Alteration autonomic control of cardiac function during hemodialysis predict cardiovascular outcomes in end stage renal disease patients

www.nature.com/scientificreports OPEN Alteration autonomic control of cardiac function during hemodialysis predict cardiovascular outcomes in end stage renal disease patients Chih-Chin Kao1,2,3, Chi-Ho Tseng 4,5, Men-Tzung Lo4,6, Ying-Kuang Lin4,7, Chien-Yi Hsu8,9,10, Yueh-Lin Wu1,2,3, Hsi-Hsien Chen1,2, Feng-Yen Lin9,10, Chen Lin4,6,11* & Chun-Yao Huang9,10,11* Dialysis-induced hemodynamic instability has been associated with increased risk of cardiovascular (CV) mortality. However, the control mechanisms beneath the dynamic BP changes and cardiac function during hemodialysis and subsequent CV events are not known. We hypothesize that the impaired hemodynamic control can be prognostic indicators for subsequent CV events in end stage renal diseaes (ESRD) patients. To explore the association of hemodynamic parameters and CV events in hemodialysis patients, we enrolled ESRD patients who received chronic hemodialysis without documented atherosclerotic cardiovascular disease and hemodynamic parameters were continuously obtained from the impedance cardiography during hemodialysis. A total of 35 patients were enrolled. 16 patients developed hospitalized CV events. The statistical properties [coefficient of variance (standard deviation / mean value; CoV)] of hourly beat-to-beat dynamics of hemodynamic parameters were calculated. The CoV of stroke volume (SV) and cardiac index (CI) between the 1st and 2nd hour of dialysis were significantly increased in patients without CV events compared to those with CV events. Higher CoV of SVdiff and CIdiff were significantly correlated with longer CV event-free survival, and the area under the receiver operating characteristic (ROC) curve showed fair overall discriminative power (0.783 and 0.796, respectively). The responses of hemodynamic control mechanisms can be independent predictive indexes for lower hospitalized CV events, which implies that these patients who have better autonomic control systems may have better CV outcomes. The risk of cardiovascular (CV) mortality in dialysis patients is approximately 9 times higher than that of the general population1, and young dialysis patients were characterized by extraordinarily high risk2. More than half of the CV events are the result of fatal arrhythmia and congestive heart failure, and some are the result of myocardial infarction3. In addition to the already identified CV risks including hypertension, hyperlipidemia, diabetes4 and electrolytes imbalance5, the intradialytic hypertension/hypotension or autonomic instability were thought to worsen their CV outcome in dialysis patients. Dialysis-induced hemodynamic instability was one of 1 Division of Nephrology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan. Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. 3Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. 4Department of Biomedical Sciences and Engineering, National Central University, Taoyuan city, Taiwan. 5Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan. 6 Center for Biotechnology and Biomedical Engineering, National Central University, Taoyuan city, Taiwan. 7Division of Nephrology, Department of Medicine, Landseed International Hospital, Taoyuan city, Taiwan. 8Institute of Clinical Medicine, National Yang Ming University, Taipei, Taiwan. 9Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Heart Institute, Taipei Medical University, Taipei, Taiwan. 10Division of Cardiology and Cardiovascular Research Center, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan. 11These authors contributed equally: Chen Lin and Chun-Yao Huang. *email: ; 2 Scientific Reports | (2019) 9:18783 | https://doi.org/10.1038/s41598-019-55001-4 1 www.nature.com/scientificreports/ www.nature.com/scientificreports Figure 1. Flow chart of the study. the most common complications, and those patients with unstable hemodynamics during hemodialysis were associated with worse outcomes6. A large retrospective cohort showed that the modest decline of BP between initiation and the end of hemodialysis was accompanied by the most favorable outcomes7. The relationship between the pre- and post-hemodialysis BP changes and all-cause mortality in the end-stage renal disease (ESRD) patients was described as “U- or J-shaped associations with lowest risk around −20 mm-Hg between post- and pre-dialysis BP in two observational studies ”8,9. Furthermore, the greater fluctuation of systolic BP (SBP) measured at 30-min intervals during dialysis was shown to be associated with higher risk of all-cause mortality and CV mortality in these patients10. The BP homeostasis is one of the most sophisticated control mechanisms that incorporates several systems interacting with each other continuously6,11,12. The relatively stable BP in a constantly changing environment is the physiologic response of continuously fine-tuning the hemodynamic variables including cardiac output [(stroke volume (SV) * heart rate (HR)] and systemic vascular resistance (SVR) by the underlying control mechanisms. Increased beat-to-beat BP variability is not only a sign of impaired control systems but also a risk factor for CV events in hypertensive patients13,14. In addition, evidence has shown that the dynamics of beat-to-beat SV or HR can serve as earlier precursors to fluid responsiveness for several critical conditions15–17 before the actual change of BP. The temporal changes of hemodynamic variables in patients undergoing dialysis can be regarded as how the control systems respond18,19 while being exposed to continuous fluid shifts and osmolarity changes. However, few studies focused on continuously monitoring the hemodynamic variables other than BP during hemodialysis, and the relationship between the alteration of cardiovascular systems during hemodialysis and CV events is yet to be reported. We hypothesize that the impaired hemodynamic control can be prognostic indicators for subsequent CV events in ESRD patients and the dynamics of the intradialytic hemodynamic parameters derived from impedance cardiography were quantified to explore the association of hemodynamic parameters and CV events in hemodialysis patients. Results Demographics of our patients. A total of 35 patients were enrolled, and the flow chart of this study is shown in Fig. 1. The mean age of our study objects was 57 ± 14 years and 24 (68.6%) were male. The mean follow-up duration was 531 ± 53 days for all patients, with a mean of 252 ± 56 days in the CV events group, and 765 ± 30 days in the non-CV events group. 16 (45.7%) of them developed CV events, and the remaining patients were event-free until the study end. The demographics are shown in Table 1. The preval (...truncated)