Prognostic Value of N-Terminal Pro-B-Type Natriuretic Peptide, Troponin-T, and Growth-Differentiation Factor 15 in Adult Congenital Heart Disease.
BACKGROUND
The number of patients with adult congenital heart disease (ACHD) is rapidly increasing. To optimize patient management, there is a great need to accurately identify high-risk patients. Still, no biomarker has been firmly established as a clinically useful prognostic tool in this group. We studied the association of N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitive troponin-T, and growth-differentiation factor 15 with cardiovascular events in ACHD.


METHODS
Clinically stable patients with ACHD who routinely visited the outpatient clinic between April 2011 and April 2013 underwent clinical assessment, electrocardiography, echocardiography, and biomarker measurement (NT-proBNP, high-sensitive troponin-T, and growth-differentiation factor 15) at the time of study inclusion. Patients were prospectively followed for the occurrence of cardiovascular events (death, heart failure, hospitalization, arrhythmia, thromboembolic events, and reintervention). Survival curves were derived by the Kaplan-Meier method, and Cox regression was performed to investigate the relation between biomarkers and events with adjustment for multiple clinical and echocardiographic variables.


RESULTS
In total, 595 patients were included (median age, 33 years; interquartile range, 25-41 years; 58% male; 90% New York Heart Association class I). Patients were followed during a median of 42 (interquartile range, 37-46) months. Of the 3 evaluated biomarkers, NT-proBNP in the upper quartile (>33.3 pmol/L) was most strongly associated with cardiovascular events (n=165, adjusted hazard ratio, 9.05 [3.24-25.3], P<0.001) and with death or heart failure (n=50, adjusted hazard ratio, 16.0 [2.04-126], P<0.001). When NT-proBNP was analyzed as a continuous variable, similar findings were retrieved. The cumulative proportion of patients with death and heart failure was only 1% in the lowest 2 NT-proBNP quartiles. Elevated NT-proBNP (>14 pmol/L), elevated high-sensitive troponin-T (>14 ng/L), and elevated growth-differentiation factor 15 (>1109 ng/L) identified those patients at highest risk of cardiovascular events (log-rank P<0.0001).


CONCLUSIONS
NT-proBNP provides prognostic information beyond a conventional risk marker model in patients with ACHD and can reliably exclude the risk of death and heart failure. Elevated levels of NT-proBNP, high-sensitive troponin-T, and growth-differentiation factor 15 identify patients at highest risk of cardiovascular events. These biomarkers therefore may play an important role in the monitoring and management of patients with ACHD.
From Department of Cardiology, Erasmus Medical Center, Rotterdam, the Netherlands (V.J.M.B., A.E.v.d.B., J.A.E., A.-R.W.S., J.A.A.E.C., M.W., F.Z., E.B., J.W.R.-H.); Cardiovascular Research School COEUR, Rotterdam, the Netherlands (V.J.M.B., J.A.E., E.B.); Department of Clinical Chemistry, Erasmus Medical Center, Rotterdam, the Netherlands (M.d.W., R.H.N.v.S.); and Department of Clinical Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands (E.B.).
Vivan J M
VJ
Baggen
From Department of Cardiology, Erasmus Medical Center, Rotterdam, the Netherlands (V.J.M.B., A.E.v.d.B., J.A.E., A.-R.W.S., J.A.A.E.C., M.W., F.Z., E.B., J.W.R.-H.); Cardiovascular Research School COEUR, Rotterdam, the Netherlands (V.J.M.B., J.A.E., E.B.); Department of Clinical Chemistry, Erasmus Medical Center, Rotterdam, the Netherlands (M.d.W., R.H.N.v.S.); and Department of Clinical Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands (E.B.).
Annemien E
AE
van den Bosch
From Department of Cardiology, Erasmus Medical Center, Rotterdam, the Netherlands (V.J.M.B., A.E.v.d.B., J.A.E., A.-R.W.S., J.A.A.E.C., M.W., F.Z., E.B., J.W.R.-H.); Cardiovascular Research School COEUR, Rotterdam, the Netherlands (V.J.M.B., J.A.E., E.B.); Department of Clinical Chemistry, Erasmus Medical Center, Rotterdam, the Netherlands (M.d.W., R.H.N.v.S.); and Department of Clinical Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands (E.B.).
Jannet A
JA
Eindhoven
From Department of Cardiology, Erasmus Medical Center, Rotterdam, the Netherlands (V.J.M.B., A.E.v.d.B., J.A.E., A.-R.W.S., J.A.A.E.C., M.W., F.Z., E.B., J.W.R.-H.); Cardiovascular Research School COEUR, Rotterdam, the Netherlands (V.J.M.B., J.A.E., E.B.); Department of Clinical Chemistry, Erasmus Medical Center, Rotterdam, the Netherlands (M.d.W., R.H.N.v.S.); and Department of Clinical Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands (E.B.).
Anne-Rose W
AW
Schut
From Department of Cardiology, Erasmus Medical Center, Rotterdam, the Netherlands (V.J.M.B., A.E.v.d.B., J.A.E., A.-R.W.S., J.A.A.E.C., M.W., F.Z., E.B., J.W.R.-H.); Cardiovascular Research School COEUR, Rotterdam, the Netherlands (V.J.M.B., J.A.E., E.B.); Department of Clinical Chemistry, Erasmus Medical Center, Rotterdam, the Netherlands (M.d.W., R.H.N.v.S.); and Department of Clinical Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands (E.B.).
Judith A A E
JA
Cuypers
From Department of Cardiology, Erasmus Medical Center, Rotterdam, the Netherlands (V.J.M.B., A.E.v.d.B., J.A.E., A.-R.W.S., J.A.A.E.C., M.W., F.Z., E.B., J.W.R.-H.); Cardiovascular Research School COEUR, Rotterdam, the Netherlands (V.J.M.B., J.A.E., E.B.); Department of Clinical Chemistry, Erasmus Medical Center, Rotterdam, the Netherlands (M.d.W., R.H.N.v.S.); and Department of Clinical Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands (E.B.).
Maarten
M
Witsenburg
From Department of Cardiology, Erasmus Medical Center, Rotterdam, the Netherlands (V.J.M.B., A.E.v.d.B., J.A.E., A.-R.W.S., J.A.A.E.C., M.W., F.Z., E.B., J.W.R.-H.); Cardiovascular Research School COEUR, Rotterdam, the Netherlands (V.J.M.B., J.A.E., E.B.); Department of Clinical Chemistry, Erasmus Medical Center, Rotterdam, the Netherlands (M.d.W., R.H.N.v.S.); and Department of Clinical Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands (E.B.).
Monique
M
de Waart
From Department of Cardiology, Erasmus Medical Center, Rotterdam, the Netherlands (V.J.M.B., A.E.v.d.B., J.A.E., A.-R.W.S., J.A.A.E.C., M.W., F.Z., E.B., J.W.R.-H.); Cardiovascular Research School COEUR, Rotterdam, the Netherlands (V.J.M.B., J.A.E., E.B.); Department of Clinical Chemistry, Erasmus Medical Center, Rotterdam, the Netherlands (M.d.W., R.H.N.v.S.); and Department of Clinical Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands (E.B.).
Ron H N
RH
van Schaik
From Department of Cardiology, Erasmus Medical Center, Rotterdam, the Netherlands (V.J.M.B., A.E.v.d.B., J.A.E., A.-R.W.S., J.A.A.E.C., M.W., F.Z., E.B., J.W.R.-H.); Cardiovascular Research School COEUR, Rotterdam, the Netherlands (V.J.M.B., J.A.E., E.B.); Department of Clinical Chemistry, Erasmus Medical Center, Rotterdam, the Netherlands (M.d.W., R.H.N.v.S.); and Department of Clinical Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands (E.B.).
Felix
F
Zijlstra
From Department of Cardiology, Erasmus Medical Center, Rotterdam, the Netherlands (V.J.M.B., A.E.v.d.B., J.A.E., A.-R.W.S., J.A.A.E.C., M.W., F.Z., E.B., J.W.R.-H.); Cardiovascular Research School COEUR, Rotterdam, the Netherlands (V.J.M.B., J.A.E., E.B.); Department of Clinical Chemistry, Erasmus Medical Center, Rotterdam, the Netherlands (M.d.W., R.H.N.v.S.); and Department of Clinical Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands (E.B.).
Eric
E
Boersma
From Department of Cardiology, Erasmus Medical Center, Rotterdam, the Netherlands (V.J.M.B., A.E.v.d.B., J.A.E., A.-R.W.S., J.A.A.E.C., M.W., F.Z., E.B., J.W.R.-H.); Cardiovascular Research School COEUR, Rotterdam, the Netherlands (V.J.M.B., J.A.E., E.B.); Department of Clinical Chemistry, Erasmus Medical Center, Rotterdam, the Netherlands (M.d.W., R.H.N.v.S.); and Department of Clinical Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands (E.B.). j.roos@erasmusmc.nl.
Jolien W
JW
Roos-Hesselink
D000328:Adult; D015331:Cohort Studies; D004452:Echocardiography / Q000379:methods*; D005260:Female; D055436:Growth Differentiation Factor 15 / Q000378:metabolism*; D006330:Heart Defects, Congenital / Q000097:blood*; D006801:Humans; D008297:Male; D020097:Natriuretic Peptide, Brain / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism*; D011379:Prognosis; D011446:Prospective Studies; D020107:Troponin T / Q000378:metabolism*
C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; D010446:Peptide Fragments; D020107:Troponin T; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain
biomarkers; congenital heart disease; intercellular signaling peptides and proteins; pro-brain natriuretic peptide (1-76); troponin