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

Lynn Ang; Sejal Gunaratnam; Yiyuan Huang; Brendan R. Dillon; Catherine L. Martin; Aaron Burant; Jacob Reiss; Pennelope Blakely; Alexi Vasbinder; Lili Zhao; Kara Mizokami-Stout; Yaling Tang; Eva L. Feldman; Alessandro Doria; Cathie Spino; Mousumi Banerjee; Salim S. Hayek; Rodica Pop-Busui

doi:10.1161/JAHA.124.036787

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

Lynn Ang, Sejal Gunaratnam, Yiyuan Huang, Brendan R. Dillon, Catherine L. Martin, Aaron Burant, Jacob Reiss, Pennelope Blakely, Alexi Vasbinder, Lili Zhao, Kara Mizokami-Stout, Yaling Tang, Eva L. Feldman, Alessandro Doria, Cathie Spino, Mousumi Banerjee, Salim S. Hayek^*, Rodica Pop-Busui^*

^*Corresponding author for this work

Preventive Medicine

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

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/in-spiration (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.

Original language	English (US)
Article number	e036787
Journal	Journal of the American Heart Association
Volume	14
Issue number	1
DOIs	https://doi.org/10.1161/JAHA.124.036787
State	Published - Jan 7 2025

Funding

These studies were supported by R01DK107956 (E. L. Feldman and R. Pop-Busui), U01DK119083 (R. Pop-Busui), the Breakthrough T1D (former Juvenile Diabetes Research Foundation) Center of Excellence at University of Michigan (R. Pop-Busui and L. Ang). R. Pop-Busui was also supported by R01DK116723 and UC4DK101108. S. S. Hayek is supported by National Heart, Lung, and Blood Institute (NHLBI) R01HL153384 and National Institute of Diabetes and Digestive and Kidney Diseases R01DK128012. A. Vasbinder is supported by a NHLBI-funded postdoctoral fellowship (T32HL007853).

Keywords

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

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1161/JAHA.124.036787

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Ang, L., Gunaratnam, S., Huang, Y., Dillon, B. R., Martin, C. L., Burant, A., Reiss, J., Blakely, P., Vasbinder, A., Zhao, L., Mizokami-Stout, K., Tang, Y., Feldman, E. L., Doria, A., Spino, C., Banerjee, M., Hayek, S. S., & Pop-Busui, R. (2025). Inflammatory Markers and Measures of Cardiovascular Autonomic Neuropathy in Type 1 Diabetes. Journal of the American Heart Association, 14(1), Article e036787. https://doi.org/10.1161/JAHA.124.036787

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title = "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/in-spiration (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",

author = "Lynn Ang and Sejal Gunaratnam and Yiyuan Huang and Dillon, \{Brendan R.\} and Martin, \{Catherine L.\} and Aaron Burant and Jacob Reiss and Pennelope Blakely and Alexi Vasbinder and Lili Zhao and Kara Mizokami-Stout and Yaling Tang and Feldman, \{Eva L.\} and Alessandro Doria and Cathie Spino and Mousumi Banerjee and Hayek, \{Salim S.\} and Rodica Pop-Busui",

note = "Publisher Copyright: {\textcopyright} 2024 The Author(s).",

year = "2025",

month = jan,

day = "7",

doi = "10.1161/JAHA.124.036787",

language = "English (US)",

volume = "14",

journal = "Journal of the American Heart Association",

issn = "2047-9980",

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Ang, L, Gunaratnam, S, Huang, Y, Dillon, BR, Martin, CL, Burant, A, Reiss, J, Blakely, P, Vasbinder, A, Zhao, L, Mizokami-Stout, K, Tang, Y, Feldman, EL, Doria, A, Spino, C, Banerjee, M, Hayek, SS & Pop-Busui, R 2025, 'Inflammatory Markers and Measures of Cardiovascular Autonomic Neuropathy in Type 1 Diabetes', Journal of the American Heart Association, vol. 14, no. 1, e036787. https://doi.org/10.1161/JAHA.124.036787

TY - JOUR

T1 - Inflammatory Markers and Measures of Cardiovascular Autonomic Neuropathy in Type 1 Diabetes

AU - Ang, Lynn

AU - Gunaratnam, Sejal

AU - Huang, Yiyuan

AU - Dillon, Brendan R.

AU - Martin, Catherine L.

AU - Burant, Aaron

AU - Reiss, Jacob

AU - Blakely, Pennelope

AU - Vasbinder, Alexi

AU - Zhao, Lili

AU - Mizokami-Stout, Kara

AU - Tang, Yaling

AU - Feldman, Eva L.

AU - Doria, Alessandro

AU - Spino, Cathie

AU - Banerjee, Mousumi

AU - Hayek, Salim S.

AU - Pop-Busui, Rodica

PY - 2025/1/7

Y1 - 2025/1/7

N2 - 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/in-spiration (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.

AB - 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/in-spiration (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.

KW - biomarkers

KW - cardiovascular autonomic neuropathy

KW - cardiovascular autonomic reflex tests

KW - heart rate variability

KW - inflammation

KW - soluble urokinase plasminogen activator receptor

KW - type 1 diabetes

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U2 - 10.1161/JAHA.124.036787

DO - 10.1161/JAHA.124.036787

M3 - Article

C2 - 39727210

AN - SCOPUS:85215146803

SN - 2047-9980

VL - 14

JO - Journal of the American Heart Association

JF - Journal of the American Heart Association

IS - 1

M1 - e036787

ER -

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

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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