Author + information
- Received January 16, 2011
- Revision received February 16, 2011
- Accepted March 7, 2011
- Published online July 19, 2011.
- Bonnie Ky, MD, MSCE⁎,†,⁎ (, )
- Benjamin French, PhD⁎,†,
- Kosha Ruparel, MS†,
- Nancy K. Sweitzer, MD, PhD‡,
- James C. Fang, MD§,
- Wayne C. Levy, MD∥,
- Douglas B. Sawyer, MD, PhD¶ and
- Thomas P. Cappola, MD, ScM⁎,⁎ ()
- ↵⁎Reprint requests and correspondence:
Dr. Bonnie Ky or Dr. Thomas P. Cappola, 3400 Spruce Street, 9054 Gates 34th and Civic Center Boulevard, 2PCAM, Philadelphia, Pennsylvania 19104
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.
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.
- Received January 16, 2011.
- Revision received February 16, 2011.
- Accepted March 7, 2011.
- American College of Cardiology Foundation