Clinical Research
Heart Failure
The Vascular Marker Soluble Fms-Like Tyrosine Kinase 1 Is Associated With Disease Severity and Adverse Outcomes in Chronic Heart Failure

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Objectives

We sought to evaluate placental growth factor (PlGF) and soluble Fms-like tyrosine kinase 1 (sFlt-1) as clinical biomarkers in chronic heart failure (HF).

Background

Vascular remodeling is a crucial compensatory mechanism in chronic HF. The angiogenic ligand PlGF and its target receptor fms-like tyrosine kinase 1 modulate vascular growth and function, but their relevance in human HF is undefined.

Methods

We measured plasma PlGF and sFlt-1 in 1,403 patients from the Penn Heart Failure Study, a multicenter cohort of chronic systolic HF. Subjects were followed for death, cardiac transplantation, or ventricular assist device placement over a median follow-up of 2 years.

Results

The sFlt-1 was independently associated with measures of HF severity, including New York Heart Association functional class (p < 0.01) and B-type natriuretic peptide (p < 0.01). Patients in the 4th quartile of sFlt-1 (>379 pg/ml) had a 6.17-fold increased risk of adverse outcomes (p < 0.01). This association was robust, even after adjustment for the Seattle Failure Model (hazard ratio: 2.54, 95% confidence interval [CI]: 1.76 to 2.27, p < 0.01) and clinical confounders including HF etiology (hazard ratio: 1.67, 95% CI: 1.06 to 2.63, p = 0.03). Combined assessment of sFlt-1 and B-type natriuretic peptide exhibited high predictive accuracy at 1 year (area under the receiver-operator characteristic curve: 0.791, 95% CI: 0.752 to 0.831) that was greater than either marker alone (p < 0.01 and p = 0.03, respectively). In contrast, PlGF was not an independent marker of disease severity or outcomes.

Conclusions

Our findings support a role for sFlt-1 in the biology of human HF. With additional study, circulating sFlt-1 might emerge as a clinically useful biomarker to assess the influence of vascular remodeling on clinical outcomes.

Key Words

heart failure
placental growth factor
soluble Flt-1

Abbreviations and Acronyms

AUC
area under the receiver-operator characteristic curve
BNP
B-type natriuretic peptide
CI
confidence interval
CV
coefficients of variation
eGFR
estimated glomerular filtration rate
HF
heart failure
HR
hazard ratio
MI
myocardial infarction
NYHA
New York Heart Association
PlGF
placental growth factor
ROC
receiver-operator characteristic
sFlt-1
soluble Fms-like tyrosine kinase receptor 1
VAD
ventricular assist device
VEGF
vascular endothelial growth factor

Cited by (0)

Dr. Ky was supported by the National Institutes of Health (NIH)/Clinical and Translational Science Award KL1 RR024132, NIH K23 HL095661-01, and the Heart Failure Society of America Research Fellowship Award. This work was also supported by NIH HL088577 (Dr. Cappola). Assay support was provided by Abbott Diagnostics. Neither the funding organizations nor Abbott Diagnostics had any role in the design or conduct of the study; collection, management, analysis, or interpretation of the data; or preparation, review, or approval of the manuscript. Dr. Levy has received research support from Thoratec, General Electric, and Heartware; has received honoraria from GlaxoSmithKline and Boehringer Ingelheim; has licensing with the ACC Toolkit, Epocrates, and Seattle Heart Failure Model; has served on the Steering Committee of Amgen and Scios; has served on the Clinical Endpoint Committee of Cardiomems; and has done consulting with stock options for Cardiac Dimensions. Dr. Cappola reports receiving research support from Abbott Diagnostics. Drs. Ky and Cappola are co-inventors on a pending intellectual property application for the use of sFlt-1 as a biomarker in heart failure. All other authors have reported that they have no relationships to disclose.