Epidemiological investigation into inflammatory and cardiovascular proteomics biomarkers of heart rate variability indices of cardiac autonomic nervous dysfunction: KORA S4/FF4 study

Objective: Cardiac autonomic nervous dysfunction (CAND) is a complication of type 2 diabetes (T2D), which can also be prevalent in individuals with prediabetes and in advanced age. The proteome could be a window to the poorly understood molecular mechanisms and unclear pathophysiology of CAND. Further insights into the relationship of proteomics biomarkers with CAND-sensitive heart rate variability (HRV) indices, especially in population-based cohorts, would be a research advance. We sought to investigate the association between circulating inflammatory and cardiovascular proteomics biomarkers and selected CAND-HRV indices in a population-based cohort.

Methodology: Using the Cooperative Health Research in the Region of Augsburg (KORA) cohort, 233 proteomics biomarkers were quantified using the targeted proximity extension assay technology in baseline (KORA S4; 1999-2001) plasma samples of 1389 individuals (64 years, 52% men). Five previously reported CAND-HRV indices (Renyi entropy of the histogram with order (alpha) 4 (Renyi4), total power of the density spectra (TP), standard deviation of word sequence (SDWS), standard deviation of the short-term normal-to-normal interval variability (SDSA), and compression entropy (CE)) were assessed at baseline in 982 individuals and in 407 individuals at baseline and at follow-up (KORA FF4; 2013-2014). Three multivariable selection methods, partial least squares, random forest, and elastic net followed by linear and linear mixed-effects models with multiple testing correction were used to determine the association between the proteomics biomarkers measured at baseline and CAND-HRV indices cross-sectionally and over time.

Results: Independent of several covariates including age, anthropometry and lifestyle factors, 10 proteins were associated with four CAND-HRV indices. C-C motif chemokine 23 (CCL23) was positively associated, while peptidoglycan recognition protein (PGLYRP1) and fibroblast growth factor 21 (FGF21) were negatively associated with Renyi4, cross-sectionally. Further, TNF-related activation-induced cytokine (TRANCE) and growth/differentiation factor 15 (GDF15) were negatively associated with CE cross-sectionally. Additionally, interleukin-6 receptor subunit alpha (IL6RA) and macrophage colony-stimulating factor (CSF1) were positively and negatively associated with TP over time, respectively. Myoglobin (MB) and agouti-related protein (AGRP) were positively and negatively associated with SDSA over time, respectively. Further, gastrotropin (GT) and AGRP were positively and negatively associated with CE over time.

Conclusion(s): This study uncovered 10 novel circulating proteins associated with CAND-HRV indices. These proteomics biomarkers could improve our understanding of the complex pathophysiology and poorly understood molecular mechanisms of CAND.

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Artikel online veröffentlicht:
28. Mai 2025