PC aggregation provides a compact summary of multivariate HRV data while discarding any redundancies in the highly correlated HRV indices. PC regression also avoids the thorny statistical issue of multiple testing, that is, the inflation of Type I error rates when testing for significance of association between a health outcome and the various individual HRV indices. The second PC, PC2, was most strongly associated with age and was the best predictor of frailty and mortality in older, disabled women. This suggests that PC2 can be a useful, compact measure not only of impaired cardiac autonomic regulation but also of reduction in multisystem physiological complexity associated with frailty and increased risk of mortality. Weak association between age and the traditional HRV indices could be due to the combination of a relatively small sample size and a high prevalence of disability.
We interpret PC2 as capturing the long-range correlation in heartbeat fluctuations across frequencies ranging from VLF to HF. Decrease in PC2 suggests decay in these long-range correlations. In this regard, PC2 is similar to the power-law exponent (PLE), which is the slope of regression line fitted to log(power) versus log(frequency), over frequencies less than 0.02 Hz (20
), that is, ultra-low frequency (ULF) and VLF oscillations. PLE becomes increasingly negative with age. PLE < −1 is associated with increased mortality risk (21
). Interestingly, no changes in ULF power but a linear decline in VLF power has been observed with aging, explaining the increasing steepness of PLE (23
). A decline in VLF will also result in a decrease in PC2. There are important differences, however, between PLE and PC2. PLE is limited to ULF and VLF oscillations, whereas PC2 incorporates LF and HF oscillations, in addition to VLF. Furthermore, PC2, being a linear combination of traditional HRV indices, can be readily determined from standard Holter summaries, whereas PLE estimation requires more sophisticated analytic procedures applied to raw spectrum. Because our Holter ECG recordings were only 2–3 hours long, the PLE, which is estimated from a 24-hour recording, could not be computed in our study. Therefore, we were unable to perform a rigorous comparative evaluation of PC2 and PLE.
Limitations of our study are (a) women-only sample, (b) sample consists of severely disabled older women, (c) cross-sectional assessment of association between frailty and HRV, (d) possibility of confounding due to measurement error in ascertainment of cardiovascular diseases and diabetes status and severity, and (e) possibility of residual confounding in the association between frailty and PC2 due to unascertained diseases and medications. We cannot infer a causal relationship between HRV and frailty due to these limitations. They also threaten the generalizability of our findings. Our findings on the associations between PC2 and outcomes, including frailty and mortality, must be replicated in clinical trials and/or in large epidemiological studies, using the loadings presented in , which are quite similar between WHAS-I and Framingham. The only major difference is in the loading of VLF on PC2. Comparing the correlation matrices () for WHAS-I and Framingham, it can be seen that the correlation between VLF and the other indices, especially LF and HF, is weaker in WHAS-I. Also, the contribution of VLF oscillations to overall variability is lesser (as indicated by a weaker correlation between VLF and SDNN). This results in VLF loading weakly on PC1 and strongly on PC2. Physiologically, this is suggestive of a breakdown in long-range correlations in heart rate time series, which might be related to the high prevalence of disability among WHAS-I participants.
There are encouraging signs that our results are potentially generalizable. Sensitivity analyses (results not shown) demonstrate that the associations of PC2 with outcomes are robust to reasonable changes in PC1 and PC2 loadings. Regression analyses reported in were repeated with PC1 and PC2 scores recomputed using Framingham loadings. Strong associations of PC2 with age, frailty, and mortality persisted. We also conducted a “homogeneous” PCA involving only the frequency domain measures, VLF, LF, and HF. Homogeneous PC2 was similar to “full” PC2 in that it assigned positive weights to VLF and LF and a negative weight to HF. It was as strongly associated with age, frailty, and mortality as full PC2, demonstrating the robustness of our conclusions.
Cardiac autonomic control is impaired in frailty. PC aggregation of traditional HRV indices provided a compact summary of this impairment and also revealed a new index (PC2), which was the better predictor of frailty and mortality in older, disabled women.