changes in management of dyspnea, including a reduction in the initial hospital admission rate, the use of intensive care, and total days in the hospital at 180 days (median, 10 days [interquartile range, 2-24 days] in the BNP group vs 14 days [interquartile range, 6-27 days] in the control group; P = .005). At 180 days, all-cause mortality was 20% in the BNP group and 23% in the control group (P = .42). Total treatment cost was significantly reduced in the BNP group (7930 dollars vs 10,503 dollars in the control group; P = .004). Analysis of incremental 180-day cost-effectiveness showed that BNP guidance resulted in lower mortality and lower cost in 80.6%, in higher mortality and lower cost in 19.3%, and in higher or lower mortality and higher cost in less than 0.1% each. Results were robust to changes in most variables but sensitive to changes in rehospitalization with BNP guidance. CONCLUSION: Testing of BNP is cost-effective in patients with acute dyspnea.

Inflammation and long-term mortality in acute congestive heart failure.

BACKGROUND: Systemic inflammation has long been recognized as a precipitator of acute congestive heart failure (CHF). The impact of inflammation on prognosis in acute CHF, however, is unknown. METHODS: This study evaluated the prognostic role of inflammation among 214 consecutive patients presenting with acute CHF to the emergency department. Patients were stratified according to C-reactive protein (CRP) levels determined on admission. The primary end point was all-cause mortality during 24-month follow-up. RESULTS: The median CRP level was 13.0 mg/L, with an intertertile range of 6.0 to 25.0 mg/L. Initial and long-term outcomes were significantly different to the detriment of patients with higher CRP levels. Patients in the highest CRP tertile significantly more often required admission to the intensive care unit (33% vs 14% in patients in the first tertile, P = .028) and died inhospital (15% vs 2% in patients in the first tertile, P = .027). Cumulative 24-month mortality rates were 33.5% in the first, 42.4% in the second, and 53.6% in the third tertile (P = .0265 by log-rank test). After multivariate adjustment, CRP remained an independent predictor of death (hazard ratio 1.4, 95% CI 1.1-1.8 for each step up in tertile, P = .044). CONCLUSIONS: Inflammation is a significant and independent predictor of long-term mortality in patients with acute CHF.

Use of B-type natriuretic peptide in the management of acute dyspnea in patients with pulmonary disease.

BACKGROUND: In patients with pulmonary disease, it is often challenging to distinguish exacerbated pulmonary disease from congestive heart failure (CHF). The impact of B-type natriuretic peptide (BNP) measurements on the management of patients with pulmonary disease and acute dyspnea remains to be defined. METHODS: This study evaluated the subgroup of 226 patients with a history of pulmonary disease included in the BASEL Study. Patients were randomly assigned to a diagnostic strategy with (n = 119, BNP group) or without (n = 107, clinical group) the use of BNP levels provided by a rapid bedside assay. Time to discharge and total cost of treatment were recorded as the primary end points. RESULTS: Baseline characteristics were similar in patients assigned to the BNP and control groups. Comorbidity was extensive, including coronary artery disease and hypertension in half of patients. The primary discharge diagnosis was CHF and exacerbated obstructive pulmonary disease in 39% and 33%, respectively. The use of BNP levels significantly reduced the need for hospital admission (81% vs 91%, P = .034). Median time to discharge was 9.0 days in the BNP group as compared with 12.0 days (P = .001) in the clinical group. Median total cost of treatment was $4841 in the BNP group as compared with $5671 in the clinical group (P = .008). Inhospital mortality was 8% in both groups. CONCLUSIONS: CHF is a major cause of acute dyspnea in patients with a history of pulmonary disease. Used in conjunction with other clinical information, rapid measurement of BNP reduced time to discharge and total treatment cost of these patients.

Emergency diagnosis of congestive heart failure: impact of signs and symptoms.

BACKGROUND: The most useful features in the diagnosis of congestive heart failure (CHF) have been poorly investigated. OBJECTIVE: To determine the utility of signs and symptoms in the diagnosis of CHF in the emergency department. METHODS: Detailed clinical data were collected prospectively from 452 consecutive patients presenting with acute dyspnea to the emergency department. By using logistic regression analysis, significant predictors for the final discharge diagnosis of CHF (adjudicated after review of all patient records, including response to therapy) were assessed. RESULTS: In 217 of 452 patients (48%), CHF was the cause of acute dyspnea. Among symptoms, the OR for CHF was highest for weight gain (OR 3.6; 95% CI 1.9 to 7.0), nocturia (OR 2.4; 95% CI 1.6 to 3.7) and paroxysmal nocturnal dyspnea (OR 2.4; 95% CI 1.6 to 3.5), and lowest for fever (OR 0.36; 95% CI 0.22 to 0.56). Among signs, the OR was highest for elevated jugular venous pressure (OR 4.3; 95% CI 2.3 to 7.9), rales (OR 3.1; 95% CI 2.1 to 4.5), lower extremity edema (OR 2.8; 95% CI 1.9 to 4.3) and hepatojugular reflux (OR 2.7; 95% CI 1.4 to 5.2), and lowest for wheezing (OR 0.38; 95% CI 0.24 to 0.61). The overall sensitivity was low. The specificity was highest for elevated jugular venous pressure and hepatojugular reflux. CONCLUSIONS: Signs and symptoms are only moderately helpful in the diagnosis of CHF in patients with acute dyspnea. This emphasizes the need for additional diagnostic tools, such as echocardiography or B-type natriuretic peptide testing.

Runx3 regulates integrin alpha E/CD103 and CD4 expression during development of CD4-/CD8+ T cells.

During thymic T cell development, immature CD4+CD8+ double-positive (DP) thymocytes develop either into CD4+CD8- Th cells or CD4-CD8+ CTLs. Differentially expressed primary factors inducing the fate of these cell types are still poorly described. The transcription factor Runx3/AML-2 Runx, runt [corrected] dominant factor; AML, acute myeloid leukemia is expressed specifically during the development of CD8 single-positive (SP) thymocytes, where it silences CD4 expression. Deletion of murine Runx3 results in a reduction of CD8 SP T cells and concomitant accumulation of CD4+CD8+ T cells, which cannot down-regulate CD4 expression in the thymus and periphery. In this study we have investigated the role of Runx3 during thymocyte development and CD4 silencing and have identified integrin alpha(E)/CD103 on CD8 SP T cells as a new potential target gene of Runx3. We demonstrate that Runx3 is necessary not only to repress CD4, but also to induce CD103 expression during development of CD8 SP T cells. In addition, transgenic overexpression of Runx3 reduced CD4 expression during development of DP thymocytes, leading to a reduced number of CD4 SP thymocytes and an increased number of CD8 SP thymocytes. This reversal is not caused by redirection of specific MHC class II-restricted cells to the CD8 lineage. Overexpression of Runx3 also up-regulated CD103 expression on a subpopulation of CD4 SP T cells with characteristics of regulatory T cells. Thus, Runx3 is a main regulator of CD4 silencing and CD103 induction and thus contributes to the phenotype of CD8 SP T cells during thymocyte development.

The use of B-type natriuretic peptide in the diagnosis of acute dyspnoea.

B-type natriuretic peptide (BNP) and NT-proBNP are currently the most prominent members of the natriuretic peptide family. These markers are secreted from both the left and the right cardiac ventricle in response to ventricular volume expansion and pressure overload. Recent studies have suggested that these neurohormones are reliably elevated in the setting of congestive heart failure and may be very helpful in its diagnosis. The use of rapid BNP testing in addition to clinical judgement increased the accuracy of the clinical evaluation. The B-Type Natriuretic Peptide for Acute Shortness of Breath Evaluation (BASEL) study showed that the increase in accuracy offered by rapid BNP testing resulted in a significant reduction of hospitalisations, use of intensive care, time to discharge and initial treatment cost.

B-type natriuretic peptide for acute dyspnea in patients with kidney disease: insights from a randomized comparison.

BACKGROUND: B-type natriuretic peptide (BNP) levels are reliably elevated in patients with congestive heart failure (CHF) and therefore helpful in its diagnosis. However, kidney disease results in elevated BNP levels independently of CHF. Accordingly, the impact of kidney disease on the benefit of BNP testing needs to be scrutinized. METHODS: This study evaluated patients with and without kidney disease [glomerular filtration rate (GFR) less than 60 mL/min/1.73 m(2)) presenting with acute dyspnea. A total of 452 consecutive patients (240 with kidney disease and 212 without kidney disease) were randomly assigned to a diagnostic strategy with (BNP group) or without (control group) the use of BNP levels provided by a rapid bedside assay. RESULTS: Patients with kidney disease were older, more often had CHF as the cause of acute dyspnea, and more often died in-hospital or within 30 days as compared to patients without kidney disease. In patients without kidney disease, BNP testing significantly reduced median time to discharge (from 9.5 days to 2.5 days) (P= 0.003) and total cost of treatment (from 7184 dollars to 4151 dollars) (P= 0.004). In contrast, in patients with kidney disease, time to discharge and total cost of treatment were similar in both groups. CONCLUSION: When applying BNP cut-off values without adjustment for the presence of kidney disease, the use of BNP levels does significantly improve the management of patients without kidney disease, but not of those with kidney disease.

Use of B-type natriuretic peptide for the management of women with dyspnea.

In studies with predominately male patients, B-type natriuretic peptide (BNP) levels have been shown to be helpful in the evaluation and management of patients who present with acute dyspnea. The effect of BNP levels on the management of women has not been defined. This study evaluated a predefined subgroup of 190 women included in a prospective randomized controlled study of BNP testing for emergency diagnosis of acute dyspnea. Patients were randomly assigned to a diagnostic strategy with (n = 93, BNP group) or without (n = 97, control group) the use of BNP levels provided by a rapid bedside assay. Women differed significantly from men in baseline characteristics, symptoms, signs, and final discharge diagnoses. The use of BNP levels decreased the need for hospital admission (73% vs 86%, p = 0.034) and intensive care (12% vs 23%, p = 0.048). Median time to discharge was 6 days in the BNP group versus 10 days in the control group (p = 0.023). Total cost of treatment was $4,781 in the BNP group (95% confidence interval 3,854 to 5,708) versus $6,843 in the control group (95% confidence interval 5,611 to 8,074, p = 0.009). In-hospital mortality rates were 4% in the BNP group and 10% in the control group (p = 0.165). Thus, used in conjunction with other clinical information, rapid measurement of BNP decreased time to discharge and total cost of treatment in women who presented with acute dyspnea.

Systemic Th1- and Th2-gene signals in atopy and asthma.

BACKGROUND: Atopic disorders have been associated with a Th-2 cytokine predominance. This study investigated Th1- and Th2-related gene expression in asthmatics, atopics and healthy individuals. METHODS: We compared Th1- and Th2-related in vivo-signals using gene expression arrays in 18 atopic asthmatics, 8 atopic non-asthmatic and 14 healthy control subjects. Purified mRNA from peripheral blood mononuclear cells was reverse-transcribed and hybridised to cDNA membranes. Group differences were assessed after standardisation with Mann-Whitney U-test. RESULTS: Atopic individuals had upregulated lymphotoxin-alpha and downregulated IFNGR1. On the other hand, they had particularly high IL-4, IL-5 and IL4R levels, together with significantly upregulated IL10. Asthmatic individuals had normal Th1-gene expression, but an upregulation og Th-2 genes. Atopic individuals had high, asthmatic individuals excessively high IL12RB1-levels. No Th-2 gene was downregulated in both atopic phenotypes. The expression of IL6R correlated with the daily dose of inhaled corticosteroids. CONCLUSIONS: Atopic individuals had a down regulation of key TH1- and Th2-genes, resulting in a balanced upregulation of Th-specific genes. In contrast, asthmatic subjects had normal Th1-gene expression but a constant upregulation of Th2-specific genes, leading to Th2-predominance.

Use of B-type natriuretic peptide in the evaluation and management of acute dyspnea.

BACKGROUND: B-type natriuretic peptide levels are higher in patients with congestive heart failure than in patients with dyspnea from other causes. METHODS: We conducted a prospective, randomized, controlled study of 452 patients who presented to the emergency department with acute dyspnea: 225 patients were randomly assigned to a diagnostic strategy involving the measurement of B-type natriuretic peptide levels with the use of a rapid bedside assay, and 227 were assessed in a standard manner. The time to discharge and the total cost of treatment were the primary end points. RESULTS: Base-line demographic and clinical characteristics were well matched between the two groups. The use of B-type natriuretic peptide levels reduced the need for hospitalization and intensive care; 75 percent of patients in the B-type natriuretic peptide group were hospitalized, as compared with 85 percent of patients in the control group (P=0.008), and 15 percent of those in the B-type natriuretic peptide group required intensive care, as compared with 24 percent of those in the control group (P=0.01). The median time to discharge was 8.0 days in the B-type natriuretic peptide group and 11.0 days in the control group (P=0.001). The mean total cost of treatment was 5,410 dollars (95 percent confidence interval, 4,516 dollars to 6,304 dollars) in the B-type natriuretic peptide group, as compared with 7,264 dollars (95 percent confidence interval, 6,301 dollars to 8,227 dollars) in the control group (P=0.006). The respective 30-day mortality rates were 10 percent and 12 percent (P=0.45). CONCLUSIONS: Used in conjunction with other clinical information, rapid measurement of B-type natriuretic peptide in the emergency department improved the evaluation and treatment of patients with acute dyspnea and thereby reduced the time to discharge and the total cost of treatment.

Morpholino antisense oligonucleotide-mediated gene knockdown during thymocyte development reveals role for Runx3 transcription factor in CD4 silencing during development of CD4-/CD8+ thymocytes.

During thymic T cell development, immature CD4(+)/CD8(+) thymocytes develop into either CD4(+)/CD8(-) helper or CD4(-)/CD8(+) CTLs. The molecular mechanisms governing the complex selection and differentiation steps during thymic T cell development are not well understood. Here we developed a novel approach to investigate gene function during thymocyte development. We transfected ex vivo isolated immature thymocytes with gene-specific morpholino antisense oligonucleotides and induced differentiation in cell or organ cultures. A morpholino oligonucleotide specific for CD8alpha strongly reduces CD8 expression. To our knowledge, this is the first demonstrated gene knockdown by morpholino oligonucleotides in primary lymphocytes. Using this approach, we show here that the transcription factor Runx3 is involved in silencing of CD4 expression during CD8 T cell differentiation. Runx3 protein expression appears late in thymocyte differentiation and is confined to mature CD8 single-positive thymocytes, whereas Runx3 mRNA is transcribed in mature CD4 and CD8 thymocytes. Therefore, Runx3 protein expression is regulated at a post-transcriptional level. The knockdown of Runx3 protein expression through morpholino oligonucleotides inhibited the development of CD4(-)/CD8(+) T cells. Instead, mature cells with a CD4(+)/CD8(+) phenotype accumulated. Potential Runx binding sites were identified in the CD4 gene silencer element, which are bound by Runx protein in EMSAs. Mutagenesis of potential Runx binding sites in the CD4 gene silencer abolished silencing activity in a reporter gene assay, indicating that Runx3 is involved in CD4 gene silencing. The experimental approach developed here should be valuable for the functional analysis of other candidate genes in T cell differentiation.