Tag: autonomic dysfunction

Chronic Fatigue Syndrome and Cardiovascular Disease: JACC State-of-the-Art Review

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a medically unexplained illness characterized by severe fatigue limiting normal daily activities for at least 6 months accompanied by problems with unrefreshing sleep, exacerbation of symptoms following physical or mental efforts (postexertional malaise [PEM]), and either cognitive reports or physiological evidence of orthostatic intolerance in the form of either orthostatic tachycardia and/or hypocapnia.

Although rarely considered to have cardiac dysfunction, ME/CFS patients frequently have reduced stroke volume with a significant inverse relation between cardiac output and PEM severity. Magnetic resonance imaging of ME/CFS patients compared with normal control subjects found significantly reduced stroke, end-systolic, and end-diastolic volumes together with reduced end-diastolic wall mass. Another cardiovascular abnormality is reduced nocturnal blood pressure assessed by 24-hour monitoring. Autonomic dysfunction is also frequently observed with postural orthostatic tachycardia and/or hypocapnia. Two consecutive cardiopulmonary stress tests may provide metabolic data substantiating PEM.

Source: Natelson BH, Brunjes DL, Mancini D. Chronic Fatigue Syndrome and Cardiovascular Disease: JACC State-of-the-Art Review. J Am Coll Cardiol. 2021 Sep 7;78(10):1056-1067. doi: 10.1016/j.jacc.2021.06.045. PMID: 34474739. https://pubmed.ncbi.nlm.nih.gov/34474739/

Reduced heart rate variability predicts fatigue severity in individuals with chronic fatigue syndrome/myalgic encephalomyelitis

Abstract:

BACKGROUND: Heart rate variability (HRV) is an objective, non-invasive tool to assessing autonomic dysfunction in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). People with CFS/ME tend to have lower HRV; however, in the literature there are only a few previous studies (most of them inconclusive) on their association with illness-related complaints. To address this issue, we assessed the value of different diurnal HRV parameters as potential biomarker in CFS/ME and also investigated the relationship between these HRV indices and self-reported symptoms in individuals with CFS/ME.

METHODS: In this case-control study, 45 female patients who met the 1994 CDC/Fukuda definition for CFS/ME and 25 age- and gender-matched healthy controls underwent HRV recording-resting state tests. The intervals between consecutive heartbeats (RR) were continuously recorded over three 5-min periods. Time- and frequency-domain analyses were applied to estimate HRV variables. Demographic and clinical features, and self-reported symptom measures were also recorded.

RESULTS: CFS/ME patients showed significantly higher scores in all symptom questionnaires (p < 0.001), decreased RR intervals (p < 0.01), and decreased HRV time- and frequency-domain parameters (p < 0.005), except for the LF/HF ratio than in the healthy controls. Overall, the correlation analysis reached significant associations between the questionnaires scores and HRV time- and frequency-domain measurements (p < 0.05). Furthermore, separate linear regression analyses showed significant relationships between self-reported fatigue symptoms and mean RR (p = 0.005), RMSSD (p = 0.0268) and HFnu indices (p = 0.0067) in CFS/ME patients, but not in healthy controls.

CONCLUSIONS: Our findings suggest that ANS dysfunction presenting as increased sympathetic hyperactivity may contribute to fatigue severity in individuals with ME/CFS. Further studies comparing short- and long-term HRV recording and self-reported outcome measures with previous studies in larger CFS/ME cohorts are urgently warranted.

Source: Escorihuela RM, Capdevila L, Castro JR, Zaragozà MC, Maurel S, Alegre J, Castro-Marrero J. Reduced heart rate variability predicts fatigue severity in individuals with chronic fatigue syndrome/myalgic encephalomyelitis. J Transl Med. 2020 Jan 6;18(1):4. doi: 10.1186/s12967-019-02184-z. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943898/ (Full article)

Autonomic dysfunction in myalgic encephalomyelitis and chronic fatigue syndrome: comparing self-report and objective measures

Myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS) have debilitating impacts on affected individuals. Core symptoms include post-exertional malaise, neurocognitive challenges, and sleep dysfunction [1]. Additionally, a significant minority of patients experience autonomic symptoms, including orthostatic intolerance, gastrointestinal disturbances, and circulation issues [2].

Several case definitions for ME and CFS require the presence of autonomic dysfunction for diagnosis [2], while other researchers have proposed an “autonomic dysfunction” subtype of ME and CFS [3]. Identifying the appropriate measures of autonomic symptomatology for individuals with ME and CFS will further contribute to understanding the role of the autonomic system in this illness.

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Source: Kemp J, Sunnquist M, Jason LA, Newton JL. Autonomic dysfunction in myalgic encephalomyelitis and chronic fatigue syndrome: comparing self-report and objective measures. Clin Auton Res. 2019 May 21. doi: 10.1007/s10286-019-00615-x. [Epub ahead of print]  https://sci-hub.se/10.1007/s10286-019-00615-x (Full article)

Impairments in cognitive performance in chronic fatigue syndrome are common, not related to co-morbid depression but do associate with autonomic dysfunction

Abstract:

OBJECTIVES: To explore cognitive performance in chronic fatigue syndrome (CFS) examining two cohorts. To establish findings associated with CFS and those related to co-morbid depression or autonomic dysfunction.

METHODS: Identification and recruitment of participants was identical in both phases, all CFS patients fulfilled Fukuda criteria. In Phase 1 (n = 48) we explored cognitive function in a heterogeneous cohort of CFS patients, investigating links with depressive symptoms (HADS). In phase 2 (n = 51 CFS & n = 20 controls) participants with co-morbid major depression were excluded (SCID). Furthermore, we investigated relationships between cognitive performance and heart rate variability (HRV).

RESULTS: Cognitive performance in unselected CFS patients is in average range on most measures. However, 0-23% of the CFS sample fell below the 5th percentile. Negative correlations occurred between depressive symptoms (HAD-S) with Digit-Symbol-Coding (r = -.507, p = .006) and TMT-A (r = -.382, p = .049). In CFS without depression, impairments of cognitive performance remained with significant differences in indices of psychomotor speed (TMT-A: p = 0.027; digit-symbol substitution: p = 0.004; digit-symbol copy: p = 0.007; scanning: p = .034) Stroop test suggested differences due to processing speed rather than inhibition. Both cohorts confirmed relationships between cognitive performance and HRV (digit-symbol copy (r = .330, p = .018), digit-symbol substitution (r = .313, p = .025), colour-naming trials Stroop task (r = .279, p = .050).

CONCLUSION: Cognitive difficulties in CFS may not be as broad as suggested and may be restricted to slowing in basic processing speed. While depressive symptoms can be associated with impairments, co-morbidity with major depression is not itself responsible for reductions in cognitive performance. Impaired autonomic control of heart-rate associates with reductions in basic processing speed.

Source: Robinson LJ, Gallagher P, Watson S, Pearce R, Finkelmeyer A, Maclachlan L, Newton JL. Impairments in cognitive performance in chronic fatigue syndrome are common, not related to co-morbid depression but do associate with autonomic dysfunction. PLoS One. 2019 Feb 5;14(2):e0210394. doi: 10.1371/journal.pone.0210394. eCollection 2019. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0210394 (Full article)

The Abnormal Cardiac Index and Stroke Volume Index Changes During a Normal Tilt Table Test in ME/CFS Patients Compared to Healthy Volunteers, are Not Related to Deconditioning

Abstract:

1.1 Background. A small study in ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) patients undergoing tilt testing, showed that, despite a normal tilt test, stroke volumes and cardiac output were lower than in healthy volunteers. Moreover, it was suggested that this difference was related to deconditioning of patients. Aim of the study. We performed table testing in 150 ME/CFS patients. Stroke volumes and cardiac output were related to the severity of the disease.

1.2 Methods and results. In the patients the severity of the disease was clinically evaluated according to the ME criteria and scored as mild, moderate or severe disease. In a subgroup of 109 patients this clinical diagnosis was confirmed by the physical functioning score of the Rand-36 questionnaire. Significantly lower physical functioning scores (indicating worse functioning) were observed in the more severely affected patients. Stroke Volume Index (SVI) and Cardiac Index (CI) were measured by suprasternal aortic Doppler imaging in the supine position, prior to the tilt, and twice during the tilt. Thirty-seven healthy volunteers underwent the same tilt protocol. In all patients and all healthy volunteers, a normal heart rate and blood pressure response was observed during the tilt. The decreases in SVI and CI during the tilt was significantly larger in patients compared to the SVI and CI decrease in HV. The decrease in SVI and CI were similar and not significantly different between the mild, moderate, and severe ME groups.

1.3 Conclusions. During a normal tilt table test decreases in SVI and CI decrease are significantly greater in ME/CFS patients than in HV, consistent with previous work. The absence of differences between patients with mild, moderate, and severe ME/CFS suggests that the decreases in stroke volumes and cardiac output are not related to deconditioning. Other factors like decreased blood volumes and autonomic dysfunction may cause this difference in the hemodynamic response between ME/CFS patients and HV.

3. Abbreviations

BMI : Body Mass Index

BSA : Body Surface Area

CFS : Chronic Fatigue Syndrome

CI : Cardiac Index

DBP : Diastolic Blood Pressure

HR : Heart Rate

HUT : Head-Up Tilt Test

HV : Healthy Volunteers

IOM : Institute of Medicine

MAP : Mean Blood Pressure

ME : Myalgic Encephalomyelitis

NMH : Neurally Mediated Hypotension

Normal BPHR : normal Blood Pressure and Heart Rate Response During HUT

OI : Orthostatic Intolerance

R36 Phys Funct : Rand-36 Physical Functioning Score

SBP : Systolic Blood Pressure

SVI : Stroke Volume Index

SVRI : Systemic Vascular Resistance Index

VTI : Time-Velocity Integral

Source: van Campen CMC, Visser FC (2018) The Abnormal Cardiac Index and Stroke Volume Index Changes During a Normal Tilt Table Test in ME/CFS Patients Compared to Healthy Volunteers, are Not Related to Deconditioning. J Thrombo Cir: JTC -107. DOI: 10.29011/ JTC -107. 000007 https://www.gavinpublishers.com/articles/Research-Article/Journal-of-Thrombosis-and-Circulation/The-Abnormal-Cardiac-Index-and-Stroke-Volume-Index-Changes-During-a-Normal-Tilt-Table-Test-in-ME-CFS-Patients-Compared-to-Healthy-Volunteers-are-Not-Related-to-Deconditioning (Full article)

Circadian rhythm abnormalities and autonomic dysfunction in patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

Abstract:

Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) patients frequently show autonomic symptoms which may be associated with a hypothalamic dysfunction. This study aimed to explore circadian rhythm patterns in rest and activity and distal skin temperature (DST) and their association with self-reported outcome measures, in CFS/ME patients and healthy controls at two different times of year.

Ten women who met both the 1994 CDC/Fukuda definition and 2003 Canadian criteria for CFS/ME were included in the study, along with ten healthy controls matched for age, sex and body mass index. Self-reported measures were used to assess fatigue, sleep quality, anxiety and depression, autonomic function and health-related quality of life. The ActTrust actigraph was used to record activity, DST and light intensity, with data intervals of one minute over seven consecutive days. Sleep variables were obtained through actigraphic analysis and from subjective sleep diary. The circadian variables and the spectral analysis of the rhythms were calculated. Linear regression analysis was used to evaluate the relationship between the rhythmic variables and clinical features. Recordings were taken in the same subjects in winter and summer.

Results showed no differences in rhythm stability, sleep latency or number of awakenings between groups as measured with the actigraph. However, daily activity, the relative amplitude and the stability of the activity rhythm were lower in CFS/ME patients than in controls. DST was sensitive to environmental temperature and showed lower nocturnal values in CFS/ME patients than controls only in winter. A spectral analysis showed no differences in phase or amplitude of the 24h rhythm, but the power of the second harmonic (12h), revealed differences between groups (controls showed a post-lunch dip in activity and peak in DST, while CFS/ME patients did not) and correlated with clinical features. These findings suggest that circadian regulation and skin vasodilator responses may play a role in CFS/ME.

Source: Cambras T, Castro-Marrero J, Zaragoza MC, Díez-Noguera A, Alegre J. Circadian rhythm abnormalities and autonomic dysfunction in patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis. PLoS One. 2018 Jun 6;13(6):e0198106. doi: 10.1371/journal.pone.0198106. eCollection 2018.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5991397/  (Full article)

Autonomic correlations with MRI are abnormal in the brainstem vasomotor centre in Chronic Fatigue Syndrome

Abstract:

Autonomic changes are often associated with the chronic fatigue syndrome (CFS), but their pathogenetic role is unclear and brain imaging investigations are lacking. The vasomotor centre and, through it, nuclei in the midbrain and hypothalamus play a key role in autonomic nervous system regulation of steady state blood pressure (BP) and heart rate (HR).

In this exploratory cross-sectional study, BP and HR, as indicators of autonomic function, were correlated with volumetric and T1- and T2-weighted spin-echo (T1w and T2w) brain MRI in 25 CFS subjects and 25 normal controls (NC). Steady state BP (systolic, diastolic and pulse pressure) and HR in two postures were extracted from 24 h blood pressure monitoring. We performed (1) MRI versus autonomic score interaction-with-group regressions to detect locations where regression slopes differed in the CFS and NC groups (collectively indicating abnormality in CFS), and (2) MRI regressions in the CFS and NC groups alone to detect additional locations with abnormal correlations in CFS.

Significant CFS regressions were repeated controlling for anxiety and depression (A&D). Abnormal regressions were detected in nuclei of the brainstem vasomotor centre, midbrain reticular formation and hypothalamus, but also in limbic nuclei involved in stress responses and in prefrontal white matter. Group comparisons of CFS and NC did not find MRI differences in these locations.

We propose therefore that these regulatory nuclei are functioning correctly, but that two-way communication between them is impaired in CFS and this affects signalling to/from peripheral effectors/sensors, culminating in inverted or magnified correlations. This single explanation for the diverse abnormal correlations detected here consolidates the conclusion for a brainstem/midbrain nerve conduction deficit inferred earlier (Barnden et al., 2015). Strong correlations were also detected in isolated NC regressions.

 

Source: Barnden LR, Kwiatek R, Crouch B, Burnet R, Del Fante P. Autonomic correlations with MRI are abnormal in the brainstem vasomotor centre in Chronic Fatigue Syndrome. Neuroimage Clin. 2016 Mar 31;11:530-7. doi: 10.1016/j.nicl.2016.03.017. ECollection 2016. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4833047/ (Full article)

 

Effects of low-dose clonidine on cardiovascular and autonomic variables in adolescents with chronic fatigue: a randomized controlled trial

Abstract:

BACKGROUND: Chronic Fatigue Syndrome (CFS) is a common and disabling condition in adolescence with few treatment options. A central feature of CFS is orthostatic intolerance and abnormal autonomic cardiovascular control characterized by sympathetic predominance. We hypothesized that symptoms as well as the underlying pathophysiology might improve by treatment with the alpha2A-adrenoceptor agonist clonidine.

METHODS: A total of 176 adolescent CFS patients (12-18 years) were assessed for eligibility at a single referral center recruiting nation-wide. Patients were randomized 1:1 by a computer system and started treatment with clonidine capsules (25 μg or 50 μg twice daily, respectively, for body weight below/above 35 kg) or placebo capsules for 9 weeks. Double-blinding was provided. Data were collected from March 2010 until October 2012 as part of The Norwegian Study of Chronic Fatigue Syndrome in Adolescents: Pathophysiology and Intervention Trial (NorCAPITAL). Effect of clonidine intervention was assessed by general linear models in intention-to-treat analyses, including baseline values as covariates in the model.

RESULTS: A total of 120 patients (clonidine group n = 60, placebo group n = 60) were enrolled and started treatment. There were 14 drop-outs (5 in the clonidine group, 9 in the placebo group) during the intervention period. At 8 weeks, the clonidine group had lower plasma norepinephrine (difference = 205 pmol/L, p = 0.05) and urine norepinephrine/creatinine ratio (difference = 3.9 nmol/mmol, p = 0.002). During supine rest, the clonidine group had higher heart rate variability in the low-frequency range (LF-HRV, absolute units) (ratio = 1.4, p = 0.007) as well as higher standard deviation of all RR-intervals (SDNN) (difference = 12.0 ms, p = 0.05); during 20° head-up tilt there were no statistical differences in any cardiovascular variable. Symptoms of orthostatic intolerance did not change during the intervention period.

CONCLUSIONS: Low-dose clonidine reduces catecholamine levels in adolescent CFS, but the effects on autonomic cardiovascular control are sparse. Clonidine does not improve symptoms of orthostatic intolerance.

TRIAL REGISTRATION: Clinical Trials ID: NCT01040429, date of registration 12/28/2009.

 

Source: Fagermoen E, Sulheim D, Winger A, Andersen AM, Gjerstad J, Godang K, Rowe PC, Saul JP, Skovlund E, Wyller VB. Effects of low-dose clonidine on cardiovascular and autonomic variables in adolescents with chronic fatigue: a randomized controlled trial. BMC Pediatr. 2015 Sep 10;15:117. doi: 10.1186/s12887-015-0428-2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4566847/ (Full article)

 

Malfunctioning of the autonomic nervous system in patients with chronic fatigue syndrome: a systematic literature review

Abstract:

INTRODUCTION: It is hypothesised that the autonomic nervous system responds differently to various stressors in patients with chronic fatigue syndrome (CFS) compared with healthy controls. The goal is to systematically review the scientific literature addressing the functioning of the autonomic nervous system in patients with CFS.

MATERIALS AND METHODS: All studies that were identified through electronic databases (PubMed and Web of Science) were screened for eligibility based on the selection criteria and assessed (two independent raters) for methodological quality using a methodological checklist for case-control studies.

RESULTS: Twenty-seven case-control studies were included. The methodological quality varied between 50% and 71·4%. Some studies showed different responses to head-up tilt and other autonomous testing.

CONCLUSION: Although comparison between the included case-control studies was difficult, we can conclude that there are differences in autonomous response between patients with CFS and healthy controls. The heart rate dynamic response during the head-up tilt test differs between patients with CFS and healthy controls, supporting the increased prevalence of postural orthostatic tachycardia syndrome. The autonomic response can be useful for the diagnosis of CFS.

© 2014 Stichting European Society for Clinical Investigation Journal Foundation.

 

Source: Van Cauwenbergh D, Nijs J, Kos D, Van Weijnen L, Struyf F, Meeus M. Malfunctioning of the autonomic nervous system in patients with chronic fatigue syndrome: a systematic literature review. Eur J Clin Invest. 2014 May;44(5):516-26. doi: 10.1111/eci.12256. https://www.ncbi.nlm.nih.gov/pubmed/24601948

 

Cerebral vascular control is associated with skeletal muscle pH in chronic fatigue syndrome patients both at rest and during dynamic stimulation

Abstract:

Cerebral blood flow (CBF) is maintained despite changing systemic blood pressure through cerebral vascular control, with such tight regulation believed to be under local tissue control. Chronic fatigue syndrome (CFS) associates with a wide range of symptoms, including orthostatic intolerance, skeletal muscle pH abnormalities and cognitive impairment.

CFS patients are known to have reduced CBF and orthostatic intolerance associates with abnormal vascular regulation, while skeletal muscle pH abnormalities associate with autonomic dysfunction. These findings point to autonomic dysfunction as the central feature of CFS, and cerebral vascular control being influenced by factors outside of the brain, a macroscopic force affecting the stability of regional regulation. We therefore explored whether there was a physiological link between cerebral vascular control and skeletal muscle pH management in CFS. Seventeen consecutive CFS patients fulfilling the Fukuda criteria were recruited from our local CFS clinical service. To probe the static scenario, CBF and skeletal muscle pH were measured at rest using MRI and (31)P magnetic resonance spectroscopy ((31)P-MRS). To examine dynamic control, brain functional MRI was performed concurrently with Valsalva manoeuvre (VM), a standard autonomic function challenge, while (31)P-MRS was performed during plantar flexion exercise.

Significant inverse correlation was seen between CBF and skeletal muscle pH at rest (r = – 0.67, p < 0.01). Prolonged cerebral vascular constriction during the sympathetic phase of VM was associated with higher pH in skeletal muscle after plantar flexion exercise (r = 0.69, p < 0.008). In conclusion, cerebral vascular control is closely related to skeletal muscle pH both at rest and after dynamic stimulation in CFS.

 

Source: He J, Hollingsworth KG, Newton JL, Blamire AM. Cerebral vascular control is associated with skeletal muscle pH in chronic fatigue syndrome patients both at rest and during dynamic stimulation. Neuroimage Clin. 2013 Jan 5;2:168-73. doi: 10.1016/j.nicl.2012.12.006. ECollection 2013. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3777833/ (Full article)