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      Established and Emerging Roles of Biomarkers in Heart Failure

      1 , 2 , 1 , 2 , 3
      Circulation Research
      Ovid Technologies (Wolters Kluwer Health)

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          Abstract

          Heart failure (HF) is a complex syndrome with an enormous societal burden in terms of cost, morbidity, and mortality. Natriuretic peptide testing is now widely used to support diagnosis, prognostication, and management of patients with HF and are incorporated into HF clinical practice guidelines. Beyond the natriuretic peptides, novel biomarkers may supplement traditional clinical and laboratory testing to improve understanding of the complex disease process of HF and possibly to personalize care for those affected through better individual phenotyping. In this review, we will discuss natriuretic peptides and the more novel biomarkers by dividing them into categories based on the major pathophysiologic pathways they represent. Given the complex physiology in HF, it is reasonable to expect that the future of biomarker testing lies in the application of multimarker testing panels, precision medicine to improve HF care delivery, and the use of biomarkers in proteomics and metabolomics to further improve HF care.

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          Most cited references89

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          Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure.

          B-type natriuretic peptide is released from the cardiac ventricles in response to increased wall tension. We conducted a prospective study of 1586 patients who came to the emergency department with acute dyspnea and whose B-type natriuretic peptide was measured with a bedside assay. The clinical diagnosis of congestive heart failure was adjudicated by two independent cardiologists, who were blinded to the results of the B-type natriuretic peptide assay. The final diagnosis was dyspnea due to congestive heart failure in 744 patients (47 percent), dyspnea due to noncardiac causes in 72 patients with a history of left ventricular dysfunction (5 percent), and no finding of congestive heart failure in 770 patients (49 percent). B-type natriuretic peptide levels by themselves were more accurate than any historical or physical findings or laboratory values in identifying congestive heart failure as the cause of dyspnea. The diagnostic accuracy of B-type natriuretic peptide at a cutoff of 100 pg per milliliter was 83.4 percent. The negative predictive value of B-type natriuretic peptide at levels of less than 50 pg per milliliter was 96 percent. In multiple logistic-regression analysis, measurements of B-type natriuretic peptide added significant independent predictive power to other clinical variables in models predicting which patients had congestive heart failure. Used in conjunction with other clinical information, rapid measurement of B-type natriuretic peptide is useful in establishing or excluding the diagnosis of congestive heart failure in patients with acute dyspnea. Copyright 2002 Massachusetts Medical Society.
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            Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury

            Introduction Acute kidney injury (AKI) can evolve quickly and clinical measures of function often fail to detect AKI at a time when interventions are likely to provide benefit. Identifying early markers of kidney damage has been difficult due to the complex nature of human AKI, in which multiple etiologies exist. The objective of this study was to identify and validate novel biomarkers of AKI. Methods We performed two multicenter observational studies in critically ill patients at risk for AKI - discovery and validation. The top two markers from discovery were validated in a second study (Sapphire) and compared to a number of previously described biomarkers. In the discovery phase, we enrolled 522 adults in three distinct cohorts including patients with sepsis, shock, major surgery, and trauma and examined over 300 markers. In the Sapphire validation study, we enrolled 744 adult subjects with critical illness and without evidence of AKI at enrollment; the final analysis cohort was a heterogeneous sample of 728 critically ill patients. The primary endpoint was moderate to severe AKI (KDIGO stage 2 to 3) within 12 hours of sample collection. Results Moderate to severe AKI occurred in 14% of Sapphire subjects. The two top biomarkers from discovery were validated. Urine insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2), both inducers of G1 cell cycle arrest, a key mechanism implicated in AKI, together demonstrated an AUC of 0.80 (0.76 and 0.79 alone). Urine [TIMP-2]·[IGFBP7] was significantly superior to all previously described markers of AKI (P 0.72. Furthermore, [TIMP-2]·[IGFBP7] significantly improved risk stratification when added to a nine-variable clinical model when analyzed using Cox proportional hazards model, generalized estimating equation, integrated discrimination improvement or net reclassification improvement. Finally, in sensitivity analyses [TIMP-2]·[IGFBP7] remained significant and superior to all other markers regardless of changes in reference creatinine method. Conclusions Two novel markers for AKI have been identified and validated in independent multicenter cohorts. Both markers are superior to existing markers, provide additional information over clinical variables and add mechanistic insight into AKI. Trial registration ClinicalTrials.gov number NCT01209169.
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              NT-proBNP testing for diagnosis and short-term prognosis in acute destabilized heart failure: an international pooled analysis of 1256 patients: the International Collaborative of NT-proBNP Study.

              Experience with amino-terminal pro-brain natriuretic peptide (NT-proBNP) testing for evaluation of dyspnoeic patients with suspected acute heart failure (HF) is limited to single-centre studies. We wished to establish broader standards for NT-proBNP testing in a study involving four sites in three continents. Differences in NT-proBNP levels among 1256 patients with and without acute HF and the relationship between NT-proBNP levels and HF symptoms were examined. Optimal cut-points for diagnosis and prognosis were identified and verified using bootstrapping and multi-variable logistic regression techniques. Seven hundred and twenty subjects (57.3%) had acute HF, whose median NT-proBNP was considerably higher than those without (4639 vs. 108 pg/mL, P 75, which yielded 90% sensitivity and 84% specificity for acute HF. An age-independent cut-point of 300 pg/mL had 98% negative predictive value to exclude acute HF. Among those with acute HF, a presenting NT-proBNP concentration >5180 pg/mL was strongly predictive of death by 76 days [odds ratio=5.2, 95% confidence interval (CI)=2.2-8.1, P<0.001]. In this multi-centre, international study, NT-proBNP testing was valuable for diagnostic evaluation and short-term prognosis estimation in dyspnoeic subjects with suspected or confirmed acute HF and should establish broader standards for use of the NT-proBNP in dyspnoeic patients.
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                Author and article information

                Journal
                Circulation Research
                Circ Res
                Ovid Technologies (Wolters Kluwer Health)
                0009-7330
                1524-4571
                August 17 2018
                August 17 2018
                : 123
                : 5
                : 614-629
                Affiliations
                [1 ]From the Cardiology Division, Massachusetts General Hospital, Boston (N.E.I., J.L.J.)
                [2 ]Harvard Medical School, Boston, MA (N.E.I., J.L.J.)
                [3 ]Baim Institute for Clinical Research, Boston, MA (J.L.J.).
                Article
                10.1161/CIRCRESAHA.118.312706
                30355136
                6156102e-ec59-4bf2-a53b-a7f882aa1f37
                © 2018
                History

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