Combination of R-R Interval and Crest Time in Assessing Complexity Using Multiscale Cross-Approximate Entropy in Normal and Diabetic Subjects

The present study aimed at testing the hypothesis that application of multiscale cross-approximate entropy (MCAE) analysis in the study of nonlinear coupling behavior of two synchronized time series of different natures [i.e., R-R interval (RRI) and crest time (CT, the time interval from foot to peakof a pulse wave)] could yield information on complexity related to diabetes-associated vascular changes. Signals of a single waveform parameter (i.e., CT) from photoplethysmography and RRI from electrocardiogram were simultaneously acquired within a period of one thousand cardiac cycles for the computation of different multiscale entropy indices from healthy young adults (n = 22) (Group 1), upper-middle aged non-diabetic subjects (n = 34) (Group 2) and diabetic patients (n = 34) (Group 3). The demographic (i.e., age), anthropometric (i.e., body height, body weight, waist circumference, body-mass index), hemodynamic (i.e., systolic and diastolic blood pressures), and serum biochemical (i.e., high- and low-density lipoprotein cholesterol, total cholesterol, and triglyceride) parameters were compared with different multiscale entropy indices including small- and large-scale multiscale entropy indices for CT and RRI [MEI(SS)(CT), MEI(LS)(CT), MEI(SS)(RRI), MEI(LS)(RRI), respectively] as well as small- and large-scale multiscale cross-approximate entropy indices [MCEI(SS), MCEI(LS), respectively]. The results demonstrated that both MEI(LS)(RRI) and MCEI(LS) significantly differentiated between Group 2 and Group 3 (all p < 0.017). Multivariate linear regression analysis showed significant associations of MEI(LS)(RRI) and MCEI(LS)(RRI,CT) with age and glycated hemoglobin level (all p < 0.017). The findings highlight the successful application of a novel multiscale cross-approximate entropy index in non-invasively identifying diabetes-associated subtle changes in vascular functional integrity, which is of clinical importance in preventive medicine.