The most important finding of this study is that the ratio of LF:HF gain for baroreflex feedback increases markedly in CFS patients in response to orthostatic stress, compared to virtually no change in normal controls. The significant increase in the gain ratio was due to a combination of increased LF gain and decreased HF gain in the CFS group, while the controls only had a reduction in HF gain. These findings indicate that mild orthostatic stress leads to a small reduction of parasympathetically mediated heart rate control in both CFS patients and controls (decreased HF gain), but a significant increase in sympathetically mediated baroreflex gain in CFS patients (increased LF gain) which is not observed in controls.
In addition, reduced HF SBP variability was observed in CFS patients compared to controls, possibly reflecting a reduced effect of respiration on RR or SBP in CFS patients.
Blood pressure variability in CFS
The mechanical effect of ventilation is a significant source of blood pressure variability in the HF range (Malpas
2002; Zhang et al.
2002). Thus, our findings of reduced HF variability of SBP, which has not been previously reported, suggest either an altered ventilatory pattern or an altered effect of respiratory activity on SBP among CFS patients. There are several reports of reduced heart rate variability in the HF range, both at rest (Stewart
2000) and during orthostatic challenge in CFS patients (Stewart
2000; Wyller et al.
2007c,
2008a). Since respiratory activity is also the primary source of heart rate variability in the HF range (Saul
1990), the reduced HF variability of SBP observed here could be due to a reduced effect of respiration on heart rate (respiratory sinus arrhythmia). However, since respiratory patterns were not controlled and a quantitative respiratory signal was not measured in these studies, the precise origin of reduced SBP variability in the HF range cannot be determined. Future research could focus on possible alterations in CFS ventilatory patterns and the relationships between ventilation and both heart rate and blood pressure in these patients.
No differences between CFS patients and controls were observed for blood pressure variability in the LF range either at rest or during LBNP. An important source of such variability is sympathetically controlled vasomotion (Malpas
2002), which consequently appears to be unaltered in CFS. Although these findings are consistent with previously reported data from our laboratory (Wyller et al.
2007c), they contrast with Stewart’s (
2000) study of adolescent CFS patients, where increased blood pressure variability was noted in the LF range during 70° head-up tilt. This apparent inconsistency could be entirely explained by different experimental protocols: First, LBNP and upright tilt, although similar in terms of physiological stress, do not result in identical hemodynamic responses. Second, LBNP of −20 mmHg used in this study, corresponding to head-up tilt of 20°–30°, represents a much milder orthostatic challenge than 70° head-up tilt and might have been insufficient to provoke a difference between the two groups.
Dynamic closed-loop baroreflex assessment in CFS
The baroreflex feedback mechanism includes both sympathetic and parasympathetic neural connections emanating from the brain stem cardiovascular control center to the sinus node (Lanfranchi and Somers
2002; Saul
1990). Because sympathetic heart rate control is relatively slow it only controls heart rate changes in the LF range, whereas the parasympathetic system has broad-band characteristics, operating in the LF as well as the HF range. Previous studies applying the same bivariate technique used here have demonstrated that during upright posture the α-gain decreases in both LF and HF ranges (Barbieri et al.
2002), presumably secondary to parasympathetic withdrawal. With the milder orthostatic stress in this study, we observed a similar decrease for both controls and CFS patients but only in the HF range. Among CFS patients, α-gain LF actually increased during LBNP. The net result was a marked and significant increase in the ratio α-gain LF/α-gain HF, strongly suggesting that in addition to the reduced parasympathetic heart rate control, there was enhanced sympathetic heart rate control mediated by the baroreflex.
The observed increase in the sympathetic component of the baroreceptor feedback with even mild orthostatic stress in CFS patients indicates
early sympathetic activation and may reflect diminished
baroreflex reserve for more severe stressors. These changes further suggest that the baroreflex may have a diminished ability to buffer a variety of internal and external influences on arterial pressure, but particularly those related to upright activity and ambulation, in line with our previous report on the combined effect of orthostatic stress and isometric exercise in CFS patients (Wyller et al.
2008b).
The function of the baroreceptor reflex has been addressed in two previous CFS studies. In a group of adolescent CFS patients and controls, Stewart (
2000) reported significantly lower α-gain in the HF as well as the LF range among CFS patients, both during rest and during 70° head-up tilt. In adult CFS patients, Peckerman et al. (
2003) reported enhanced decline in baroreceptor sensitivity upon standing as compared to controls. However, the sequential method adopted in the latter study does not allow separate estimation of LF and HF gain, making it most sensitive for parasympathetic heart rate control. Differences from the current study might be explained by different inclusion criteria, experimental protocols and mathematical algorithms. Taken together, however, like this study, they indicate a sympathetic predominance of baroreflex heart rate control during orthostatic stress in CFS patients.
Cardiovascular dysregulation in CFS
In agreement with past reports, the findings from this study confirm that CFS patients have functional disturbances of the autonomic nervous system affecting cardiovascular regulation. The underlying mechanism for this disturbance has been disputed.
One possibility would be that CFS patients suffer from absolute or relative hypovolemia, which has indeed been reported previously (Farquhar et al.
2002; Streeten
2001; Streeten et al.
2000; Hurwitz et al.
2009). However, detailed studies of baroreflex function with techniques similar to ours have revealed a reduced LF baroreflex gain at rest following blood donation (Triedman et al.
1993) and furosemide treatment (Iwasaki et al.
2000) and a further attenuation of LF baroreflex gain in hypovolemic individuals during orthostatic stress (Triedman et al.
1993). Moreover, an attenuation of LF baroreflex gain has been demonstrated during experimentally induced hypovolemia by LBNP (Barbieri et al.
2002). Contrasting these results, we found equal LF baroreflex gain among controls and CFS patients at rest and increased LF baroreflex gain in CFS patients during orthostatic stress, making hypovolemia an unlikely explanation.
A second possibility would be cardiovascular deconditioning due to physical inactivity in CFS patients (De Lorenzo et al.
1998). The deconditioning influence on cardiovascular control appears to be partly a consequence of concomitant hypovolemia (Iwasaki et al.
2000), adding to the relevance of the reasoning above. Furthermore, in adults, both sedentary and gravitational deconditionings seem to be associated with attenuated sympathetic responsiveness during orthostatic stress (Levine et al.
1991; Sun et al.
2003), and endurance training in sedentary individuals tends to increase LF baroreflex gain at rest (Iwasaki et al.
2003). In a previous study of healthy adolescents, the degree of aerobic fitness did not predict cardiac autonomic responses during head-up tilt (Brunetto et al.
2005). Finally, no one of the CFS patients in this study was permanently bedridden, and previous evidence suggests that intermittent exposure to gravity during a bed-rest period is sufficient to prevent gravitational deconditioning (Sun et al.
2003; Zhang et al.
2000). Taken together, cardiovascular deconditioning does not seem to explain the results reported in this study.
A third possible explanation is a discrete disturbance of CNS autonomic control, such as temporary central resetting, redefining the homeostatic range of the baroreflex (Goldstein
2001). The smaller negative value for α-phase LF among CFS patients as compared to controls during LBNP suggests a shortened response time within the sympathetic part of the baroreflex, possibly caused by central enhancement of neural transmission. Furthermore, as orthostatic challenge neither altered feedforward β-gain nor DBP variability in the LF range differently among CFS patients, the sympathetic predominance does not seem to be a reflection of blood pressure buffering, further pointing towards a central mechanism. Central resetting is not a common feature of orthostatic challenge, but does occur during aerobic exercise, resulting in attenuation of parasympathetic and predominance of sympathetic heart rate control (Macor et al.
1996; Spadacini et al.
2006), analogous to what we report in this study.
Data quality and study limitations
The responses among healthy adolescents to LBNP were similar in all respect to responses among healthy adults in previously reported LBNP experiments from our institutions, supporting the validity of this study (Barbieri et al.
2002). Furthermore, coherence values were well above 0.5 for all computed bivariate spectra, supporting the validity of the calculated gain and phase values.
Blood and/or plasma volume were not measured, leaving the question of hypovolemia unresolved. Finally, respiratory activity has been shown to change during orthostatic challenge and could therefore influence cardiovascular variability (Cooke et al.
1999); however, ventilation was not controlled for in this study.
Our findings of cardiovascular dysregulation point towards a discrete disturbance of CNS autonomic control in CFS patients. This may represent a distinct pathophysiologic phenomenon possibly conceptualized as a mismatch phenomenon, in which sensory input during orthostatic challenge evokes a disproportional or ‘untuned’ autonomic response. This concept is compliant with recently proposed theories of CFS pathophysiology, such as the theory of central sensitization (Yunus
2007) and our recently proposed theory of sustained arousal (Wyller et al.
2009). On a more general level, such a concept is in line with recent models on the mechanistic link between psychosocial stressors and cardiovascular morbidity (Goldstein
2001; Lucini et al.
2008). Further research should aim at exploring these relations in more detail, both in CFS and other related disorders.