title: Prognostic relevance of the interaction between short-term, metronome-paced heart rate variability, and inflammation: results from the population-based CARLA cohort study.
abstract: OBJECTIVE
  To determine the interaction between HRV and inflammation and their association with cardiovascular/all-cause mortality in the general population.
  
  
  RESULTS
  Subjects of the CARLA study (n = 1671; 778 women, 893 men, 45-83 years of age) were observed for an average follow-up period of 8.8 years (226 deaths, 70 cardiovascular deaths). Heart rate variability parameters were calculated from 5-min segments of 20-min resting electrocardiograms. High-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), and soluble tumour necrosis factor-alpha receptor type 1 (sTNF-R1) were measured as inflammation parameters. The HRV parameters determined included the standard deviation of normal-to-normal intervals (SDNN), the root-mean-square of successive normal-interval differences (RMSSD), the low- and high-frequency (HF) power, the ratio of both, and non-linear parameters [Poincaré plot (SD1, SD2, SD1/SD2), short-term detrended fluctuation analysis]. We estimated hazard ratios by using covariate-adjusted Cox regression for cardiovascular and all-cause mortality incorporating an interaction term of HRV/inflammation parameters. Relative excess risk due to interactions (RERIs) were computed. We found an interaction effect of sTNF-R1 with SDNN (RERI: 0.5; 99% confidence interval (CI): 0.1-1.0), and a weaker effect with RMSSD (RERI: 0.4; 99% CI: 0.0-0.9) and HF (RERI: 0.4; 99% CI: 0.0-0.9) with respect to cardiovascular mortality on an additive scale after covariate adjustment. Neither IL-6 nor hsCRP showed a significant interaction with the HRV parameters.
  
  
  CONCLUSIONS
  A change in TNF-α levels or the autonomic nervous system influences the mortality risk through both entities simultaneously. Thus, TNF-α and HRV need to be considered when predicating mortality.
authors.affiliation: Institute of Medical Epidemiology, Biostatistics and Informatics, Martin-Luther-University Halle-Wittenberg, Halle/Saale, Germany daniel.medenwald@arcor.de.
authors.forename: Daniel
authors.initials: D
authors.lastname: Medenwald
authors.affiliation: Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Cees A
authors.initials: CA
authors.lastname: Swenne
authors.affiliation: Department of Medicine III, Martin-Luther-University Halle-Wittenberg, Halle/Saale, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Loppnow
authors.affiliation: Department of Medical Informatics, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Jan A
authors.initials: JA
authors.lastname: Kors
authors.affiliation: Institute of Medical Epidemiology, Biostatistics and Informatics, Martin-Luther-University Halle-Wittenberg, Halle/Saale, Germany.
authors.forename: Diana
authors.initials: D
authors.lastname: Pietzner
authors.affiliation: Institute of Medical Epidemiology, Biostatistics and Informatics, Martin-Luther-University Halle-Wittenberg, Halle/Saale, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Tiller
authors.affiliation: Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig, Leipzig, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Thiery
authors.affiliation: Department of Medicine III, Martin-Luther-University Halle-Wittenberg, Halle/Saale, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Nuding
authors.affiliation: Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Karin H
authors.initials: KH
authors.lastname: Greiser
authors.affiliation: Institute of Medical Epidemiology, Biostatistics and Informatics, Martin-Luther-University Halle-Wittenberg, Halle/Saale, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Haerting
authors.affiliation: Department of Medicine III, Martin-Luther-University Halle-Wittenberg, Halle/Saale, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Werdan
authors.affiliation: Institute of Medical Epidemiology, Biostatistics and Informatics, Martin-Luther-University Halle-Wittenberg, Halle/Saale, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kluttig
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001341:Autonomic Nervous System / Q000503:physiopathology*; D002097:C-Reactive Protein / Q000032:analysis; D002318:Cardiovascular Diseases / Q000097:blood / Q000175:diagnosis / Q000401:mortality / Q000503:physiopathology*; D002423:Cause of Death; D004562:Electrocardiography; D005260:Female; D005858:Germany; D006321:Heart / Q000294:innervation*; D006339:Heart Rate; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000175:diagnosis / Q000401:mortality / Q000503:physiopathology*; D018836:Inflammation Mediators / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D011446:Prospective Studies; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000097:blood; D012307:Risk Factors; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: C508600:IL6 protein, human; D018836:Inflammation Mediators; D015850:Interleukin-6; D047888:Receptors, Tumor Necrosis Factor, Type I; C506235:TNFRSF1A protein, human; D014409:Tumor Necrosis Factor-alpha; D002097:C-Reactive Protein
keywords: CRP; Cardiovascular mortality; General population; Heart rate variability; Interleukin 6; Tumour necrosis factor-alpha