Cardiovascular Biomarkers and Incident Heart Failure

Study Questions:

What are the associations of 12 cardiovascular biomarkers with heart failure with preserved ejection fraction (HFpEF) versus HF with reduced EF (HFrEF)?


This study included four longitudinal community-based cohorts that had prospective ascertainment of incident HFpEF (left ventricular EF [LVEF] ≥50%) and HFrEF (LVEF <50%). These included the Cardiovascular Health Study (1989-1990; 1992-1993 for supplemental African-American cohort), the Framingham Heart Study (1995-1998), the Multi-Ethnic Study of Atherosclerosis (2000-2002), and the Prevention of Renal and Vascular End-stage Disease study (1997-1998). The authors performed a data analysis from June 25, 2015, to November 9, 2017. Biomarkers included were N-terminal pro–B-type natriuretic peptide or brain natriuretic peptide, high-sensitivity troponin (hs-Tn) T or I, C-reactive protein (CRP), urinary albumin-to-creatinine ratio (UACR), renin-to-aldosterone ratio, D-dimer, fibrinogen, soluble suppressor of tumorigenicity, galectin-3, cystatin C, plasminogen activator inhibitor-1 (PAI-1), and interleukin-6. The main outcome measures included development of incident HFpEF and incident HFrEF. They assessed the incremental effect of each biomarker on its association with HFpEF and HFrEF. They compared C-statistics between models with clinical covariates alone (based on a previously validated prediction model) and models including both clinical covariates and the given biomarker.


In the final study cohort of 22,756 participants (12,087 women and 10,669 men; mean [SD] age, 60 [13] years) with a median follow-up period of 12 years, 633 participants developed incident HFpEF, and 841 developed HFrEF. The investigators, using models adjusted for clinical risk factors of HF (such as age, sex, race/ethnicity, systolic blood pressure, hypertension treatment, body mass index, diabetes, smoking status, presence of LV hypertrophy, and left bundle branch block), found that two biomarkers were significantly associated with incident HFpEF: UACR (hazard ratio [HR], 1.33; 95% confidence interval [CI], 1.20-1.48; p < 0.001) and natriuretic peptides (HR, 1.27; 95% CI, 1.16-1.40; p < 0.001), with suggestive associations for hs-Tn (HR, 1.11; 95% CI, 1.03-1.19; p = 0.008), PAI-1 (HR, 1.22; 95% CI, 1.03-1.45; p = 0.02), and fibrinogen (HR, 1.12; 95% CI, 1.03-1.22; p = 0.01). Six biomarkers were associated with incident HFrEF: natriuretic peptides (HR, 1.54; 95% CI, 1.41-1.68; p < 0.001), UACR (HR, 1.21; 95% CI, 1.11-1.32; p < 0.001), hs-Tn (HR, 1.37; 95% CI, 1.29-1.46; p < 0.001), cystatin C (HR, 1.19; 95% CI, 1.11-1.27; p < 0.001), D-dimer (HR, 1.22; 95% CI, 1.11-1.35; p < 0.001), and CRP (HR, 1.19; 95% CI, 1.11-1.28; p < 0.001). The study authors reported that natriuretic peptides and hs-Tn were more strongly associated with HFrEF compared with HFpEF. Specifically, a 1-SD increase in log-transformed natriuretic peptides was associated with a 1.5-fold increased risk of future HFrEF (95% CI, 1.41-1.68) compared with a 1.3-fold increased risk of HFpEF (95% CI, 1.16-1.40; p = 0.005 for difference). Similarly, a 1-SD increase in hs-Tn was associated with a 1.4-fold increased risk of HFrEF (95% CI, 1.29-1.46), whereas hs-Tn was more weakly associated with HFpEF (HR, 1.11; 95% CI, 1.03-1.19; p = 0.008; p < 0.001 for difference).


The study authors concluded that biomarkers of renal dysfunction, endothelial dysfunction, and inflammation were associated with incident HFrEF, whereas only natriuretic peptides and UACR were associated with HFpEF.


This study of ‘big data’ suggests that using a panel of biomarkers may be a better tool for management of HF. Prospective studies are needed to confirm these findings and the potential clinical utility of a multimarker strategy of managing HF patients.

Clinical Topics: Anticoagulation Management, Dyslipidemia, Heart Failure and Cardiomyopathies, Lipid Metabolism, Novel Agents, Acute Heart Failure, Heart Failure and Cardiac Biomarkers

Keywords: Aldosterone, Biological Markers, C-Reactive Protein, Creatinine, Cystatin C, Fibrin Fibrinogen Degradation Products, Fibrinogen, Galectin 3, Heart Failure, Inflammation, Interleukin-6, Natriuretic Peptide, Brain, Natriuretic Peptides, Outcome Assessment (Health Care), Peptide Fragments, Plasminogen Activator Inhibitor 1, Protein C Inhibitor, Renin, Salivary Cystatins, Stroke Volume, Troponin T, Troponin I

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