Alfons Gegenhuber

Diagnostic accuracy of B type natriuretic peptide and amino terminal proBNP in the emergency diagnosis of heart failure.

Objective: To compare head to head the diagnostic accuracy of B type natriuretic peptide (BNP) and the amino terminal fragment of its precursor hormone (NT-proBNP) for congestive heart failure (CHF) in an emergency setting. Methods: 251 consecutive patients presenting to the emergency department with dyspnoea as a chief complaint were prospectively studied. Patients with acute coronary syndromes were excluded. The diagnosis of CHF was based on the Framingham score for CHF plus echocardiographic evidence of systolic or diastolic dysfunction. Blood concentrations of BNP and NT-proBNP were measured by two commercially available assays (Abbott and Roche methods). The diagnostic accuracies of BNP and NT-proBNP were assessed by receiver operating characteristic curve analysis. Results: Areas under the curve for BNP and NT-proBNP in patients with dyspnoea caused by CHF (n  =  137) and in patients with dyspnoea attributable to other reasons (n  =  114) did not differ significantly (area under the curve 0.916 v 0.903, p  =  0.277, statistical power 94%). Cut off concentrations with the highest diagnostic accuracy were 295 ng/l for BNP (sensitivity 80%, specificity 86%, diagnostic accuracy 83%) and 825 ng/l for NT-proBNP (sensitivity 87%, specificity 81%, diagnostic accuracy 84%). Evaluation of discordant false classifications at these cut off concentrations showed no advantage for either BNP nor NT-proBNP in the biochemical diagnosis of CHF (17 misclassifications by BNP and 14 by NT-proBNP, p  =  0.720). In the population studied, age, sex, and renal function had no impact on the diagnostic utility of both tests when compared by logistic regression models. Conclusions: BNP and NT-proBNP may be equally useful as an aid in the diagnosis of CHF in short of breath patients presenting to the emergency department.

Increased Plasma Concentrations of Soluble ST2 are Predictive for 1-Year Mortality in Patients with Acute Destabilized Heart Failure

BACKGROUND The soluble isoform of the interleukin-1 receptor family member ST2 (sST2) has been implicated in heart failure. The aim of the present study was to evaluate the capability of sST2 as a prognostic marker in patients with acute destabilized heart failure. METHODS sST2 plasma concentrations were obtained in 137 patients with acute destabilized heart failure attending the emergency department of a tertiary care hospital. The endpoint was defined as all-cause mortality, and the study participants were followed up for 365 days. RESULTS Of the 137 patients enrolled, 41 died and 96 survived during follow-up. At baseline the median sST2 plasma concentration was significantly higher in the patients who died than in those who survived (870 vs 342 ng/L, P <0.001). Kaplan-Meier curve analyses demonstrated that the risk ratios for mortality were 2.45 (95% CI, 0.88-6.31; P = 0.086) and 6.63 (95% CI, 2.55-10.89; P <0.001) in the second tercile (sST2, 300-700 ng/L; 11 deaths vs 34 survivors) and third tercile (sST2, >700 ng/L; 25 deaths vs 21 survivors) of sST2 plasma concentrations compared with the first tercile (sST2, < or =300 ng/L; 5 deaths vs 41 survivors). In multivariable Cox proportional-hazards regression analyses, an sST2 plasma concentration in the upper tercile was a strong and independent predictor of all-cause mortality. CONCLUSIONS Increased sST2 concentrations determined in plasma samples drawn from patients with acute destabilized heart failure at their initial presentation indicate increased risk of future mortality. Increased sST2 plasma concentrations are independently and strongly associated with one-year all-cause mortality in these patients.

Long-term stability of endogenous B-type natriuretic peptide (BNP) and amino terminal proBNP (NT-proBNP) in frozen plasma samples.

Abstract The aim of the present study was to assess the long-term stability of endogenous B-type natriuretic peptide (BNP) and amino terminal proBNP (NT-proBNP) in plasma samples stored at –20°C without addition of protease inhibitors (e.g., aprotinin). Stability of BNP and NT-proBNP was tested in 60 EDTA plasma samples with BNP values between 30 and 420 pg/ml. Initial BNP and NT-proBNP plasma concentrations were determined within four hours after blood collection using the AxSYM BNP and the Elecsys NT-proBNP assays. Subsequently, all samples were stored at –20°C and were thawed for the second BNP and NT-proBNP determination on the two instruments after one day, 30 days, 60 days, 90 days and 120 days, respectively. Mean recovery (i.e., residual immunoreactivity) of BNP and NT-proBNP expressed in percent of the initial value for the given time interval of storage was calculated. Mean recovery of BNP was less than 70% after one day of storage at –20°C and decreased to less than 50% after two to four months of storage (e.g., recovery of endogenous BNP after three months of storage at –20°C ranging from 0% to 71%). In contrast, mean recovery of NT-proBNP was generally greater than 90%, irrespective of the duration of storage at –20°C (e.g., recovery of endogenous NT-proBNP after three months of storage at –20°C ranging from 91% to 112%). In conclusion, the determination of endogenous BNP with the AxSYM assay using frozen plasma samples may not be valid under the conditions tested. In contrast, NT-proBNP as measured by the Elecsys assay may be stored at –20°C for at least four months without a relevant loss of the immunoreactive analyte.

Evaluation of novel biomarkers for the diagnosis of acute destabilised heart failure in patients with shortness of breath

Objective: The evaluation of novel biomarkers for the diagnosis of acute destabilised heart failure (HF). Design: Prospectively conducted study on diagnostic accuracy. Setting: Emergency department of a tertiary care hospital. Patients: 251 consecutive patients presenting to the emergency department with dyspnoea as the chief complaint. Main outcome measures: Index tests were plasma concentrations of 10 biomarkers (BNP, MR-proANP, MR-proADM, copeptin, CT-proET-1, ST2, adiponectin, chromogranin A, proguanylin and prouroguanylin). The reference standard was the diagnosis of acute destabilised HF, which was based on the Framingham score for HF plus echocardiographic evidence of systolic or diastolic dysfunction. Results: Median plasma concentrations of all 10 biomarkers were higher in patients with dyspnoea attributable to acute destabilised HF (n = 137) than in patients with dyspnoea attributable to other reasons (n = 114). Applying receiver operating characteristic curve (ROC) analyses, areas under the curve (AUCs) for BNP (0.92) and MR-proANP (0.88) were significantly higher than the AUCs of the other eight biomarkers (MR-proADM, 0.75; adiponectin, 0.73; CT-proET-1, 0.72; proguanylin, 0.68; ST2, 0.67; prouroguanylin, 0.62; copeptin, 0.62; and chromogranin A, 0.56). In multivariate logistic regression analysis only increased BNP and MR-proANP concentrations remained independent markers for the diagnosis of HF. Both markers alone or in combination added similar diagnostic information besides all clinical information available in the emergency department. Conclusions: The data showed that BNP and MR-proANP were the only independent diagnostic markers of HF. Both markers provided similar diagnostic information and were clinically useful as an aid in the diagnosis of acute destabilised HF in an emergency setting.

Prognostic value of established and novel biomarkers in patients with shortness of breath attending an emergency department.

OBJECTIVES Acute dyspnea is a common cause for emergency department visits. The aim of this study was to evaluate the prognostic value of established and novel biomarkers in patients with acute dyspnea. DESIGN AND METHODS We measured 10 biomarkers [B-type natriuretic peptide (BNP), midregional pro-A-type natriuretic peptide (MR-proANP), midregional-proadrenomedullin (MR-proADM), copeptin, C-terminal endothelin-1 precursor fragment (CT-proET-1), soluble ST2 (sST2), chromogranin A (CgA), adiponectin, proguanylin, and prouroguanylin] in 251 consecutive patients with acute dyspnea presenting to the emergency department of a tertiary care hospital. Outcome measure was all-cause mortality at 1 year. RESULTS At baseline decedents (n=62) had significantly higher median plasma concentrations of all 10 biomarkers than survivors (n=189). Applying univariate Cox proportional-hazard regression analyses, all biomarkers were significant outcome predictors displaying risk ratios (RR) from 1.4 to 2.4 (per 1 SD increase in log transformed values). In multivariate Cox proportional-hazard regression analysis, however, only MR-proANP (RR 1.6; 95% CI, 1.1-2.2; p=0.008), sST2 (RR 1.7; 95% CI, 1.3-2.3; p<0.001), and CgA (RR 1.5; 95% CI, 1.2-1.9, p<0.001) were independently associated with 1-year mortality. We provide a possible explanation for the complementary prognostic value of those three biomarkers in our cohort, where coincidence of heart failure and inflammatory pulmonary disease was common and also related to worse outcome. CONCLUSIONS Our evaluation of biomarkers in patients with acute dyspnea suggests that MR-proANP, sST2, and CgA are strong, independent and complementary outcome predictors. MR-proANP is considered a specific marker of cardiac stretch, sST2 might reflect both inflammation and cardiac stretch, and CgA obviously indicates neuroendocrine activation in various diseases.

Chromogranin A and C-terminal endothelin-1 precursor fragment add independent prognostic information to amino-terminal proBNP in patients with acute destabilized heart failure

BACKGROUND The aim of this study was to evaluate the prognostic value of chromogranin A (CgA) and C-terminal endothelin-1 precursor fragment (CT-proET-1) in patients with acute destabilized heart failure. METHODS 137 consecutive patients with acute destabilized heart failure attending the emergency department of a tertiary care hospital were prospectively enrolled. Plasma concentrations of CgA, CT-proET-1, and amino-terminal proBNP (NT-proBNP) were measured at baseline. The endpoint was defined as all-cause mortality; the study participants were followed up for 365 days. RESULTS Decedents (n=41) had higher median plasma concentrations of CgA (9.7 vs. 6.0 nmol/L; p=0.002), CT-proET-1 (120 vs. 72 pmol/L; p=0.006), and NT-proBNP (5112 vs. 2610 ng/L; p<0.001) at baseline than survivors (n=96). Applying Cox proportional-hazards regression analyses, increased CgA (>6.6 nmol/L), CT-proET-1 (>79 pmol/L), and NT-proBNP (>3275 ng/L) revealed significant risk ratios of 1.96 (95% CI, 1.04-3.70) for CgA, 2.56 (95% CI, 1.33-4.95) for CT-proET-1, and 2.05 (95% CI, 1.09-3.87) for NT-proBNP. When the cohort was stratified according to median CgA and NT-proBNP concentrations, and to median CT-proET-1 and NT-proBNP concentrations, respectively, Cox proportional-hazards regression analyses showed the highest risk for death in patients with both increased CgA and NT-proBNP (risk ratio, 3.65; 95% CI, 1.44-9.28), and increased CT-proET-1 and NT-proBNP (risk ratio, 4.03; 95% CI, 1.61-8.88). CONCLUSIONS Our study demonstrates that increased CgA and CT-proET-1 plasma concentrations at the initial presentation of patients with acute destabilized heart failure in the emergency department add independent prognostic information in addition to NT-proBNP measurement.

Prognostic value of increased adiponectin plasma concentrations in patients with acute destabilized heart failure

OBJECTIVES To evaluate the prognostic value of adiponectin in patients with acute destabilized heart failure. DESIGN AND METHODS Adiponectin was measured in 137 consecutive heart failure patients attending an emergency department. The endpoint was 1-year all-cause mortality. RESULTS In Cox proportional-hazards regression, an adiponectin plasma concentration>24.1 mg/L had a risk ratio of 2.46 (95% CI, 1.24-4.87), independently of classical risk factors and B-type natriuretic peptide. CONCLUSIONS Adiponectin predicts mortality in patients with acute destabilized heart failure.

Behandlung des hypertensiven Notfalls

Definition, Pathophysiologie, Therapie:Hypertensive Notfälle sind akute Erkrankungen, die mit einer massiven Erhöhung des Blutdrucks und bedrohlichen Endorganschäden einhergehen. Bei einem Großteil der Patienten mit einem hypertensiven Notfall besteht eine chronische Hochdruckkrankheit, wobei eine fehlende Patientencompliance oder eine insuffiziente antihypertensive Therapie in der überwiegenden Zahl der Fälle zu diesem lebensbedrohlichen Zustandsbild führt. Es kann ein hypertensiver Notfall jedoch auch bei Normotensiven auftreten, z. B. im Rahmen einer Präeklampsie oder Eklampsie, aber auch bei akuter Nephritis. Patienten mit einem hypertensiven Notfall sollten auf einer Intensivstation oder Überwachungsstation aufgenommen werden. Die Therapie sollte frühzeitig, d. h. bereits in der präklinischen Phase, begonnen werden, wobei die Wahl des jeweiligen Antihypertensivums sich vor allem nach der Art des Endorganschadens richtet. In der Regel wird intravenös zu verabreichenden Substanzen der Vorzug gegeben. Am häufigsten werden Urapidil, Betablocker wie Esmolol oder Metoprolol, Nitroglycerin, Labetolol und Calciumantagonisten verwendet. Die meisten extrazerebralen Endorgandysfunktionen profitieren von einer sehr raschen Blutdrucksenkung, wobei allerdings der mittlere arterielle Blutdruck nicht mehr als 20–25% vom Ausgangswert innerhalb der ersten 120 Minuten absinken sollte. Ein rascheres Absinken führt durch die veränderte Autoregulationskurve zu einer Minderdurchblutung der Organe und damit weiteren Verschlechterung. Ausnahmen stellen die akute Aortendissektion und das kardiale Lungenödem dar, hier sollte sehr rasch eine Normalisierung des Blutdrucks angestrebt werden.Definition, Pathophysiology, Therapy:The hypertensive crisis is characterized by a massive, acute rise in blood pressure. Patients with underlying hypertensive disease usually have an increase in systolic blood pressure values > 220 mmHg and diastolic values > 120 mmHg. The severity of the condition, however, is not determined by the absolute blood pressure level but by the magnitude of the acute increase in blood pressure. Thus, in the presence of primarily normotensive baseline values (such as those in eclampsia), even a systolic blood pressure > 170 mmHg may lead to a life-threatening condition. The most important causes are non-compliance (reduction or interruption of therapy), inadequate therapy, endocrine disease, renal (vessel) disease, pregnancy and intoxication (drugs). The management of this condition greatly depends on whether the patient has a hypertensive crisis with organ manifestation (hypertensive emergency) or a crisis without organ manifestation (hypertensive urgency). By documenting the medical history, the medical status and by simple diagnostic procedures, the differential diagnosis can be established at the emergency site within a very short period of time. In the absence of organ manifestations (hypertensive urgency) the patient may have non-specific symptoms such as palpitations, headache, malaise and a general feeling of illness in addition to the increase in blood pressure. In a hypertensive urgency the patient’s blood pressure should not be reduced within a few minutes but within a period of 24 to 48 hours. Such adjustment can be achieved on an out-patient basis, however, only if the patient can be followed up adequately for early detection of a renewed attack. In the absence of follow-up facilities, the patient’s blood pressure should be reduced over a period of 4 to 6 hours, if necessary in an out-patient emergency service. While intravenous medication is given preference when a rapid effect is desired, oral medication may be used for gradual reduction on an out-patient basis, depending on the patient’s medical history and on any underlying chronic disease.Organ manifestations in the course of a hypertensive emergency concern the cardiovascular system and are associated with the symptoms of acute left-ventricular heart failure, the acute coronary syndrome or acute aortic dissection. In the brain the patient may have symptoms of hypertensive encephalopathy, hemorrhage, ischemia; in the kidney he/she may develop acute failure. The patient’s blood pressure should be reduced rapidly during the treatment. It should not be reduced to the normal value, but by approximately 20–30% of the baseline value. The reason for a stepwise reduction in blood pressure is the fact that patients with chronic hypertension have an altered autoregulation curve. Acute normotension would lead to hypoperfusion in these patients. Those with aortic dissection or pulmonary edema are excepted from the rule of gradual blood pressure reduction. In the presence of these diseases, blood pressure must be reduced rapidly to normal values. Patients with a hypertensive emergency should always be admitted to the hospital. Parenteral treatment is given preference, since the effect of the treatment is rapid and occurs within a calculable period of time. Thus, parenteral treatment can also be better regulated than medication administered orally or by the sublingual route. Several antihypertensives are available for this purpose. The selection of the substance greatly depends on the existing organ failure as well as the reliable effectiveness and the regulability of the applied antihypertensive.

Analytical and clinical evaluation of a rapid quantitative lateral flow immunoassay for measurement of soluble ST2 in human plasma.

BACKGROUND Soluble ST2 (sST2) is gaining growing interest as a biomarker in heart failure. So far, the ELISA-format is widely used for commercially available ST2 assays, which hampers their use in clinical routine. Recently, a rapid quantitative lateral flow immunoassay for the measurement of sST2 in human plasma has been developed. METHODS We evaluated precision and linearity of the ASPECT-PLUS ST2 test, and performed an analytical and clinical assay comparison with the MBL and the PRESAGE ST2 ELISAs. We measured sST2 with these three assays in a clinical cohort of 251 consecutive patients with acute dyspnea as the chief compliant (i.e., 137 patients with dyspnea attributable to heart failure and 114 patients with dyspnea attributable to other reasons). RESULTS Within-run and total coefficients of variation of the ASPECT-PLUS ST2 test were < 17% and the assay was linear across its measurement range. We found a constant and proportional bias between the MBL ST2 assay, the PRESAGE ST2 assay and the ASPECT-PLUS ST2 test, respectively. However, at the proposed cut-off of 35 ng/mL, sST2 results obtained with the PRESAGE ST2 assay and the ASPECT-PLUS ST2 test were similar. Testing clinically, the three assays deemed equally useful for the diagnosis of heart failure (AUC, 0.670 for the MBL ST2 assay vs. 0.626 for the PRESAGE ST2 assay vs. 0.630 for the ASPECT-PLUS ST2 test) and for the prediction of 1-year mortality in dyspnoeic patients (AUC, 0.743 for the MBL assay vs. 0.742 for the PRESAGE ST2 assay vs. 0.752 for the ASPECT-PLUS ST2 test). CONCLUSION The ASPECT-PLUS test meets the analytical requirements for point-of-care testing. Test results of the ASPECT-PLUS ST2 and the PRESAGE ST2 methods were comparable at the proposed cut-off, and the diagnostic/prognostic capabilities of the three methods were similar.

Plasma concentrations of novel cardiac biomarkers before and after hemodialysis session.

OBJECTIVES Biomarkers are useful for establishing disease severity or prognosis in patients with chronic kidney disease. The aim of our study was to determine the plasma concentrations of novel cardiovascular biomarkers in patients on chronic hemodialysis in the context of published upper reference limits (URL) of these biomarkers; and to compare the plasma concentrations of those same analytes before and after hemodialysis session. DESIGN AND METHODS Plasma concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP), mid-regional pro-A-type natriuretic peptide (MR-proANP), mid-regional pro-adrenomedullin (MR-proADM), C-terminal pro-endothelin-1 (CT-proET-1), C-terminal pro-arginine vasopressin (CT-proAVP, also known as Copeptin) and soluble ST2 (sST2) were measured in 28 patients before and after dialysis session. Of the 28 patients with conventional hemodialysis, 24 had low-flux hemofiltration and 4 had high-flux hemodiafiltration. RESULTS Median plasma concentrations of the biomarkers obtained before hemodialysis were as follows: NT-proBNP, 11,307ng/L (URL, 500ng/L); MR-proANP, 778pmol/L (URL, 250pmol/L); MR-proADM, 2.57nmol/L (URL, 0.52nmol/L); median CT-proET-1, 252pmol/L (URL, 75pmol/L); median CT-proAVP, 142pmol/L (URL, 19pmol/L); and median sST2, 27ng/mL (URL, 50ng/mL). Median relative analyte changes after low-flux vs. high-flux dialysis compared to predialysis values were +19% vs. -43% for NT-proBNP; +7% vs. -45% for MR-proANP; -2% vs. -63% for MR-proADM; -19% vs. -61% for CT-proET-1; +13% vs. -64% for CT-proAVP; and +2% vs. +3% for sST2. CONCLUSIONS Plasma concentrations of the investigated biomarkers were markedly increased in chronic hemodialysis patients (with the exception of sST2). After hemodialysis session, analyte concentrations (with the exception of sST2) decreased significantly using a high-flux membrane but not if using a low-flux membrane.