Hemodynamic Determinants of the Biologic Variation of N-Terminal Pro-B-Type Natriuretic Peptide in Patients With Stable Systolic Chronic Heart Failure.

BACKGROUND CONTEXT: Biologic variation of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in chronic heart failure (CHF) may affect blood levels and risk stratification. The sources of NT-proBNP variation are unknown. METHODS AND RESULTS: We performed NT-proBNP measurements and clinical and hemodynamic assessments in 50 patients with heart failure with reduced ejection fraction (HFrEF) who met criteria for clinical stability over 2 time intervals. Hemodynamic variables were measured with the use of inert gas rebreathing and impedance cardiography. Heart rhythm was monitored with the use of external electrocardiographic event recorders throughout the study. Determinants of NT-proBNP-levels and both absolute (ΔNT-proBNPabs) and relative (ΔNT-proBNP%) changes at 1-week and 2-week intervals were identified with the use of univariable and multivariable linear mixed-effects models and linear regression analyses, respectively. Clinical and hemodynamic variables did not significantly change between study visits. The individual variation of NT-proBNP at 2 weeks was 9.2% (range 3.9%-18.6%). Weight and glomerular filtration rate were independently associated with baseline NT-proBNP concentrations (P = .01 and P = .005, respectively). There was no relationship between absolute and relative changes of NT-proBNP at 1-week intervals and changes in clinical and hemodynamic variables. Absolute change of NT-proBNP at 2-week intervals was associated with absolute change in left cardiac work index (P = .008), and relative change in NT-proBNP at 2-week intervals was determined by relative change of thoracic fluid content index (P = .008) and diastolic blood pressure (P = .01). The coefficients of determination (R2) for the multivariable models with Δ1wkNT-proBNPabs, Δ2-weeksNT-proBNPabs, Δ1wkNT-proBNP%, and Δ2wksNT-proBNP% as dependent variables were 0.21, 0.19, 0.10, and 0.32, respectively. CONCLUSIONS: In patients with stable HFrEF, changes in clinical and hemodynamic variables only marginally contribute to the variation of NT-proBNP.

Biological variation of the cardiac index in patients with stable chronic heart failure: inert gas rebreathing compared with impedance cardiography.

AIMS: In chronic heart failure (CHF), changes in cardiac function define the course of the disease. The cardiac index (CI) is the most adequate indicator of cardiac function. Interpretation of serial CI measurements, however, requires knowledge of the biological variation of CI. Because measurements of CI can be confounded by the clinical situation or the method applied, biological variation might be subject to the same confounders. METHODS AND RESULTS: We prospectively included 50 CHF patients who met rigid criteria for clinical stability. CI was measured by both inert gas rebreathing (IGR) and impedance cardiography (ICG) in weekly intervals over 3 weeks-each measurement performed at rest (IGRrest/ICGrest) and during low-exercise 10 Watt pedalling (IGR10W/ICG10W). Intra-class correlation coefficients (ICCs), reference change values, and minimal important differences of CI were determined for IGRrest, ICGrest, IGR10W, and ICG10W. Impedance cardiography and IGR showed moderate agreement at rest (20% (6-36)) and good agreement at 10 Watt (-4% (-23-16)). Depending on time interval, measurement modality for CI, and mode, ICC ranged between 0.42 and 0.78, ICC values for IGR were lower than those for ICG. Reference change value ranged between 3 and 15%, and minimal important difference ranged between 0.2 and 0.5 L/min/m2. Values for IGR were lower at rest and higher at 10 Watt than those for ICG. CONCLUSION: Non-invasive measurements of CI are stable over time. Measurement modalities for CI, however, are not interchangeable. Biological variation is less pronounced when obtained by ICG. The influence of low-level exercise on stability of CI depends on the measurement modality.

Urinary excretion of high molecular weight adiponectin is an independent predictor of decline of renal function in type 2 diabetes.

Adiponectin and urinary adiponectin excretions have been ascribed a function in glomerular physiology and seem to indicate vascular disease in diabetes. The aim of this study was to compare the urinary excretion of albumin and adiponectin as predictors for decline of renal function in patients with type 2 diabetes and early kidney disease. Over 141 patients were screened for renal function (estimated GFR, ml/min*1.73 m(2)), albumin excretion rate (AER, mg/24 h), total as well as high molecular weight (HMW) urinary adiponectin excretion (ng/mol u-creatinine). AER and adiponectin excretion were studied as predictors of renal function after 1 year. After 1 year, 36 patients were in the upper quartile of eGFR decline and defined as progressors (delta eGFR = - 12.3 ± 6.3) while the remaining 105 patients were defined as non-progressors (delta eGFR = 1.4 ± 6.0). At baseline, HMW-adiponectin excretion was positively correlated with HbA1c (p < 0.001) and negatively with eGFR (p < 0.001), but not with AER (p = 0.14). Progressors showed increased urinary HMW-adiponectin at baseline (158[IQR41/479] vs. 65[24/168] ng/mol; p < 0.01), while total adiponectin (182[101/1534] vs. 345[118/1361] ng/mol) and AER (48[23/109] vs. 46[25/108] mg/24 h) excretion showed no differences between the groups. Multivariate logistic regression showed that HMW-adiponectin excretion was an independent predictor of renal progression in all patients (OR 1.86 [95 % CI 1.34-2.59]; p < 0.01), especially in those (n = 45) with normal AER at baseline (OR 2.16 [95 % CI 1.1-4.56]; p < 0.05). Urinary HMW-adiponectin but not AER improved the prediction of progressors in ROC analysis (AUC 0.72 [95 % CI 0.63-0.81] vs. 0.80 [95 % CI 0.71-0.90], p < 0.05). In conclusion, urinary HMW-adiponectin excretion may identify diabetes patients at increased risk for progression of kidney disease.

Urinary adiponectin excretion rises with increasing albuminuria in type 1 diabetes.

AIM: Urinary adiponectin (u-adiponectin) excretion has been suggested to reflect early glomerular damage. Inspired by this, we studied the levels of u-adiponectin in type 1 diabetic patients with different levels of urinary albumin excretion (UAE). METHODS: U-adiponectin was analysed by ELISA in type 1 diabetic patients: Fifty-eight with normoalbuminuria (<30mg albumin/24h), 43 with persistent microalbuminuria (30-300mg/24h) and 44 with persistent macroalbuminuria (>300mg/24h). For comparison, a control group of 55 healthy individuals was included. RESULTS: U-adiponectin increased with increasing levels of UAE (p<0.01). U-adiponectin median (interquartile range): Normoalbuminuria 0.38 (0.14-1.31), microalbuminuria 1.12 (0.20-2.68), macroalbuminuria 9.20 (1.10-23.35) and controls 0.09 (0.06-0.24) µg/g creatinine. Levels were unrelated to sex, age, cholesterol, diastolic BP and BMI. U-adiponectin was weakly associated with increasing systolic BP and HbA1c (r(2)<0.1, p<0.05), but strongly related to increasing UAE (r(2)=0.57, p<0.001) and decreasing eGFR (r(2)=0.26, p<0.001). The relationship between UAE and u-adiponectin was significant in all groups and independent of eGFR, BMI, BP and HbA1c. Furthermore, u-adiponectin was associated with markers of tubular damage (p<0.01). CONCLUSION: U-adiponectin rises with increasing levels of UAE in patients with type 1 diabetes. This is in accordance with the hypothesis that loss of adiponectin may reflect glomerular and/or tubular damage.

Placental growth factor supports neuroendocrine tumor growth and predicts disease prognosis in patients.

Placental growth factor (PlGF), a VEGF-homolog implicated in tumor angiogenesis and adaptation to antiangiogenic therapy, is emerging as candidate target in malignancies. Here, we addressed the expression, function, and prognostic value of PlGF in neuroendocrine tumors (NETs). PlGF was determined in NET patients' sera collected retrospectively (n=88) and prospectively (n=87) using Roche-Elecsys and correlated with clinicopathological data. Tumoral PlGF was evaluated by immunohistochemistry, effects of PlGF on proliferation and migration in vitro were assessed using different NET cell lines and effects on tumor growth in vivo in orthotopic xenografts. Circulating and tumoral PlGF was elevated in patients with pancreatic NETs (pNETs) compared with control sera and respective healthy tissue. De novo PlGF expression occurred primarily in the tumor stroma, suggesting paracrine stimulatory circuits. Indeed, PlGF enhanced NET proliferation and migration in vitro and, conversely, neutralizing antibodies to PlGF reduced tumor growth in vivo. Elevated circulating PlGF levels in NET patients correlated with advanced tumor grading and were associated with reduced tumor-related survival in pNETs. Subsequent determinations confirmed and extended our observation of elevated PlGF levels in a prospective cohort of grade 1 and grade 2 pNETs (n=30) and intestinal NETs (n=57). In low-grade pNETs, normal circulating PlGF levels were associated with better survival. In intestinal NETs, circulating PlGF above median emerged as an independent prognostic factor for shorter time-to-progression in multivariate analyses. These data assign to PlGF a novel function in the pathobiology of NETs and propose PlGF as a prognostic parameter and therapeutic target.

Tubular markers are associated with decline in kidney function in proteinuric type 2 diabetic patients.

UNLABELLED: Our aim was to investigate u-NGAL, u-KIM1 and p-FGF23 and prediction of decline in kidney function in type 2 diabetic patients with proteinuria. METHODS: We performed a follow-up study, follow-up median (range) 3.5 (1-5) years. At baseline u-NGAL, u-KIM1 and p-FGF23 (ELISA) was measured and patients were followed yearly with estimated(e)-GFR (MDRD) and u-albumin. RESULTS: We included 177 patients (44 women), mean age (SD) 59 (9) years. eGFR 90 (24) ml/min/1.73 m(2) at baseline, u-albumin: median (interquartile range) 104 (39-238) mg/24 h. Patients with levels of u-KIM1 in the highest quartile had a greater decline in eGFR than patients with the lowest quartile 6.0 (5.4) versus 3.2 (5.5) ml/min/1.73 m(2) per year (p=0.02). u-NGAL in the highest versus lowest quartile eGFR decline: 5.1 (4.7) and 2.8 (7.1)ml/min/1.73 m(2) per year (p=0.07). Higher values of u-NGAL and u-KIM1 were associated with enhanced decline in eGFR (R=0.16 and R=0.19, p<0.05), however not after adjustment for progression promoters. p-FGF23 was not predictive of decline in eGFR. CONCLUSION: Higher levels of markers of tubular damage are associated with a faster decline in eGFR. However, since this is not independent of known progression promoters, measurement of tubular markers does not give additional prognostic information.

The effect of RAAS blockade on markers of renal tubular damage in diabetic nephropathy: u-NGAL, u-KIM1 and u-LFABP.

AIM: Blockade of the renin-angiotensin-aldosterone system (RAAS) affects both the glomerulus and tubules. We aimed to investigate the effect of irbesartan on the tubular markers: urinary (u) neutrophil gelatinase associated protein (NGAL), Kidney injury molecule 1 (KIM1) and liver-fatty acid-binding protein (LFABP). METHODS: A substudy of a double-masked, randomized, cross-over study including 52 patients with type 2 diabetes, hypertension and microalbuminuria. After 2 months washout of all antihypertensive medication except bendroflumethiazid, patients were treated in random order with irbesartan 300, 600 and 900 mg for 2 months. END POINTS: Urinary tubular markers at baseline and after each treatment period (ELISA), 24-h blood pressure, glomerular filtration rate (GFR, (51)CrEDTA) and 24-h urine albumin excretion (UAER). RESULTS: Fifty-two patients completed the study (41 male). Age (mean (SD)): 58(10) years and diabetes duration 13(8) years. Baseline GFR was 101(24) and UAER (geometric mean [95%CI]) 133 (103-172) mg/24 h. With increasing doses of irbesartan (300, 600, 900 mg) u-KIM1 was reduced with 15%, 10% and 15% (p = 0.07 between 300 mg vs. baseline and no difference between doses). Patients with high u-KIM1 at baseline (above median) had a 32% reduction in u-KIM1 during treatment (p = 0.01). No significant decline in U-NGAL compared to baseline. U-LFABP increased during treatment (p < 0.01). CONCLUSIONS: Irbesartan treatment reduced levels of the tubular marker u-KIM1 in patients with type 2 diabetes and microalbuminuria. u-NGAL changed insignificantly and u-LFABP increased. More studies with longer follow up are needed to determine the role of tubular markers in monitoring treatment effect and prediction of prognosis in diabetic nephropathy.

High sensitive troponin T and heart fatty acid binding protein: novel biomarker in heart failure with normal ejection fraction? A cross-sectional study.

BACKGROUND: High sensitive troponin T (hsTnT) and heart fatty acid binding protein (hFABP) are both markers of myocardial injury and predict adverse outcome in patients with systolic heart failure (SHF). We tested whether hsTnT and hFABP plasma levels are elevated in patients with heart failure with normal ejection fraction (HFnEF). METHODS: We analyzed hsTnT, hFABP and N-terminal brain natriuretic peptide in 130 patients comprising 49 HFnEF patients, 51 patients with asymptomatic left ventricular diastolic dysfunction (LVDD), and 30 controls with normal diastolic function. Patients were classified to have HFnEF when the diagnostic criteria as recommended by the European Society of Cardiology were met. RESULTS: Levels of hs TnT and hFABP were significantly higher in patients with asymptomatic LVDD and HFnEF (both p < 0.001) compared to controls. The hsTnT levels were 5.6 [0.0-9.8] pg/ml in LVDD vs. 8.5 [3.9-17.5] pg/ml in HFnEF vs. <0.03 [< 0.03-6.4] pg/ml in controls; hFABP levels were 3029 [2533-3761] pg/ml in LVDD vs. 3669 [2918-4839] pg/ml in HFnEF vs. 2361 [1860-3081] pg/ml in controls. Furthermore, hsTnT and hFABP levels were higher in subjects with HFnEF compared to LVDD (p = 0.015 and p = 0.022). CONCLUSION: In HFnEF patients, hsTnT and hFABP are elevated independent of coronary artery disease, suggesting that ongoing myocardial damage plays a critical role in the pathophysiology. A combination of biomarkers and echocardiographic parameters might improve diagnostic accuracy and risk stratification of patients with HFnEF.

Fator de diferenciação de crescimento 15: um novo biomarcador em pacientes com disfunção diastólica? / Growth-differentiation factor-15: a novel biomarker in patients with diastolic dysfunction? / Factor de diferenciación de crecimiento 15: ¿un nuevo biomarcador en pacientes con disfunción diastólica?

FUNDAMENTO: O fator de diferenciação de crescimento-15 ou GDF-15, uma citocina de resposta ao estresse relacionada ao fator transformador de crescimento beta (TGF-ß), está elevado e independentemente relacionado à prognóstico adverso na insuficiência cardíaca sistólica. OBJETIVO: O objetivo do presente estudo é investigar os níveis plasmáticos de GDF-15 em pacientes com disfunção diastólica pré-clínica ou insuficiência cardíaca com fração de ejeção normal (ICFEN). MÉTODOS: Avaliamos 119 pacientes com fração de ejeção (FE) normal, encaminhados à angiografia coronariana eletiva, dos quais 75 (63 por cento) tinham doença arterial coronariana (DAC). Os indivíduos foram classificados como tendo disfunção diastólica ventricular esquerda leve (DDVE grau I, n = 61), ICFEN (DDVE grau II ou III, n = 38) ou função diastólica normal (controles, n = 20). Em um subgrupo de 20 indivíduos, alterações no débito cardíaco (DC) foram medidas através de reinalação de gás inerte (Innocor®) em resposta a um teste hemodinâmico ortostático. RESULTADOS: Os níveis de GDF-15 na ICFEN [mediana 1,08, variação interquartil (0,88-1,30) ng/ml] eram significantemente mais altos do que nos controles [0,60 (0,50-0,71) ng/ml, p = 0,003] e em pacientes com DDVE grau I [0,78 (0,62-1,04) ng/ml, p < 0.001]. Além disso, os níveis de GDF-15 estavam significantemente elevados em pacientes com DDVE grau I, em comparação aos controles (p = 0,003). Adicionalmente, GDF-15 estava correlacionado com os marcadores ecocardiográficos de disfunção diastólica e estava correlacionado com a magnitude da resposta do CO à alteração na posição do corpo de ereta para supina (r = -0,67, p = 0,005). CONCLUSÃO: Os níveis de GDF-15 estão elevados em indivíduos com ICFEN e podem diferenciar função diastólica normal de DDVE. Além disso, os níveis de GDF-15 estão associados com uma redução na resposta do DC no teste hemodinâmico ortostático.

BACKGROUND: Growth differentiation factor-15 (GDF-15), a stress-responsive transforming growth factor-ß-related cytokine, is elevated and independently related to an adverse prognosis in systolic heart failure. OBJECTIVE: This study aimed to investigate plasma levels of GDF-15 in patients with preclinical diastolic dysfunction or heart failure with normal ejection fraction (HFnEF). METHODS: We evaluated 119 patients with normal ejection fraction referred for an elective coronary angiography, 75 (63 percent) of whom had coronary artery disease. Subjects were classified as having either mild left ventricular diastolic dysfunction (LVDD grade I, n = 61), HFnEF (LVDD grade II or III, n = 38) or normal diastolic function (controls, n = 20). In a subgroup of 20 subjects, changes in cardiac output (CO) were measured by inert gas rebreathing (InnocorTM) in response to an orthostatic hemodynamic test. RESULTS: Growth differentiation factor-15 levels in HFnEF [median 1.08, interquartile range (0.88-1.30) ng/ml] were significantly higher than in controls [0.60 (0.50-0.71) ng/ml, p = 0.003] and in patients with LVDD grade I [0.78 (0.62-1.04) ng/ml, p < 0.001]. In addition, GDF-15 was significantly elevated in patients with LVDD grade I compared to controls (p = 0.003). Furthermore, GDF-15 was correlated with echocardiographic markers of diastolic dysfunction and was correlated with the magnitude of CO response to the change in body position from standing to supine (r = -0.67, p = 0.005). CONCLUSION: Growth differentiation factor-15 levels are elevated in subjects with HFnEF and can differentiate normal diastolic function from asymptomatic LVDD. In addition, GDF-15 is associated with a reduced cardiac output response in the orthostatic hemodynamic test.

FUNDAMENTO: El factor de diferenciación de crecimiento-15 o GDF-15, una citocina de respuesta al estrés relacionada con el factor transformador de crecimiento beta (TGF-ß), es elevado y está independientemente relacionado con el pronóstico adverso en la insuficiencia cardíaca sistólica. OBJETIVO: El objetivo del presente estudio es investigar los niveles plasmáticos de GDF-15 en pacientes con disfunción diastólica preclínica o insuficiencia cardíaca con fracción de eyección normal (ICFEN). MÉTODOS: Evaluamos a 119 pacientes con fracción de eyección (FE) normal, derivados a angiografía coronaria electiva, de los cuales 75 (63 por ciento), tenían enfermedad arterial coronaria (EAC). Los individuos fueron clasificados como teniendo una disfunción diastólica ventricular izquierda leve (DDVI grado I, n = 61), ICFEN (DDVI grado II o III, n = 38), o función diastólica normal (controles, n = 20). En un subgrupo de 20 individuos, las alteraciones en el débito cardíaco (DC), se midieron a través de una nueva inhalación de gas inerte (Innocor®) en respuesta a un test hemodinámico ortostático. RESULTADOS: Los niveles de GDF-15 en la ICFEN [mediana 1,08, variación intercuartil (0,88-1,30) ng/ml], eran significantemente más altos que en los controles [0,60 (0,50-0,71) ng/ml, p = 0,003] y en los pacientes con DDVI grado I [0,78 (0,62-1,04) ng/ml, p < 0,001]. Además, los niveles de GDF-15 estaban significantemente elevados en los pacientes con DDVI grado I, en comparación con los controles (p = 0,003). Por añadidura, el GDF-15 estaba correlacionado con los marcadores ecocardiográficos de disfunción diastólica y con la magnitud de la respuesta del DC a la alteración en la posición del cuerpo variando de la posición erecta a la posición supina (r = -0,67, p = 0,005). CONCLUSIÓN: Los niveles de GDF-15 están elevados en individuos con ICFEN y pueden diferenciar una función diastólica normal de DDVI. Además, los niveles de GDF-15 están asociados con una reducción en la respuesta del DC en el test hemodinámico ortostático.

Growth-differentiation factor-15: a novel biomarker in patients with diastolic dysfunction?

BACKGROUND: Growth differentiation factor-15 (GDF-15), a stress-responsive transforming growth factor-ß-related cytokine, is elevated and independently related to an adverse prognosis in systolic heart failure. OBJECTIVE: This study aimed to investigate plasma levels of GDF-15 in patients with preclinical diastolic dysfunction or heart failure with normal ejection fraction (HFnEF). METHODS: We evaluated 119 patients with normal ejection fraction referred for an elective coronary angiography, 75 (63%) of whom had coronary artery disease. Subjects were classified as having either mild left ventricular diastolic dysfunction (LVDD grade I, n = 61), HFnEF (LVDD grade II or III, n = 38) or normal diastolic function (controls, n = 20). In a subgroup of 20 subjects, changes in cardiac output (CO) were measured by inert gas rebreathing (InnocorTM) in response to an orthostatic hemodynamic test. RESULTS: Growth differentiation factor-15 levels in HFnEF [median 1.08, interquartile range (0.88-1.30) ng/ml] were significantly higher than in controls [0.60 (0.50-0.71) ng/ml, p = 0.003] and in patients with LVDD grade I [0.78 (0.62-1.04) ng/ml, p < 0.001]. In addition, GDF-15 was significantly elevated in patients with LVDD grade I compared to controls (p = 0.003). Furthermore, GDF-15 was correlated with echocardiographic markers of diastolic dysfunction and was correlated with the magnitude of CO response to the change in body position from standing to supine (r = -0.67, p = 0.005). CONCLUSION: Growth differentiation factor-15 levels are elevated in subjects with HFnEF and can differentiate normal diastolic function from asymptomatic LVDD. In addition, GDF-15 is associated with a reduced cardiac output response in the orthostatic hemodynamic test.

Biological variation of high sensitive Troponin T in stable heart failure patients with ischemic or dilated cardiomyopathy.

INTRODUCTION: High sensitive Troponin (hsTn) assays enable detection of minimal marker elevation in heart failure patients previously deemed Troponin negative. Biovariability, reference change values (RCV), and index of individuality (II) have not been previously described for hsTnT although serial testing is important in interpreting low concentrations. For these values, a difference between ischemic heart disease (IHD) and dilated cardiomyopathy (dCMP) appears conceivable. METHODS: Change in hsTnT was determined alongside with clinical variables in 41 patients with stable chronic systolic dysfunction at 2-week-, 1-month-, 2-month-, and 3-month-intervals (IHD n = 17; dCMP n = 24). RESULTS: HsTnT was detectable in all patients. Individual hsTnT-variations at 2-week, 1-month, 2-month, and 3-month follow-up were 7.2, 22.6, 28.9, and 15.7%, respectively, corresponding to RCVs of 20.1, 62.5, 80.0, and 43.3%, respectively, for crude values. For log-normalised values, individual variations were 3.2, 2.8, 2.7, and 3.5%, respectively, corresponding to RCVs of 8.8, 7.9, 7.6, and 9.7%, respectively. The II was 0.03 to 0.33 according to interval. Aetiology of heart failure was not a consistent determinant of variation (p = 0.28; p = 0.07; p = 0.98; p = 0.03 for 2-week, 1-month, 2-month, and 3-month follow-up, respectively). CONCLUSION: While short-term biological variation of hsTnT is low, it becomes relatively more important for intermediate follow-up. It is not related to aetiology of heart failure. The corresponding indices of individuality indicate high individuality of values.

Tubular markers do not predict the decline in glomerular filtration rate in type 1 diabetic patients with overt nephropathy.

Recent studies have shown that both glomerular and tubulointerstitial damage are important factors in the pathophysiology and progression of diabetic nephropathy. To examine whether markers of tubular damage are useful in monitoring the progression of disease, we measured urinary levels of neutrophil gelatinase-associated lipocalin (NGAL), liver-fatty acid-binding protein (LFABP), and kidney injury molecule-1 (KIM-1) in a 3-year intervention study of 63 type 1 diabetic patients with kidney disease. The baseline mean glomerular filtration rate (GFR) was 87 ml/min per 1.73 m(2) and urinary albumin excretion 1141 mg/24 h. Patients with the highest compared with the lowest quartile of urinary NGAL at baseline had higher urinary KIM-1 levels and a significant decrease in their GFR each year. Using linear regression analysis, we found that elevated urinary NGAL and KIM-1 concentrations were associated with a faster decline in GFR, but not after adjustment for known promoters of progression. Urinary LFABP was not related to decline in GFR. Losartan treatment (100 mg/day) reduced urinary KIM-1 by 43% over a 12-month period. Thus, urine biomarker measurements in patients with type 1 diabetic nephropathy did not provide additional prognostic information to that of known progression promoters.

Comparison of the new high sensitive cardiac troponin T with myoglobin, h-FABP and cTnT for early identification of myocardial necrosis in the acute coronary syndrome.

BACKGROUND: We sought to determine the performance of the new high sensitivity cardiac troponin T assay (TnThs) for early diagnosis of myocardial infarction in patients with suspected acute coronary syndrome (ACS) and compare it with the fourth generation cTnT assay, myoglobin and heart-type fatty acid binding protein (h-FABP). METHODS: Ninety-four patients with diagnosis of suspected ACS without ST-segment elevation admitted to our chest pain unit were included. Patients were divided according to time from onset of symptoms to presentation into an early presenter group (<4 h) and a late presenter group (≥4 h). A median of six samples (range 2-8) were available per patient. The diagnostic performance of TnThs was assessed using ROC analysis. Areas under the curve (AUC) of baseline and follow-up results of TnThs, cTnT, myoglobin, and h-FABP were compared using c statistics. RESULTS: The TnThs assay allows an excellent prediction of non-ST-segment elevation myocardial infarction (non-STEMI) at presentation, particularly among late presenters. A follow-up sample improves diagnostic performance in a time-dependent manner. The AUC of TnThs was superior to cTnT at all time points. The performance of TnThs was at least as good as myoglobin and h-FABP at presentation and during follow-up. CONCLUSIONS: A baseline sample of TnThs allows an earlier prediction of non-STEMI than the less sensitive and precise fourth generation cTnT assay. Probably, this excellent performance of TnThs at baseline and follow-up could obviate the need for other early markers of necrosis in future.

High-sensitivity cardiac troponin T for early prediction of evolving non-ST-segment elevation myocardial infarction in patients with suspected acute coronary syndrome and negative troponin results on admission.

BACKGROUND: We sought to determine the diagnostic performance of the new high-sensitivity cardiac troponin T (hs-cTnT) assay for early detection of non-ST-segment myocardial infarction (NSTEMI) in patients with acute coronary syndrome. METHODS: We enrolled patients with retrospectively confirmed unstable angina or NSTEMI and an initially negative cTnT concentration and compared the performance of baseline concentrations and serial changes in concentration within 3 and 6 h. Percentage change criteria included >or=20% delta change and ROC-optimized value. RESULTS: Based on the standard fourth-generation cTnT result of >or=0.03 microg/L, an evolving NSTEMI was diagnosed in 26 patients, and 31 patients were classified as having unstable angina. With the use of the hs-cTnT assay at the 99th-percentile cutoff, the percentage of NSTEMI cases detected increased gradually from 61.5% on presentation to 100% within 6 h, and the overall number of MI diagnoses increased by 34.6% (35 vs 26 cases). A delta change >or=20% or >or=ROC-optimized value of >117% within 3 h or >or=243% within 6 h yielded a specificity of 100% at sensitivities between 69% and 76%. The standard cTnT at the 99th percentile was less sensitive than hs-cTnT for early diagnosis of MI on presentation, and follow-up samples obtained within the initial 3 h demonstrated very low specificity of cTnT compared with hs-cTnT. CONCLUSIONS: The high-sensitivity cTnT assay increases the number of NSTEMI diagnoses and enables earlier detection of evolving NSTEMI. A doubling of the hs-cTnT concentration within 3 h in the presence of a second concentration >or=99th percentile is associated with a positive predictive value of 100% and a negative predictive value of 88%.

Reference change values and determinants of variability of NT-proANP and GDF15 in stable chronic heart failure.

Biovariability, reference change values (RCV), and index of individuality (IOI) have not been previously described for NT-proANP or GDF15. Also, the relation of changes of these markers to other clinical variables or biomarkers is unknown. In 41 patients with stable chronic systolic dysfunction, NT-proANP and GDF15 were measured alongside with clinical variables/markers comprising NT-proBNP, hsTnT, and hsCRP at four sampling intervals (2 weeks, 1-, 2-, 3-month intervals). At 2 weeks, 1-, 2-, and 3-month-follow-up, individual NT-proANP variations were 27.1, 22.5, 28.9, 15.6%, respectively, corresponding to RCVs of 53.2, 62.4, 80.2, and 43.2%, respectively. For GDF15, the respective individual variations were 6.8, 4.1, 5.5, 6.8%, corresponding to RCVs of 18.8, 11.5, 15.3 and 18.8%. Neither changes of NT-proANP or GDF15 correlated with changes in any of the clinical variables or biomarkers examined except for GDF15 with renal function. Baseline hormonal levels and clinical variables did not consistently influence the extent of change. The IOI was 0.19-0.35 according to interval for NT-proANP and 0.06-0.09 for GDF 15. In patients with CHF preselected for clinical stability changes of NT-proANP at intermediate follow-up do not correlate with changes in other variables; changes of GDF15 inversely correlate with renal function. The extent of change in both markers is not related to baseline hormonal levels or other baseline variables. RCVs are high for NT-proANP and low for GDF15, while inter-individual variation is high in GDF15 and intermediate in NT-proANP.

Variability of N-terminal probrain natriuretic peptide in stable chronic heart failure and its relation to changes in clinical variables.

BACKGROUND: We investigated the variability of N-terminal probrain natriuretic peptide (NT-proBNP) and its relation to known confounding variables in patients with stable chronic heart failure who were on a stable optimized medication regimen. METHODS: At 4 sampling intervals (14-day, 1-month, 2-month, and 3-month) the results for NT-proBNP measurements and several clinical variables were measured in samples from 41 patients with chronic systolic dysfunction who met 21 prespecified criteria for stability. RESULTS: Mean within-person NT-proBNP variabilities expressed as percentage CV were 17.6%, 18.9%, 15.5%, and 16.2% at 14-day, 1-month, 2-month, and 3-month follow-up, respectively, and the corresponding reference change values were 34.6%, 52.5%, 43.1%, and 45.0%, respectively. Within-person variability of NT-proBNP was not found to be associated with renal function, weight, or waist circumference. Likewise, age, sex, baseline NT-proBNP, New York Heart Association functional class, and ejection fraction did not influence variability of NT-proBNP. The index of individuality ranged from 0.07-0.15 depending on the time interval between test results. CONCLUSIONS: Although other reported studies have revealed variations in the range of 80%, in this prespecified stable heart-failure population variation of NT-proBNP at 14-day, 1-month, 2-month, and 3-month follow-up was lower and was not related to renal function or weight. In view of the low index of individuality we observed, within-person variation is quite low compared to between-person variation. Consideration of these facts is important for the interpretation of clinical trials and the use of NT-proBNP in monitoring patients with heart failure.

NT-proBNP is increased in healthy pregnancies compared to non-pregnant controls.

Serum concentrations of the amino-terminal pro-B-type natriuretic peptide (NT-proBNP) may be used to monitor cardiac function during pregnancy but normal values are not established for this purpose. Therefore, we investigated NT-proBNP in normotensive healthy pregnancies compared to a non-pregnant control group. Serum NT-proBNP was measured in 94 normotensive, healthy pregnant women (32+/-6 years) every five weeks beginning from 12th gestational week (GW) in a longitudinal study and compared to a non-pregnant control group of 521 women (32+/-7 years). Pooled median serum NT-proBNP levels (25th; 75th percentile) were significantly higher in pregnant women compared to non-pregnant women (56 (33; 95) pg/ml vs. 38 (22; 62) pg/ml (p<0.001)). NT-proBNP increased during pregnancy to 73 (51; 124) pg/ml in the 11+6 to 15+6 GW (p<0.001). However, NT-proBNP levels from 23+0 GW towards term were comparable to non-pregnant controls. NT-proBNP is significantly elevated in healthy pregnancies until mid-pregnancy. As preeclampsia and gestational hypertension are associated with increased NT-proBNP, our results have to be considered in future diagnostic approaches using NT-proBNP for these pathologic conditions.

GB virus C (GBV-C) infection in hepatitis C virus (HCV)/HIV-coinfected patients receiving HCV treatment: importance of the GBV-C genotype.

BACKGROUND: Persistent GB virus C (GBV-C) coinfection leads to slower human immunodeficiency virus (HIV) progression. Despite the existence of multiple GBV-C genotypes, their relevance to the progression of HIV disease is unknown. We therefore investigated (1) the prevalence and genotype of GBV-C in hepatitis C virus (HCV)/HIV-coinfected patients and (2) the impact of HCV treatment on GBV-C RNA clearance. METHODS: We retrospectively studied 130 HCV/HIV-coinfected patients initiating HCV therapy. Anti-E2 enzyme-linked immunosorbent assay, reverse-transcription polymerase chain reaction (PCR), and real-time PCR were used to detect and quantify GBV-C infection. GBV-C genotype was determined by sequencing the 5' untranslated region. RESULTS: GBV-C infection (past or current) was identified in 111 (85%) of the patients. Ongoing GBV-C replication was detected in 40 patients. Coinfection with GBV-C genotype 2 was associated with significantly higher CD4(+) cell counts. After 24 weeks of HCV therapy, GBV-C RNA clearance was observed in 50% of patients, although this was not associated with changes in HIV load or with CD4(+) cell counts. Sustained GBV-C RNA clearance was observed in 31% of patients with GBV-C RNA detected at baseline. CONCLUSIONS: GBV-C coinfection was extremely common. GBV-C RNA clearance with HCV therapy was associated with neither short-term loss of HIV control nor impaired immune status. The association of GBV-C genotype 2 with higher CD4(+) cell counts merits further study.

Reference interval determination for N-terminal-B-type natriuretic peptide (NT-proBNP): a study in blood donors.

We assessed reference values in a group of apparently healthy blood donors. A total of 1980 blood donors was recruited and tested for the presence of NT-proBNP using a newly developed electrochemiluminescence immunoassay (ECLIA) method. NT-proBNP clustered in all blood donors below the age of 50 years and an upper limit of normal (ULN) was found to be 84 pg/ml for males and 146 pg/ml for females. Mean NT-proBNP values increased with increasing age which was due to an increasing number of individuals exceeding the ULN. Age- and gender-appropriate NT-proBNP levels decreased with increasing hemoglobin levels. Hemoglobin but not creatinine levels influenced the NT-proBNP concentration in this cohort. The upper limit of normal can be used in clinical studies to further assess groups of diseased individuals to define clinical cutoffs.

GB virus C infection in children with perinatal human immunodeficiency virus infection.

BACKGROUND: GB virus C (GBV-C) infection occurs in 20-40% of human immunodeficiency virus (HIV)-infected adults, and coinfection is associated with improved HIV disease outcome. METHODS: To determine the prevalence of GBV-C infection in children who were perinatally infected with HIV, we conducted a cross-sectional prevalence survey in a cohort of perinatally infected HIV-positive children selected from a large, multicenter observational protocol. A blood specimen was obtained and tested for GBV-C viremia with the use of a qualitative GBV-C RNA assay and screened for past GBV-C infection with enzyme-linked immunosorbent assay to detect antibodies to the GBV-C envelope protein E2 (E2 Ab). RESULTS: The 354 children who participated in the substudy were relatively healthy, with a median CD4 of 784 cells/mm and median HIV-1 viral load of 1055 copies/mL. The prevalence of GBV-C viremia was 20 of 353 or 5.7% (95% confidence interval, 3.5-8.6%), and the prevalence of E2 Ab was 12 of 354 or 3.4% (95% confidence interval, 1.8-5.8%). GBV-C viremic patients were older than patients without past GBV-C infection (median age, 12.8 years versus 10.7 years). Median CD4 lymphocyte counts were highest in subjects without GBV-C infection and lowest in those with E2 Ab. CONCLUSIONS: GBV-C prevalence rates are lower in children with perinatal HIV infection than those reported for HIV-infected adults. With the exception of evidence that GBV-C viremic children had lower rates of Centers for Disease Control and Prevention HIV disease category C disease before GBV-C testing, we did not find evidence of improved HIV disease outcome in coinfected patients, but the number of HIV/GBV-C-coinfected children was small.