Relations of circulating GDF-15, soluble ST2, and troponin-I concentrations with vascular function in the community: The Framingham Heart Study

Abstract

Background and aims: Growth differentiation factor-15 (GDF-15), soluble (s)ST2, and high-sensitivity troponin-I (hs-TnI) are associated with incident cardiovascular disease (CVD) including heart failure, yet the underlying mechanisms are not fully understood. We investigated if GDF-15, sST2, and hs-TnI are related to subclinical vascular dysfunction in the community, which may explain the relations of these biomarkers with CVD.

Methods: We evaluated 1823 Framingham Study participants (mean age 61 ± 10 years, 54% women) who underwent routine assessment of vascular function. We related circulating GDF-15, sST2, and hs-TnI concentrations to measures of arterial stiffness (carotid-femoral pulse wave velocity, CFPWV; augmentation index; and forward pressure wave amplitude, FW), endothelial-dependent vasodilation (flow-mediated dilation, FMD), and baseline and hyperemic brachial flow velocities using linear regression adjusting for standard risk factors.

Results: After multivariable adjustment, GDF-15 levels were positively associated with CFPWV (0.044 [95% confidence interval 0.007-0.081] standard deviation [SD] change per SD increase in loge[GDF-15], p = 0.02) and FW (0.076 [0.026-0.126] SD change per SD increase in loge[GDF-15], p = 0.003) and inversely related to FMD (-0.051 [-0.101-0.0003] SD change per SD increase in loge[GDF-15], p = 0.048). sST2 was positively associated with CFPWV (0.032 [0.0005-0.063] SD change per SD increase in loge[sST2], p = 0.046), and hs-TnI inversely associated with hyperemic flow velocity (-0.041 [-0.082-0.0004] SD change per SD increase in loge[hs-TnI], p = 0.048).

Conclusion: In our community-based investigation, individual cardiac stress biomarkers were differentially related to select aspects of vascular function. These findings may contribute to the associations of circulating GDF-15, sST2, and hs-TnI with incident CVD and heart failure.

Keywords: Biomarkers; Endothelial function; GDF-15; General population; ST2; Troponin I; Vascular stiffness.

Figure 1. A-C – Unadjusted means of different vascular measures according to tertiles of biomarkers

Legend: Unadjusted means with standard deviations (error bar) for various vascular measures by tertiles of biomarker (T1-T3). AI=augmentation index, HF=hyperemic flow, FW=forward pressure wave amplitude, CFPWV=carotid-femoral pulse wave velocity, BF=baseline flow velocity, FMD=flow-mediated dilation. AI, HF, and FW values refer to the left hand Y-axis, and CFPWV, BF, and FMD refer to the right hand Y-axis.

Figure 1. A-C – Unadjusted means of different vascular measures according to tertiles of biomarkers

Legend: Unadjusted means with standard deviations (error bar) for various vascular measures by tertiles of biomarker (T1-T3). AI=augmentation index, HF=hyperemic flow, FW=forward pressure wave amplitude, CFPWV=carotid-femoral pulse wave velocity, BF=baseline flow velocity, FMD=flow-mediated dilation. AI, HF, and FW values refer to the left hand Y-axis, and CFPWV, BF, and FMD refer to the right hand Y-axis.

Figure 1. A-C – Unadjusted means of different vascular measures according to tertiles of biomarkers

Legend: Unadjusted means with standard deviations (error bar) for various vascular measures by tertiles of biomarker (T1-T3). AI=augmentation index, HF=hyperemic flow, FW=forward pressure wave amplitude, CFPWV=carotid-femoral pulse wave velocity, BF=baseline flow velocity, FMD=flow-mediated dilation. AI, HF, and FW values refer to the left hand Y-axis, and CFPWV, BF, and FMD refer to the right hand Y-axis.

Figure 2. Association of various vascular measures with biomarkers based on multivariable linear regression

Legend: Association of biomarkers with different vascular measures. The units on the x-axis refer to changes in standard deviations for each standard deviation increase in log_e(biomarker). CFPWV= carotid-femoral pulse wave velocity (ms/m), AI=augmentation index (%), FW=forward pressure wave amplitude (mm Hg), BF=baseline flow velocity (mm Hg), HF=hyperemic flow velocity (cm/s), FMD=flow-mediated dilation (%). Model 1 was adjusted for age, height, and sex; model 2 was adjusted for model 1 plus weight, heart rate, mean arterial blood pressure, total/HDL cholesterol ratio, triglycerides, glucose, diabetes, prevalent CVD, anti-hypertensive medication, lipid lowering medication, smoking, and hormone replacement therapy; Model 3 was adjusted for model 2 plus log_e(BNP), log_e(NT-proANP), log_e(renin), log_e(hs-CRP), log_e(GDF-15), log_e(sST2), and log_e(hs-TnI).