The LF/HF ratio does not accurately measure cardiac sympatho-vagal balance

Power spectral analysis of the beat-tobeat variations of heart rate or the heart period (R–R interval) has become widely used to quantify cardiac autonomic regulation (Appel et al., 1989; Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology, 1996; Berntson et al., 1997; Denver et al., 2007; Thayler et al., 2010; Billman, 2011). This technique partitions the total variance (the “power”) of a continuous series of beats into its frequency components, typically identifying two or three main peaks: Very Low Frequency (VLF) <0.04Hz, Low Frequency (LF), 0.04–0.15Hz, and High Frequency (HF) 0.15–0.4Hz. It should be noted that the HF peak is shifted to a higher range (typically 0.24–1.04Hz) in infants and during exercise (Berntson et al., 1997). The HF peak is widely believed to reflect cardiac parasympathetic nerve activity while the LF, although more complex, is often assumed to have a dominant sympathetic component (Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology, 1996; Berntson et al., 1997; Billman, 2011). Based upon these assumptions, Pagani and co-workers proposed that the ratio of LF to HF (LF/HF) could be used to quantify the changing relationship between sympathetic and parasympathetic nerve activities (i.e., the sympatho-vagal balance) (Pagani et al., 1984, 1986; Malliani et al., 1991) in both health and disease. However, this concept has been challenged (Kingwell et al., 1994; Koh et al., 1994; Hopf et al., 1995; Eckberg, 1997; Houle and Billman, 1999; Billman, 2011). Despite serious and largely under-appreciated limitations, the LF/HF ratio has gained wide acceptance as a tool to assess cardiovascular autonomic regulation where increases in LF/HF are assumed to reflect a shift to “sympathetic dominance” and decreases in this index correspond to a “parasympathetic dominance.” Therefore, it is vital to provide a critical assessment of the assumptions upon which this concept is based. The hypothesis that LF/HF accurately reflects sympatho-vagal balance rests upon several interrelated assumptions as follows (modified from Eckberg, 1997): (1) cardiac sympathetic nerve activity is a major, if not the exclusive, factor responsible for the LF peak of the heart rate power spectrum; (2) cardiac parasympathetic is exclusively responsible for the HF peak of the heart rate power spectrum; (3) disease or physiological challenges provoke reciprocal changes in cardiac sympathetic and parasympathetic nerve activity (i.e., increases in cardiac parasympathetic nerve activity are always accompanied with corresponding reductions in cardiac sympathetic nerve activity and vice versa); and (4) there is a simple linear interaction between the effects of cardiac sympathetic and cardiac parasympathetic nerve activity on heart rate variability (HRV). As previously noted, frequency domain analysis of HRV usually reveals two or more peaks, a lower frequency (<015Hz) and a higher frequency peak (>0.15Hz) that are often assumed to correspond to cardiac sympathetic and cardiac parasympathetic neural activity, respectively (Pagani et al., 1984, 1986; Malliani et al., 1991). However, accumulating evidence clearly demonstrates that this assumption is naïve and greatly oversimplifies the complex non-linear interactions between the sympathetic and the parasympathetic divisions of the autonomic nervous system (Berntson et al., 1997; Eckberg, 1997; Parati et al., 2006; Billman, 2009, 2011). This is particularly true with regards to the relationship between LF power and cardiac sympathetic regulation (Randall et al., 1991; Ahmed et al., 1994; Kingwell et al., 1994; Hopf et al., 1995; Eckberg, 1997; Houle and Billman, 1999; Parati et al., 2006; Billman, 2009, 2011). The LF peak of the heart rate power spectrum is reduced by at least 50% by either cholinergic antagonists or selective parasympathectomy (Akselrod et al., 1981; Randall et al., 1991; Houle and Billman, 1999). Importantly, this peak is not completely eliminated by the combination of selective denervation and betaadrenoceptor blockade (Randall et al., 1991);∼25% of the peak remains after this treatment. As a consequence, LF/HF often actually increases from baseline values when both parasympathetic and adrenergic nerve activity have been blocked. For example, using the data reported by Randall and co-workers (Randall et al., 1991), LF/HF increased from a baseline value of 1.1–8.4 when selective parasympathetic denervation was combined with beta-adrenergic receptor blockade, falsely suggesting a major shift to sympathetic dominance! In a similar manner, interventions that would be expected to increase cardiac sympathetic activity, such as acute exercise or myocardial ischemia, not only failed to increase LF power but actually provoked significant reductions in this variable (Houle and Billman, 1999), once again yielding LF/HF values that are difficult to interpret. Indeed, despite large increases in heart rate, LF/HF ratio was largely unaffected by either acute myocardial ischemia, exercise, or the cholinergic antagonist atropine sulfate (Houle and Billman, 1999). Finally, direct recording of sympathetic nerve activity failed to correlate with LF power in either healthy subjects or patients with heart failure (Hopf et al., 1995; Notarius and Floras, 2001; Jardine et al., 2002; Moak et al.,