Association of blood biomarkers with cardiovascular and kidney adverse outcomes in people with heart failure with preserved ejection fraction

Greater than 50% of people with chronic kidney disease have left ventricular hypertrophy and are at risk for developing heart failure with preserved ejection fraction (HFpEF). Up to 56% of those with HF suffer from kidney function decline estimated using glomerular filtration rate (GFR). Worsening kidney function itself leads to worse cardiovascular (CV) outcomes, creating a deleterious cycle. Early biomarkers to accurately identify which individuals are at risk for both adverse CV outcomes and GFR decline are lacking.

We aimed to identify candidate circulating proteins that would be associated with (a) composite of CV death, HF hospitalization, or aborted cardiac arrest, (b) decline in GFR, and (c) whether treatment with spironolactone vs. placebo would ameliorate the association.

We analyzed baseline serum levels of 92 candidate serum biomarkers using Olink proteomics in 214 participants with HFpEF from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial, a double-blind randomized trial to evaluate whether spironolactone reduced the incidence of the CV composite. GFR was determined using a combination of serum creatinine and cystatin C measurements using the 2021 CKDEPI equation. Multivariable Cox proportional hazards were used to test the association of the proteins with the CV composite, adjusted for race and diabetes mellitus. Linear mixed-effects models stratified by treatment group and adjusted for age, sex, diabetes mellitus, NYHA class, BMI, and protein x treatment interaction were used to test the association between change in protein level and change in GFR from baseline to 12 months. P for interaction <0.1 was considered significant.

Doubling of 4 proteins was associated with the CV composite [HR (95% CI)]: EPHB4 [2.64 (1.40, 4.97)]; LTBR [2.47 (1.26, 4.85)]; PLC [3.49 (1.68, 7.25)]; TFF3 [2.52 (1.70, 3.73)], in adjusted models (Table). Increase in 6 biomarker levels from baseline to 12 months was associated with a GFR decline [(mL/min/1.73 m²) (95% CI)]: CCL16 [-6.4 (-8.7, -4.0)]; EPHB4 [-10.0 (-13.0, -7.1)]; IGFBP7) [-6.8 (-9.2, -4.3)]; LTBR [-11.7 (-14.7, -8.7)]; PLC [-9.1 (-11.6, -6.7)]; TFF3 [-11.2 (-13.5, -8.9)], in adjusted models (Table). The magnitude of GFR decline from baseline to 12 months was greater in those assigned to placebo vs. spironolactone, though this did not reach statistical significance for all 6 biomarkers (Table and Figure).

We identified 6 circulating biomarkers associated with adverse CV and kidney outcomes in HFpEF. Although the interaction term of protein x treatment did not reach statistical significance for all biomarkers, likely due to sample size, there was a trend in the magnitude of association such that spironolactone may attenuate decline in GFR. These proteins should be studied in larger populations as early biomarkers of risk for both CV and kidney outcomes in people with HF.TableFigure