Increased concentrations of amino-terminal prohormone brain-type natriuretic peptide (NT-proBNP) are associated with cardiovascular morbidity and mortality, but little is known about their relationship to chronic inflammation. Patients with rheumatoid arthritis (RA) have chronic inflammation, increased arterial stiffness and accelerated coronary atherosclerosis. We tested the hypothesis that NT-proBNP concentrations are elevated in patients with RA, and are associated with coronary artery calcification and markers of inflammation.
In 159 subjects with RA (90 patients with early RA and 69 patients with longstanding RA) without heart failure and 88 control subjects, we measured serum concentrations of NT-proBNP, interleukin (IL)-6, and tumor necrosis factor-α (TNF-α), and coronary calcification.
NT-proBNP concentrations were elevated in patients with long-standing RA [median (IQR): 142.8 (54.8–270.5) pg/mL] and those with early RA [58.1 (19.4–157.6) pg/mL] compared to controls [18.1 (3.2–46.0) pg/mL, P<0.001]. In patients with RA, NT-proBNP concentrations were associated with age (ρ=0.35, P<0.001), IL-6 (ρ=0.33, P<0.001), TNF-α (ρ=0.23, P=0.003), CRP (ρ=0.21, P=0.01), coronary calcium score (ρ=0.30, P<0.001), systolic blood pressure (ρ=0.30, p<0.001), and disease activity (ρ=0.29, P<0.001). After adjustment for age, race and sex the associations between NT-proBNP concentrations and disease activity (P<0.001), TNF-α (P<0.001), IL-6 (P=0.04) and CRP concentrations (P=0.02) remained significant, but those with systolic blood pressure (P=0.10) and coronary calcium score (P=0.27) were attenuated.
NT-proBNP concentrations are increased in patients with RA without clinical heart failure and may indicate subclinical cardiovascular disease and a chronic inflammatory state.
rheumatoid arthritis; inflammation; atherosclerosis; B-type natriuretic peptide; NT-proBNP
To evaluate the ability of six biomarkers to improve prediction of cardiovascular events among persons with established coronary artery disease.
Cardiovascular risk algorithms are designed to predict the initial onset of coronary artery disease, but are less effective in persons with pre-existing coronary artery disease.
We examined the association of N-terminal prohormone brain natriuretic peptide (Nt-proBNP), cystatin C, albuminuria, C-reactive protein (CRP), interleukin-6 (IL-6), and fibrinogen with cardiovascular events in 979 Heart and Soul Study participants with coronary artery disease after adjusting for demographic, lifestyle and behavior variables; cardiovascular risk factors, cardiovascular disease severity, medication use and left ventricular ejection fraction. The outcome was a composite of stroke, myocardial infarction, or coronary heart disease death during an average of 3.5 years of follow-up.
During follow-up, 142 (15%) participants developed cardiovascular events. The highest quartiles (versus lower 3 quartiles) of five biomarkers were individually associated with cardiovascular risk after multivariate analysis: Nt-proBNP Hazard Ratio=2.13 (95% confidence interval, 1.43 - 3.18); cystatin C 1.72 (1.10 - 2.70); albuminuria 1.71 (1.15 - 2.54); CRP 2.00 (1.40 - 2.85); and IL-6 1.76 (1.22 - 2.53). When all biomarkers were included in multivariable analysis, only Nt-proBNP, albuminuria and CRP remained significant predictors of events [HR (95% CI), 1.88 (1.23 - 2.85), 1.63 (1.09 - 2.43), 1.82 (1.24 - 2.67) respectively]. The area under the receiver operator curve (AUC) for clinical predictors alone was 0.73 (95% CI, 0.68-0.78); adding Nt-proBNP, albuminuria and CRP significantly increased the AUC to 0.77 (95% CI, 0.73-0.82, p<0.005).
Among persons with prevalent coronary artery disease, biomarkers reflecting hemodynamic stress, kidney damage, and inflammation added significant risk discrimination for cardiovascular events.
biomarkers; coronary artery disease; cardiovascular events; N-terminal prohormone brain natriuretic peptide; cystatin C; albuminuria; C-reactive protein; interleukin-6; fibrinogen
Myocardial perfusion imaging (MPI) can detect myocardial perfusion abnormalities but many examinations are without pathological findings. This study examines whether circulating biomarkers can be used as screening modality prior to MPI.
243 patients with an intermediate risk of CAD or with known CAD with renewed suspicion of ischemia were referred to MPI. Blood samples were analyzed for N-terminal fragment of the prohormone brain natriuretic peptide (NT-proBNP), YKL-40, IL-6, matrix metalloproteinase 9 (MMP-9) and high sensitive C-reactive protein (hsCRP). Patients with myocardial perfusion defects had elevated levels of NT-proBNP (p<0.0001), YKL-40 (p = 0.03) and IL-6 (p = 0.03) but not of hsCRP (p = 0.58) nor of MMP-9 (p = 0.14). The NT-proBNP increase was observed in both genders (p<0.0001), whereas YKL-40 (p = 0.005) and IL-6 (p = 0.02) were elevated only in men. A NT-proBNP cut off-concentration at 25 ng/l predicted a normal MPI with a negative predictive value >95% regardless of existing CAD.
20-25% of patients suspected of CAD could have been spared a MPI by using a NT-proBNP cut-off concentration at 25 ng/l with a negative predictive value >95%. NT-proBNP has the potential use of being a screening marker of CAD before referral of the patient to MPI.
Acute decompensated heart failure is one of the most important causes of hospitalisation worldwide. Natriuretic peptides have shown their usefulness in the diagnosis and management of heart failure. Their variations during hospitalisation also appear useful to predict outcomes. In particular, data from the literature demonstrate that reduction from admission to discharge of brain natriuretic peptide and N-terminal prohormone brain natriuretic peptide in these patients is a predictor of future cardiovascular events.
The present review will cover the mechanisms of release and the potential pathophysiological role of different natriuretic peptides in critically ill patients. By focusing on the cardiovascular system, possible implications of natriuretic peptides for diagnosis and treatment will be presented. In critical illness such as sepsis, trauma or major surgery, systemic hypotension and an intrinsic myocardial dysfunction occur. Impairment of the cardiovascular system contributes to poor prognosis in severe human sepsis. Natriuretic peptides have emerged as valuable marker substances to detect left ventricular dysfunction in congestive heart failure of different origins. Increased plasma levels of circulating natriuretic peptides, atrial natriuretic peptide, N-terminal pro-atrial natriuretic peptide, brain natriuretic peptide and its N-terminal moiety N-terminal pro-brain natriuretic peptide have also been found in critically ill patients. All of these peptides have been reported to reflect left ventricular dysfunction in these patients. The increased wall stress of the cardiac atria and ventricles is followed by the release of these natriuretic peptides. Furthermore, the release of atrial natriuretic peptide and brain natriuretic peptide might be triggered by members of the IL-6-related family and endotoxin in the critically ill. Apart from the vasoactive actions of circulating natriuretic peptides and their broad effects on the renal system, anti-ischemic properties and immunological functions have been reported for atrial natriuretic peptide. The early onset and rapid reversibility of left ventricular impairment in patients with good prognosis associated with a remarkably augmented plasma concentration of circulating natriuretic peptides suggest a possible role of these hormones in the monitoring of therapy success and the estimation of prognosis in the critically ill.
critical illness; cytokines; heart failure; natriuretic peptides
This study sought to characterize factors influencing amino-terminal pro-B-type natriuretic peptide (NT-proBNP) and to evaluate the ability of NT-proBNP to detect left ventricular (LV) dysfunction in a large community sample.
Secretion of BNP increases in cardiac disease, making BNP an attractive biomarker. Amino-terminal proBNP, a fragment of the BNP prohormone, is a new biomarker. We evaluated factors influencing NT-proBNP in normal patients and compared the ability of NT-proBNP and BNP to detect LV dysfunction in a large community sample.
Amino-terminal pro-BNP was determined in plasma samples of a previously reported and clinically and echocardiographically characterized random sample (n = 1,869, age ≥ 45 years) of Olmsted County, Minnesota.
In normal patients (n = 746), female gender and older age were the strongest independent predictors of higher NT-proBNP. Test characteristics for detecting an LV ejection fraction ≤ 40% or ≤ 50% were determined in the total sample with receiver operating characteristic curves. Amino-terminal pro-BNP had significantly higher areas under the curve for detecting an LV ejection fraction ≤ 40% or ≤ 50% than BNP in the total population and in several male and age subgroups, whereas areas were equivalent in female subgroups. Age- and gender-adjusted cutpoints improved test characteristics of NT-proBNP. Both assays detected patients with systolic and/or moderate to severe diastolic dysfunction to a similar degree, which was less robust than the detection of LV systolic dysfunction alone.
Amino-terminal pro-BNP in normal patients is affected primarily by gender and age, which should be considered when interpreting values. Importantly, in the entire population sample NT-proBNP performed at least equivalently to BNP in detecting LV dysfunction and was superior in some subgroups in detecting LV systolic dysfunction.
Identification of individuals at high risk for cardiovascular events is important for the optimal use of primary and secondary prevention measures.
To determine whether plasma levels of amino terminal fragment of the prohormone brain-type natriuretic peptide (NT-proBNP) predict cardiovascular events or death independent of other available prognostic tests.
Design, Setting, and Participants
Prospective cohort study (2000–2002) of 987 individuals in California with stable coronary heart disease in the Heart and Soul Study, who were followed up for a mean of 3.7 (range, 0.1–5.3) years.
Main Outcome Measures
The association of baseline NT-proBNP levels with death or cardiovascular events (myocardial infarction, stroke, or heart failure). Traditional clinical risk factors, echocardiographic measures, ischemia, other biomarkers, and New York Heart Association classification were adjusted for to determine whether NT-proBNP levels were independent of other prognostic factors. Receiver operating characteristic (ROC) curves were used to assess the incremental prognostic value of adding NT-proBNP level to these other measures.
A total of 256 participants (26.2%) had a cardiovascular event or died. Each increasing quartile of NT-proBNP level (range of quartile 1, 8.06–73.95 pg/mL; quartile 2, 74–174.5 pg/mL; quartile 3, 175.1–459 pg/mL; quartile 4, ≥460 pg/mL) was associated with a greater risk of cardiovascular events or death, ranging from 23 of 247 (annual event rate, 2.6%) in the lowest quartile to 134 of 246 (annual event rate, 19.6%) in the highest quartile (unadjusted hazard ratio [HR] for quartile 4 vs quartile 1, 7.8; 95% confidence interval [CI], 5.0–12.1; P<.001). Each SD increase in log NT-proBNP level (1.3 pg/mL) was associated with a 2.3-fold increased rate of adverse cardiovascular outcomes (unadjusted HR, 2.3; 95% CI, 2.0–2.6; P<.001), and this association persisted after adjustment for all of the other prognostic measures (adjusted HR, 1.7; 95% CI, 1.3–2.2; P<.001). The addition of NT-proBNP level to standard clinical assessment and complete echocardiographic parameters significantly improved the area under the ROC curves for predicting subsequent adverse cardiovascular outcomes (0.80 for clinical risk factors and echocardiographic parameters plus log NT-proBNP vs 0.76 for clinical risk factors and echocardiographic parameters only; P=.006).
Elevated levels of NT-proBNP predict cardiovascular morbidity and mortality, independent of other prognostic markers, and identify at-risk individuals even in the absence of systolic or diastolic dysfunction by echocardiography. Level of NT-proBNP may help guide risk stratification of high-risk individuals, such as those with coronary heart disease.
Disease activity in patients with rheumatoid arthritis (RA) is associated with increased cardiovascular morbidity and mortality, of which N-terminal pro-brain natriuretic peptide (NT-proBNP) is a predictor. Our objective was to examine the cross-sectional and longitudinal associations between markers of inflammation, measures of RA disease activity, medication used in the treatment of RA, and NT-proBNP levels (dependent variable).
Two hundred thirty-eight patients with RA of less than 4 years in duration were followed longitudinally with three comprehensive assessments of clinical and radiographic data over a 10-year period. Serum samples were frozen and later batch-analyzed for NT-proBNP levels and other biomarkers. Bivariate, multivariate, and repeated analyses were performed.
C-reactive protein (CRP) levels at baseline were cross-sectionally associated with NT-proBNP levels after adjustment for age and gender (r2 adjusted = 0.23; P < 0.05). At the 10-year follow-up, risk factors for cardiovascular disease were recorded. Duration of RA and CRP levels were independently associated with NT-proBNP in the final model that was adjusted for gender, age, and creatinine levels (r2 adjusted = 0.38; P < 0.001). In the longitudinal analyses, which adjusted for age, gender, and time of follow-up, we found that repeated measures of CRP predicted NT-proBNP levels (P < 0.001).
CRP levels are linearly associated with levels of NT-proBNP in cross-sectional and longitudinal analyses of patients with RA. The independent associations of NT-proBNP levels and markers of disease activity with clinical cardiovascular endpoints need to be further investigated.
In patients with heart failure (HF), N-terminal prohormone brain natriuretic peptide (NT-ProBNP) is a standard prognostic indicator. In addition, uric acid (UA) was recently established as a prognostic marker for poor outcome in chronic HF. The aim of this study was to determine the combined role of UA and NT-ProBNP as prognostic markers for short-term outcomes of acute heart failure (AHF).
The levels of UA and NT-ProBNP were determined in 193 patients (age, 69 ± 13 years; 76 males) admitted with AHF. Patients were followed for 3 months and evaluated for cardiovascular events, defined as cardiac death and/or readmission for HF.
Of the 193 patients, 23 (11.9%) died and 20 (10.4%) were readmitted for HF during the 3-month follow-up period. Based on univariate analysis, possible predictors of short-term cardiovascular events were high levels of UA and NT-ProBNP, low creatinine clearance, no angiotensin converting enzyme inhibitors or angiotensin receptor blockers, and old age. Multivariate Cox hazard analysis showed that UA levels were independently associated with increased incidence of cardiovascular events (hazard ratio, 1.115; 95% confidence interval, 1.006 to 1.235; p = 0.037). Kaplan-Meier survival analysis revealed that patients with UA levels > 8.0 mg/dL and NT-ProBNP levels > 4,210 pg/mL were at highest risk for cardiac events (p = 0.01).
The combination of UA and NT-ProBNP levels appears to be more useful than either marker alone as an independent predictor for short-term outcomes in patients with AHF.
Uric acid; Natriuretic peptides; Heart failure
This study evaluated the relationship between natriuretic peptide levels and a wide range of echocardiography parameters in a population of thirty-three patients with poorly regulated type 2 diabetes, and no known heart failure. Natriuretic peptides brain natriuretic peptide (BNP) and N-terminal prohormone BNP (NT-proBNP) were measured. Transthoracic echocardiography was performed and cardiac volumes and ejection fraction were measured. Doppler and tissue Doppler were measured and diastolic function was stratified according to recent guidelines. Very few echocardiography parameters were correlated with BNP or NT-proBNP levels. However, left atrial end-systolic volume indexed for body surface area was correlated with natural logarithm (ln) BNP and ln NT-proBNP (r = 0.62 and r = 0.60; P < 0.05). There were significant differences in ln BNP and ln NT-proBNP levels between those with normal and those with abnormal diastolic function (1.4 vs 3.1; P < 0.001 and 3.4 vs 5.8; P < 0.001). This study showed that very few echocardiography parameters were correlated with BNP or NT-proBNP levels in patients with poorly regulated type 2 diabetes, which in part contradicts previous studies in other diabetic populations. The exception was left atrial end-systolic volume that showed a moderate correlation with BNP or NT-proBNP levels. There were significant differences in BNP and NT-proBNP levels between the group with normal left ventricular diastolic function and the group with abnormal diastolic function.
type 2 diabetes; natriuretic peptides; echocardiography
Congestive heart failure is underdiagnosed in patients with chronic obstructive pulmonary disease (COPD). Pulmonary congestion on chest radiograph at admission for acute exacerbation of COPD (AECOPD) is associated with an increased risk of mortality. A standardized evaluation of chest radiographs may enhance prognostic accuracy.
We aimed to evaluate whether a standardized, liberal assessment of pulmonary congestion is superior to the routine assessment in identifying patients at increased risk of long-term mortality, and to investigate the association of heart failure with N-terminal prohormone of brain natriuretic peptide (NT-proBNP) concentrations.
Material and methods
This was a prospective cohort study of 99 patients admitted for AECOPD. Chest radiographs obtained on admission were routinely evaluated and then later evaluated by blinded investigators using a standardized protocol looking for Kerley B lines, enlarged vessels in the lung apex, perihilar cuffing, peribronchial haze, and interstitial or alveolar edema, defining the presence of pulmonary congestion. Adjusted associations with long-term mortality and NT-proBNP concentration were calculated.
The standardized assessment was positive for pulmonary congestion in 32 of the 195 radiographs (16%) ruled negative in the routine assessment. The standardized assessment was superior in predicting death during a median follow up of 1.9 years (P=0.022), and in multivariable analysis, only the standardized assessment showed a significant association with mortality (hazard ratio 2.4, 95% confidence interval [CI] 1.2–4.7) (P=0.016) and NT-proBNP (relative concentration 1.8, CI 1.2–2.6) (P=0.003).
By applying a standardized approach when evaluating pulmonary congestion on chest radiographs during AECOPD, a group of patients with increased risk of dying, possibly due to heart failure, is identified.
heart failure; radiograph; NT-proBNP; mortality; X-ray; cephalization
N-terminal pro B-type natriuretic peptide (NT-proBNP) is a product of cleavage of the cardiac prohormone pro B-type natriuretic peptide into its active form. It has proven to be a useful biomarker in left heart failure. However, studies examining the utility of serial measurements of NT-proBNP in pulmonary arterial hypertension (PAH) patients have shown mixed results. We compared three methods of predicting adverse clinical outcomes in PAH patients: the change in 6 minute walk distance (6MWD), the change in absolute levels of NT-proBNP and the change in log-transformed levels of NT-proBNP. All PAH patients presenting from March-June 2007 were screened. Patients who were clinically unstable, had abnormal renal function or hemoglobin levels or lacked a prior NT-proBNP were excluded. 63 patients were followed up for adverse clinical outcomes (defined as death, transplantation, hospitalisation for right heart failure, or need for increased therapy). Three methods were used to predict adverse events, i.e.: (a) comparing a 6MWD performed in March-June 2007 and a previous 6MWD. A decrease in 6MWD of ≥30m was used to predict clinical deterioration; (b) comparing a NT-proBNP value measured in March-June 2007 and a previous NT-proBNP. An increase in NT-proBNP of ≥250pg/ml was used to predict clinical deterioration (250pg/ml represented approximately 30% change from the baseline median value of NT-proBNP for this cohort); and (c) comparing the loge equivalents of two consecutive NT-proBNP values. We used the formula: loge(current NT-proBNP) - loge(previous NT-proBNP)=x. A value of x≥+0.26 was used to predict adverse events. This is equivalent to a 30% change from baseline, and hence is comparable to the chosen cut-off for absolute levels of NT-proBNP. A loge difference of ≥+0.26 identifies patients at risk of adverse events with a specificity of 98%, a sensitivity of 60%, a positive predictive value of 89%, and a negative predictive value of 90%. A drop in 6MWD of ≥30m has a specificity of 29%, a sensitivity of 73%, a positive predictive value of 24% and a negative predictive value of 24%. It seems possible to risk-stratify apparently stable PAH patients by following the changes in their serial log-transformed NT-proBNP values. In this small pilot study, this method was better than relying on changes in the actual levels of NT-proBNP or changes in 6MWD. This needs to be validated prospectively in a larger cohort.
N-terminal pro B-type natriuretic peptide; 6-minute walk distance; biomarker
Measurement of prohormones representing different pathophysiological pathways could enhance risk stratification in patients with community-acquired pneumonia (CAP) and other lower respiratory tract infections (LRTI).
We assessed clinical parameters and five biomarkers, the precursor levels of adrenomedullin (ADM), endothelin-1 (ET1), atrial-natriuretic peptide (ANP), anti-diuretic hormone (copeptin), and procalcitonin in patients with LRTI and CAP enrolled in the multicenter ProHOSP study. We compared the prognostic accuracy of these biomarkers with the pneumonia severity index (PSI) and CURB65 (Confusion, Urea, Respiratory rate, Blood pressure, Age 65) score to predict serious complications defined as death, ICU admission and disease-specific complications using receiver operating curves (ROC) and reclassification methods.
During the 30 days of follow-up, 134 serious complications occurred in 925 (14.5%) patients with CAP. Both PSI and CURB65 overestimated the observed mortality (X2 goodness of fit test: P = 0.003 and 0.01). ProADM or proET1 alone had stronger discriminatory powers than the PSI or CURB65 score or any of either score components to predict serious complications. Adding proADM alone (or all five biomarkers jointly) to the PSI and CURB65 scores, significantly increased the area under the curve (AUC) for PSI from 0.69 to 0.75, and for CURB65 from 0.66 to 0.73 (P < 0.001, for both scores). Reclassification methods also established highly significant improvement (P < 0.001) for models with biomarkers if clinical covariates were more flexibly adjusted for. The developed prediction models with biomarkers extrapolated well if evaluated in 434 patients with non-CAP LRTIs.
Five biomarkers from distinct biologic pathways were strong and specific predictors for short-term adverse outcome and improved clinical risk scores in CAP and non-pneumonic LRTI. Intervention studies are warranted to show whether an improved risk prognostication with biomarkers translates into a better clinical management and superior allocation of health care resources.
The identification of those persons in the population who have the highest risk of future cardiovascular events is important for targeting intensive preventive efforts. This can be reliably done using a handful of long since established risk factors. The unmet need for new molecular biomarkers for prediction of cardiovascular events in the general population is therefore low. In order for a new biomarker to be used clinically for risk prediction, a statistically significant association of levels of the biomarker to adverse outcome is not enough, but the biomarker should also be demonstrated to add discriminative capacity beyond established risk factors. In contrast to the limited value of new biomarkers for risk prediction, their usefulness for unraveling the pathophysiology of cardiovascular disease is large. The myocardium is the source of a vast number of interesting biomarkers, of which a few may be useful for risk prediction in the general population. Two of these, troponin-I and the N-terminal fragment of brain natriuretic peptide, have passed tests of added discriminatory value. Numerous other biomarkers produced by cardiomyocytes or non-cardiomyocytes in the myocardium are promising, and if they are not proven useful for risk prediction, they will unquestionably enhance our understanding of cardiovascular disease.
Risk; epidemiology; population; biomarker; peptide; myocardium
Chronic intravascular hemolysis leads to nitric oxide (NO) depletion and pulmonary hypertension in sickle cell disease. To test whether this pathophysiology occurs in malaria, we examined 53 children admitted to hospital with severe malaria (excluding cerebral malaria) and 31 age-matched controls in Mali.
Severity of hemolysis was assessed from plasma free hemoglobin (Hb) and arginase-1 levels. NO metabolism was assessed by whole blood nitrite levels and plasma NO consumption. Effects on the cardiovascular system and endothelial function were assessed by using echocardiography to measure peak tricuspid regurgitant jet velocity (TRV) and from plasma levels of N-terminal prohormone brain natriuretic peptide (NT-proBNP) and soluble vascular cell adhesion molecule-1 (sVCAM-1).
Children with severe malaria had higher plasma Hb and arginase-1 levels, reduced whole blood nitrite levels and increased NO consumption relative to controls. They also had increased pulmonary arterial pressures (p < 0.05) with elevated levels of NT-proBNP and sVCAM-1 (p < 0.001).
Children with severe malaria have increased pulmonary pressures and myocardial wall stress. These complications are consistent with NO depletion from intravascular hemolysis, and indicate that the pathophysiologic cascade from intravascular hemolysis to NO depletion and its cardiopulmonary effects is activated in children with severe malaria.
malaria; Plasmodium falciparum; nitric oxide (NO); intravascular hemolysis; whole blood nitrite; NO consumption; tricuspid regurgitation velocity (TRV); NT-proBNP; myocardial wall stress; sVCAM-1; endothelial dysfunction
Urotensin II (UII) is a vasoactive peptide secreted by endothelial cells. Increased plasma UII concentration was observed in patients with heart failure, liver cirrhosis, diabetic nephropathy and renal insufficiency. In patients with myocardial infarction both increased and decreased plasma UII concentrations were demonstrated. The aim of this study was to analyze whether plasma UII concentration reflects the severity of acute coronary syndrome (ACS).
Material and methods
One hundred and forty-nine consecutive patients with ACS, without age limit, were enrolled in the study. In all patients plasma concentration of creatinine, creatine kinase isoenzyme MB (CK-MB), troponin C, N-terminal prohormone of brain natriuretic peptide (NT-pro BNP), and UII were assessed, and echocardiography was performed in order to assess the degree of left ventricular hypertrophy, ejection fraction (EF) and mass (LVM).
In patients with the highest risk (TIMI 5-7) plasma UII concentration was significantly lower than in those with low risk (TIMI 1-2): 2.61±1.47 ng/ml vs. 3.60±2.20 ng/ml. Significantly lower plasma UII concentration was found in patients with increased concentration of troponin C (2.60±1.52 ng/ml vs. 3.41±2.09 ng/ml). There was a significant negative correlation between plasma UII concentration and TIMI score or concentration of troponin C, but not CK-MB. Borderline correlation between plasma UII and ejection fraction (R = 0.157; p=0.063) or NT-proBNP (R = − 0.156; p=0.058) was found.
Decreased plasma urotensin II concentration in patients with ACS could be associated with more severe injury of myocardium.
urotensin II; acute coronary syndrome
Acute decompensated congestive heart failure (ADCHF) is a common etiology of dyspnea in emergency department (ED) patients. Delayed diagnosis of ADCHF increases morbidity and mortality. Two cardiac biomarkers, N-terminal-pro brain natriuretic peptide (NT-proBNP) and brain natriuretic peptide (BNP) have demonstrated excellent sensitivity in diagnostic accuracy studies, but the clinical impact on patient-oriented outcomes of these tests remains in question.
Does emergency physician awareness of BNP or NT-proBNP level improve ADCHF patient-important outcomes including ED length of stay, hospital length of stay, cardiovascular mortality, or overall health care costs?
Five trials have randomized clinicians to either knowledge of or no knowledge of ADCHF biomarker levels in ED patients with dyspnea and some suspicion for heart failure. In assessing patient-oriented outcomes such as length-of-stay, return visits, and overall health care costs, the randomized controlled trials fail to provide evidence of unequivocal benefit to patients, clinicians, or society.
Clinician awareness of BNP or NT-proBNP levels in ED dyspnea patients does not necessarily improve outcomes. Future ADCHF biomarker trials must assess patient-oriented outcomes in conjunction with validated risk-stratification instruments.
natriuretic peptide; congestive heart failure; outcomes; cost-effectiveness
The identification of patients at highest risk for adverse outcome who are presenting with acute dyspnea to the emergency department remains a challenge. This study investigates the prognostic value of Copeptin, the C-terminal part of the vasopressin prohormone alone and combined to N-terminal pro B-type natriuretic peptide (NT-proBNP) in patients with acute dyspnea.
We conducted a prospective, observational cohort study in the emergency department of a university hospital and enrolled 287 patients with acute dyspnea.
Copeptin levels were elevated in non-survivors (n = 29) compared to survivors at 30 days (108 pmol/l, interquartile range (IQR) 37 to 197 pmol/l) vs. 18 pmol/l, IQR 7 to 43 pmol/l; P < 0.0001). The areas under the receiver operating characteristic curve (AUC) to predict 30-day mortality were 0.83 (95% confidence interval (CI) 0.76 to 0.90), 0.76 (95% CI 0.67 to 0.84) and 0.63 (95% CI 0.53 to 0.74) for Copeptin, NT-proBNP and BNP, respectively (Copeptin vs. NTproBNP P = 0.21; Copeptin vs. BNP P = 0.002). When adjusted for common cardiovascular risk factors and NT-proBNP, Copeptin was the strongest independent predictor for short-term mortality in all patients (HR 3.88 (1.94 to 7.77); P < 0.001) and especially in patients with acute decompensated heart failure (ADHF) (HR 5.99 (2.55 to 14.07); P < 0.0001). With the inclusion of Copeptin to the adjusted model including NTproBNP, the net reclassification improvement (NRI) was 0.37 (P < 0.001). An additional 30% of those who experienced events were reclassified as high risk, and an additional 26% without events were reclassified as low risk.
Copeptin is a new promising prognostic marker for short-term mortality independently and additive to natriuretic peptide levels in patients with acute dyspnea.
Natriuretic peptides (NPs) are hormones which are mainly secreted from heart and have important natriuretic and kaliuretic properties. There are four different groups NPs identified till date [atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), C-type natriuretic peptide (CNP) and dendroaspis natriuretic peptide, a D-type natriuretic peptide (DNP)], each with its own characteristic functions. The N-terminal part of the prohormone of BNP, NT-proBNP, is secreted alongside BNP and has been documented to have important diagnostic value in heart failure. NPs or their fragments have been subjected to scientific observation for their diagnostic value and this has yielded important epidemiological data for interpretation. However, little progress has been made in harnessing the therapeutic potential of these cardiac hormones.
Atrial natriuretic peptide; B-type natriuretic peptide; heart failure; natriuretic peptides; NT-proBNP
Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are important biomarkers in the diagnosis and risk stratification for heart failure (HF). These peptides are synthesized as inactive precursors, pro-ANP and pro-BNP, which are converted to biologically active 28-amino-acid ANP and 32-amino-acid BNP, respectively. Most immunoassays currently used in the clinical setting, however, do not determine precise molecular forms of these natriuretic peptides, which may vary depending on the pathophysiological state of HF. Analysis from chromatography-based studies reveals that in HF, inactive pro-ANP and pro-BNP forms often predominate. This indicates that the bioactive forms of natriuretic peptides may not be processed proportionally in patients with advanced HF. Distinguishing the bioactive natriuretic peptides from their inactive forms in plasma may help to define the role of these peptides in the pathogenesis of HF and provide new insights into the treatment of the disease.
biomarker; atria natriuretic peptide; B-type or brain natriuretic peptide; heart failure
We compared the diagnostic accuracy of N-terminal prohormone brain natriuretic peptide (NT-proBNP) with that of echocardiography in the evaluation of left ventricular diastolic dysfunction after coronary artery bypass grafting.
Thirty patients were studied prospectively. Patients who had recent myocardial infarction, unstable angina pectoris, or low ejection fraction with systolic dysfunction were excluded. Two blood samples were obtained: before anesthetic induction and on the 7th postoperative day. Levels of NT-proBNP were measured by electrochemiluminescence immunoassay. Comprehensive echocardiographic Doppler examinations were performed on admission and on the 7th postoperative day. Relationships between NT-proBNP levels and echocardiographic indices were evaluated by correlation, multiple linear regression, and receiver-operating characteristic curve analysis.
There were significant and correlated worsenings in diastolic stage as determined both by echocardiographic indices and NT-proBNP levels. Early transmitral-to-early diastolic annular velocity ratio (E/Ea) was found to correlate with both NT-proBNP and postoperative diastolic functional stage (r=0.78, P <0.001). Mitral E/Ea was significantly more sensitive than were NT-proBNP levels in predicting diastolic functional stage. The area under the receiver-operating characteristic curve for NT-proBNP was significantly lower than that of mitral E/Ea (mean difference, 0.12; P=0.024). The NT-proBNP had 87.5% sensitivity and 55% specificity, whereas E/Ea had 87.5% sensitivity and 86.4% specificity.
Plasma NT-proBNP levels are significantly related to mitral E/Ea ratio, which is a predictor of diastolic stage. Therefore, elevated NT-proBNP levels may indicate the time for a Doppler echocardiographic evaluation and identify a subgroup of patients at high risk who need closer monitoring during the early postoperative period.
Diastole/physiology; echocardiography; heart ventricles; left ventricular dysfunction; myocardial ischemia/diagnosis; natriuretic peptide, brain/blood/diagnostic use; predictive value of tests; pro-brain natriuretic peptide; sensitivity and specificity; ventricular dysfunction, left/blood/diagnosis/physiology
The aim of this study was to assess longitudinal systolic function and mechanical synchrony parameters derived from advanced speckle tracking echocardiography (STE) and to determine their correlation with N-terminal prohormone of brain natriuretic peptide (NT-proBNP). Their influence on heart failure (HF) outcomes at a one-year follow-up, not clarified in previous studies, was also examined.
Advanced STE was performed from August 2009 to January 2012 in 103 chronic HF patients at the University Kebangsaan Malaysia Medical Center to assess their longitudinal systolic function and synchrony parameters; NT-proBNP blood measurement was taken at the same time.
Longitudinal cardiac velocity; strain; strain rate; displacement; intraventricular mechanical dyssynchrony based on the standard deviation (SD) of time to peak systolic strain rate (Tsr-SD); displacement, and antero-septal to posterior (AS-P) delay were associated with cardiac events. In multivariate analysis, NT-proBNP and AS-P delay were identified as independent predictors for cardiac events. Significant correlations were found between NT-proBNP and longitudinal velocity; displacement; strain; strain rate, and ejection fraction. Log NT-proBNP levels correlated moderately with the SD of time to peak displacement and to peak strain, and there was a small correlation with maximal differences and SD of time to peak velocity. A multiple linear analysis revealed that NT-proBNP levels significantly correlated to age, ejection fraction and velocity.
Advanced STE is a promising technique which accelerates the clinical application of the quantification of myocardial function and synchrony. STE parameters and NT-proBNP have the ability to identify patients at higher risk of death and hospitalisation.
Heart Failure; Echocardiography; Left Ventricular Dysfunction; N-terminal pro-BNP
Metabolic syndrome is associated with intravascular inflammation, as determined by increased levels of inflammatory biomarkers and an increased risk of ischemic atherothrombotic events. Evidence suggests that atherothrombosis and intravascular inflammation share predictive biomarkers, including high-sensitivity C-reactive protein, CD40 ligand, P-selectin, and N-terminal pro-brain natriuretic peptide.
Patients who had metabolic syndrome were randomized to receive clopidogrel 75 mg/day plus aspirin 81 mg/day (n = 89) or placebo plus aspirin 81 mg/day (n = 92) for 9 weeks to assess the efficacy of each treatment in suppression of inflammatory markers. Change from baseline in the levels of high-sensitivity C-reactive protein, CD40 ligand, P-selectin, and N-terminal pro-brain natriuretic peptide at 6 weeks was assessed to evaluate each treatment.
There was a significant difference at Week 6 in model-adjusted CD40-ligand levels in favor of clopidogrel plus aspirin compared with placebo plus aspirin in both the intent-to-treat population (difference between least-squares means = −186.5; 95% confidence interval, −342.3 to −30.8; P = 0.02) and the per-protocol population (P = 0.05). No significant differences were observed between the treatment arms for high-sensitivity C-reactive protein, P-selectin, and N-terminal pro-brain natriuretic peptide. There were no deaths or serious adverse events in either treatment arm.
Data from this study suggest that clopidogrel can decrease the expression of the CD40-ligand biomarker.
Aspirin/therapeutic use; biological markers/blood; CD40 ligand/drug effects; clopidogrel/therapeutic use; C-reactive protein/drug effects; inflammation; metabolic syndrome X; platelet aggregation inhibitors/therapeutic use; probrain natriuretic peptide, N-terminal/drug effects; P-selectin/drug effects
Prior studies have conflicted regarding how much information novel biomarkers add to cardiovascular risk assessment.
To evaluate the utility of biomarkers for predicting cardiovascular risk when added to conventional risk factors, using contemporary biomarkers and newer statistical approaches.
Design, Setting, Participants
Between 1991 and 1994, 5067 participants (mean age 58, 60% women) without cardiovascular disease from a prospective cohort in Malmö, Sweden underwent measurement of C-reactive protein (CRP), mid-regional-pro-atrial natriuretic peptide, N-terminal pro-B-type natriuretic peptide (N-BNP), mid-regional-pro-adrenomedullin (MR-proADM), lipoprotein-associated phospholipase-2, and cystatin C. Participants were followed until 2006. First cardiovascular events (myocardial infarction, stroke, coronary death) were ascertained using the Swedish national hospital discharge and cause-of-death registers. Low-, intermediate-, and high-risk were defined as 10-year risks of <6%, 6–19%, or ≥20%, respectively.
Main Outcome Measures
Incident cardiovascular and coronary events.
During median follow-up of 12.8 years, there were 418 cardiovascular and 230 coronary events. Models with conventional risk factors had c-statistics of 0.758 (95% confidence interval [CI], 0.734–0.781) and 0.760 (0.730–0.789) for cardiovascular and coronary events. Biomarkers retained in backward-elimination models were N-BNP and CRP for cardiovascular events, and N-BNP and MR-proADM for coronary events, which raised the c-statistic by 0.007 (p=0.04) and 0.009 (p=0.08), respectively. The proportion of participants reclassified was modest (8% for cardiovascular risk, 5% for coronary risk). The net reclassification improvement (NRI) was non-significant for cardiovascular events (0.0%, 95%CI, −4.3%–4.3%) and coronary events (4.7%, −0.76%–10.1%). Greater improvements were observed in analyses restricted to intermediate-risk individuals (cardiovascular events: 7.4%, 95%CI, 0.7%–14.1% [p=0.03]; coronary events: 14.6%, 5.0%–24.2% [p=0.003]). However, correct re-classification was almost entirely confined to down-classification of individuals without events, rather than up-classification of those with events.
Selected biomarkers may be used to predict future cardiovascular events, but the gains over conventional risk factors are minimal. Risk classification improved in intermediate-risk individuals, mainly through the identification of those unlikely to develop events.
Measurement of B type natriuretic peptide and its N terminal prohormone (NTproBNP) can now be performed routinely by automated high‐throughput immunoassays. The study compared measurement of NTproBNP with measurement of N terminal pro‐atrial natriuretic peptide (NTproANP) for detection of ventricular systolic dysfunction in primary care.
734 subjects aged >45 years (349 men and 385 women, median age 58 years, range 45–89, interquartile range 51–67 years) from seven representative general practices attended for echocardiography with determination of ejection fraction and completed a questionnaire. Blood samples were collected into gel serum separation tubes (Becton–Dickinson, Franklin Lakes, New Jersey, USA), the serum separated and aliquots stored frozen at −70°C until analyses. Samples were analysed for NTproBNP (Roche Diagnostics, Lewes, UK; coefficient of variation (CV) 3.2–2.4%) and for NTproANP (Biomedica, Vienna, Austria; CV 5.6–10.1%). Echocardiography was used as the diagnostic “gold standard”, with ventricular systolic dysfunction defined as abnormal when there was an ejection fraction of ⩽40%. Patients were dichotomised by ejection fraction from 50% to 30%, and receiver operating characteristic curves constructed and the area under the curve (AUC) compared.
At 40% ejection fraction, NTproANP and NTproBNP showed AUCs of, respectively, 0.738 (0.601–0.875) and 0.973 (0.958–0.989), p<0.004.
NTproBNP is superior to NTproANP for detection of systolic dysfunction.