3.5 Resting heart rate
The most commonly assessed HR parameter was (RHR), which was assessed in 43 studies (patients n = 1766, controls n = 1291). Studies varied regarding the body position used to assess RHR, with 16 studies (patients n = 1059, controls n = 548) using a seated/reclined position (RHRseated), and 26 (patients n = 707, controls n = 743) using a supine position (RHRsupine). Meta-analysis revealed ME/CFS patients had a RHR that was ∼4 beats/minute faster compared to controls (MD ± 95% CI = 4.14 ± 1.30, P < .001; Fig. 2), but with significant heterogeneity between studies (P < .001, I2 = 62%). Subgroup analysis revealed a similar difference between ME/CFS patients and controls for RHRsupine (4.02 ± 2.11, P < .001), and RHRseated (4.53 ± 2.40, P < .001), with significant heterogeneity amongst studies evaluating RHRsupine (P < .001, I2 = 73%).
3.6 Maximal heart rate
HRmax was reported in 20 studies (patients n = 989, controls n = 568), which used 2 different exercise modalities (cycling, 13 studies; and treadmill walking, 7 studies) to elicit a maximal response. Five studies (patients n = 111, controls n = 123) – four of which employed a cycling protocol – based the attainment of a maximal response on accepted criteria and assessed true HRmax, while the remaining 15 studies (patients n = 878, controls n = 445) only reported the highest HR achieved during testing, and is likely to represent symptom limited peak HR (HRpeak), rather than a true HRmax.
Meta-analysis showed HRmax values were found to be lower for ME/CFS patients compared to controls (–13.81 ± 4.14, P < .001, Fig. 3), but were also affected by significant heterogeneity (P < .001, I2 = 78%). Subgroup analysis showed the difference between ME/CFS patients and controls was considerable in studies which measured symptom limited HRpeak (–16.62 ± 4.68, P < .001), with significant heterogeneity between studies (P < .001, I2 = 74%). Comparatively, in studies which assessed true HRmax the difference between ME/CFS patients and controls was smaller, albeit still significant (–5.81 ± 3.34, P < .001), with no heterogeneity present (P = .88, I2 = 0%).
3.7 Heart rate during submaximal exercise
HR during submaximal exercise was reported by 14 studies (patients n = 837, controls n = 496), with 10 studies using cycling exercise, and 4 studies using treadmill walking exercise (Table 1 ). Six studies (patients n = 539, controls n = 313) reported HR at a particular submaximal exercise ‘threshold’ (anaerobic threshold [AT], ventilatory threshold [VT], or lactate threshold [LT]), which were representative of the transition from predominately aerobic to predominately anaerobic energy systems (HRthreshold). In addition, nine studies reported a steady state HR response (HRsteadystate) at a given submaximal workload, with Blackwood et al reporting HR's at both a light absolute workload, and at a workload designed to elicit 85% of maximal HR. Seven (patients n = 244, controls n = 129) studies reported HRsteadystate during workloads that were likely below submaximal exercise threshold (AT, VT or LT), while 3 studies[27,36,67] (patients n = 54, controls n = 54) reported a HRsteadystate that was likely to be at or above submaximal exercise threshold (AT, VT, or LT).
Given the variations in the ways exercise HR was recorded and reported, with different thresholds being assessed in addition to varying exercise intensities at, above or below those thresholds, meta-analysis was performed separately for each HR parameter assessed during submaximal exercise. Analysis of HRthreshold revealed a moderate difference, with HRs being lower in ME/CFS patients compared to healthy controls (SMD ± 95% CI = –0.44 ± 0.31, P = .005), albeit with significant heterogeneity (P = .04, I2 = 56%; Fig. 4). No difference was found between ME/CFS patients and controls for HRsteadystate for workloads that were either likely below (0.09 ± 0.30, P = .59) or likely above submaximal exercise threshold (AT, VT, or LT) (0.30 ± 0.69, P = .40).
3.8 Heart rate during head-up tilt testing
Nine studies (patients n = 285, controls n = 257) reported HR in response to HUTT (HRtilt) (Table 1 ). Eight studies (patients n = 208, controls n = 188) reported an absolute HR value during HUTT (peak HR, end HR, etc) and 3 studies (patients n = 77, controls n = 69) reported the ΔHR in response to HUTT.[41,43,66] Meta-analysis revealed HRtilt was higher in ME/CFS patients than it was in controls (SMD ± 95% CI = 0.92 ± 0.24, P < .001; Fig. 5). Subgroup analysis revealed that HRtilt was increased in ME/CFS patients compared to controls, regardless of whether data were reported as the peak HR during a short (1.23 ± 0.40, P < .001) or long (0.86 ± 0.36, P < .001) duration HUTT, or if data were reported as the ΔHR during HUTT (0.74 ± 0.44, P = .001).
3.9 Orthostatic heart rate response
The orthostatic HR response (HROR) was reported in 6 studies (patients n = 197, controls n = 131) (Table 1 ). Five studies[28,29,59,62,68] reported HROR in response to standing up after a period of supine rest, while 1 study reported the effect of standing up following sitting. Meta-analysis showed HROR was higher for ME/CFS patients compared to controls (SMD ± 95% CI = 0.50 ± 0.27, P < .001; Fig. 6). Subgroup analysis revealed there was a moderate difference when HROR was reported as the ΔHR upon moving from lying/sitting to standing, with ME/CFS patients having a higher ΔHR than controls (0.86 ± 0.46, P < .001), with a similar finding, albeit of a smaller magnitude, also found for the peak HR obtained upon standing (0.34 ± 0.27, P = .01).
3.10 Resting heart rate variability
Measures of resting HRV (HRVrest) were reported in 13 studies (patients n = 294, controls n = 270) (Table 1 ). Seven studies recorded HRVrest in a supine position, while 3 [39,45,84] recorded HRVrest while seated/reclined. Two studies[60,85] recorded HRVrest during overnight sleep. Frequency domain HRVrest measures were used in 12 studies, with 1 study reporting only time domain analyses, and 2 studies[31,45] reporting both frequency and time domain analyses.
Parameters of HRVrest from included studies were meta-analysed separately. ME/CFS patients had a higher ratio between low frequency and high frequency power (LF/HF) (SMD ± 95% CI = 0.20 ± 0.25, P = .11) than controls, and a lower high frequency power (HFP) (–0.34 ± 0.22, P = .002) and root mean of the sum of squares of beat to beat deviations (RMSSD) (–0.37 ± 0.32, P
= .02) (Fig. 7). No differences were found for low frequency power (LFP) (0.39 ± 0.22, P < .001), Vagal Power (–1.86 ± 2.08, P = .08), or sleeping LF/HF ratio (–0.52 ± 2.48, P
= .68), with significant heterogeneity for Vagal Power (P = .006, I2 = 87%), and sleeping LF/HF (P < .001, I2 = 96%).
3.11 Heart rate variability during head-up tilt testing
Two studies (patients n = 40, controls n = 24) reported HRV during HUTT[40,69] (HRVtilt) (Table 1 ). Both studies reported exclusively frequency domain parameters, with each reporting on LFP, HFP, and LF/HF ratio. Meta-analysis found no difference between ME/CFS patients and controls for LFP (SMD ± 95% CI = 0.44 ± 0.87, P = .32; Fig. 8), HF power (0.29 ± 0.51, P = .27), or LF/HF ratio (0.35 ± 0.51, P = .18).
3.12 Heart rate during mental task(s)
Five studies (patients n = 107, controls n = 116) reported the HR response to a mental task (HRmentaltask) (Table 1 ). Subgroup analysis revealed no significant effect for HRmentaltask when reported as the average HR during the tasks in 4 studies 6451, (SMD ± 95% CI = 0.25 ± 0.32, P = .57) (Fig. 9). One study reported HRmentaltask as the ΔHR during task, again with no significant difference between ME/CFS and controls (-0.29 ± 0.45, P = .21).
3.13 Daily average heart rate
Daily average HR (HRdailyaverage) was reported in 2 studies[58,87] (patients n = 80, controls n = 162) (Table 1 ). Both studies used the same measurement techniques and reported data in the same way – HR data were measured through ECG monitoring, and both studies reported the average HR over 24 hours. Meta-analysis revealed no difference between the ME/CFS patients and controls (SMD ± 95% CI = 0.11 ± 0.27, P = .45; Fig. 10), with no heterogeneity between the studies (P = .56, I2 = 0%).
3.14 Post-exertional heart rate recovery
HRR was reported in only 2 articles (patients n = 108, controls n = 72), both of which used similar methods to elicit and record HRR (Table 1 ). Meta-analysis found no difference in HRR between ME/CFS patients and controls (MD ± 95% CI = –11.78 ± 13.72, P = .09; Fig. 11), with results affected by significant statistical heterogeneity (P = .003, I2 = 89%).
This review found a number of differences in HR parameters between patients with ME/CFS and controls. Meta-analysis identified that compared to controls, patients with ME/CFS exhibited higher resting HR (RHR), lower maximal/peak HR (HRmax/HRpeak), higher HR responses to HUTT (HRtilt) and moving from sitting to standing (HROR), and lower HR at submaximal exercise threshold (HRthreshold). Resting HRV (HRVrest) parameters also differed between ME/CFS patients and controls, with patients exhibiting higher LFP and lower HFP. Taken together, these results tend to suggest reduced vagal modulation and increased sympathetic modulation of HR in patients with ME/CFS. Included studies were generally of a moderate to good quality, and although confounding factors were rarely identified and dealt with it is unlikely that the quality of included articles played a major role on the results of this meta-analysis.
4.1 Resting heart rate (RHR)
RHR was higher for ME/CFS patients compared to controls, regardless of whether assessed when supine or seated. The higher RHR likely reflects a decrease in parasympathetic and increase in sympathetic cardiac modulation as multiple studies have shown that both parasympathetic blockade and an increase in sympathetic autonomic control result in an increase in RHR.[88,89] Interestingly, the analysis of RHRsupine was affected by significant heterogeneity, which was not the case for RHRseated. Very few studies made any effort to control breathing rate in either body position, and it is likely that the potential difference in breathing rates between studies may account for some of the variation in RHR values reported. Although RHR appears to be higher for patients with ME/CFS than controls, the average difference between groups (4.33 ± 1.42 bpm) is less than the typical day to day variation of RHR reported in the literature (∼5 bpm). Therefore, while the increased RHR experienced by ME/CFS patients may indicate an altered autonomic balance, it may not be a clinically relevant finding as the large amount of day to day variation in RHR will limit its potential utility as a diagnostic marker in ME/CFS. It must be acknowledged that there was a large amount of variability in the methods utilised to capture RHR data in the included studies including the duration of rest utilised, with rest periods ranging from ≤ 5 minutes to 30 minutes, while 15 studies did not report the duration of rest utilised.
4.2 Heart rate variability (HRVrest and HRVtilt)
In addition to ME/CFS patients having a higher RHR, they exhibited differences in HRVrest that also suggest the presence of reduced parasympathetic and increased sympathetic cardiac autonomic modulation. ME/CFS patients had lower HFP and RMSSD, with both parameters representing primarily parasympathetic cardiac modulation.[92,93] ME/CFS patients also had a higher LF/HF ratio than controls, indicating increased sympathetic and decreased parasympathetic HR modulation compared to controls. The effect sizes for the differences between ME/CFS patients and controls were consistently small (albeit significant), and this may explain why no significant effect was found for other HRVrest parameters which had fewer included studies. LFP, for example, reflects a combination of parasympathetic and sympathetic modulation of HR vagal cardiac modulation in a similar manner to HFP, however the small number of included studies for this parameter may limited the ability for the current meta-analysis to identify a significant effect. Although it is important to note that the effect sizes seen for the HRVrest analyses were small, and there were noticeably fewer included studies than for the analysis of parameters such as RHR, the consistent effect on HRV parameters (RMSSD HFP, LF/HF ratio) suggests that HRVrest may be a useful marker of autonomic dysfunction in ME/CFS patients to assist with the diagnosis of the condition. Interestingly, analysis of HRVtilt found no difference in any parameter between ME/CFS patients and controls, indicating there is no difference in HRV between the groups when an autonomic stressor is introduced, although again, this may be due to the small number of included studies (n = 2).
4.3 Maximal heart rate (HRmax)
Meta-analysis also revealed a lower HRmax in ME/CFS patients compared to controls, which may represent further evidence of increased sympathetic modulation of HR. Lower HRmax was found between ME/CFS patients and controls for studies which used set criteria to determine if a maximal effort had been produced and likely reported true HRmax, as well as studies which did not use a criteria approach and likely reported symptom-limited peak HR (HRpeak). Despite obvious differences arising from the 2 approaches, the fact that HRmax was lower in ME/CFS patients in studies when criterion measures were applied suggests that there is a lowering of true HRmax in patients with ME/CFS compared with controls. When considered in the context of resting HRV measures indicating increased sympathetic and decreased parasympathetic tone, the lower HRmax in ME/CFS patients may be due to resting sympathetic hyperactivity. Alterations in blood pressure variability have also been found in ME/CFS patients[12,95,96] which indicate increased sympathetic autonomic regulation, and it is possible that prolonged pathological sympathetic activity has led to ME/CFS patients’ autonomic effectors (such as heart and blood vessels) becoming resistant to sympathetic autonomic stimulation through downregulation of receptors, thus contributing to the lower HRmax identified in this review. Additionally, patients with congestive heart failure have been shown to exhibit abnormally high levels of sympathetic activity, combined with decreased cardiac norepinephrine, suggesting that periods of increased sympathetic neural tone may result in a depletion of cardiac sympathetic neurotransmitters. However, despite the clear differences in HRmax/HRpeak between ME/CFS patients and controls, it is likely to have limited usefulness as a diagnostic marker in ME/CFS. It is notoriously difficult to elicit a reliable and valid maximal effort in clinical populations and the high intensity exercise required to elicit HRmax is likely to cause a significant exacerbation of symptoms for ME/CFS patients. Additionally, the wide variability in individual HRmax values (standard deviation ∼ 10 bpm) suggests that, despite the apparent differences between patients and controls, the diagnostic accuracy at an individual level would be low.
The assessment of peak HRmax/HRpeak in the included studies was affected by numerous methodological issues which impacted on the consistency of results seen during studies which assessed symptom limited HRpeak, rather than true HRmax. The effect on true HRmax was very consistent, with minimal heterogeneity (P = .88, I2 = 0%), compared to those which measured HRpeak where the heterogeneity between studies was much larger (P < .0001, I2 = 74%). The heterogeneity in the studies which used reported HRpeak is likely, in part, due to differences in encouragement given to participants during the maximal exercise testing. Some studies[78,79] reported that no encouragement was given during testing, while others[42,70] reported that verbal encouragement was given in an attempt to elicit a maximal response. Regular verbal encouragement during maximal exercise testing has been shown to elicit a greater maximum effort compared to when no encouragement is given. As ME/CFS patients (similarly to most chronic health conditions) have been shown to catastrophize their symptoms of pain, leading to a negative effect on exercise performance, the use of regular verbal encouragement during maximal exercise tests in ME/CFS may be particularly important in order to elicit a valid maximal response in this population. The ability for the included studies to elicit a valid maximal response in the patient group can be established from analysis of the percentage of age predicted HRmax achieved during data collection. Across the studies which reported HRpeak/true HRmax, the percentage of age predicted HRmax obtained in each study varied from 99% in the study by Sargent et al which relied on a criterion approach, to 75% in a study by VanNess et al which reported symptom limited HRpeak. One study did not report the age of the participants, so predicted maximal HR was unable to be calculated. The 3 highest % age predicted HRmax attained by studies were all those which employed a criterion based approach to determine if a maximal effort was given[38,72,77] suggesting this approach may result in better assessment of HRmax in this clinical population
4.4 Heart rate response to head-up tilt testing (HRtilt)
In addition to the evidence of sympathetic overactivity in ME/CFS patients provided by analysis of RHR, HRVrest, and HRmax, the results from the analysis of HRtilt further suggest an altered autonomic balance in ME/CFS patients compared to controls, revealing that ME/CFS patients had a significantly higher HR during HUTT, in addition to a higher ΔHR in response to HUTT. This difference in HRtilt is potentially due to an increased sympathetic tone which may be exhibited ME/CFS patients. Additionally, Timmers et al found a blunted plasma norepinephrine response to HUTT in patients who experienced presyncope without preceding tachycardia, further indicating the presence of altered autonomic function during HUTT in ME/CFS patients. However, it must be acknowledged that variability existed in the methodology utilised to collect HRtilt data. While studies were generally consistent in the tilt methodology used, (all studies using a 70° tilt, with the exception of Freeman and Komaroff who used a 60° tilt) thre was large variability in the durations of tilt employed: 3 studies utilised durations of ≤10 minutes,[40,43,56] while the remainder used durations of 30 to 40 minutes.
4.5 Orthostatic heart rate response (HROR)
Similar to the findings for HRtilt, ME/CFS patients were also found to have an increased HROR compared to controls. This finding is not surprising given the well-known co-morbidities of ME/CFS and postural orthostatic tachycardia syndrome (POTS). Multiple studies have found that rates of POTS are significantly higher in ME/CFS populations,[103,104] and the greater HROR seen in ME/CFS participants may be due to an increased sympathetic/parasympathetic balance.[68,105] Similar to HRtilt however, significant variability existed in the methodologies utilised to collect HROR data which limits the ability to draw definite conclusions about the patterns observed. For example, 5 studies[28,29,59,62,68] reported HROR in response to standing up after a period of supine rest, while 1 study reported the effect of standing up following sitting, with durations spent in the resting position prior to standing also varying across studies (from 10 minutes to 30 minutes. Further, durations of standing differed greatly, ranging from short (2 minutes[46,62]) to long (60 minutes).
Although the results of the meta-analysis suggest that ME/CFS patients have an altered autonomic balance compared to controls – consisting of higher resting sympathetic and lower resting parasympathetic cardiac modulation – it could be argued that these findings reflect the physical deconditioning that has been found in some ME/CFS patients. Due to the exacerbation of post-exertional malaise which commonly occurs as a result of physical activity in this population, ME/CFS patients are candidates for physical deconditioning as a consequence of exercise avoidance.[102,107] For example, physical deconditioning is a potential cause of the increased RHR experienced by ME/CFS patients. Previous work by De Lorenzo et al, which was subsequently confirmed by Miwa and Fujita, found that ME/CFS patients had a reduced left ventricular size and mass, and such reductions in left ventricular size and mass are typically associated with deconditioning in healthy individuals. Additionally, multiple studies have shown that a decreased level of aerobic fitness is associated with a lower vagal and increased sympathetic tone which can be reversed through aerobic training,[110,111] implying the altered HRVrest found in ME/CFS patients may result from the deconditioning typical of ME/CFS, rather than being a direct cause or symptom of the syndrome. Further, the elevated HRtilt for ME/CFS patients may also potentially be due to physical deconditioning. LaManca et al measured stroke volume during HUTT in ME/CFS patients, and found stroke volume decreased in a similar manner to that seen in other deconditioned populations, and suggested the increased HRtilt witnessed during that study attempted to counteract a hypovolaemic state which had led to decreased preload and decreased stroke volume. Similar observations have been made by other studies in ME/CFS populations.[43,66]
4.6 HR during submaximal exercise
The finding of lower HRs at submaximal exercise threshold, such as AT, LT, or VT (HRthreshold) in ME/CFS participants compared to controls may be further indication of potential physical deconditioning, given that it is well established that an increased level of aerobic fitness is associated with a later onset of submaximal exercise threshold.[113–115] Interestingly, in 4 of the 5 studies which reported on HR at VT/AT,[38,41,78,80] ME/CFS participants had a lower peak VO2 than controls, providing further evidence of deconditioning while the fifth study was underpowered to find a difference between the 2 groups for this parameter. It is important to note that the analysis of HRthreshold was affected by significant, moderate heterogeneity (I2 = 56%), which likely resulted from the different methods used to quantify submaximal exercise threshold. Three of the studies[38,78,80] used the V-Slope method to determine VT, while De Becker et al used an RER < 1.0 to determine that AT had been reached, and Sargent et al calculated lactate threshold using the method of Beaver et al. Hodges et al reported on HR at VT, but did not state the method used to quantify VT. Indeed there remains debate as to whether or not there is a relationship between AT, LT, and VT, with some arguing for a strong physiological link between the thresholds, and others believing the similar timing of the 2 thresholds to be purely coincidental. The study by Sargent et al which assessed HR at LT found no difference between ME/CFS patients and controls. Comparatively, 3 other studies which assessed HR at VT/AT found that HR was lower for patients than controls.[41,78,80] While this suggests plasma lactate measures may differ from ventilatory measures in their ability to reflect differences between ME/CFS patients and controls, the differences in VO2max in the studies which assessed HR at AT/VT suggest these differences may also result from physical deconditioning in the ME/CFS patients. Interestingly, there was no difference in the HRsteadystate of ME/CFS patients and controls. It is well known that HRsteadystate in response to equal workload is generally higher in individuals with a lower level of aerobic fitness[117,118] and 2 of the 3 studies which reported both HRsteadystate and VO2max[27,78] found lower VO2max values for ME/CFS patients when compared to healthy controls. Therefore, it is surprising that there was no difference between the HRsteadystate values reported between ME/CFS patients and controls in response to an equal workload.
4.7 Other heart rate parameters (HRdailyaverage, HRmentaltask, HRR)
No difference was found between ME/CFS patients and controls for HRdailyaverage, HRmentaltask, or HRR, potentially due to the small number of included studies for each parameter. HRmentaltask was reported in 5 studies, while HRdailyaverage[58,87] and HRR[73,87] were both reported in 2 studies. Given that ME/CFS patients had a higher RHR than controls, it may be expected that a similar difference would be apparent during tasks which do not require physical exertion, such as a mental task. Similarly, it may be expected that ME/CFS patients would have a higher HRdailyaverage compared to controls due to a combination of physical deconditioning and an apparent sympathetic dominance at rest, however this does not appear to be the case. With regard to HRdailyaverage, this may be due to increased patterns of exercise avoidance that ME/CFS patients exhibit[107,119] leading to lower daily physical activity, and therefore an overall similar HRdailyaverage compared to controls. No difference was found between ME/CFS patients and controls with regard to post exercise HRR. The analysis only included 2 studies,[73,87] and was affected by significant statistical heterogeneity (P = .003, I2 = 89%), likely due to the small number of included studies. One study found a 19 bpm difference between ME/CFS patients and controls, and the other found no difference. Regardless, HRR is unlikely to be a suitable marker for use in an ME/CFS patient group, not only because of the lack of current evidence indicating any difference between patients and controls, but also because the assessment of HRR has been found to require exercise intensities of 88% of maximal HR in order to minimise day-to-day variation in athletes. Given the difficulties that many ME/CFS patients may have in attempting to attain this elevated HR, the reliability of HRR may therefore be diminished in ME/CFS patients, in addition to the fact that high intensity exercise can exacerbate ME/CFS symptoms.
Interestingly, of the studies which reported maximal HR in ME/CFS patients, the majority that also reported VO2max (10 of 17) found a lower VO2max in ME/CFS patients compared to controls, which could suggest that deconditioning is common in ME/CFS. However, of these studies, four of them were those which used a criterion approach to determine if a valid maximal effort had been given, and these studies found no difference in VO2max between ME/CFS and controls, implying that many ME/CFS patients may not be deconditioned compared to controls, but are unable to produce a valid voluntary maximal effort, possibly due to kinesiophobia.[102,107] While some studies have found differences in aerobic fitness between ME/CFS patients and controls, and it is possible that deconditioning may be a potential explanation for some of the differences in HR parameters seen between ME/CFS patients and controls, the equivocal findings regarding aerobic fitness parameters (with some studies reporting a difference between ME/CFS and controls,[42,74] and others not[38,75]) suggest that deconditioning cannot explain all of the variance in HR parameters between ME/CFS patients and controls. Rather, it is likely that an altered cardiac autonomic balance is present in ME/CFS patients, typified by increased sympathetic and decreased parasympathetic cardiac autonomic control. In any case, while deconditioning through avoidance of physical activity may have had an effect on the HR analyses in this meta-analysis, it is important to note that physical deconditioning is not a potential cause of ME/CFS, but rather it occurs as a consequence due to symptoms (i.e. fatigue, pain) reducing the capacity for participation in physical activity which may be further compounded by active avoidance of activity even when able, for fear of inducing post-exertional malaise and severe exacerbation of symptoms.
This review and meta-analysis included ME/CFS patients who were diagnosed with any of a number of recognised criteria. Although the 1994 CDC criteria was by far the most commonly used criteria in the included studies, it may not be the most effective tool for clinical diagnoses, a function for which it was never intended. In recent times, the ‘Canadian Criteria’ (CCC) and the International Consensus Criteria on ME/CFS (ICC) have been preferred by many clinicians as they require the patient to experience an acute worsening of symptoms with exercise, something which was not required as part of the 1988 or 1994 CDC definitions. However, very few of the articles included in this review employed the CCC or the ICC as their diagnostic criteria. Given the differences between the diagnostic criteria, it cannot be discounted that there are differences in the characteristics of the illnesses between studies which used different diagnostic criteria. Future research in ME/CFS populations should ideally report the number of included participants who met the 1994 CDC criteria (made to standardise research), and what number met the ICC or CCC (made for better clinical diagnosis).
Where possible, this review attempted to explain the reasons for any statistical heterogeneity that was identified during the meta-analysis process. Although this heterogeneity may be the result of methodological issues, it is likely that the results for each study are affected by the disease severity of included patients, in addition to the duration of illness. While some included studies[34,59] did classify patients into subcategories based on symptom severity, the majority of included studies did not. With particular regard to the HR parameters recorded during or following exercise (HRmax, HRR, exercise HR), selection bias is a potential issue that may limit the validity of the results from included studies, as patients who were more severely affected would be less likely to volunteer for exercise-based studies. Additionally, given that ME/CFS patients may be affected by cardiovascular deconditioning as a result of their condition, conceivably, ME/CFS patients who have had the illness for a longer duration are likely to have experienced greater deconditioning, and this increased deconditioning may explain some of the statistical heterogeneity witnessed for some parameters. Additionally, it must be acknowledged that it was not possible to analyse results based on other factors (e.g., level of physical activity) due to the under-reporting of such details within included studies, or a tendency to report all results within a single sample despite differences in participant characteristics (e.g., male or female).
Numerous HR parameters have been reported on in ME/CFS patients, with wide variations in study design and data acquisition methods, including body position and the duration/intensity of interventions (HUTT, exercise etc). Meta-analysis revealed significant differences between patients and controls in a number of parameters, including patients having: higher RHR, HRtilt, orthostatic HR response, and LF/HF ratio; and lower HRmax, HRthreshold, HFP and RMSSD. These differences suggest an altered regulation of HR in ME/CFS patients that is suggestive of reduced vagal and increased sympathetic modulation of heart rate. It does not appear that any of the currently used HR parameters have the sensitivity to detect the presence of ME/CFS on their own, as demonstrated by the presence of high levels of statistical heterogeneity and methodological issues which limit the usefulness of these parameters. However, the results of this review suggest that there are quantifiable differences in autonomic HR regulation in ME/CFS patients, and future research in ME/CFS populations should therefore focus on determining if there are additional HR parameters which have diagnostic utility in this group.
Conceptualization: Maximillian James Nelson, Jonathan D. Buckley, Rebecca L. Thomson, Kade Davison.
Data curation: Maximillian James Nelson, Jasvir S Bahl.
Formal analysis: Maximillian James Nelson, Jasvir S Bahl.
Investigation: Maximillian James Nelson, Jasvir S Bahl, Jonathan D. Buckley, Rebecca L. Thomson, Kade Davison.
Methodology: Maximillian James Nelson, Jonathan D. Buckley, Rebecca L. Thomson, Kade Davison.
Project administration: Jonathan D. Buckley.
Supervision: Jonathan D. Buckley, Rebecca L. Thomson, Kade Davison.
Validation: Maximillian James Nelson.
Writing – original draft: Maximillian James Nelson.
Writing – review & editing: Maximillian James Nelson, Jasvir S Bahl, Jonathan D. Buckley, Rebecca L. Thomson, Kade Davison.
Maximillian James Nelson orcid: 0000-0003-1759-1428.
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Keywords:Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.
autonomic dysfunction; chronic fatigue syndrome; fatigue; heart rate; myalgic encephalomyelitis