Circulating Biomarkers Identified for the Prognosis of Heart Failure With Preserved Ejection Fraction

gloved hand holding test tubes, biomarkers
Levels of a set of circulating biomarkers were found to be elevated in patients with HFpEF.

Levels of a set of circulating biomarkers indicative of extracellular matrix homeostasis were found to be elevated in patients with heart failure (HF) with preserved ejection fraction (EF; HFpEF), and were reduced after treatment with sacubitril/valsartan, according to results of a multicenter, double-blind, randomized clinical trial published in the Journal of the American College of Cardiology.

In this study, data from the Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction trial, in which patients from North America, Europe, Asia, and Latin America with chronic HF with HFpEF were randomly assigned 1:1 to receive sacubitril/valsartan or valsartan alone, were analyzed. Eligible participants (n=1135) were >50 years, had signs and symptoms of HF,  New York Heart Association functional classes II to IV, left ventricular ejection fraction (LVEF) ≥45%, and structural heart disease. In addition, participants had to be on diuretic therapy, and had recently been hospitalized for HF. The study’s primary endpoint was a composite of hospitalizations for HF and cardiovascular death.

The levels of biomarkers N-terminal propeptide of collagen I (PINP) and III (PIIINP), tissue inhibitor of matrix metalloproteinase 1 (TIMP-1), carboxyl-terminal telopeptide of collagen type I (CITP), and soluble suppressor of tumorigenicity 2 (sST2) were measured at baseline and 48 weeks.

The 2 treatment groups were well-balanced for all demographic, regional distribution, comorbidities, heart health characteristics, and prescribed medications at baseline, but not for the number of previous strokes (P =.007) and the presence of hypertension (P =.017).

The median levels of biomarkers examined at baseline were: sST2, 24 ng/mL (interquartile range [IQR], 19-29 ng/mL); TIMP-1, 129 ng/mL (IQR, 108-156 ng/mL); PINP, 38 ng/mL (IQR, 29-51 ng/mL); PIIINP, 4.4 ng/mL (IQR, 3.6-5.5 ng/mL); and CITP, 6.0 ng/mL (IQR, 4.7-8.0 ng/mL).

After 16 weeks of treatment participants assigned sacubitril/valsartan vs valsartan alone had reductions in: TIMP-1, 8% (95% CI, 6%-10%; P <.001); sST2, 4% (95% CI, 1%-7%; P =.002); and PIIINP, 3% (95% CI, 0%-6%; P =.04), and an increase in CITP (4%; 95% CI, 1%-8%; P =.02). At the 48-week follow-up, the reductions in TIMP-1 and sST2 were maintained among participants taking sacubitril/valsartan.

Cardiovascular death and total HF hospitalizations were increased in patients with higher levels of TIMP-1, sST2, PIIINP, and CITP (P <.001 for all) in an unadjusted analysis. However, after adjusting for baseline clinical covariates and the other 4 biomarkers examined, TIMP-1 was the only biomarker whose increased levels remained associated with a greater risk for the primary endpoint relative risk ratio, 1.36 (95% CI, 1.15-1.61; P <.001).

A study limitation is that although sST2 and PINP biomarkers have been approved by the United States Food and Drug Administration for the use in medical practice, TIMP-1, PIIINP, and CITP have only been indicated for research use, making their applicability in a clinical setting uncertain.

“[T]hese data suggest that biomarkers reflecting [extracellular matrix] homeostasis are elevated in HFpEF, altered by sacubitril/valsartan, and have important prognostic value,” concluded the study authors.


Cunningham J W, Claggett B L, O’Meara, et al. Effect of Sacubitril/Valsartan on Biomarkers of Extracellular Matrix Regulation in Patients With HFpEF. J Am Coll Cardiol. 2020;76(5):503-14.