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Circulation. 2004 Apr 27;109(16):1955-9. Epub 2004 Mar 29.
Clinical usefulness of very high and very low levels of C-reactive protein across the full range of Framingham Risk Scores.
Ridker PM, Cook N.
Donald W. Reynolds Center for Cardiovascular Research and the Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass 02215, USA.

> BACKGROUND: High-sensitivity C-reactive protein (hsCRP) is a strong independent risk factor for cardiovascular events, and levels of hsCRP of <1, 1 to <3, and > or =3 mg/L have been suggested to define low-, moderate-, and high-risk groups. However, the positive predictive value of very low (<0.5 mg/L) and very high levels of hsCRP (>10.0 mg/L) is uncertain. METHODS AND RESULTS: Baseline levels of hsCRP were evaluated among 27 939 apparently healthy women who were followed up for myocardial infarction, stroke, coronary revascularization, or cardiovascular death. Crude and Framingham Risk Score (FRS)-adjusted relative risks (RRs) of incident cardiovascular events were calculated across a full range of hsCRP levels. Cardiovascular risks increased linearly from the very lowest (referent) to the very highest levels of hsCRP. Crude RRs for those with baseline hsCRP levels of <0.5, 0.5 to <1.0, 1.0 to <2.0, 2.0 to <3.0, 3.0 to <4.0, 4.0 to <5.0, 5.0 to <10.0, 10.0 to <20.0, and > or =20.0 mg/L were 1.0, 2.2, 2.5, 3.1, 3.7, 4.2, 4.9, 6.3, and 7.6, respectively (P for trend <0.001). After adjustment for FRS, these risks were 1.0, 1.6, 1.6, 1.7, 1.9, 2.2, 2.3, 2.8, and 3.1 (P for trend <0.001). All risk estimates remained significant in analyses stratified by FRS and after control for diabetes. Of the total cohort, 15.1% had hsCRP <0.50 mg/L, and 5.4% had hsCRP >10.0 mg/L. CONCLUSIONS: Both very low (<0.5 mg/L) and very high (>10 mg/L) levels of hsCRP provide important prognostic information on cardiovascular risk. hsCRP is clinically useful for risk prediction across a full range of values and across a full range of FRS.

Am Coll Cardiol. 2002 Jun 19;39(12):1917-23.
Systemic inflammation in unstable angina is the result of myocardial necrosis.
Cusack MR, Marber MS, Lambiase PD, Bucknall CA, Redwood SR.
Department of Cardiology, Rayne Institute, St. Thomas' Hospital, London, United Kingdom.

OBJECTIVES: We investigated whether the source of the acute phase response in unstable angina (UA) lay within the culprit coronary plaque or distal myocardium. BACKGROUND: An inflammatory response is an important component of the acute coronary syndromes. However, its origin and mechanism remain unclear. METHODS: In 94 stable patients undergoing coronary angiography, the relationship between systemic levels of tumor necrosis factor (TNF)-alpha, interleukin-6 (IL-6) and C-reactive protein (CRP) and extent of atherosclerosis was studied. The temporal relationship between these markers and troponin T (TnT) was determined in 91 patients with UA. Cytokine levels were measured in the aortic root and coronary sinus of 36 unstable patients. RESULTS: There was no relationship found between stable coronary atherosclerosis and inflammatory marker levels. Compared with this group, admission levels of IL-6 (3.6 +/- 0.3 ng/ml vs. 10.7 +/- 1.7 ng/ml, p < 0.05) and CRP (2.3 +/- 0.1 mg/l vs. 4.6 +/- 0.6 mg/l, p < 0.05) were elevated in patients with UA. In this group, IL-6 and CRP remained elevated in those who subsequently experienced major adverse cardiac events. This inflammatory response occurred in parallel to the appearance of TnT. Both TNF-alpha (19.2 +/- 3.4 ng/ml vs. 17.1 +/- 3.3 ng/ml, p < 0.001) and IL-6 (10.3 +/- 1.4 ng/ml vs. 7.7 +/- 1.1 ng/ml, p < 0.01) were elevated in the coronary sinus compared with aortic root in patients with UA. This was principally observed in those who were TnT positive. There was no cytokine gradient across the culprit plaque. CONCLUSIONS: There is an intracardiac inflammatory response in UA that appears to be the result of low-grade myocardial necrosis. The ruptured plaque does not appear to contribute to the acute phase response.

JAMA. 2005 Feb 2;293(5):572-80.
Comment in: ACP J Club. 2005 Jul-Aug;143(1):25. JAMA. 2005 May 25;293(20):2467-8; author reply 2468.
Risk stratification for in-hospital mortality in acutely decompensated heart failure: classification and regression tree analysis.
Fonarow GC, Adams KF Jr, Abraham WT, Yancy CW, Boscardin WJ; ADHERE Scientific Advisory Committee, Study Group, and Investigators.
Ahmanson-UCLA Cardiomyopathy Center, University of California, Los Angeles Medical Center, Los Angeles, CA 90095, USA.

CONTEXT: Estimation of mortality risk in patients hospitalized with acute decompensated heart failure (ADHF) may help clinicians guide care. OBJECTIVE: To develop a practical user-friendly bedside tool for risk stratification for patients hospitalized with ADHF. DESIGN, SETTING, AND PATIENTS: The Acute Decompensated Heart Failure National Registry (ADHERE) of patients hospitalized with a primary diagnosis of ADHF in 263 hospitals in the United States was queried with analysis of patient data to develop a risk stratification model. The first 33,046 hospitalizations (derivation cohort; October 2001-February 2003) were analyzed to develop the model and then the validity of the model was prospectively tested using data from 32,229 subsequent hospitalizations (validation cohort; March-July 2003). Patients had a mean age of 72.5 years and 52% were female. MAIN OUTCOME MEASURE: Variables predicting mortality in ADHF. RESULTS: When the derivation and validation cohorts are combined, 37,772 (58%) of 65,275 patient-records had coronary artery disease. Of a combined cohort consisting of 52,164 patient-records, 23,910 (46%) had preserved left ventricular systolic function. In-hospital mortality was similar in the derivation (4.2%) and validation (4.0%) cohorts. Recursive partitioning of the derivation cohort for 39 variables indicated that the best single predictor for mortality was high admission levels of blood urea nitrogen (> or =43 mg/dL [15.35 mmol/L]) followed by low admission systolic blood pressure (<115 mm Hg) and then by high levels of serum creatinine (> or =2.75 mg/dL [243.1 micromol/L]). A simple risk tree identified patient groups with mortality ranging from 2.1% to 21.9%. The odds ratio for mortality between patients identified as high and low risk was 12.9 (95% confidence interval, 10.4-15.9) and similar results were seen when this risk stratification was applied prospectively to the validation cohort. CONCLUSIONS: These results suggest that ADHF patients at low, intermediate, and high risk for in-hospital mortality can be easily identified using vital sign and laboratory data obtained on hospital admission. The ADHERE risk tree provides clinicians with a validated, practical bedside tool for mortality risk stratification.

Eur J Heart Fail. 2005 Oct;7(6):953-7.
Clinical deterioration in established heart failure: What is the value of BNP and weight gain in aiding diagnosis?
Lewin J, Ledwidge M, O'loughlin C, McNally C, McDonald K.
St Vincent's University Hospital Heart Failure Unit, Elm Park, Dublin 4, Ireland.

BACKGROUND: Weight gain and increase in B-Type Natriuretic Peptide have been advocated as means of aiding diagnosis of heart failure. However, there are few data to support the use of these criteria in diagnosing clinical deterioration in patients with established disease. AIMS: This prospective study examines the sensitivity and specificity of absolute and relative changes in BNP and weight in determining the early onset of clinical deterioration in patients with established heart failure. METHODS: All patients who presented to the outpatient clinic with completed self-reported daily weight books, baseline BNP measurement, outpatient BNP measurement and assessment by a cardiologist blinded to BNP and weight were included. Each patient was determined as clinically stable (CS) or in clinical deterioration (CD). Receiver operating characteristic (ROC) curves and sensitivity and specificity calculations for various absolute and relative BNP and weight changes were carried out. RESULTS: Weight and BNP changes were examined in 34 CS presentations (mean age 69.5+/-16.1 years) and 43 CD presentations (mean age 70.0+/-10.6 years). ROC analysis demonstrated that neither weight nor BNP changes in absolute or relative values predicted clinical deterioration in this study population adequately (AUC values ranging from 0.64 to 0.66). CONCLUSIONS: These data demonstrate that increase in body weight and BNP in isolation are not sensitive in assessing clinical deterioration in established heart failure. These observations may need to be emphasized in patient education and to physicians involved in assessment of heart failure patients.

J Am Coll Cardiol. 2004 Nov 16;44(10):1988-95.
Acute changes in circulating natriuretic peptide levels in relation to myocardial ischemia.
Sabatine MS, Morrow DA, de Lemos JA, Omland T, Desai MY, Tanasijevic M, Hall C, McCabe CH, Braunwald E.
TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.

OBJECTIVES: The aim of this study was to determine the effect of transient myocardial ischemia on circulating natriuretic peptide levels. BACKGROUND: Natriuretic peptides are released by the heart in response to wall stress. We hypothesized that transient myocardial ischemia would cause acute changes in circulating natriuretic peptide levels. METHODS: B-type natriuretic peptide (BNP), N-terminal fragment of BNP pro-hormone (NT-pro-BNP), and N-terminal fragment of atrial natriuretic peptide pro-hormone (NT-pro-ANP) levels were measured in 112 patients before, immediately after, and 4 h after exercise testing with nuclear perfusion imaging. RESULTS: Baseline levels of BNP were associated with the subsequent severity of provoked ischemia, with median levels of 43, 62, and 101 pg/ml in patients with none, mild-to-moderate, and severe inducible ischemia, respectively (p = 0.03). Immediately after exercise, the median increase in BNP was 14.2 pg/ml in patients with mild-to-moderate ischemia (p = 0.0005) and 23.7 pg/ml in those with severe ischemia (p = 0.017). In contrast, BNP levels only rose by 2.3 pg/ml in those who did not develop ischemia (p = 0.31). A similar relationship was seen between baseline NT-pro-BNP levels and inducible ischemia, but the changes in response to ischemia were less pronounced. NT-pro-ANP levels rose with exercise in both ischemic and non-ischemic patients. When added to traditional clinical predictors of ischemia, a post-stress test BNP >or=80 pg/ml remained a strong and independent predictor of inducible myocardial ischemia (odds ratio 3.0, p = 0.025). CONCLUSIONS: Transient myocardial ischemia was associated with an immediate rise in circulating BNP levels, and the magnitude of rise was proportional to the severity of ischemia. These findings demonstrate an important link between the severity of an acute ischemic insult and the circulating levels of BNP.

Am Heart J. 2004 Oct;148(4):612-20.
N-terminal B-type natriuretic peptide predicts extent of coronary artery disease and ischemia in patients with stable angina pectoris.
Weber M, Dill T, Arnold R, Rau M, Ekinci O, Muller KD, Berkovitsch A, Mitrovic V, Hamm C.
Department of Cardiology, Kerckhoff Heart Center, Bad Nauheim, Germany.

BACKGROUND: B-type natriuretic peptide (BNP) and its N-terminal fragment (NT-proBNP) are elevated in patients with acute coronary syndromes and are closely linked to prognosis. Because there is only a small amount of data available concerning NT-proBNP in patients with stable angina pectoris, we aimed to determine whether NT-proBNP is of additional diagnostic value in these patients. METHODS AND RESULTS: Ninety-four patients with stable angina pectoris were prospectively included. All patients underwent exercise testing and coronary angiography, and 91 patients received thallium-201 single-photon emission computed tomography myocardial scintigraphy. NT-proBNP was analyzed at rest and after exercise testing. NT-proBNP was elevated in patients with inducible myocardial ischemia shown by single-photon emission computed tomography (396 +/- 80 pg/mL vs 160 +/- 101 pg/mL; P <.01) closely linked to the extent of coronary artery disease (CAD) (no CAD, 148 +/- 29 pg/mL; 1- or 2-vessel disease, 269 +/- 50 pg/mL; 3-vessel disease 624 +/- 186 pg/mL; P <.01). In a multivariate analysis, NT-proBNP was an independent predictor for CAD. The area under the curve of the receiver operating characteristic curve was 0.72 for NT-proBNP to predict CAD. Using an optimized cut off level of 214 pg/mL, CAD can be predicted with high accuracy. The total test efficiency of exercise testing can be improved from 1.46 to 1.52 when combined with NT-proBNP measurement. CONCLUSION: NT-proBNP is elevated in patients with stable angina pectoris and has a close correlation to disease severity. Combining the measurement of NT-proBNP with exercise testing, the test accuracy for predicting severe CAD can be improved. Our data show an incremental value of NT-proBNP in the diagnostic process of stable angina pectoris.

J Am Coll Cardiol. 2004 Nov 16;44(10):1980-7.
Detection of exercise-induced ischemia by changes in B-type natriuretic peptides.
Foote RS, Pearlman JD, Siegel AH, Yeo KT.
Department of Medicine, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire 03756, USA.

OBJECTIVES: The purpose of this study was to examine the effect of exercise-induced ischemia on levels of B-type natriuretic peptide (BNP) and its inactive N-terminal fragment (NT-pro-BNP)and to determine whether measurement of these peptides can improve the diagnostic accuracy of exercise testing. BACKGROUND: The ability of exercise testing to detect coronary artery disease (CAD) is limited by modest sensitivity and specificity. B-type natriuretic peptides (NT-pro-BNP and BNP) are released by ventricular myocytes in response to wall stress. We hypothesized that exercise-induced ischemia results in increased wall stress and triggers release of NT-pro-BNP and BNP. METHODS: A total of 74 patients with known CAD, normal left ventricular function, and normal resting levels of NT-pro-BNP and BNP who were referred for exercise testing with radionuclide imaging, and 21 healthy volunteers, were enrolled. Blood was drawn before and after maximal exercise and analyzed for NT-pro-BNP and BNP. RESULTS: Of the patients with CAD, 40 had ischemia on perfusion images and 34 did not. Median post-exercise increases in NT-pro-BNP and BNP (DeltaNT-pro-BNP and DeltaBNP) were approximately four-fold higher in the ischemic group than in the nonischemic group (DeltaNT-pro-BNP 14.5 vs. 4 pg/ml, p < 0.0001; DeltaBNP 36.5 vs. 7.5 pg/ml, p < 0.0001). In volunteers, median DeltaNT-pro-BNP was almost identical to that of the nonischemic patient group. At equal specificity to the electrocardiogram (ECG) (58.8%), the sensitivities of DeltaNT-pro-BNP and DeltaBNP for detecting ischemia were 90% and 80%, respectively; in contrast, the sensitivity of the exercise ECG was 37.5%. CONCLUSIONS: Measurement of exercise-induced increases in BNPs more than doubles the sensitivity of the exercise test for detecting ischemia with no loss of specificity.

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