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      NT-proBNP Predicts Cardiovascular Death in the General Population Independent of Left Ventricular Mass and Function: Insights from a Large Population-Based Study with Long-Term Follow-Up

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          Abstract

          Aims

          B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) predict cardiovascular endpoints in patients and all-cause death in the general population. This was assigned to their association with clinical cardiac remodelling defined as changes in size, shape and function of the heart. The aim of this study was to evaluate whether NT-proBNP and BNP were associated with cardiovascular and overall death independent of clinical cardiac remodelling measured by echocardiography as left ventricular hypertrophy (LVH), diastolic dysfunction and left ventricular ejection fraction (EF).

          Methods and Results

          In a general population-based cohort study from Germany (KORA-S3) with subjects’ baseline age ranging from 25 to 74 years, cardiac morphology and function were assessed as left ventricular mass (LVM), diastolic dysfunction and EF by echocardiography and circulating NT-proBNP and BNP were measured at baseline. In 1,223 subjects with mortality follow-up information, we examined the association of baseline NT-proBNP and BNP with cardiovascular mortality (number of deaths = 52, median follow-up time = 12.9years) using Cox regression without and with adjustment for cardiovascular risk factors, LVM, diastolic dysfunction and EF. The risk of cardiovascular mortality increased with higher NT-proBNP levels measured at baseline (hazard ratio HR = 1.67 per unit increment in logNT-proBNP, p = 2.78*10 −4, adjusted for age and sex). This increased risk persisted after adjustment for cardiovascular risk factors, LVM, diastolic dysfunction and EF (HR = 1.73; p = 0.047). When excluding subjects with relevant LVH (LVM to body surface area > 149g/m 2 in men / 122g/m 2 in women), the NT-proBNP association with mortality was still significant (n = 1,138; number of deaths = 35; HR = 1.48; p = 0.04). We found similar results for BNP.

          Conclusion

          Our data confirms NT-proBNP and BNP as predictor of cardiovascular mortality in a large general population-based study with long-term follow-up. Our study extends previously published population-based studies to younger and potentially healthier individuals without relevant LVH, diastolic dysfunction or LVD.

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          Most cited references28

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          Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiograms.

          We have presented recommendations for the optimum acquisition of quantitative two-dimensional data in the current echocardiographic environment. It is likely that advances in imaging may enhance or supplement these approaches. For example, three-dimensional reconstruction methods may greatly augment the accuracy of volume determination if they become more efficient. The development of three-dimensional methods will depend in turn on vastly improved transthoracic resolution similar to that now obtainable by transesophageal echocardiography. Better resolution will also make the use of more direct methods of measuring myocardial mass practical. For example, if the epicardium were well resolved in the long-axis apical views, the myocardial shell volume could be measured directly by the biplane method of discs rather than extrapolating myocardial thickness from a single short-axis view. At present, it is our opinion that current technology justifies the clinical use of the quantitative two-dimensional methods described in this article. When technically feasible, and if resources permit, we recommend the routine reporting of left ventricular ejection fraction, diastolic volume, mass, and wall motion score.
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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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              Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic.

              Approximately half of patients with overt congestive heart failure (CHF) have diastolic dysfunction without reduced ejection fraction (EF). Yet, the prevalence of diastolic dysfunction and its relation to systolic dysfunction and CHF in the community remain undefined. To determine the prevalence of CHF and preclinical diastolic dysfunction and systolic dysfunction in the community and determine if diastolic dysfunction is predictive of all-cause mortality. Cross-sectional survey of 2042 randomly selected residents of Olmsted County, Minnesota, aged 45 years or older from June 1997 through September 2000. Doppler echocardiographic assessment of systolic and diastolic function. Presence of CHF diagnosis by review of medical records with designation as validated CHF if Framingham criteria are satisfied. Subjects without a CHF diagnosis but with diastolic or systolic dysfunction were considered as having either preclinical diastolic or preclinical systolic dysfunction. The prevalence of validated CHF was 2.2% (95% confidence interval [CI], 1.6%-2.8%) with 44% having an EF higher than 50%. Overall, 20.8% (95% CI, 19.0%-22.7%) of the population had mild diastolic dysfunction, 6.6% (95% CI, 5.5%-7.8%) had moderate diastolic dysfunction, and 0.7% (95% CI, 0.3%-1.1%) had severe diastolic dysfunction with 5.6% (95% CI, 4.5%-6.7%) of the population having moderate or severe diastolic dysfunction with normal EF. The prevalence of any systolic dysfunction (EF < or =50%) was 6.0% (95% CI, 5.0%-7.1%) with moderate or severe systolic dysfunction (EF < or =40%) being present in 2.0% (95% CI, 1.4%-2.5%). CHF was much more common among those with systolic or diastolic dysfunction than in those with normal ventricular function. However, even among those with moderate or severe diastolic or systolic dysfunction, less than half had recognized CHF. In multivariate analysis, controlling for age, sex, and EF, mild diastolic dysfunction (hazard ratio, 8.31 [95% CI, 3.00-23.1], P<.001) and moderate or severe diastolic dysfunction (hazard ratio, 10.17 [95% CI, 3.28-31.0], P<.001) were predictive of all-cause mortality. In the community, systolic dysfunction is frequently present in individuals without recognized CHF. Furthermore, diastolic dysfunction as rigorously defined by comprehensive Doppler techniques is common, often not accompanied by recognized CHF, and associated with marked increases in all-cause mortality.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                6 October 2016
                2016
                : 11
                : 10
                : e0164060
                Affiliations
                [1 ]Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany
                [2 ]Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
                [3 ]Institute of Epidemiology II, Helmholtz Zentrum Muenchen, German Research Centre for Environmental Health, Neuherberg, Germany
                [4 ]Deutsches Herzzentrum Muenchen, Technische Universitaet Muenchen, and DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
                [5 ]Klinikum Amberg, Amberg, Germany
                Ospedale del Cuore G Pasquinucci Fondazione Toscana Gabriele Monasterio di Massa, ITALY
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                • Conceptualization: AD KS IMH AL.

                • Data curation: AD KS MEZ CM AP IMH AL.

                • Formal analysis: AD KS MEZ IMH AL.

                • Funding acquisition: KS HS LSM AP IMH AL.

                • Investigation: AD KS MEZ CM HS CB LSM AP IMH AL.

                • Methodology: AD KS MEZ CM HS CB LSM AP IMH AL.

                • Project administration: AD KS CM HS LSM AP IMH AL.

                • Resources: AD KS CM HS CB LSM AP IMH AL.

                • Supervision: KS HS LSM AP IMH AL.

                • Validation: AD KS MEZ CM HS CB LSM AP IMH AL.

                • Visualization: AD KS IMH AL.

                • Writing – review & editing: MEZ CM HS CB LSM AP.

                Article
                PONE-D-16-15318
                10.1371/journal.pone.0164060
                5053441
                27711172
                732c6b57-d6f6-4832-9dd0-5d5f5ff94715
                © 2016 Dietl et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 15 April 2016
                : 19 September 2016
                Page count
                Figures: 2, Tables: 4, Pages: 16
                Funding
                Funded by: German Federal Ministry of Science and Research
                Funded by: State of Bavaria
                Funded by: funder-id http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;
                Award ID: LU 562/3-1, Germany
                Award Recipient :
                Funded by: Competence Network of Heart Failure
                Award ID: BMBF-01GI0205, Germany
                Funded by: Roche Diagnostics
                Award Recipient :
                Funded by: University Hospital Regensburg
                Award ID: ReForM-A
                Award Recipient :
                The KORA research platform and the KORA Augsburg studies are financed by the Helmholtz Zentrum Muenchen, German Research Centre for Environmental Health which is funded by the German Federal Ministry of Science and Research (Berlin, Germany) and by the State of Bavaria (Germany). The study was further supported by the Deutsche Forschungsgemeinschaft (LU 562/3-1, Germany) and the Competence Network of Heart Failure (BMBF-01GI0205, Germany). Roche Diagnostics has provided kits for assessment of NT-proBNP free of charge, but it did not play a role in the study design, in the collection, analysis, and interpretation of data, in the writing of the manuscript or in the decision to submit the manuscript for publication.
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