Lori B. Daniels

Mid-Region Pro-Hormone Markers for Diagnosis and Prognosis in Acute Dyspnea: Results From the BACH (Biomarkers in Acute Heart Failure) Trial

OBJECTIVES Our purpose was to assess the diagnostic utility of mid-regional pro-atrial natriuretic peptide (MR-proANP) for the diagnosis of acute heart failure (AHF) and the prognostic value of mid-regional pro-adrenomedullin (MR-proADM) in patients with AHF. BACKGROUND There are some caveats and limitations to natriuretic peptide testing in the acute dyspneic patient. METHODS The BACH (Biomarkers in Acute Heart Failure) trial was a prospective, 15-center, international study of 1,641 patients presenting to the emergency department with dyspnea. A noninferiority test of MR-proANP versus B-type natriuretic peptide (BNP) for diagnosis of AHF and a superiority test of MR-proADM versus BNP for 90-day survival were conducted. Other end points were exploratory. RESULTS MR-proANP (> or =120 pmol/l) proved noninferior to BNP (> or =100 pg/ml) for the diagnosis of AHF (accuracy difference 0.9%). In tests of secondary diagnostic objectives, MR-proANP levels added to the utility of BNP levels in patients with intermediate BNP values and with obesity but not in renal insufficiency, the elderly, or patients with edema. Using cut-off values from receiver-operating characteristic analysis, the accuracy to predict 90-day survival of heart failure patients was 73% (95% confidence interval: 70% to 77%) for MR-proADM and 62% (95% confidence interval: 58% to 66%) for BNP (difference p < 0.001). In adjusted multivariable Cox regression, MR-proADM, but not BNP, carried independent prognostic value (p < 0.001). Results were consistent using NT-proBNP instead of BNP (p < 0.001). None of the biomarkers was able to predict rehospitalization or visits to the emergency department with clinical relevance. CONCLUSIONS MR-proANP is as useful as BNP for AHF diagnosis in dyspneic patients and may provide additional clinical utility when BNP is difficult to interpret. MR-proADM identifies patients with high 90-day mortality risk and adds prognostic value to BNP. (Biomarkers in Acute Heart Failure [BACH]; NCT00537628).

Minimally Elevated Cardiac Troponin T and Elevated N-Terminal Pro-B-Type Natriuretic Peptide Predict Mortality in Older Adults: Results From the Rancho Bernardo Study

OBJECTIVES This study investigated the prognostic value of detectable cardiac troponin T (TnT) and elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels in a population of community-dwelling older adults. BACKGROUND Minimally elevated levels of TnT, a marker of cardiomyocyte injury, have been found in small subsets of the general population, with uncertain implications. A marker of ventricular stretch, NT-proBNP has clinical utility in many venues, but its long-term prognostic value in apparently healthy older adults and in conjunction with TnT is unknown. METHODS Participants were 957 older adults from the Rancho Bernardo Study with plasma NT-proBNP and TnT measured at baseline (1997 to 1999) and followed up for mortality through July 2006. RESULTS Participants with detectable TnT (>/=0.01 ng/ml, n = 39) had an increased risk of all-cause and cardiovascular death (adjusted hazard ratio [HR] by Cox proportional hazards analysis: 2.06; 95% confidence interval [CI]: 1.29 to 3.28, p = 0.003 for all-cause mortality; HR: 2.06, 95% CI: 1.03 to 4.12, p = 0.040 for cardiovascular mortality); elevated NT-proBNP also predicted an increased risk of all-cause and cardiovascular mortality (adjusted HR per unit-log increase in NT-proBNP: 1.85, 95% CI: 1.36 to 2.52, p < 0.001 for all-cause mortality; HR: 2.51, 95% CI: 1.55 to 4.08, p < 0.001 for cardiovascular mortality). Those with both elevated NT-proBNP and detectable TnT had poorer survival (HR for high NT-proBNP and detectable TnT vs. low NT-proBNP and any TnT: 3.20, 95% CI: 1.91 to 5.38, p < 0.001). Exclusion of the 152 participants with heart disease at baseline did not materially change the TnT mortality or NT-proBNP mortality associations. CONCLUSIONS Apparently healthy adults with detectable TnT or elevated NT-proBNP levels are at increased risk of death. Those with both TnT and NT-proBNP elevations are at even higher risk, and the increased risk persists for years.

Relation of Duration of Symptoms With Response to Thrombolytic Therapy in Pulmonary Embolism

Five previous trials of pulmonary embolism (PE) thrombolysis showed individually that duration of symptoms did not affect lung scan reperfusion or angiographic clot lysis. We conducted an overview of 308 patients from these trials. Using 262 pairs of pre- and postlysis lung scans and 222 pairs of angiograms, we evaluated the relation between duration of PE symptoms and changes in reperfusion and/or clot lysis following thrombolysis. When comparing baseline and 24-hour post-thrombolysis lung scans, 77% of patients overall demonstrated improvement, including 69% who were treated 6 to 14 days after onset of symptoms. We detected an inverse relation between duration of symptoms and improvement on post-treatment lung scan reperfusion scores. For each additional day of symptoms before PE thrombolysis, there was a decrement of 0.8% of lung tissue reperfusion on lung scanning (95% confidence interval [CI], 0.2% to 1.4%, p = 0.008). Adjustment for age and baseline lung scan defect had little effect on the results Similarly, on angiography, less clot lysis immediately following thrombolysis was observed in the group of patients with the longest duration of symptoms compared with those with the shortest symptom duration (mean = 1.0 score unit of angiographic improvement in those with symptoms for > or = 6 days vs 1.7 score units for < or = 1 day of symptoms, p = 0.03). This inverse relation between duration of symptoms and response to thrombolysis indicates that thrombolytic treatment should commence as soon as possible after PE is diagnosed. However, thrombolysis is still useful in patients who have had symptoms for 6 to 14 days.

Copeptin Helps in the Early Detection of Patients With Acute Myocardial Infarction Primary Results of the CHOPIN Trial (Copeptin Helps in the early detection Of Patients with acute myocardial INfarction)

OBJECTIVES The goal of this study was to demonstrate that copeptin levels <14 pmol/L allow ruling out acute myocardial infarction (AMI) when used in combination with cardiac troponin I (cTnI) <99 th percentile and a nondiagnostic electrocardiogram at the time of presentation to the emergency department (ED). BACKGROUND Copeptin is secreted from the pituitary early in the course of AMI. METHODS This was a 16-site study in 1,967 patients with chest pain presenting to an ED within 6 hours of pain onset. Baseline demographic characteristics and clinical data were collected prospectively. Copeptin levels and a contemporary sensitive cTnI (99 th percentile 40 ng/l; 10% coefficient of variation 0.03 μg/l) were measured in a core laboratory. Patients were followed up for 180 days. The primary outcome was diagnosis of AMI. Final diagnoses were adjudicated by 2 independent cardiologists blinded to copeptin results. RESULTS AMI was the final diagnosis in 156 patients (7.9%). A negative copeptin and cTnI at baseline ruled out AMI for 58% of patients, with a negative predictive value of 99.2% (95% confidence interval: 98.5 to 99.6). AMIs not detected by the initial cTnI alone were picked up with copeptin >14 pmol/l in 23 (72%) of 32 patients. Non-ST-segment elevation myocardial infarctions undetected by cTnI at 0 h were detected with copeptin >14 pmol/l in 10 (53%) of 19 patients. Projected average time-to-decision could be reduced by 43% (from 3.0 h to 1.8 h) by the early rule out of 58% of patients. Both abnormal copeptin and cTnI were predictors of death at 180 days (p < 0.0001 for both; c index 0.784 and 0.800, respectively). Both were independent of age and each other and provided additional predictive value (all p < 0.0001). CONCLUSIONS Adding copeptin to cTnI allowed safe rule out of AMI with a negative predictive value >99% in patients presenting with suspected acute coronary syndromes. This combination has the potential to rule out AMI in 58% of patients without serial blood draws.

Increased 90-Day Mortality in Patients With Acute Heart Failure With Elevated Copeptin Secondary Results From the Biomarkers in Acute Heart Failure (BACH) Study

Background— In patients with heart failure (HF), increased arginine vasopressin concentrations are associated with more severe disease, making arginine vasopressin an attractive target for therapy. However, AVP is difficult to measure due to its in vitro instability and rapid clearance. Copeptin, the C-terminal segment of preprovasopressin, is a stable and reliable surrogate biomarker for serum arginine vasopressin concentrations. Methods and Results— The Biomarkers in Acute Heart Failure (BACH) trial was a 15-center, diagnostic and prognostic study of 1641 patients with acute dyspnea; 557 patients with acute HF were included in this analysis. Copeptin and other biomarker measurements were performed by a core laboratory at the University of Maryland. Patients were followed for up to 90 days after initial evaluation for the primary end point of all-cause mortality, HF-related readmissions, and HF-related emergency department visits. Patients with copeptin concentrations in the highest quartile had increased 90-day mortality ( P <0.001; hazard ratio, 3.85). Mortality was significantly increased in patients with elevated copeptin and hyponatremia ( P <0.001; hazard ratio, 7.36). Combined end points of mortality, readmissions, and emergency department visits were significantly increased in patients with elevated copeptin. There was no correlation between copeptin and sodium ( r =0.047). Conclusions— This study showed significantly increased 90-day mortality, readmissions, and emergency department visits in patients with elevated copeptin, especially in those with hyponatremia. Copeptin was highly prognostic for 90-day adverse events in patients with acute HF, adding prognostic value to clinical predictors, ser um sodium, and natriuretic peptides. Clinical Trial Registration— URL: . Unique identifier: [NCT00537628][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00537628&atom=%2Fcirchf%2F4%2F5%2F613.atomBackground— In patients with heart failure (HF), increased arginine vasopressin concentrations are associated with more severe disease, making arginine vasopressin an attractive target for therapy. However, AVP is difficult to measure due to its in vitro instability and rapid clearance. Copeptin, the C-terminal segment of preprovasopressin, is a stable and reliable surrogate biomarker for serum arginine vasopressin concentrations. Methods and Results— The Biomarkers in Acute Heart Failure (BACH) trial was a 15-center, diagnostic and prognostic study of 1641 patients with acute dyspnea; 557 patients with acute HF were included in this analysis. Copeptin and other biomarker measurements were performed by a core laboratory at the University of Maryland. Patients were followed for up to 90 days after initial evaluation for the primary end point of all-cause mortality, HF-related readmissions, and HF-related emergency department visits. Patients with copeptin concentrations in the highest quartile had increased 90-day mortality (P<0.001; hazard ratio, 3.85). Mortality was significantly increased in patients with elevated copeptin and hyponatremia (P<0.001; hazard ratio, 7.36). Combined end points of mortality, readmissions, and emergency department visits were significantly increased in patients with elevated copeptin. There was no correlation between copeptin and sodium (r=0.047). Conclusions— This study showed significantly increased 90-day mortality, readmissions, and emergency department visits in patients with elevated copeptin, especially in those with hyponatremia. Copeptin was highly prognostic for 90-day adverse events in patients with acute HF, adding prognostic value to clinical predictors, ser um sodium, and natriuretic peptides. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00537628.

Growth-Differentiation Factor-15 Is a Robust, Independent Predictor of 11-Year Mortality Risk in Community-Dwelling Older Adults The Rancho Bernardo Study

Background— Growth-differentiation factor-15 (GDF-15) is emerging as a prognostic marker in patients with cardiovascular disease (CVD), but its prognostic value in community-dwelling adults has not been reported. We hypothesized that GDF-15 would add incremental power for prediction of mortality in a population of community-dwelling older adults without known heart disease. Methods and Results— We measured plasma GDF-15, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and C-reactive protein levels in 1391 Rancho Bernardo Study participants, mean age 70 years, with no history of CVD and followed them for a mean of 11 years. In models adjusted for traditional CVD risk factors, GDF-15 was a robust predictor of all-cause, cardiovascular, and noncardiovascular mortality. GDF-15 was a stronger predictor of all-cause mortality than either NT-proBNP or C-reactive protein (hazard ratio [95% confidence interval] per SD log10 units 1.5 [1.3 to 1.8], P<0.0001 for GDF-15 versus 1.3 [1.2 to 1.5], P<0.0001 for NT-proBNP; C-reactive protein was not a significant predictor). Among biomarkers considered, only GDF-15 predicted noncardiovascular death (hazard ratio 1.6 [1.4 to 2.0], P<0.0001). Growth differentiation factor-15 improved discrimination and modestly but significantly improved reclassification for all-cause and noncardiovascular mortality with borderline improvement for cardiovascular mortality; NT-proBNP significantly improved reclassification for all-cause and for cardiovascular mortality; C-reactive protein did not improve reclassification for any end point tested. Participants in the highest quartile of both GDF-15 and NT-proBNP had an increased risk of death compared with participants with only NT-proBNP elevated (hazard ratio 1.5 [1.1 to 2.0], P=0.01). Conclusions— Growth differentiation factor-15 is a strong predictor of all-cause, cardiovascular, and noncardiovascular mortality in community-dwelling older individuals, adding incremental value to traditional risk factors and to NT-proBNP and C-reactive protein levels.

Lipoprotein-Associated Phospholipase A2 Is an Independent Predictor of Incident Coronary Heart Disease in an Apparently Healthy Older Population: The Rancho Bernardo Study

OBJECTIVES Lipoprotein-associated phospholipase A2 (Lp-PLA2) levels predict incident coronary heart disease (CHD) in adults without known CHD, independent of heart disease risk factors. We examined whether the independent association was apparent in older adults. BACKGROUND Serum levels of Lp-PLA2, an enzyme that hydrolyzes oxidized phospholipids to yield potentially proatherogenic particles, have been associated with CHD and may help predict cardiovascular risk. METHODS Participants were 1,077 community-dwelling men and women, median age 72 years, who had no known CHD at baseline (1984 to 1987) when blood samples and risk factor data were collected. Participants were followed for CHD events for a mean of 16 years, through 2002. Cox proportional hazards regression models were used to examine the association of serum Lp-PLA2 with incident CHD (myocardial infarction, angina, or coronary revascularization). RESULTS The Lp-PLA2 levels positively correlated with age (r = 0.09), body mass index (r = 0.11), low-density lipoprotein (r = 0.37), triglycerides (r = 0.25), and C-reactive protein (r = 0.10), and negatively correlated with high-density lipoprotein (r = -0.27) (all p < 0.05). During follow-up, 228 participants had incident CHD events. Lipoprotein-associated phospholipase A2 levels in the second, third, and fourth quartiles predicted an increased risk of CHD compared with the lowest quartile (hazard ratios 1.66, 1.80, and 1.89, respectively; p < 0.05 for each). This association persisted after adjusting for C-reactive protein and other CHD risk factors. CONCLUSIONS Elevated Lp-PLA2 levels predict CHD events in apparently healthy older adults, independent of CHD risk factors.

Midregion Prohormone Adrenomedullin and Prognosis in Patients Presenting With Acute Dyspnea : Results From the BACH (Biomarkers in Acute Heart Failure) Trial

OBJECTIVES The aim of this study was to determine the prognostic utility of midregion proadrenomedullin (MR-proADM) in all patients, cardiac and noncardiac, presenting with acute shortness of breath. BACKGROUND The recently published BACH (Biomarkers in Acute Heart Failure) study demonstrated that MR-proADM had superior accuracy for predicting 90-day mortality compared with B-type natriuretic peptide (area under the curve: 0.674 vs. 0.606, respectively, p < 0.001) in acute heart failure. METHODS The BACH trial was a prospective, 15-center, international study of 1,641 patients presenting to the emergency department with dyspnea. Using this dataset, the prognostic accuracy of MR-proADM was evaluated in all patients enrolled for predicting 90-day mortality with respect to other biomarkers, the added value in addition to clinical variables, as well as the added value of additional measurements during hospital admission. RESULTS Compared with B-type natriuretic peptide or troponin, MR-proADM was superior for predicting 90-day all-cause mortality in patients presenting with acute dyspnea (c index = 0.755, p < 0.0001). Furthermore, MR-proADM added significantly to all clinical variables (all adjusted hazard ratios: >3.28), and it was also superior to all other biomarkers. MR-proADM added significantly to the best clinical model (bootstrap-corrected c index increase: 0.775 to 0.807; adjusted standardized hazard ratio: 2.59; 95% confidence interval: 1.91 to 3.50; p < 0.0001). Within the model, MR-proADM was the biggest contributor to the predictive performance, with a net reclassification improvement of 8.9%. Serial evaluation of MR-proADM performed in patients admitted provided a significant added value compared with a model with admission values only (p = 0.0005). More than one-third of patients originally at high risk could be identified by the biomarker evaluation at discharge as low-risk patients. CONCLUSIONS MR-proADM identifies patients with high 90-day mortality and adds prognostic value to natriuretic peptides in patients presenting with acute shortness of breath. Serial measurement of this biomarker may also prove useful for monitoring, although further studies will be required. (Biomarkers in Acute Heart Failure [BACH]; NCT00537628).

Utility of Right Ventricular Tei Index in the Noninvasive Evaluation of Chronic Thromboembolic Pulmonary Hypertension Before and After Pulmonary Thromboendarterectomy

OBJECTIVES We evaluated the utility of tissue Doppler-derived right ventricular (RV) Tei (or myocardial performance) index in patients with chronic thromboembolic pulmonary hypertension (CTEPH) before and after pulmonary thromboendarterectomy (PTE) and assessed correlations with mean pulmonary artery pressure (mPAP), pulmonary vascular resistance (PVR), and cardiac output (CO). BACKGROUND The assessment of RV function is limited with 2-dimensional echocardiography. The RV Tei index, an indicator of RV myocardial performance, is derived by Doppler measurements and is unaffected by RV geometry. The use of tissue Doppler imaging (at the lateral tricuspid annulus) for RV Tei index calculation is simple and eliminates the need for pulsed-wave Doppler recordings of both RV inflow and outflow. METHODS Ninety-three patients with CTEPH were prospectively studied along with 13 control patients. Right ventricular tissue Doppler imaging and right heart catheterization were performed before and after PTE. Right ventricular Tei index was compared with values of mPAP, PVR, and CO with the use of linear regression. RESULTS Right ventricular Tei index was 0.52 +/- 0.19 in patients with CTEPH and 0.27 +/- 0.09 in control patients (p < 0.0001). After PTE, RV Tei index decreased to 0.33 +/- 0.10 (p < 0.0001). Pulmonary vascular resistance correlated well with RV Tei index before (r = 0.78, p < 0.0001) and after (r = 0.67, p < 0.0001) surgery. Also, the absolute change in Tei index in each patient after PTE correlated well with the concomitant change in PVR (r = 0.75, p < 0.0001). RV Tei index did not correlate as well with mPAP (pre-operatively: r = 0.55, p < 0.0001; post-operatively: r = 0.26, p = 0.03) or CO (pre-operatively: r = 0.57, p < 0.0001; post-operatively: r = 0.43, p < 0.0001). CONCLUSIONS These results demonstrate a correlation between RV Tei index and right heart hemodynamics (particularly PVR) in CTEPH. Because PVR is difficult to estimate noninvasively -- and yet correlates with disease severity -- the RV Tei index may be a valuable noninvasive parameter for monitoring disease severity in CTEPH and outcome after PTE.

Use of procalcitonin for the diagnosis of pneumonia in patients presenting with a chief complaint of dyspnoea: results from the BACH (Biomarkers in Acute Heart Failure) trial.

Biomarkers have proven their ability in the evaluation of cardiopulmonary diseases. We investigated the utility of concentrations of the biomarker procalcitonin (PCT) alone and with clinical variables for the diagnosis of pneumonia in patients presenting to emergency departments (EDs) with a chief complaint of shortness of breath.