Blood Biomarkers Associated with Adverse Outcomes in Heart Failure

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Project Abstract We aim to investigate which biomarkers are most useful in identifying increased risk for adverse cardiovascular (CV) and kidney outcomes in patients with heart failure with preserved ejection fraction (HFpEF) and with reduced ejection fraction (HFrEF). This is imperative because chronic kidney disease (CKD) is common among patients with heart failure and associated with adverse outcomes. Up to 56% of patients with heart failure suffer from kidney function decline, subsequently leading to worse CV outcomes, but biomarkers to accurately identify which patients are at risk for decline in kidney glomerular filtration rate (GFR) are lacking. This not only limits prognostication, but makes clinical decisions regarding eligibility of patients with HFrEF for advanced therapies very challenging. Kidney disease can be assessed using GFR, which can be estimated using serum creatinine (eGFRcr), cystatin C (eGFRcys), or a weighted average of the two (eGFRcr-cys). It is unknown whether eGFRcr, eGFRcys, or eGFRcr-cys is better at predicting CV outcomes among patients with HFpEF or HFrEF. Additionally, soluble suppression of tumorogenicity 2 (ST2), and galectin-3 are easily obtainable blood biomarkers that may be associated with CKD progression and increased mortality, predominantly in patients with HFrEF, but have not been tested in patients with HFpEF. These biomarkers will be useful in understanding which patients are at increased risk of GFR decline and adverse CV events. Moreover, identifying such biomarkers will pave the way for future studies to better understand kidney disease pathogenesis in the setting of heart failure. To answer these questions, we plan to obtain specimens from the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist trial (TOPCAT), a study population with HFpEF available in BioLINCC. Of 3445 participants, 220 have serum samples available at baseline and one year for analysis. We plan to measure serum cystatin C, ST2, and galectin-3. Our other biomarker of interest, serum creatinine, is already available in the dataset. We will use these data to: Aim 1a, test the association between baseline and increasing levels of serum ST2 and galectin-3 with the composite outcome of aborted cardiac arrest, heart failure hospitalization, or cardiovascular (CV) death; Aim 1b, test the association between baseline and increasing levels of serum ST2 and galectin-3 and the outcome of change in eGFRcr-cys from baseline to 1 year; Aim 2, investigate which GFR estimate is more predictive of the composite outcome; and Aim 3, analyze data from the Registry Evaluation of Vital Information for Ventricular Assist Devices in Ambulatory Life (REVIVAL), which is also publicly available in BioLINCC and has baseline serum creatinine and cystatin C measurements available, to evaluate which GFR estimate is the best predictor of all-cause mortality and a composite of heart failure hospitalization and CV death in patients with HFrEF. The overarching hypotheses are that (1) serum ST2 and galectin-3 are biomarkers associated with adverse CV and kidney outcomes in HFpEF patients; (2) eGFRcr-cys is the best GFR estimate to predict adverse outcomes in patients with HFpEF and HFrEF.