Inflammatory Markers and Measures of Cardiovascular Autonomic Neuropathy in Type 1 Diabetes

Abstract

Background: Cardiovascular autonomic neuropathy (CAN) and inflammation predict more severe outcomes in type 1 diabetes (T1D). However, the link between CAN and inflammation in T1D remains unclear. We examined associations between CAN measures and inflammatory biomarkers in individuals with T1D.

Methods and results: In a cross-sectional study, we measured cardiovascular autonomic reflex tests and heart rate variability (established CAN measures) and a panel of 39 inflammatory biomarkers, including soluble urokinase plasminogen activator receptor (suPAR), in T1D participants of the TINSAL-T1DN (Targeting Inflammation with Salsalate in Individuals with T1D Neuropathy) trial (n=57, discovery), and the PERL (Preventing Early Renal Loss in Diabetes) trial (n=468, validation). Amongst 39 inflammatory biomarkers measured in TINSAL-T1DN, suPAR levels had the strongest negative correlations with CAN measures: expiration/inspiration (r=-0.48), Valsalva (r=-0.28), 30:15 (r=-0.37), SD of the normal RR interval (r=-0.37), and root mean square of differences of successive RR intervals (r=-0.31) (all P<0.05). Findings were validated in PERL. In unadjusted analyses, median suPAR levels significantly differed between the lowest and highest SD of the normal RR interval tertiles (3.79 versus 3.12 ng/mL, P<0.001) and root mean square of differences of successive RR intervals (3.76 versus 3.17 ng/mL, P<0.001). After adjusting for covariates (age, sex, hemoglobin A1c, and estimated glomerular filtration rate), median suPAR values remained significantly elevated in the lowest tertiles of SD of the normal RR interval (P=0.004) and root mean square of differences of successive RR intervals (P=0.006).

Conclusions: Amongst several inflammatory biomarkers, suPAR, an immune-mediated glycoprotein, has a singular association with CAN measures. The potential of targeting suPAR as a disease-modifying approach for CAN in T1D warrants further exploration.

Registration: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT02936843, NCT02017171.

Keywords: biomarkers; cardiovascular autonomic neuropathy; cardiovascular autonomic reflex tests; heart rate variability; inflammation; soluble urokinase plasminogen activator receptor; type 1 diabetes.

Figure 1. Inflammatory biomarker correlations with CAN measures in TINSAL‐T1DN.

Spearman's rank correlation coefficients of inflammatory markers to CAN measures. Blue and red represent positive and negative correlations, respectively. Both a deeper color and more elliptical shape indicate a stronger association. CAN indicates cardiovascular autonomic neuropathy; EGF, estimated glomerular filtration; E/I ratio, expiration/inspiration ratio; FGF‐2; HR, heart rate; IFNa2, interferon alpha 2; IFNg, interferon γ; IL, interleukin; LFA, low‐frequency power; MCP; MIP; RFA, high‐frequency power; RMSSD, root mean square of the differences of successive RR intervals; SDNN, standard deviation of the normal RR interval; suPAR, soluble urokinase plasminogen activator receptor; TGFa, transforming growth factor‐α; TINSAL‐T1DN, Targeting Inflammation with Salsalate in Individuals with T1D Neuropathy; Val.Average; and VEGF, vascular endothelial growth factor.

Figure 2. Violin plots demonstrating the distributions of suPAR across tertile groups of CAN measures in TINSAL‐T1DN.

A, 30:15 ratio; (B) SDNN; (C) RMSSD; (D) LFA; (E) RFA; and (F) LFA/RFA ratio. CAN indicates cardiovascular autonomic neuropathy; LFA low‐frequency power; RFA, high‐frequency power; RMSSD, root mean square of the differences of successive RR intervals; SDNN, standard deviation of the normal RR interval; suPAR, soluble urokinase plasminogen activator receptor; and TINSAL‐T1DN, Targeting Inflammation with Salsalate in Individuals with T1D Neuropathy.

Figure 3. suPAR ratios between tertile groups of CAN measures in TINSAL‐T1DN.

In the forest plots, the black squares represent the estimated suPAR ratios, and the bars represent 95% CIs. P values are also shown. Model 1: univariable analysis; Model 2: multivariable analysis, adjusted for age, sex, and HbA1c. CAN indicates cardiovascular autonomic neuropathy; HbA1c, glycated hemoglobin; LFA, low‐frequency power; RFA, high‐frequency power; RMSSD, root mean square of the differences of successive RR intervals; SDNN, standard deviation of the normal RR interval; suPAR, soluble urokinase plasminogen activator receptor; and TINSAL‐T1DN, Targeting Inflammation with Salsalate in Individuals with T1D Neuropathy.

Figure 4. suPAR ratios between tertile groups of CAN measures in PERL.

In the forest plots, the black squares represent the estimated suPAR ratios, and the bars represent 95% CIs. P values are also shown. Model 1: univariable analysis; Model 2: multivariable analysis adjusted for age, sex, and HbA1c; Model 3: multivariable analysis further adjusted for eGFR in addition to parameters adjusted in Model 2. CAN indicates cardiovascular autonomic neuropathy; eGFR, estimated glomerular filtration rate; HbA1c, glycated hemoglobin; PERL, Preventing Early Renal Function Loss in Diabetes; RMSSD, root mean square of the differences of successive RR intervals; SDNN, standard deviation of the normal RR interval; and suPAR, soluble urokinase plasminogen activator receptor.

Figure 5. Violin plots demonstrating the distributions of suPAR across tertile groups of CAN measures in PERL.

A, RMSSD; and B, SDNN. CAN indicates cardiovascular autonomic neuropathy; PERL, Preventing Early Renal Function Loss in Diabetes; RMSSD, root mean square of the differences of successive RR intervals; SDNN, standard deviation of the normal RR interval; and suPAR, soluble urokinase plasminogen activator receptor.