GDF-15, MRproADM, CTproET1 und CTproAVP bei Patienten mit asymptomatischer diastolischer Dysfunktion

Zusammenfassung

Hintergrund und Fragestellung | Die Rolle von Biomarkern bei asymptomatischer diastolischer Dysfunktion (DD) ist bislang wenig untersucht. Die vorliegende Arbeit untersuchte daher die klinischen Assoziationen und diagnostischen Fähigkeiten verschiedener Biomarker bei asymptomatischer DD.

Methodik | 188 gesunde Probanden (linksventrikuläre Ejektionsfraktion ≥ 50 %, 50–85 Jahre) ohne kardiovaskuläre Risikofaktoren wurden prospektiv im Rahmen einer bevölkerungsbasierten Beobachtungsstudie rekrutiert. Von diesen hatten n = 103 eine echokardiografisch definierte DD (Grad ≥ 1), n = 85 Patienten ohne DD wurden dem Kontrollkollektiv (KON) zugeordnet.

• Anamnese,

• körperliche Untersuchung,

• 6-Minuten-Gehtest,

• Lebensqualitätserhebung (Short Form Health Survey: SF-36-Fragebogen),

• EKG,

• transthorakale Echokardiografie sowie

• Blutentnahmen zur Erfassung von Routineparametern und Biomarkern

  • GDF-15,

  • NTproBNP,

  • MRproANP,

  • MRproADM,

  • CTproET1,

  • CTproAVP

wurden standardisiert durchgeführt.

Ergebnisse | GDF-15, MRproADM und CTproAVP waren in der DD-Gruppe im Vergleich zur Kontrollgruppe signifikant erhöht:

• GDF-15 (p = 0,002),

• NTproBNP (p = 0,390),

• MRproANP (p = 287),

• MRproADM (p < 0,001),

• CTproET1 (p = 0,393) und

• CTproAVP (p = 0,003).

Es zeigte sich für GDF-15, MRproADM und CTproAVP eine signifikante Assoziation zum Vorliegen einer DD (Grad ≥ 1). Diese Assoziationen waren jedoch nach multipler Adjustierung nicht mehr nachweisbar. Zum linksventrikulären Füllungsindex (E / e’) als kontinuierlichen Parameter der diastolischen Funktion zeigten NTproBNP, MRproANP, MRproADM, nicht aber GDF-15, CTproET1 und CTproAVP signifikante bivariate Korrelationen. Diese Assoziationen waren nach multipler Adjustierung nicht mehr nachweisbar. Keiner der untersuchten Biomarker zeigte in den ROC-Analysen eine ausreichende Diskriminationsfähigkeit zur Unterscheidung zwischen DD und gesunden Probanden.

Folgerungen | Im Gegensatz zu NTproBNP, MRproANP und CTproET1 waren die Plasmakonzentrationen von GDF-15, MRproADM und CT-proAVP bei Probanden mit einer DD im Vergleich zur Kontrollgruppe signifikant erhöht. Nach Adjustierung für Alter, Geschlecht, BMI und GFR war der Zusammenhang der Biomarker zur DD und zu E / e’ nicht mehr nachweisbar. Keiner der untersuchten Biomarker zeigte eine ausreichende diskriminatorische Fähigkeit zur Detektion einer DD.

Abstract

Background: The role of biomarkers in asymptomatic diastolic dysfunction (DD) has not been investigated so far. The aim of the study was to evaluate the clinical associations and the diagnostic property of different biomarkers in patients with asymptomatic DD.

Methods: Within a population based observational study, healthy participants (50–85 years) with an LVEF ≥ 50 % and no cardiovascular risk factor were prospectively identified. Patients were classified as having either DD (grade ≥ 1, n = 103) or no DD (CON: n = 85). All patients underwent physical examination including medical history, six-minute-walk-testing, QoL (SF-36), comprehensive echocardiography and blood sampling to measure routine values and specified biomarkers (NTproBNP, MRproANP, GDF-15, MRproADM, CTproET1, CTproAVP).

Results: In the DD-group plasma concentration of GDF-15 (p = 0,002), MRproADM (p < 0,001), and CTproAVP (p = 0,003) were significantly higher than in the CON-group. In contrast, NTproBNP (p = 0,390), MRproANP (p = 287), and CTproET1 (p = 0,393) did not differ. GDF-15, MRproADM and CTproAVP were significantly associated with the presence of DD. However, the significance of the seen associations was lost after multiple adjustments. NTproBNP, MRproANP, and MRproADM were significantly related to E / e’ as a continuous measure of diastolic function. The significance of the seen associations was lost after multiple adjustments. In ROC analyses, none of the investigated biomarkers was able to relevantly improve the diagnosis of DD.

Conclusion: In patients with asymptomatic DD plasma concentrations of GDF-15, MRproADM and CT-proAVP were significantly higher when compared with controls. In contrast, NTproBNP, MRproANP and CTproET1 did not differ. After adjustment for age, sex, BMI and renal function, no significant association between DD or E / e’ and different biomarkers could be observed. Furthermore, none of the investigated biomarkers was able to substantially improve the diagnosis of DD.

Schlüsselwörter

Diastolische Dysfunktion - Biomarker

Keywords

Diastolic dysfunction - biomarkers

• Literatur

• 1 Bhatia RS, Tu JV, Lee DS et al. Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med 2006; 355: 260-269
• 2 Braunwald E. Biomarkers in heart failure. N Engl J Med 2008; 358: 2148-2159
• 3 Bursi F, Weston SA, Redfield MM et al. Systolic and diastolic heart failure in the community. JAMA 2006; 296: 2209-2216
• 4 Cheung BM, Li CY, Wong LY. Adrenomedullin: its role in the cardiovascular system. Semin Vasc Med 2004; 4: 129-134
• 5 Cozza EN, Gomez-Sanchez CE, Foecking MF, Chiou S. Endothelin binding to cultured calf adrenal zona glomerulosa cells and stimulation of aldosterone secretion. J Clin Invest 1989; 84: 1032-1035
• 6 Devereux RB, Alonso DR, Lutas EM et al. Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol 1986; 57: 450-458
• 7 Dinh W, Füth R, Lankisch M et al. Growth-differentiation factor-15: a novel biomarker in patients with diastolic dysfunction?. Arq Bras Cardiol 2011; 97: 65-75
• 8 Edelmann F, Gelbrich G, Düngen HD et al. Exercise training improves exercise capacity and diastolic function in patients with heart failure with preserved ejection fraction: results of the Ex-DHF (Exercise training in Diastolic Heart Failure) pilot study. J Am Coll Cardiol 2011; 58: 1780-1791
• 9 Edelmann F, Stahrenberg R, Polzin F et al. Impaired physical quality of life in patients with diastolic dysfunction associates more strongly with neurohumoral activation than with echocardiographic parameters: quality of life in diastolic dysfunction. Am Heart J 2011; 161: 797-804
• 10 Elmas E, Lang S, Dempfle CE et al. Diagnostic performance of mid-regional pro-adrenomedullin as an analyte for the exclusion of left ventricular dysfunction. Int J Cardiol 2007; 128: 107-111
• 11 Hanehira T, Kohno M, Yoshikawa J. Endothelin production in cultured vascular smooth muscle cells--modulation by the atrial, brain, and C-type natriuretic peptide system. Metabolism 1997; 46: 487-493
• 12 Hemsén A, Franco-Cereceda A, Matran R et al. Occurrence, specific binding sites and functional effects of endothelin in human cardiopulmonary tissue. Eur J Pharmacol 1990; 191: 319-328
• 13 Ishimitsu T, Ono H, Minami J, Matsuoka H. Pathophysiologic and therapeutic implications of adrenomedullin in cardiovascular disorders. Pharmacol Ther 2006; 111: 909-927
• 14 Kasner M, Westermann D, Steendijk P et al. Utility of Doppler echocardiography and tissue Doppler imaging in the estimation of diastolic function in heart failure with normal ejection fraction: a comparative Doppler-conductance catheterization study. Circulation 2007; 116: 637-647
• 15 Kempf T, Eden M, Strelau J et al. The transforming growth factor-beta superfamily member growth-differentiation factor-15 protects the heart from ischemia / reperfusion injury. Circ Res 2006; 98: 351-360
• 16 Kitzman DW, Little WC, Brubaker PH et al. Pathophysiological characterization of isolated diastolic heart failure in comparison to systolic heart failure. JAMA 2002; 288: 2144-2150
• 17 Lang RM, Bierig M, Devereux RB et al. Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005; 18: 1440-1463
• 18 Morgenthaler NG, Struck J, Alonso C, Bergmann A. Measurement of midregional proadrenomedullin in plasma with an immunoluminometric assay. Clin Chem 2005; 51: 1823-1829
• 19 Ommen SR, Nishimura RA, Appleton CP et al. Clinical utility of Doppler echocardiography and tissue Doppler imaging in the estimation of left ventricular filling pressures: A comparative simultaneous Doppler-catheterization study. Circulation 2000; 102: 1788-1794
• 20 Owan TE, Hodge DO, Herges RM et al. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 2006; 355: 251-259
• 21 Paulus WJ, Tschöpe C, Sanderson JE et al. How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology. Eur Heart J 2007; 28: 2539-2550
• 22 Redfield MM, Rodeheffer RJ, Jacobsen SJ et al. Plasma brain natriuretic peptide to detect preclinical ventricular systolic or diastolic dysfunction: a community-based study. Circulation 2004; 109: 3176-3181
• 23 Stahrenberg R, Edelmann F, Mende M et al. The novel biomarker growth differentiation factor 15 in heart failure with normal ejection fraction. Eur J Heart Fail 2010; 12: 1309-1316
• 24 Stoiser B, Mörtl D, Hülsmann M et al. Copeptin, a fragment of the vasopressin precursor, as a novel predictor of outcome in heart failure. Eur J Clin Invest 2006; 6: 771-778
• 25 Tschöpe C, Kasner M, Westermann D et al. The role of NT-proBNP in the diagnostics of isolated diastolic dysfunction: correlation with echocardiographic and invasive measurements. Eur Heart J 2005; 26: 2277-2284
• 26 Uraizee I, Cheng S, Hung CL et al. Relation of N-terminal pro-B-type natriuretic peptide with diastolic function in hypertensive heart disease. Am J Hypertens 2013; 26: 1234-1241
• 27 Vasan RS, Larson MG, Benjamin EJ et al. Congestive heart failure in subjects with normal versus reduced left ventricular ejection fraction: prevalence and mortality in a population-based cohort. J Am Coll Cardiol 1999; 33: 1948-1955
• 28 Wachter R, Lüers C, Kleta S et al. Impact of diabetes on left ventricular diastolic function in patients with arterial hypertension. Eur J Heart Fail 2007; 9: 469-476
• 29 Wang TJ, Larson MG, Levy D et al. Impact of age and sex on plasma natriuretic peptide levels in healthy adults. Am J Cardiol 2002; 90: 254-258
• 30 Xu J, Kimball TR, Lorenz JN et al. GDF15/MIC-1 functions as a protective and antihypertrophic factor released from the myocardium in association with SMAD protein activation. Circ Res 2006; 98: 342-350
• 31 Yu CM, Cheung BM, Leung R et al. Increase in plasma adrenomedullin in patients with heart failure characterised by diastolic dysfunction. Heart 2001; 6: 155-160
• 32 Zile MR, Baicu CF, Gaasch WH. Diastolic heart failure – abnormalities in active relaxation and passive stiffness of the left ventricle. N Engl J Med 2004; 350: 1953-1959
• 33 Redfield MM, Jacobsen SJ, Burnett Jr JC et al. Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic. JAMA 2003; 289: 194-202