Roland R.J. van Kimmenade

Galectin-3, cardiac structure and function, and long-term mortality in patients with acutely decompensated heart failure

To determine the relationship between galectin‐3 concentrations and cardiac structure in patients with acute dyspnoea, and to evaluate the impact of galectin‐3 independent of echocardiographic measurements on long‐term mortality.

Red blood cell distribution width and 1-year mortality in acute heart failure.

Red blood cell distribution width (RDW) predicts mortality in chronic heart failure (HF) and stable coronary artery disease. The prognostic value of RDW in more acute settings such as acute HF, and its relative prognostic value compared with more established measures such as N‐terminal pro‐brain natriuretic peptide (NT‐proBNP), remains unknown.

Emerging Biomarkers in Heart Failure

BACKGROUND Until recently, biomarker testing in heart failure (HF) syndromes has been viewed as an elective supplement to diagnostic evaluation of patients suspected to suffer from this condition. This approach to the use of biomarker testing contrasts with other cardiovascular diagnoses such as acute myocardial infarction, for which biomarkers are integral to disease process definition, risk stratification, and in some cases treatment decision making. CONTENT In this review we consider various perspectives on the evaluation of biomarkers in HF. In addition, we examine recent advances in the understanding of established biomarkers in HF (such as the natriuretic peptides), the elucidation of novel biomarkers potentially useful for the evaluation and management of patients with HF, and the growing understanding of important and relevant comorbidities in HF. We also review candidate biomarkers from a number of classes: (a) myocyte stretch, (b) myocyte necrosis, (c) systemic inflammation, (d) oxidative stress, (e) extracellular matrix turnover, (f) neurohormones, and (g) biomarkers of extracardiac processes, such as renal function. SUMMARY Novel applications of established biomarkers of HF as well as elucidation and validation of emerging assays for HF syndromes have collectively led to a growing interest in the more widespread use of such testing in patients affected by the diagnosis.

Incremental value of biomarkers to clinical variables for mortality prediction in acutely decompensated heart failure: the Multinational Observational Cohort on Acute Heart Failure (MOCA) study.

AIM This study aims to evaluate the incremental value of plasma biomarkers to traditional clinical variables for risk stratification of 30-day and one-year mortality in acutely decompensated heart failure (ADHF). METHODS AND RESULTS Through an international collaborative network, individual patient data on 5306 patients hospitalized for ADHF were collected. The all-cause mortality rate was 11.7% at 30 days and 32.9% at one year. The clinical prediction model (age, gender, blood pressure on admission, estimated glomerular filtration rate <60 mL/min/1.73 m(2), sodium and hemoglobin levels, and heart rate) had a c-statistic of 0.74 for 30-day mortality and 0.73 for one-year mortality. Several biomarkers measured at presentation improved risk stratification when added to the clinical model. At 30 days, the net reclassification improvement (NRI) was 28.7% for mid-regional adrenomedullin (MR-proADM; p<0.001) and 25.5% for soluble (s)ST2 (p<0.001). At one year, sST2 (NRI 10.3%), MR-proADM (NRI 9.1%), amino-terminal pro-B-type natriuretic peptide (NT-proBNP; NRI 9.1%), mid-regional proatrial natriuretic peptide (MR-proANP; NRI 7.4%), B-type natriuretic peptide (NRI 5.5%) and C-reactive protein (CRP; NRI 5.3%) reclassified patients with ADHF (p<0.05 for all). CRP also markedly improved risk stratification of patients with ADHF as a dual biomarker combination with MR-proADM (NRI 36.8% [p<0.001] for death at 30 days) or with sST2 (NRI 20.3%; [p<0.001] for one-year mortality). CONCLUSION In this study, biomarkers provided incremental value for risk stratification of ADHF patients. Biomarkers such as sST2, MR-proADM, natriuretic peptides and CRP, reflecting different pathophysiologic pathways, add prognostic value to clinical risk factors for predicting both short-term and one-year mortality in ADHF.

Serum Levels of the Interleukin-1 Receptor Family Member ST2, Cardiac Structure and Function, and Long-Term Mortality in Patients With Acute Dyspnea

Background—ST2, a biomarker of cardiomyocyte stretch, powerfully predicts poor outcomes in patients with acute dyspnea, but nothing is known about associations between soluble ST2 (sST2) and cardiac structure and function, or whether sST2 retains prognostic meaning in the context of such measures. Methods and Results—One hundred thirty-four dyspneic patients with and without decompensated heart failure had echocardiography during index admission and vital status was ascertained at 4 years. Echocardiographic and clinical correlates of sST2 as well as independent predictors of death at 4 years were identified. sST2 correlated with left ventricular end-systolic dimensions/volumes and left ventricular ejection fraction. sST2 was inversely associated with right ventricular fractional area change (&rgr;=−0.18; P=0.046), higher right ventricular systolic pressure (&rgr;=0.26; P=0.005), and right ventricular hypokinesis (P<0.001) and was correlated with tissue Doppler Ea wave peak velocity, but not to other indices of diastolic function. In multivariate regression, independent predictors of sST2 included right ventricular systolic pressure (t=2.29; P=0.002), left ventricular ejection fraction (t=−2.15; P=0.05) and dimensions (end systolic, t=2.57; end diastolic, t=2.98; both P<0.05), amino-terminal pro-B-type natriuretic peptide (t=3.31; P=0.009), heart rate (t=2.59; P=0.01), and presence of jugular venous distension (t=2.00; P=0.05). In a Cox proportional hazards model that included echocardiographic results and other biomarkers, sST2 independently predicted death at 4 years (hazard ratio=2.70; P=0.003). Conclusions—Among dyspneic patients with and without acute heart failure, sST2 concentrations are associated with prevalent cardiac abnormalities on echocardiography, a more decompensated hemodynamic profile and are associated with long-term mortality, independent of echocardiographic, clinical, or other biochemical markers of risk.

Renal Clearance of B-Type Natriuretic Peptide and Amino Terminal Pro-B-Type Natriuretic Peptide A Mechanistic Study in Hypertensive Subjects

OBJECTIVES This study sought to compare the renal clearance mechanisms of B-type natriuretic peptide (BNP) and amino terminal pro-B-type natriuretic peptide (NT-proBNP). BACKGROUND The small molecular weight proteins (SMWPs) BNP and NT-proBNP both inversely correlate with glomerular filtration rate (GFR). Whether this association is causal or confounding is unknown and has been the basis of widespread speculation. METHODS We combined measurements of BNP and NT-proBNP concentrations in the renal arteries and veins of 165 subjects undergoing renal arteriography with invasive renal plasma flow (RPF) measurements and echocardiography. Fractional extraction (FE) of BNP and NT-proBNP was computed. RESULTS The BNP and NT-proBNP concentrations correlated similarly to GFR (r = -0.35 and r = -0.30, respectively; p < 0.001 for both) but the NT-proBNP/BNP serum ratio was negatively associated with GFR (r = -0.21, p = 0.008). Median FE(BNP) was 0.21 (interquartile range [IQR] 0.16 to 0.22) for left and 0.22 (IQR 0.17 to 0.29) for right kidneys. Median FE(NT-proBNP) was 0.16 (IQR 0.09 to 20) for left and 0.18 (IQR 0.12 to 0.22) for right kidneys. The FE(BNP) correlated with GFR (left: r = 0.26, p = 0.008; right: r = 0.21, p = 0.03) as did FE(NT-proBNP) (left: r = 0.25, p = 0.005; right: r = 0.20, p = 0.02). Although FE(BNP) and FE(NT-proBNP) correlated strongly with each other (left: r = 0.66; right: r = 0.60; p < 0.001 for both), left and right FE(NT-proBNP/BNP) ratios were not influenced by GFR (r = 0.10, p = 0.30 and r = 0.08, p = 0.43, respectively). Multivariate analyses confirmed that FE was not independently associated with BNP or NT-proBNP concentrations. CONCLUSIONS Contrary to widespread belief (but in line with the renal physiology of SMWP), BNP and NT-proBNP are equally dependent on renal function for their clearance.

Amino-Terminal Pro–B-Type Natriuretic Peptide Testing in Renal Disease

Concentrations of amino-terminal pro-B-type natriuretic peptides (NT-proBNP) are typically higher in patients with chronic kidney disease (CKD) than in those without CKD. These elevated levels of NT-proBNP in patients with CKD do not simply reflect the reduced clearance of the peptide; rather, they largely reflect a true-positive finding, identifying the presence of heart disease in these patients, while similarly indicating prognosis as well. Although modestly stronger inverse correlations exist between renal function and NT-proBNP compared with B-type natriuretic peptide (BNP), the dependence of both peptides on renal clearance is similar. Across the range of CKD, correlations between BNP and NT-proBNP remain strong, and the prognostic impact of NT-proBNP in patients with CKD is preserved. When evaluating the patient with acute dyspnea and CKD, both BNP and NT-proBNP are affected similarly, with higher decision limits necessary compared with patients with preserved renal function. Importantly, when using NT-proBNP to evaluate a patient with dyspnea and impaired renal function, the recommended cut points of 450, 900, and 1,800 ng/L for those aged <50, 50-75, and >75 years, respectively, do not require further adjustment for renal function. Thus, NT-proBNP testing remains useful for the diagnostic and prognostic evaluation of patients with CKD.

Association Between Elevated Blood Glucose and Outcome in Acute Heart Failure Results From an International Observational Cohort

OBJECTIVE The aim of this analysis was to assess the association between elevated blood glucose level and mortality in acute heart failure (AHF). BACKGROUND Elevated blood glucose has been reported to be prognostically meaningful in patients with cardiac diagnoses, such as coronary artery disease. The short-term prognostic impact of hyperglycemia in AHF is unknown, however. METHODS In a multinational cohort of AHF, we examined the ability of blood glucose concentrations at presentation to predict all-cause mortality by 30 days. Fully adjusted models for prognosis included a previous diagnosis of diabetes mellitus as a covariate. RESULTS A total of 6,212 subjects with AHF (mean age, 72 years; 52.5% male) were studied; the median blood glucose concentration on arrival at the hospital was 7.5 mmol/l (135 mg/dl), and 41% had a previous diagnosis of diabetes mellitus (DM). After 30 days, 618 patients (10%) had died. Compared with survivors, decedents had significantly higher median blood glucose concentrations (8.9 mmol/l vs. 7.4 mmol/l; p < 0.0001). In the fully adjusted model, an elevated blood glucose level was an independent predictor of 30-day mortality in AHF (odds ratio: 2.19; 95% confidence interval: 1.69 to 2.83; p < 0.001). The risk associated with an elevated blood glucose level appeared consistent across all subgroups of patients, including patients with preserved (hazard ratio: 5.41; 95% confidence interval: 2.44 to 12.0; p < 0.0001) and impaired systolic function (hazard ratio: 2.37; 95% confidence interval: 1.57 to 3.59; p < 0.0001). Furthermore, in reclassification analyses, elevated blood glucose added significant prognostic information to clinical parameters alone (4.4% net reclassification improvement; p = 0.01). CONCLUSIONS Among patients with AHF, blood glucose concentrations at presentation are powerfully prognostic for 30-day mortality, independent of a diagnosis of diabetes mellitus or other clinical variables. Because blood glucose is easily modifiable, it may represent a valid target for therapeutic intervention.

Prospective, Comprehensive Assessment of Cardiac Troponin T Testing After Coronary Artery Bypass Graft Surgery

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

Hyponatremia, natriuretic peptides, and outcomes in acutely decompensated heart failure: results from the International Collaborative of NT-proBNP Study

Background— Hyponatremia is a well-known predictor of mortality in patients with acutely decompensated heart failure. Associations between hyponatremia and other prognostic variables in acutely decompensated heart failure, such as amino-terminal pro-B type natriuretic peptide remain unclear. Methods and Results— Six hundred twenty-eight patients presenting to the emergency department with acutely decompensated heart failure were studied. All were hospitalized. Serum sodium (Na) concentration at presentation was examined as a function of mortality at 1 year, alone and relative to other predictors of death. Hyponatremia (Na ≤135 mmol/L) was diagnosed in 24%(n=149) patients. Compared with those without hyponatremia, those affected were less likely to be male or to have hypertension or coronary artery disease but were more likely to have severe symptoms, to be anemic, and to have higher amino-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations (all P ≤0.05). When examined as a function of Na deciles (ranging from Na <132 mmol/L to Na ≤142 mmol/L), a U-shaped association was found between Na level and 1-year mortality. In multivariate Cox proportional hazards analysis, hyponatremia was an independent predictor of 1-year mortality (hazards ratio=1.72; 95% CI=1.22 to 2.37; P =0.001) as was an NT-proBNP concentration above the median value of 4690 pg/mL (hazards ratio=1.49; 95% CI=1.10 to 2.00; P =0.009). Those with hyponatremia and more elevated NT-proBNP were more likely to develop worsening renal function during their hospitalization and had highest rates of 1-year death. Notably, however, hyponatremia predicted only 1-year mortality in those with an elevated NT-proBNP. Conclusion— Hyponatremia is associated with adverse outcome in patients with acutely decompensated heart failure; however, the prognostic value of low Na is mainly evident in those with more pronounced elevation of NT-proBNP concentrations.Background—Hyponatremia is a well-known predictor of mortality in patients with acutely decompensated heart failure. Associations between hyponatremia and other prognostic variables in acutely decompensated heart failure, such as amino-terminal pro-B type natriuretic peptide remain unclear. Methods and Results—Six hundred twenty-eight patients presenting to the emergency department with acutely decompensated heart failure were studied. All were hospitalized. Serum sodium (Na) concentration at presentation was examined as a function of mortality at 1 year, alone and relative to other predictors of death. Hyponatremia (Na ≤135 mmol/L) was diagnosed in 24% (n=149) patients. Compared with those without hyponatremia, those affected were less likely to be male or to have hypertension or coronary artery disease but were more likely to have severe symptoms, to be anemic, and to have higher amino-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations (all P≤0.05). When examined as a function of Na deciles (ranging from Na <132 mmol/L to Na ≤142 mmol/L), a U-shaped association was found between Na level and 1-year mortality. In multivariate Cox proportional hazards analysis, hyponatremia was an independent predictor of 1-year mortality (hazards ratio=1.72; 95% CI=1.22 to 2.37; P=0.001) as was an NT-proBNP concentration above the median value of 4690 pg/mL (hazards ratio=1.49; 95% CI=1.10 to 2.00; P=0.009). Those with hyponatremia and more elevated NT-proBNP were more likely to develop worsening renal function during their hospitalization and had highest rates of 1-year death. Notably, however, hyponatremia predicted only 1-year mortality in those with an elevated NT-proBNP. Conclusion—Hyponatremia is associated with adverse outcome in patients with acutely decompensated heart failure; however, the prognostic value of low Na is mainly evident in those with more pronounced elevation of NT-proBNP concentrations.