Growth differentiation factor 15 in heart failure with preserved vs. reduced ejection fraction.
OBJECTIVE
Growth differentiation factor 15 (GDF15) is a cytokine highly expressed in states of inflammatory stress. We aimed to study the clinical correlates and prognostic significance of plasma GDF15 in heart failure with preserved ejection fraction (HFpEF) vs. reduced ejection fraction(HFrEF), compared with N-terminal pro-brain natriuretic peptide (NT-proBNP), an indicator of haemodynamic wall stress.


METHODS
Plasma GDF15 and NT-proBNP were prospectively measured in 916 consecutive patients with HFrEF (EF <50%; n = 730) and HFpEF (EF ≥50%; n = 186), and measured again at 6 months in 488 patients. Patients were followed up for a composite outcome of death or first HF rehospitalization.


RESULTS
Median GDF15baseline values were similarly elevated in HFpEF [2862 (1812 represent the 25th percentile and 4176 represent the 75th percentile) ng/L] and HFrEF [2517 (1555, 4030) ng/L] (P = 0.184), whereas NT-proBNP was significantly lower in HFpEF than HFrEF (1119 ng/L vs. 2335 ng/L, P < 0.001). Independent correlates of GDF15baseline were age, systolic blood pressure, New York Heart Association (NYHA) class, diabetes, atrial fibrillation, sodium, haemoglobin, creatinine, diuretic therapy, high sensitivity troponin T (hsTnT) and NT-proBNP (all P < 0.05). During a median follow-up of 23 months, there were 379 events (307 HFrEF, 72 HFpEF). GDF15 remained a significant independent predictor for composite outcome even after adjusting for important clinical predictors including hsTnT and NT-proBNP (adjusted hazard ratio 1.76 per 1 Ln U, 95% confidence interval 1.39-2.21; P < 0.001), regardless of HF group (Pinteraction  = 0.275). GDF15baseline provided incremental prognostic value when added to clinical predictors, hsTnT and NT-proBNP (area under receiver operating characteristic curve increased from 0.720 to 0.740, P < 0.019), with a net reclassification improvement of 0.183 (P = 0.004). Patients with ≥20% GDF156months increase had higher risk for composite outcome (adjusted hazard ratio 1.68, 95% confidence interval 1.15-2.45; P = 0.007) compared with those with GDF156months within ± 20% of baseline.


CONCLUSIONS
The similarly elevated levels and independent prognostic utility of GDF15 in HFrEF and HFpEF suggest that beyond haemodynamic stress (NT-proBNP), inflammatory injury (GDF15) may play an important role in both HF syndromes.
SingHealth Internal Medicine Residency Program, Singapore Health Services, Singapore.
Michelle M Y
MM
Chan
Department of Medicine, Section of Cardiovascular Medicine, Boston University, Boston, MA, USA.
Rajalakshmi
R
Santhanakrishnan
Cardiovascular Research Institute, National University of Singapore, Singapore.
Jenny P C
JP
Chong
Investigational Medicine Unit, National University Health System Singapore, Singapore.
Zhaojin
Z
Chen
Saw Swee Hock School of Public Health, National University of Singapore, Singapore.
Bee Choo
BC
Tai
Cardiovascular Research Institute, National University of Singapore, Singapore.
Oi Wah
OW
Liew
Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Tze Pin
TP
Ng
Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Lieng H
LH
Ling
National Heart Centre Singapore, Singapore.
David
D
Sim
Changi General Hospital, Singapore.
Kui Toh G
KT
Leong
Tan Tock Seng Hospital and Apex Heart Clinic, Gleneagles Hospital, Singapore.
Poh Shuan Daniel
PS
Yeo
Khoo Teck Puat Hospital, Singapore.
Hean-Yee
HY
Ong
Singapore General Hospital and Duke-NUS Graduate Medical School, Singapore.
Fazlur
F
Jaufeerally
National University Heart Centre Singapore, Singapore.
Raymond Ching-Chiew
RC
Wong
National University Heart Centre Singapore, Singapore.
Ping
P
Chai
Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Adrian F
AF
Low
Cardiovascular Research Institute, National University of Singapore, Singapore.|Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Arthur M
AM
Richards
Cardiovascular Research Institute, National University of Singapore, Singapore.|Yong Loo Lin School of Medicine, National University of Singapore, Singapore.|Christchurch Heart Institute, University of Otago, Christchurch, New Zealand.
Carolyn S P
CS
Lam
D000368:Aged; D015415:Biomarkers / Q000097:blood; D005260:Female; D055436:Growth Differentiation Factor 15 / Q000097:blood*; D006333:Heart Failure / Q000097:blood / Q000175:diagnosis / Q000453:epidemiology / Q000503:physiopathology; D006801:Humans; D007249:Inflammation / Q000097:blood; D008297:Male; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain / Q000097:blood; D010359:Patient Readmission / Q000706:statistics & numerical data; D010446:Peptide Fragments / Q000097:blood; D011379:Prognosis; D016016:Proportional Hazards Models; D012372:ROC Curve; D012846:Singapore / Q000453:epidemiology; D013318:Stroke Volume; D016019:Survival Analysis
D015415:Biomarkers; D055436:Growth Differentiation Factor 15; D010446:Peptide Fragments; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain
Growth differentiation factor 15; Heart failure with preserved ejection fraction; Natriuretic peptides; Prognosis