{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T00:25:51Z","timestamp":1791591951252,"version":"4.3.4"},"reference-count":52,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2025,1,7]]},"abstract":"<jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods and Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      In a cross\u2010sectional 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\u2010T1DN (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\u2010T1DN, suPAR levels had the strongest negative correlations with CAN measures: expiration\/inspiration (\n                      <jats:italic>r<\/jats:italic>\n                      =\u22120.48), Valsalva (\n                      <jats:italic>r<\/jats:italic>\n                      =\u22120.28), 30:15 (\n                      <jats:italic>r<\/jats:italic>\n                      =\u22120.37), SD of the normal RR interval (\n                      <jats:italic>r<\/jats:italic>\n                      =\u22120.37), and root mean square of differences of successive RR intervals (\n                      <jats:italic>r<\/jats:italic>\n                      =\u22120.31) (all\n                      <jats:italic>P<\/jats:italic>\n                      &lt;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\u2009ng\/mL,\n                      <jats:italic>P<\/jats:italic>\n                      &lt;0.001) and root mean square of differences of successive RR intervals (3.76 versus 3.17\u2009ng\/mL,\n                      <jats:italic>P<\/jats:italic>\n                      &lt;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 (\n                      <jats:italic>P<\/jats:italic>\n                      =0.004) and root mean square of differences of successive RR intervals (\n                      <jats:italic>P<\/jats:italic>\n                      =0.006).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">Amongst several inflammatory biomarkers, suPAR, an immune\u2010mediated glycoprotein, has a singular association with CAN measures. The potential of targeting suPAR as a disease\u2010modifying approach for CAN in T1D warrants further exploration.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Registration<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      URL:\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/www.clinicaltrials.gov\">https:\/\/www.clinicaltrials.gov<\/jats:ext-link>\n                      ; Unique identifiers: NCT02936843, NCT02017171.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/jaha.124.036787","type":"journal-article","created":{"date-parts":[[2024,12,27]],"date-time":"2024-12-27T06:35:16Z","timestamp":1735281316000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":13,"title":["Inflammatory Markers and Measures of Cardiovascular Autonomic Neuropathy in Type 1 Diabetes"],"prefix":"10.1161","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7133-9886","authenticated-orcid":false,"given":"Lynn","family":"Ang","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes University of Michigan Ann Arbor MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sejal","family":"Gunaratnam","sequence":"additional","affiliation":[{"name":"Life Science Informatics University of Michigan Ann Arbor MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5568-8517","authenticated-orcid":false,"given":"Yiyuan","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Biostatistics University of Michigan Ann Arbor MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brendan R.","family":"Dillon","sequence":"additional","affiliation":[{"name":"Department of Medicine NYU Grossman School of Medicine New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine L.","family":"Martin","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes University of Michigan Ann Arbor MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron","family":"Burant","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes University of Michigan Ann Arbor MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob","family":"Reiss","sequence":"additional","affiliation":[{"name":"Quality Department University of Michigan Ann Arbor MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9677-3010","authenticated-orcid":false,"given":"Pennelope","family":"Blakely","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Cardiology University of Texas Medical Branch Galveston TX USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1380-5364","authenticated-orcid":false,"given":"Alexi","family":"Vasbinder","sequence":"additional","affiliation":[{"name":"Biobehavioral Nursing and Health Informatics University of Washington School of Nursing Seattle WA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6366-8206","authenticated-orcid":false,"given":"Lili","family":"Zhao","sequence":"additional","affiliation":[{"name":"Corewell Health William Beaumont University Hospital Royal Oak MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6933-2586","authenticated-orcid":false,"given":"Kara","family":"Mizokami\u2010Stout","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes University of Michigan Ann Arbor MI USA"},{"name":"Ann Arbor Veteran Affairs Hospital Ann Arbor MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaling","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Epidemiology Joslin Diabetes Center Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva L.","family":"Feldman","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Michigan Ann Arbor MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3830-4304","authenticated-orcid":false,"given":"Alessandro","family":"Doria","sequence":"additional","affiliation":[{"name":"Department of Epidemiology Joslin Diabetes Center Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6157-6738","authenticated-orcid":false,"given":"Cathie","family":"Spino","sequence":"additional","affiliation":[{"name":"Department of Biostatistics University of Michigan Ann Arbor MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5901-822X","authenticated-orcid":false,"given":"Mousumi","family":"Banerjee","sequence":"additional","affiliation":[{"name":"Department of Biostatistics University of Michigan Ann Arbor MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0180-349X","authenticated-orcid":false,"given":"Salim S.","family":"Hayek","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Cardiology University of Texas Medical Branch Galveston TX USA"},{"name":"Department of Internal Medicine, Division of Cardiology University of Michigan Ann Arbor MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2042-1350","authenticated-orcid":false,"given":"Rodica","family":"Pop\u2010Busui","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes University of Michigan Ann Arbor MI USA"},{"name":"Department of Internal Medicine, Division of Endocrinology, Diabetes and Clinical Nutrition Oregon Health and Science University Portland OR USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.autneu.2020.102646"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.2337\/dc16-2042"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jdiacomp.2022.108334"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.2337\/ds18-0036"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.2337\/dc08-0107"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2008.05.005"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jns.2006.03.011"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.2174\/138945008783431718"},{"key":"e_1_3_2_10_2","article-title":"Activation of GABA(B) receptor suppresses diabetic neuropathic pain through toll\u2010like receptor 4 signaling pathway in the spinal dorsal horn","author":"Liu P","year":"2018","unstructured":"Liu P, Yuan HB, Zhao S, Liu FF, Jiang YQ, Guo YX, Wang XL. Activation of GABA(B) receptor suppresses diabetic neuropathic pain through toll\u2010like receptor 4 signaling pathway in the spinal dorsal horn. Mediat Inflamm. 2018;6016272.","journal-title":"Mediat Inflamm"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1186\/1742-2094-10-69"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11892-016-0727-5"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-016-9702-z"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.2147\/DMSO.S319863"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.eclinm.2020.100649"},{"key":"e_1_3_2_16_2","article-title":"Circulating inflammatory markers are inversely associated with heart rate variability measures in type 1 diabetes","author":"Wegeberg AL","year":"2020","unstructured":"Wegeberg AL, Okdahl T, Fl\u00f8yel T, Brock C, Ejskjaer N, Riahi S, Pociot F, St\u00f8rling J, Brock B. Circulating inflammatory markers are inversely associated with heart rate variability measures in type 1 diabetes. Mediat Inflamm. 2020;3590389.","journal-title":"Mediat Inflamm"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jdiacomp.2019.06.001"},{"key":"e_1_3_2_18_2","article-title":"Deficits in systemic biomarkers of neuroinflammation and growth factors promoting nerve regeneration in patients with type 2 diabetes and polyneuropathy","volume":"7","author":"Ziegler D","year":"2019","unstructured":"Ziegler D, Strom A, B\u00f6nhof GJ, Kannenberg JM, Heier M, Rathmann W, Peters A, Meisinger C, Roden M, Thorand B. Deficits in systemic biomarkers of neuroinflammation and growth factors promoting nerve regeneration in patients with type 2 diabetes and polyneuropathy. BMJ Open Diabetes Res Care. 2019;7:e000752.","journal-title":"BMJ Open Diabetes Res Care"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/0165-1838(91)90042-2"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00406.2002"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1002\/cphy.c130051"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1916624"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jdiacomp.2021.107949"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.2337\/dc14-0445"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1002\/dmrr.1239"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1111\/jdi.13635"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.2337\/db23-0247"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.2337\/dc18-1427"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.2337\/dc16-1397"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.2337\/diacare.27.12.2942"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.2337\/dc17-2062"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.diabres.2020.108235"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1111\/pedi.12633"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.2337\/dci22-0014"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.2337\/dc10-0125"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1002\/ejhf.2432"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.2337\/db21-225-OR"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.2337\/diacare.29.02.06.dc05-1242"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.2215\/CJN.11441114"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehm018"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1111\/eci.12070"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI158788"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11886-023-01991-7"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.2337\/dc21-2102"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1506362"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ekir.2017.02.001"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.14740\/jocmr4459"},{"key":"e_1_3_2_48_2","doi-asserted-by":"crossref","unstructured":"Zhu K Mukherjee K Wei C Hayek SS Collins A Gu C Corapi K Altintas MM Wang Y Waikar SS et\u00a0al. Truncated suPAR simultaneously causes kidney disease and autoimmune diabetes mellitus. bioRxiv2022 489589.","DOI":"10.1101\/2022.04.26.489589"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.117.008194"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-022-02454-6"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1911481"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.165740"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI124793"}],"container-title":["Journal of the American Heart Association"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/JAHA.124.036787","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,25]],"date-time":"2025-02-25T05:55:31Z","timestamp":1740462931000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/JAHA.124.036787"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,7]]},"references-count":52,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2025,1,7]]}},"alternative-id":["10.1161\/JAHA.124.036787"],"URL":"https:\/\/doi.org\/10.1161\/jaha.124.036787","relation":{},"ISSN":["2047-9980"],"issn-type":[{"value":"2047-9980","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,7]]},"assertion":[{"value":"2024-05-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-10-28","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-12-27","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e036787"}}