Association of the Novel Inflammatory Marker GlycA and Incident Heart Failure and Its Subtypes of Preserved and Reduced Ejection Fraction: The Multi-Ethnic Study of Atherosclerosis

Abstract

Background: GlycA, a nuclear magnetic resonance composite marker of systemic inflammation, reflects serum concentration and glycosylation state of main acute phase reactants. Prior studies have shown plasma GlycA levels were associated with cardiovascular disease even after adjusting for other inflammatory markers. However, little is known about the association of GlycA with the heart failure (HF) subtypes: heart failure with preserved ejection fraction (HFpEF) or heart failure with reduced ejection fraction. We examined the association of GlycA with incident HF and its subtypes in a multiethnic cohort.

Methods: We studied 6507 Multi-Ethnic Study of Atherosclerosis participants aged 45 to 84 without baseline cardiovascular disease or HF who had data on GlycA and incident hospitalized HF. We used multivariable-adjusted Cox hazards models to evaluate the association of GlycA with incident total HF, HFpEF, and heart failure with reduced ejection fraction. Models were adjusted for sociodemographics, cardiovascular disease risk factors, and inflammatory biomarkers.

Results: The mean (SD) for age was 62 (10) years and for GlycA was 375 (82) μmol/L; 53% women. Over a median follow-up of 14.0 years, participants in the highest quartile of GlycA, compared with the lowest, experienced increased risk of developing any HF (hazard ratio, 1.48 [95% CI, 1.01-2.18]) in fully adjusted models. However, this increased risk was only seen for HFpEF (2.18 [1.15-4.13]) and not heart failure with reduced ejection fraction [1.06 (0.63-1.79)]. There was no significant interaction by sex, age, or race/ethnicity.

Conclusions: GlycA was associated with an increased risk of any HF, and in particular, HFpEF. Future studies should examine mechanisms that might explain differential association of GlycA with HF subtypes, and whether therapeutic lowering of GlycA can prevent HFpEF development. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00005487.

Keywords: biomarkers; cardiovascular diseases; heart failure; inflammation; risk factors.

Figures

Figure 1.

Flow diagram illustrating study sample inclusion and exclusion criteria.

Figure 2.

Adjusted* restricted cubic spline models showing the association of GlycA levels with hazard ratio of (A) HF, (B) HFpEF, (C) HFrEF. *Spline models adjusted for age, sex, and race/ethnicity, MESA site, education, health insurance, BMI, smoking status, pack-years of smoking, physical activity, systolic blood pressure, use of antihypertensive medication, total cholesterol, HDL- cholesterol, use of lipid-lowering medications, diabetes, eGFR, ln(CRP), ln(IL-6) and ln(Fibrinogen). The 4 knots are at 5th, 25th, 65th and 95th percentiles. Black curves represent the HR for the type of HF by proportion of population with the respective GlycA concentration. The 95% CI is represented by the gray shadow.

Figure 2.

Adjusted* restricted cubic spline models showing the association of GlycA levels with hazard ratio of (A) HF, (B) HFpEF, (C) HFrEF. *Spline models adjusted for age, sex, and race/ethnicity, MESA site, education, health insurance, BMI, smoking status, pack-years of smoking, physical activity, systolic blood pressure, use of antihypertensive medication, total cholesterol, HDL- cholesterol, use of lipid-lowering medications, diabetes, eGFR, ln(CRP), ln(IL-6) and ln(Fibrinogen). The 4 knots are at 5th, 25th, 65th and 95th percentiles. Black curves represent the HR for the type of HF by proportion of population with the respective GlycA concentration. The 95% CI is represented by the gray shadow.

Figure 2.

Adjusted* restricted cubic spline models showing the association of GlycA levels with hazard ratio of (A) HF, (B) HFpEF, (C) HFrEF. *Spline models adjusted for age, sex, and race/ethnicity, MESA site, education, health insurance, BMI, smoking status, pack-years of smoking, physical activity, systolic blood pressure, use of antihypertensive medication, total cholesterol, HDL- cholesterol, use of lipid-lowering medications, diabetes, eGFR, ln(CRP), ln(IL-6) and ln(Fibrinogen). The 4 knots are at 5th, 25th, 65th and 95th percentiles. Black curves represent the HR for the type of HF by proportion of population with the respective GlycA concentration. The 95% CI is represented by the gray shadow.