Physicians' Academy for Cardiovascular Education

Biomarker measurements improve the stratification of adults with congenital heart disease

Baggen VJM, et al, Circulation, 2016

Prognostic Value of N-Terminal Pro-B-Type Natriuretic Peptide, Troponin-T, and Growth-Differentiation Factor 15 in Adult Congenital Heart Disease


Baggen VJM, van den Bosch AE, Eindhoven JA, et al.
Circulation 2016; published online ahead of print
 

Background

In the last 50 years, surgical treatment of children with congenital heart disease has improved substantially, and approximately 90% of them survive into adulthood [1]. As a consequence, the number of patients with adult congenital heart disease (ACHD) is increasing, and most of them have residual cardiac abnormalities, as well as an increased risk for heart failure (HF) and arrhythmias [2]. Little is available for the timely identification of disease progression in these patients [3]. On the other hand, there are data supporting that natriuretic peptides, high-sensitive troponin-T (hs-TnT) and growth-differentiation factor- 15 (GDF-15) levels are related to intermediate prognostic markers, such as ventricular function or exercise capacity, in ACHD patients [4-6].
 
In this prospective study, the association between circulating concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP), hs-TnT and GDF-15 and the composite endpoint of CV events was evaluated in a large cohort of stable patients with ACHD (n=593).
 

Main results

During a median follow-up period of 41.8 (IQR: 36.6-46.1) months:
  • The primary composite endpoint of a CV event occurred in 165 patients (28%).
  • The secondary composite endpoint of death or HF occurred in 50 patients (8%).
  • Kaplan-Meier estimates of event-free survival were 87% at year one, 79% at year two and 74% at year three.
  • HF-free survival was 96% at year one, 94% at year two and 92% at year three.
 
Biomarkers and clinical outcomes:
  • In patients with a NT-proBNP level below the median (<15.2 pmol/L) the cumulative proportion of death and HF was 1%. Crude HR for 4th quartile for primary endpoint was 7.31 (95% CI: 4.35-12.3) compared to 1st quartile, and was for secondary endpoint 44.7 (95% CI: 6.14-326). P trend all quartiles for both endpoints < 0.001, which remained similar after adjustment.
  • The risk of the primary and secondary composite endpoint for patients in the fourth hs-TnT quartile (>7.7 ng/L) was significantly higher compared with the risk for patients in the first quartile (<3 ng/L): primary endpoint 4th quartile crude HR was 3.27 (95% CI: 2.15-4.97) compared to 1st quartile, secondary endpoint 4th quartile crude HR was 25.3 (95% CI: 6.05-106). P trend all quartiles for both endpoints < 0.001. For the primary endpoint, this was not significant anymore after adjustment (P trend = 0.191), although the secondary endpoint remained significant (P trend <0.001).
  • Patients in the 4th GDF-15 quartile (>867 ng/L) had a significantly higher risk of the primary and secondary composite endpoint compared with the risk for patients in the 1st quartile (<487 ng/L): primary endpoint 4th quartile crude HR was 3.63 (95% CI: 2.26-5.84) compared to 1st quartile, secondary endpoint 4th quartile crude HR was 33.7 (95% CI: 4.60-247), P trend all quartiles for both endpoints < 0.001. This remained significant after adjustment (P trend = 0.007 and 0.001 resp.)
  • Patients with elevated levels of all three biomarkers were at highest risk (CV event-free survival at the end of follow-up was 27%, HF-free survival 51%) and hs-TnT and GDF-15 levels could further discriminate between higher of lower risk.
  • When all three biomarkers were analysed as logarithmically transformed continuous variables in a multivariable model, one standard deviation increase in NT-proBNP (adjusted HR: 1.85; 95% CI: 1.51-2.25; P < 0.001) and GDF-15 (adjusted HR: 1.20; 95% CI: 1.04-1.40; P = 0.014) was independently associated with the primary endpoint, hs-TnT was not (adjusted HR: 1.09; 95% CI: 0.93-1.29; P = 0.286).
 
C-indexes of risk marker models for the primary endpoint:
  • Clinical variables only: C-index of 0.69; 95% CI: 0.64-0.73.
  • Clinical plus ECG plus echocardiography variables: C-index of 0.74; 95% CI: 0.70-0.79.
  • Clinical plus biomarker variables: C-index of 0.74; 95% CI: 0.66-0.82.
  • Full model including all variables: C-index of 0.80; 95% CI: 0.74-0.87.
 

Conclusion

In ACHD patients, NT-proBNP was strongly associated with CV events and particularly patients with a low risk of death and HF could be accurately identified with the lowest NT-proBNP levels (<15.2 pmol/L). In ACHD patients with high NT-proBNP levels, hs-TnT and GDF-15 levels could further discriminate patients at highest risk of CV events and patients with high levels of all biomarkers were at highest risk. These data support the use of these biomarkers for the optimisation of follow-up and management strategies in patients with ACHD.
 
Find this article online at Circulation
 

References

1. Tennant PW, Pearce MS, Bythell M, et al. 20-year survival of children born with congenital anomalies: a population-based study. Lancet. 2010;375:649-56.
2. Kantor PF and Redington AN. Pathophysiology and management of heart failure in repaired congenital heart disease. Heart Fail Clin. 2010;6:497-506.
3. Moons P, Engelfriet P, Kaemmerer H, et al, and Expert Committee of Euro Heart Survey on Adult Congenital Heart D. Delivery of care for adult patients with congenital heart disease in Europe: results from the Euro Heart Survey. Eur Heart J. 2006;27:1324-30.
4. Eindhoven JA, van den Bosch AE, Ruys TP, et al. N-terminal pro-B-type natriuretic peptide and its relationship with cardiac function in adults with congenital heart disease. J Am Coll Cardiol. 2013;62:1203-12.
5. Eindhoven JA, Roos-Hesselink JW, van den Bosch AE, et al. High-sensitive troponin-T in adult congenital heart disease. Int J Cardiol. 2015;184:405-11.
6. Eindhoven JA, van den Bosch AE, Oemrawsingh RM, et al. Release of growth differentiation factor 15 and associations with cardiac function in adult patients with congenital heart disease. Int J Cardiol. 2016;202:246-51.