Identifying Cardiovascular Risk by Nonlinear Heart Rate Dynamics Analysis: Translational Biomarker from Mice to Humans

Figures

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  Figure 1. Linear heart rate measures in mice. Heart rate (A) and SDNN (B) as a function of treatment according to their Euclidian clustering (C). Clustering is based on the two parameters (A,B) weighed with equal contribution. Blue values and labels indicate behavioral interventions. HR (A) and SDNN values (B) indicate the generally inverse relation between these two measures. Values are based on 18 min ECG recordings in mice. Asterisks denote significant differences versus control group values: * p < 0.05, ** p < 0.01, *** p < 0.001.

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  Figure 2. Nonlinear measures in mice. DFA measures αfast (A) and αslow (B) as a function of treatment according to Euclidian clustering (C). Clustering is based on the two parameters (A,B) weighed with equal contribution. Blue values and labels indicate behavioral interventions. Partial (yellow boxes) to complete (red boxes) decoupling of physiological regulatory systems (autonomic nervous system control) are visible at both edges of the cluster with the inner range covering physiological values. Values are based on 18 min ECG recordings in mice. Asterisks denote significant differences versus control group values: * p < 0.05, ** p < 0.01, *** p < 0.001.

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  Figure 3. Comparison of linear and nonlinear clustering. Euclidian clustering is based on linear time-domain (NN and SDNN, as shown in Figure 1C) and nonlinear DFA measures (αfast and αslow, as shown in Figure 2C). Clustering differences are presented between the linear measures (according to sympathetic (SNS) and parasympathetic nervous system (PNS) tone, as indicated by arrows (↑, ↓)), and nonlinear measures (from physiology to pathology as extremes), as indicated by lines between the two dendrograms. Smallest and largest positional differences are indicated by green and red lines, respectively. Pathology is characterized by PNS overactivation, which is similarly clustered by linear and nonlinear measures. In contrast, PNS inhibition by robinul (glycopyrrolate, R), atropine (A) and sotalol plus atropine (SA) is differently clustered. Additional abbreviations: 6, 6-OH-dopamine; 8, 8-OH-DPAT; An, anesthesia by ketamine/xylazine; Co, control; D, DSP-4; Do, dobutamine; H, hexamethonium; I, isoproterenol; N, neuropeptide Y; Ni, sodium nitroprusside; No, novelty; oC, ovine CRF; P, phenylephrine; Re, restraint; S, sotalol; Sl, sleep; Z, zatebradine.

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  Figure 4. Examples of 5 heartbeat interval time series (note the different Y-axis ranges; (left panels)), and corresponding DFA scaling coefficients (right panels) of five patients evaluated for potential cardiac infarction due to acute chest pain and who did not display any ECG alterations (no sign of infarction). These 5 out of 323 patients were identified in a blinded study as high-risk patients for cardiac death based on the strong deviation of DFA coefficients for αslow and/or αfast from the physiological value of α~1. Three patients (b113, b141 and b159) were admitted to the intensive care unit (ICU). Two patients (b100 and b137) were sent home with telemetric ECG recording but in retrospect should have been admitted to the hospital (modified from [27]).