Frailty and Impaired Cardiac Autonomic Control: New Insights From Principal Components Aggregation of Traditional Heart Rate Variability Indices

HEALTHY human functioning requires the integration of a complex network of physiological systems (eg, respiratory, cardiovascular, neuroendocrine, immune, and metabolic) that enable the organism to maintain homeostasis in the face of internal and external stressors. Age-related deterioration in homeostatic regulatory mechanisms leads to a loss of complexity in their output. For example, the degradation of autonomic control mechanisms results in a loss of complexity in heart rate signal (1,2). Impaired homeostatic regulation, reflected by this loss of complexity, compromises the ability to respond properly to stressors. Frailty is a state of critical loss of physiological complexity that results in heightened vulnerability to stressors (3). Frail older adults can be vulnerable to stressors such as new medications, viral infections, or emotional trauma. Frailty has been described as a geriatric wasting syndrome, characterized by decreased strength, low physical activity, depleted energy, and unintentional weight loss (4). Evidence that a phenotype of frailty is predictive of adverse outcomes independent of advanced age and disease (5) supports the hypothesis that frailty possesses an independent etiology (6–8). Risk assessment tools are needed for predicting older adults at high risk for becoming frail and for accurately identifying those who are vulnerable to stressors. In addition to information from traditional geriatric assessments, physiological measures of homeostatic integrity may be valuable components of such risk assessment tools. Attention has recently been focused on developing measures to describe the dynamics of physiological systems and on using them to distinguish healthy function from diseases. Much of this work has investigated how cardiovascular homeostasis is maintained by multiple physiological control systems, chief among them, the autonomic nervous system (ANS). Cardiac control by the ANS can be examined by studying the heart rate signal derived from digitized electrocardiogram (ECG) (9,10). A popular approach is to characterize the variability in the time between successive heartbeats. Methods to quantify heart rate variability (HRV) can be broadly classified into two categories: (a) traditional time and frequency domain measures and (b) measures based on nonlinear dynamics (11). This article has two objectives: (1) to demonstrate that the cardiac autonomic function, as reflected by HRV, is impaired in frail older adults and (2) to develop a novel, integrative index of HRV that aggregates the traditional time and frequency domain measures. The aggregate index is a linear combination of the log-transformed indices obtained using a principal components analysis (PCA), a powerful and versatile tool for multivariate analysis (12). We test whether (a) the structure of dominant PCs is consistent across multiple studies (Women's Health and Aging Study-I [WHAS-I] and Framingham), (b) PC2 is correlated with age (independently of diseases), (c) PC2 is associated with frailty (independently of age and diseases), and (d) PC2 is a predictor of 5-year mortality (independently of age and diseases).