Multiple Cardiac Biomarker Testing Among Patients With Acute Dyspnea From the ICON-RELOADED Study.

BACKGROUND: Among patients with acute dyspnea, concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T, and insulin-like growth factor binding protein-7 predict cardiovascular outcomes and death. Understanding the optimal means to interpret these elevated biomarkers in patients presenting with acute dyspnea remains unknown. METHODS AND RESULTS: Concentrations of NT-proBNP, high-sensitivity cardiac troponin T, and insulin-like growth factor binding protein-7 were analyzed in 1448 patients presenting with acute dyspnea from the prospective, multicenter International Collaborative of NT-proBNP-Re-evaluation of Acute Diagnostic Cut-Offs in the Emergency Department (ICON-RELOADED) Study. Eight biogroups were derived based upon patterns in biomarker elevation at presentation and compared for differences in baseline characteristics. Of 441 patients with elevations in all 3 biomarkers, 218 (49.4%) were diagnosed with acute heart failure (HF). The frequency of acute HF diagnosis in this biogroup was higher than those with elevations in 2 biomarkers (18.8%, 44 of 234), 1 biomarker (3.8%, 10 of 260), or no elevated biomarkers (0.4%, 2 of 513). The absolute number of elevated biomarkers on admission was prognostic of the composite end point of mortality and HF rehospitalization. In adjusted models, patients with one, 2, and 3 elevated biomarkers had 3.74 (95% confidence interval [CI], 1.26-11.1, P = .017), 12.3 (95% CI, 4.60-32.9, P < .001), and 12.6 (95% CI, 4.54-35.0, P < .001) fold increased risk of 180-day mortality or HF rehospitalization. CONCLUSIONS: A multimarker panel of NT-proBNP, hsTnT, and IGBFP7 provides unique clinical, diagnostic, and prognostic information in patients presenting with acute dyspnea. Differences in the number of elevated biomarkers at presentation may allow for more efficient clinical risk stratification of short-term mortality and HF rehospitalization.

N-Terminal Pro-B-Type Natriuretic Peptide in the Emergency Department: The ICON-RELOADED Study.

BACKGROUND: Contemporary reconsideration of diagnostic N-terminal pro-B-type natriuretic peptide (NT-proBNP) cutoffs for diagnosis of heart failure (HF) is needed. OBJECTIVES: This study sought to evaluate the diagnostic performance of NT-proBNP for acute HF in patients with dyspnea in the emergency department (ED) setting. METHODS: Dyspneic patients presenting to 19 EDs in North America were enrolled and had blood drawn for subsequent NT-proBNP measurement. Primary endpoints were positive predictive values of age-stratified cutoffs (450, 900, and 1,800 pg/ml) for diagnosis of acute HF and negative predictive value of the rule-out cutoff to exclude acute HF. Secondary endpoints included sensitivity, specificity, and positive (+) and negative (-) likelihood ratios (LRs) for acute HF. RESULTS: Of 1,461 subjects, 277 (19%) were adjudicated as having acute HF. The area under the receiver-operating characteristic curve for diagnosis of acute HF was 0.91 (95% confidence interval [CI]: 0.90 to 0.93; p < 0.001). Sensitivity for age stratified cutoffs of 450, 900, and 1,800 pg/ml was 85.7%, 79.3%, and 75.9%, respectively; specificity was 93.9%, 84.0%, and 75.0%, respectively. Positive predictive values were 53.6%, 58.4%, and 62.0%, respectively. Overall LR+ across age-dependent cutoffs was 5.99 (95% CI: 5.05 to 6.93); individual LR+ for age-dependent cutoffs was 14.08, 4.95, and 3.03, respectively. The sensitivity and negative predictive value for the rule-out cutoff of 300 pg/ml were 93.9% and 98.0%, respectively; LR- was 0.09 (95% CI: 0.05 to 0.13). CONCLUSIONS: In acutely dyspneic patients seen in the ED setting, age-stratified NT-proBNP cutpoints may aid in the diagnosis of acute HF. An NT-proBNP <300 pg/ml strongly excludes the presence of acute HF.

Usefulness of low-dose dobutamine echocardiography to predict response and outcome in patients undergoing cardiac resynchronization therapy.

A substantial proportion of patients who meet the current guidelines for cardiac resynchronization therapy (CRT) fail to respond to this pacing modality. Although appropriate patient selection and left ventricular (LV) lead location have been ascribed as determinants of CRT response, the interaction among contractile reserve, dynamics of dyssynchrony, and lead location is not well understood. The present study prospectively evaluated the effect of contractile reserve and dobutamine-induced changes in LV synchrony, in relation to the LV lead location, as predictors of the response to CRT. In the present study, 31 patients were prospectively evaluated and underwent low-dose dobutamine echocardiography. The dobutamine-induced increase in ejection fraction (contractile reserve [CR]) was measured, and the most mechanically delayed segment was identified to classify patients into 2 groups. Group 1 had a CR of >20% and a LV lead position concordant with the mechanically delayed segment. Group 2 included the remaining patients (i.e., low CR, discordant LV lead position, or both). Patients in group 1 were significantly more likely to have an echocardiographic response at 6 months (80% of group 1 vs 29% of group 2, p = 0.018) and had an improved 2-year heart failure hospitalization-free survival rate (90% in group 1 vs 33% in group 2, p = 0.006). In conclusion, low-dose dobutamine echocardiography provides information that can help to predict responders to CRT. The response rates and heart failure hospitalization-free survival were improved in those patients with a CR >20% and an LV lead tip concordant with the most delayed mechanical segment.

Preload dependency of left ventricular torsion: the impact of normal saline infusion.

BACKGROUND: left ventricular (LV) rotation results from contraction of obliquely oriented myocardial fibers. The net difference between systolic apical counterclockwise rotation and basal clockwise rotation is left ventricular torsion (LVT). Although LVT is altered in various cardiac diseases, determinants of LVT are incompletely understood. METHODS AND RESULTS: LV end-diastolic volume, LV apical and basal rotation, peak systolic LVT, and peak early diastolic untwisting rate were measured by speckle-tracking echocardiography in healthy subjects (n=8) before and after infusion of a weight-based normal saline bolus (2.1±0.3 L). Saline infusion led to a significant increase in end-diastolic LV internal diameter (45.9±3.7 versus 47.6±4.2 mm; P=0.002) and LV end-diastolic volume (90.0±21.6 versus 98.3±19.6 mL; P=0.01). Stroke volume (51.3±10.9 versus 63.0±15.5 mL; P=0.003) and cardiac output (3.4±0.8 versus 4.4±1.5 L/min; P=0.007) increased, whereas there was no change in heart rate and blood pressure. There was a significant increase in the magnitude of peak systolic apical rotation (7.5±2.4° versus 10.5±2.8°; P<0.001) but no change in basal rotation (-4.1±2.3° versus -4.8±3.1°; P=0.44). Accordingly, peak systolic LVT increased by 33% after saline infusion (11.2±1.3° versus 14.9±1.7°; P<0.001). This saline-induced increase in LVT was associated with a marked increase in peak early diastolic untwisting rate (72.3±21.4 versus 136.8±30.0 degrees/s; P<0.001). CONCLUSIONS: peak systolic LVT and peak early diastolic untwisting rate are preload-dependent. Changes in LV preload should be considered when interpreting results of future LVT studies.

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

AIMS: 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. METHODS AND RESULTS: One hundred and fifteen patients presenting to the emergency department with acute dyspnoea who had galectin-3 levels and detailed echocardiographic studies on admission were studied. Galectin-3 levels were associated with older age (r = 0.26, P = 0.006), lower creatinine clearance (r = -0.42, P < 0.001), and higher levels of N-terminal-proBNP (r = 0.39, P < 0.001). Higher galectin-3 levels were associated with tissue Doppler E/E(a) ratio (r = 0.35, P = 0.01), a lower right ventricular (RV) fractional area change (r = -0.19, P = 0.05), higher RV systolic pressure (r = 0.37, P < 0.001), and more severe mitral (r = 0.30, P = 0.001) or tricuspid regurgitation (r = 0.26, P = 0.005). In patients diagnosed with heart failure (HF), the association between galectin-3 and valvular regurgitation and RV systolic pressure persisted. In a multivariate Cox regression model, galectin-3 remained a significant predictor of 4-year mortality independent of echocardiographic markers of risk. Dyspnoeic patients with HF and galectin-3 levels above the median value had a 63% mortality; patients less than the median value had a 37% mortality (P = 0.003). CONCLUSION: Among dyspnoeic patients with and without ADHF, galectin-3 concentrations are associated with echocardiographic markers of ventricular function. In patients with ADHF, a single admission galectin-3 level predicts mortality to 4 years, independent of echocardiographic markers of disease severity.

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 (rho=-0.18; P=0.046), higher right ventricular systolic pressure (rho=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.

Association between troponin T and impaired left ventricular relaxation in patients with acute decompensated heart failure with preserved systolic function.

AIMS: To examine relationships between cardiac troponin T (cTnT) and parameters of left ventricular (LV) structure and function in patients with acute destabilized heart failure (HF) with preserved LV ejection fraction. METHODS AND RESULTS: In 44 patients with acute heart failure (HF) with preserved left ventricular (LV) ejection fraction, parameters of LV structure and function were assessed via comprehensive two-dimensional Doppler echocardiography. There was no correlation between cTnT and LV wall thickness, left atrial volume index, or transmitral E wave velocity or deceleration time. There were associations between cTnT and LV end-diastolic dimension (r = -0.34, P = 0.02) and LV mass index (r = 0.32; P = .04). A lower tissue Doppler Ea wave peak velocity was associated with higher cTnT concentrations (r = -0.90, P < 0.001). In multivariate analyses, only LV end-diastolic dimension (t = 2.2; P = 0.04), LV mass index (t = 2.3; P = .03), and tissue Doppler Ea wave peak velocity (t = -4.7; P < .001) emerged as significant predictors of cTnT. CONCLUSION: In patients with HF with preserved LV ejection fraction, cTnT is strongly associated with the extent of LV relaxation abnormalities and LV mass.

Amino-terminal pro-B-type natriuretic peptide testing for the diagnosis or exclusion of heart failure in patients with acute symptoms.

When used for the evaluation of patients with acute symptoms in the emergency department setting, amino-terminal pro-B-type natriuretic peptide (NT-proBNP) testing is highly sensitive and specific for the diagnosis or exclusion of acute destabilized heart failure (HF), with results comparable to those reported for B-type natriuretic peptide (BNP) testing. When used for the diagnostic evaluation of the patient with possible HF, NT-proBNP testing returns information that may be superior to clinical judgment. However, the optimal application of NT-proBNP is in concert with history and physical examination, adjunctive testing, and with the knowledge of the differential diagnosis of an elevated NT-proBNP level. Studies indicate a dual use for NT-proBNP, both to exclude acute HF (where NT-proBNP concentrations <300 ng/L have a 98% negative predictive value), as well as to identify the diagnosis. To identify acute HF in patients with dyspnea, an age-independent NT-proBNP cut point of 900 ng/L has a similar value as that reported for a BNP value of 100 ng/L. However, age stratification of NT-proBNP using cut points of 450, 900, and 1,800 ng/L (for age groups of <50, 50-75, and >75 years) reduces false-negative findings in younger patients, reduces false-positive findings in older patients, and improves the overall positive predictive value of the marker without a change in overall sensitivity or specificity. Clinically validated, cost-effective algorithms for the use of NT-proBNP testing exist. Therefore, the logical use of NT-proBNP for the evaluation of the patient with suspected acute HF is useful, cost-effective, and may reduce adverse outcomes compared with standard clinical evaluation without natriuretic peptide testing.

Integrating functional and anatomical information to facilitate cardiac resynchronization therapy.

Multiple imaging modalities are required in patients receiving cardiac resynchronization therapy. We have developed a strategy to integrate echocardiographic and angiographic information to facilitate left ventricle (LV) lead position. Full three-dimensional LV-volumes (3DLVV) and dyssynchrony maps were acquired before and after resynchronization. At the time of device implantation, 3D-rotational coronary venous angiography was performed. 3D-models of the veins were then integrated with the pre- and post-3DLVV. In the case displayed, prior to implantation, the lateral wall was delayed compared to the septum. The LV lead was positioned into the vein over the most delayed region, resulting in improved LV synchrony.