Sex and Rate Change Differences in QT/RR Hysteresis in Healthy Subjects

Abstract

While it is now well-understood that the extent of QT interval changes due to underlying heart rate differences (i.e., the QT/RR adaptation) needs to be distinguished from the speed with which the QT interval reacts to heart rate changes (i.e., the so-called QT/RR hysteresis), gaps still exist in the physiologic understanding of QT/RR hysteresis processes. This study was designed to address the questions of whether the speed of QT adaptation to heart rate changes is driven by time or by number of cardiac cycles; whether QT interval adaptation speed is the same when heart rate accelerates and decelerates; and whether the characteristics of QT/RR hysteresis are related to age and sex. The study evaluated 897,570 measurements of QT intervals together with their 5-min histories of preceding RR intervals, all recorded in 751 healthy volunteers (336 females) aged 34.3 ± 9.5 years. Three different QT/RR adaptation models were combined with exponential decay models that distinguished time-based and interval-based QT/RR hysteresis. In each subject and for each modelling combination, a best-fit combination of modelling parameters was obtained by seeking minimal regression residuals. The results showed that the response of QT/RR hysteresis appears to be driven by absolute time rather than by the number of cardiac cycles. The speed of QT/RR hysteresis was found decreasing with increasing age whilst the duration of individually rate corrected QTc interval was found increasing with increasing age. Contrary to the longer QTc intervals, QT/RR hysteresis speed was faster in females. QT/RR hysteresis differences between heart rate acceleration and deceleration were not found to be physiologically systematic (i.e., they differed among different healthy subjects), but on average, QT/RR hysteresis speed was found slower after heart rate acceleration than after rate deceleration.

Keywords: QT/RR adaptation; QT/RR hysteresis; age influence; best-fit models; healthy subjects; non-linear regression modelling; sex differences.

Figure 1

Example of short-term QT/RR relationship. The top panel shows a 10-s electrocardiogram of a 22-year-old healthy female. The recording shows substantial sinus arrhythmia. The shortest and longest RR intervals were 1,019 and 1,528 ms, respectively. The red and blue arrows mark QRS complexes preceded by the shortest and longest RR intervals, respectively. The bottom panel shows images of superimposed QRS-T complexes of all the 12 leads of these complexes (in the respective colours). The QT interval measurements ensuring morphological correspondence (Hnatkova et al., 2009) of both complexes led to the same QT interval of 411 ms. Thus, relating each of the QT intervals of the tracing to the preceding RR interval (or assuming a substantial immediate beat-to-beat effect of each RR interval on the subsequent QT interval) would have led to substantial inaccuracy (for instance, if these two QT interval measurements are corrected for the preceding RR interval using the Fridericia Formula, a physiologically non-sensical beat-to-beat QTc change of more than 50 ms is calculated).

Figure 2

Characteristic of the study population and electrocardiographic measurements. Top panel shows cumulative distributions of the ages of investigated subjects. The middle panel shows cumulative distributions of the 90% ranges of intra-subject heart rates in study subjects (that is, in each study subject, difference between the 5th and 95th percentiles of heart rates at which the QT interval was measured was calculated, and the panel shows the cumulative distribution of these differences). The bottom panel shows the cumulative distributions of the intra-subject 5th and 95th percentiles of the RR interval slopes preceding QT interval measurements (that is, for each subject, 60-s slopes of RR interval durations vs. their index numbers were obtained for each RR history of QT interval measurements, and the graphs show the distribution of the intra-subject 5th and 95th percentiles of these slopes. In each subject, the 5th percentile corresponded to heart rate deceleration, distributions below 0, and the 95th percentile corresponded to heart rate acceleration, distributions above 0). In each graph, the red and blue lines correspond to the female and male subjects, respectively.

Figure 3

Cumulative distributions of intra-subject residuals of QT/RR^H regression models for the curvature model (top panel), linear model (middle panel), and log-log model (bottom panel). In each of the panels, the red and blue lines correspond to females and males, respectively; the full and dashed lines correspond to the time-based and interval-based QT/RR hysteresis models, respectively.

Figure 4

Scatter diagrams of the intra-individual differences among the different QT/RR^H regression models (all combined with the time-based QT/RR hysteresis model). The top panel shows the differences between the residuals of the linear and curvature models and the residuals of the curvature model, the middle panel shows the differences between the residuals of the log-log and curvature models and the residuals of the curvature model, and the bottom panel shows the differences between the residuals of the log-log and linear models and the residuals of the linear model. In each panel, the red circle and blue square marks correspond to females and males, respectively. The red and blue horizontal lines show the mean values of the residual differences in females and males, respectively. The light-coloured red and blue bands show the spans of mean ± standard deviation of the residual differences in females and males, respectively; the light-coloured violet bands show the overlap of the mean ± standard deviation bands between both sexes.

Figure 5

Cumulative distributions of the subject-specific characteristics of the curvature QT/RR^H model combined with time-based curvature QT/RR hysteresis model. The distributions of model curvature (parameter γ), mean heart rate derived from the RR^H values, and mean individually corrected QTc intervals are shown in the top, middle, and bottom panels, respectively. The red and blue lines correspond to females and males, respectively.

Figure 6

Cumulative distributions of intra-subject slopes of QT/RR^H regression models for the curvature model (top panel), linear model (middle panel), and log-log model (bottom panel). In each of the panels, the red and blue lines correspond to females and males, respectively; the full and dashed lines correspond to the time-based and interval-based QT/RR hysteresis models, respectively.

Figure 7

Cumulative distributions of QT/RR hysteresis time-constants derived from the combination with the QT/RR^H curvature model (top panel), linear model (middle panel), and log-log model (bottom panel). In each of the panels, the red and blue lines correspond to females and males, respectively.

Figure 8

Cumulative distributions of QT/RR hysteresis interval constants derived from the combination with the QT/RR^H curvature model (top panel), linear model (middle panel), and log-log model (bottom panel). In each of the panels, the red and blue lines correspond to females and males, respectively.

Figure 9

Scatter diagrams of the intra-individual differences among regression residuals comparing the interval-based and time-different QT/RR hysteresis models. The differences between the residuals and the residuals of the time-based QT/RR hysteresis model are shown for the QT/RR^H curvature model in the top panel, linear model in the middle panel, and log-log model in the bottom panel. In each panel, the red circle and blue square marks correspond to females and males, respectively. The red and blue horizontal lines show the mean values of the residual differences in females and males, respectively. The light-coloured red and blue bands show the spans of mean ± standard deviation of the residual differences in females and males, respectively; the light-coloured violet bands show the overlap of the mean ± standard deviation bands between both sexes.

Figure 10

Scatter diagrams showing age influence on the subject-specific curvatures of the QT/RR^H curvature model combined with time-based QT/RR hysteresis (top panel), on the subject-specific hysteresis time-constants of the QT/RR^H curvature model (middle panel), and on the mean of individually corrected QTC intervals of the QT/RR^H curvature model combined with time-based QT/RR hysteresis (bottom panel). In each panel, the red circle and blue square marks correspond to females and males, respectively. The red and blue lines show the linear regression models between the displayed characteristics and age, the light-coloured red and blue bands show the 95% confidence intervals of the linear regressions, and the light-coloured violet areas show the overlaps among the regression confidence intervals of both sexes.

Figure 11

Cumulative densities of subject-specific differences among hysteresis time constants during heart rate acceleration and deceleration. The top, middle, and bottom panels show the differences for the curvature, linear, and log-log QT/RRH models, respectively. In each panel, the red and blue lines correspond to females and males, respectively.

Figure 12

Cumulative densities of subject-specific differences among hysteresis interval constants during heart rate acceleration and deceleration. The top, middle, and bottom panels show the differences for the curvature, linear, and log-log QT/RR^H models, respectively. In each panel, the red and blue lines correspond to females and males, respectively.

Figure 13

Scatter diagrams of subject-specific differences among hysteresis time constants during heart rate acceleration and deceleration plotted against their intra-subject averages. The top, middle, and bottom panels show the differences for the curvature, linear, and log-log QT/RR^H models, respectively. In each panel, the red circle and blue square marks correspond to females and males, respectively. The red and blue horizontal lines show the mean values of the residual differences in females and males, respectively. The light-coloured red and blue bands show the spans of mean ± standard deviation of the residual differences in females and males, respectively; the light-coloured violet bands show the overlap of the mean ± standard deviation bands between both sexes.

Figure 14

Scatter diagrams of subject-specific differences among hysteresis interval constants during heart rate acceleration and deceleration plotted against their intra-subject averages. The top, middle, and bottom panels show the differences for the curvature, linear, and log-log QT/RR^H models, respectively. In each panel, the red circle and blue square marks correspond to females and males, respectively. The red and blue horizontal lines show the mean values of the residual differences in females and males, respectively. The light-coloured red and blue bands show the spans of mean ± standard deviation of the residual differences in females and males, respectively; the light-coloured violet bands show the overlap of the mean ± standard deviation bands between both sexes.

Figure 15

Example of the effect of incorporating QT/RR hysteresis correction to the study of QT/RR relationship. The data (1,440 separate measurements) were obtained in a 32-year-old female. The QT intervals (the same values in all panels) are related to the duration of RR interval preceding the QT measurement (top left panel), RR interval average over 10 s preceding the QT measurement (top right panel), RR interval average over 20 s preceding the QT measurement (bottom left panel), and RR interval duration corrected by a subject-specific exponential decay model of QT/RR hysteresis (bottom right panel). Note the changes in the compactness of the QT/RR relationship.