Is reduced heart rate variability associated with functional somatic disorders? A cross-sectional population-based study; DanFunD.

OBJECTIVES: It has been hypothesised that functional somatic disorders (FSD) could be initiated by sympathetic predominance in the autonomic nervous system as measured by low heart rate variability (HRV). Earlier studies on the association between HRV and FSD are small case-control studies hampered by selection bias and do not consider the great overlap between the various FSDs. The aim of the present study is to assess any associations between HRV and various FSDs and whether chronic stress confounds such an association. DESIGN: A cross-sectional general population-based study. SETTING: The Danish Study of Functional Somatic Disorders conducted 2013-2015 in 10 municipalities in the western part of Greater Copenhagen, Denmark. PARTICIPANTS: A total of 6891 men and women aged 18-72 years were included in the analyses after exclusion of 602 persons with missing HRV data. Various delimitations of FSD (chronic fatigue, chronic widespread pain, irritable bowel and bodily distress syndrome) were identified by validated questionnaires and diagnostic interviews. HRV parameters in time and frequency domains were calculated from successive beat-to-beat heart rate (HR) data using the 'E-motion' HR monitor device during 7 min of supine rest. Chronic stress was assessed by Cohen's self-perceived stress scale. OUTCOME MEASURES: Logistic regression analyses were used to calculate possible associations between the various delimitations of FSD and HRV adjusting for chronic stress. RESULTS: Persons with FSD had a slightly higher mean HR and lower HRV as measured by time domain parameters, whereas associations with frequency domain parameters were not consistent. Adjusting for chronic stress attenuated associations slightly. CONCLUSION: The study supports a sympathetic predominance in persons with FSD, which could not be entirely explained by chronic stress. However, it is not possible to conclude whether the association is a causal factor to or a consequence of FSD.

Tattoo-associated sarcoidosis from a nuclear medicine perspective.

Tattoo-associated sarcoidosis is characterized by granulomas in tattoos with or without the involvement of other organ systems such as the lungs and eyes. 18F-fluorodeoxyglucose (18F-FDG PET is a nuclear medicine imaging study that can differentiate between metabolically over-active areas and normal tissue. Thus, this review finds that 18F-FDG-PET/CT imaging can be used to image inflammatory activity in tattoos and in case of papulonodular tattoo reaction be used to investigate possible systemic sarcoidosis.

Comment: Letter to the editor regarding the article "Anti-osteoporotic treatment after hip fracture remains alarmingly low".

This is a letter to the editor on the article "Anti-osteoporotic treatment after hip fracture remains alarmingly low" Dan Med J 2022;69(10):A01220010.

Diagnostic Value of Composite and Simplified FDG-PET/CT Scores in Polymyalgia Rheumatica and the Influence of Recent Glucocorticoid Treatment-A Retrospective Diagnostic Cohort Study.

[18F]Fluorodeoxyglucose positron emission tomography (FDG-PET) is increasingly used to demonstrate inflammation in specific sites typical for polymyalgia rheumatica (PMR). Scoring systems based on FDG uptake have been proposed to increase diagnostic accuracy. METHODS: Retrospective inclusion of 198 consecutive patients ≥40 years of age referred for FDG-PET from the Department of Rheumatology. We assessed the degree of FDG uptake in predilection sites visually, as well as semiquantitatively, and through logistic regression analyses, we evaluated the performance of existing scoring systems as well as a new, simplified scoring system, against the final clinical diagnosis at 6 months after the FDG-PET scan. RESULTS: We found high diagnostic accuracy for the diagnosis of PMR (range 0.74-0.91) using most of the existing scoring systems in glucocorticoid-naïve patients. A simplified scoring system including only periarticular FDG uptake in the shoulders and the ischiogluteal bursae retained high sensitivity and specificity (0.92 and 0.86, respectively). We found a detrimental effect on diagnostic accuracy in all scoring systems in patients treated with glucocorticoids within 4 weeks prior to FDG-PET. CONCLUSION: Most FDG-PET scoring systems perform well for the diagnosis of PMR, and there is no loss of either sensitivity or specificity in the simplest scoring systems evaluating FDG uptake in only a few selected anatomical regions. However, systemic glucocorticoid treatment up to 4 weeks prior to FDG-PET has a markedly detrimental effect on the diagnostic accuracy of all scoring systems.

Prognostic implications of myocardial perfusion imaging by 82-rubidium positron emission tomography in male and female patients with angina and no perfusion defects.

AIMS: Myocardial perfusion imaging with 82-rubidium positron emission tomography (82Rb-PET) is increasingly used to assess stable coronary artery disease (CAD). We aimed to evaluate the prognostic value of 82Rb-PET-derived parameters in patients with symptoms suggestive of CAD but no significant reversible or irreversible perfusion defects. METHODS AND RESULTS: Among 3726 consecutive patients suspected of stable CAD who underwent 82Rb-PET between January 2018 and August 2020, 2175 had no regional perfusion defects. Among these patients, we studied the association of 82Rb-PET-derived parameters with a composite endpoint of all-cause mortality, hospitalization for unstable angina pectoris, acute myocardial infarction, heart failure, or ischaemic stroke. During a median follow up of 1.7 years (interquartile range 1.1-2.5 years), there were 148 endpoints. Myocardial blood flow (MBF) reserve (MFR), MBF during stress, left ventricular ejection fraction (LVEF), LVEF-reserve, heart rate reserve, and Ca score were associated with adverse outcomes. In multivariable Cox model adjusted for patient and 82Rb-PET characteristics, MFR < 2 (hazard ratio (HR) 1.75, 95% confidence interval (CI) 1.24-2.48), LVEF (HR 1.38 per 10% decrease, 95% CI 1.24-1.54), and LVEF-reserve (HR 1.19 per 5% decrease, 95% CI 1.07-1.31) were significant predictors of endpoints. Results were consistent in subgroups defined by gender, history of ischaemic heart disease, low LVEF, and atrial fibrillation. CONCLUSION: MFR, LVEF, and LVEF-reserve derived from 82Rb-PET provide prognostic information on cardiovascular outcomes in patients with no perfusion defects. This may aid in identifying patients at risk and might provide an opportunity for preventive interventions.

Normative values of short-term heart rate variability in a cross-sectional study of a Danish population. The DanFunD study.

AIMS: The autonomic nervous system includes parasympathetic and sympathetic components that monitor and regulate most of the bodily functions and play a central role in the physiology and homeostasis of the human body. Heart rate variability is a non-invasive tool for quantification of rhythmic fluctuations in heart rate that reflects the function of the autonomic nervous system. The study aims to describe the heart rate variability distribution in the general population, stratified in sex and age groups, which is currently insufficiently described. METHODS: A cross-sectional population-based study recruited participants in 10 municipalities in the western part of the greater Copenhagen area in Denmark, including 6891 men and women aged 18-72 years (participation rate was 29.5%). Short-term heart rate variability measures were obtained and related to age and gender. RESULTS: Both time and frequency domain measures showed a huge variation in the different sex and age groups. Women had a higher median heart rate than men, and the association with age was U-shaped. Measures indicating a predominance of the parasympathetic component in relation to the sympathetic component were more frequent in women and younger age groups. CONCLUSIONS: Both sex and age influence the heart rate variability in this adult Danish population. Therefore, our age- and sex-related reference values of heart rate variability in the time and frequency domain should be used in further epidemiological and clinical research.

Autonomic nervous system activity in primary Raynaud's phenomenon: Heart rate variability, plasma catecholamines and [123 I]MIBG heart scintigraphy.

BACKGROUND AND AIM: Primary Raynaud's phenomenon (pRP) is characterized by an exaggerated response to cold, resulting in the whitening typically of the fingers and toes. The patients are generally perceived as healthy individuals with a benign condition. However, the condition has been associated with increased cardiovascular mortality and changes in autonomic nervous system activity. This study aimed to investigate whether pRP is associated with pervasive changes in autonomic nervous activity. The hypothesis was that patients with pRP have increased sympathetic nervous activity. METHODS: The autonomic nervous activity of 22 patients with pRP was investigated by means of heart rate variability (HRV) and the plasma catecholamine response to head-up tilt and compared with 22 age- and gender-matched controls. In addition, the patients were examined with a [123 I]metaiodobenzylguanidine heart scintigraphy and compared with an external control group. RESULTS: The plasma norepinephrine response to head-up tilt was significantly lower in the patient group than in the control group. Similarly, the heart scintigraphy revealed a lower heart-to-mediastinum ratio in the patient group than in the control group. HRV analysis did not reveal significant differences between the groups. CONCLUSION: The findings of the study showed that the autonomic nervous activity of patients with pRP was altered compared with the activity of healthy individuals. This was observed both during rest and after positional stress, but the findings did not uniformly concur with our initial hypothesis.

Bioenergetic and Proteomic Profiling of Immune Cells in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients: An Exploratory Study.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a heterogeneous, debilitating, and complex disease. Along with disabling fatigue, ME/CFS presents an array of other core symptoms, including autonomic nervous system (ANS) dysfunction, sustained inflammation, altered energy metabolism, and mitochondrial dysfunction. Here, we evaluated patients' symptomatology and the mitochondrial metabolic parameters in peripheral blood mononuclear cells (PBMCs) and plasma from a clinically well-characterised cohort of six ME/CFS patients compared to age- and gender-matched controls. We performed a comprehensive cellular assessment using bioenergetics (extracellular flux analysis) and protein profiles (quantitative mass spectrometry-based proteomics) together with self-reported symptom measures of fatigue, ANS dysfunction, and overall physical and mental well-being. This ME/CFS cohort presented with severe fatigue, which correlated with the severity of ANS dysfunction and overall physical well-being. PBMCs from ME/CFS patients showed significantly lower mitochondrial coupling efficiency. They exhibited proteome alterations, including altered mitochondrial metabolism, centred on pyruvate dehydrogenase and coenzyme A metabolism, leading to a decreased capacity to provide adequate intracellular ATP levels. Overall, these results indicate that PBMCs from ME/CFS patients have a decreased ability to fulfill their cellular energy demands.

Translation and linguistic validation of the Composite Autonomic Symptom Score COMPASS 31 in Danish.

INTRODUCTION: The Composite Autonomic Symptom Score (COMPASS 31) is a validated self-assessment questionnaire quantifying the severity and distribution of autonomic symptoms across six domains (orthostatic intolerance, vasomotor, secretomotor, gastrointestinal, bladder and pupillomotor functions) by scoring 31 clinically selected questions. The aim of this study was to translate into Danish and validate the Danish version of COMPASS 31. METHODS: The original (US) English version of the COMPASS 31 questionnaire was translated into Danish via forward/backward translation and validated in accordance with a protocol set forth by the Autonomic Group at the Mayo Clinic. Ten healthy controls and 20 patients with disorders associated with a variable degree of autonomic dysfunction were enrolled - all bilingual (Danish mother tongue, proficiency in English). RESULTS: A total of 20 patients (16 women, aged 48 + 17 years) and ten healthy controls (six women, aged 40 + 19 years) were included. Test-retest reliability was high with no consistent bias, and the Danish version of the COMPASS 31 significantly correlated with the English version of the COMPASS 31 in both total score and all sub-scores. Patients scored significantly higher on the COMPASS 31 questionnaire than healthy controls (34.0 (26.5-49.2) versus 2.3 (1.6-24.3) (median (interquartile ranges); p = 0.01). CONCLUSIONS: We present a Danish version of the COMPASS 31 - a validated self-reported questionnaire allowing for the quantification of autonomic dysfunction. We hope this Danish version will be implemented in both clinical practice and research settings in Denmark. FUNDING: none. TRIAL REGISTRATION: not relevant.

Characteristics and early outcomes of patients hospitalised for COVID-19 in North Zealand, Denmark.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) is an ongoing pandemic associated with significant morbidity and mortality worldwide. Limited data are available describing the clinical presentation and outcomes of hospitalised COVID-19 patients in Europe. METHODS: This was a single-centre retrospective chart review of all patients with COVID-19 admitted to the North Zealand Hospital in Denmark between 1 March and 4 May 2020. Main outcomes include major therapeutic interventions during hospitalisation, such as invasive mechanical ventilation, as well as death. RESULTS: A total of 115 patients were included, including four infants. The median age of adults was 68 years and 40% were female. At admission, 55 (50%) patients had a fever, 29 (26%) had a respiratory rate exceeding 24 breaths/minute, and 78 (70%) received supplemental oxygen. The prevalence of co-infection was 13%. Twenty patients (18%) (median age: 64 years; 15% female) were treated in the intensive care unit. Twelve (10.4%) received invasive mechanical ventilation and three (2.6%) renal replacement therapy. Nine patients (8%) developed pulmonary embolism. Sixteen patients (14%) died. Among patients requiring mechanical ventilation (n = 12), seven (6.1%) were discharged alive, four (3.4%) died and one (0.9%) was still hospitalised. CONCLUSION: In this cohort of hospitalised COVID-19 patients, mortality was lower than in other Danish and European case series. FUNDING: none. TRIAL REGISTRATION: not relevant.

Complex syndromes of chronic pain, fatigue and cognitive impairment linked to autoimmune dysautonomia and small fiber neuropathy.

Chronic fatigue syndrome, postural orthostatic tachycardia syndrome, complex regional pain syndrome and silicone implant incompatibility syndrome are a subject of debate among clinicians and researchers. Both the pathogenesis and treatment of these disorders require further study. In this paper we summarize the evidence regarding the role of autoimmunity in these four syndromes with respect to immunogenetics, autoimmune co-morbidities, alteration in immune cell subsets, production of autoantibodies and presentation in animal models. These syndromes could be incorporated in a new concept of autoimmune neurosensory dysautonomia with the common denominators of autoantibodies against G-protein coupled receptors and small fiber neuropathy. Sjogren's syndrome, which is a classical autoimmune disease, could serve as a disease model, illustrating the concept. Development of this concept aims to identify an apparently autoimmune subgroup of the disputable disorders, addressed in the review, which may most benefit from the immunotherapy.

A model-based analysis of autonomic nervous function in response to the Valsalva maneuver.

The Valsalva maneuver (VM) is a diagnostic protocol examining sympathetic and parasympathetic activity in patients with autonomic dysfunction (AD) impacting cardiovascular control. Because direct measurement of these signals is costly and invasive, AD is typically assessed indirectly by analyzing heart rate and blood pressure response patterns. This study introduces a mathematical model that can predict sympathetic and parasympathetic dynamics. Our model-based analysis includes two control mechanisms: respiratory sinus arrhythmia (RSA) and the baroreceptor reflex (baroreflex). The RSA submodel integrates an electrocardiogram-derived respiratory signal with intrathoracic pressure, and the baroreflex submodel differentiates aortic and carotid baroreceptor regions. Patient-specific afferent and efferent signals are determined for 34 control subjects and 5 AD patients, estimating parameters fitting the model output to heart rate data. Results show that inclusion of RSA and distinguishing aortic/carotid regions are necessary to model the heart rate response to the VM. Comparing control subjects to patients shows that RSA and baroreflex responses are significantly diminished. This study compares estimated parameter values from the model-based predictions to indices used in clinical practice. Three indices are computed to determine adrenergic function from the slope of the systolic blood pressure in phase II [α (a new index)], the baroreceptor sensitivity (ß), and the Valsalva ratio (γ). Results show that these indices can distinguish between normal and abnormal states, but model-based analysis is needed to differentiate pathological signals. In summary, the model simulates various VM responses and, by combining indices and model predictions, we study the pathologies for 5 AD patients.NEW & NOTEWORTHY We introduce a patient-specific model analyzing heart rate and blood pressure during a Valsalva maneuver (VM). The model predicts autonomic function incorporating the baroreflex and respiratory sinus arrhythmia (RSA) control mechanisms. We introduce a novel index (α) characterizing sympathetic activity, which can distinguish control and abnormal patients. However, we assert that modeling and parameter estimation are necessary to explain pathologies. Finally, we show that aortic baroreceptors contribute significantly to the VM and RSA affects early VM.

[Myalgic encephalomyelitis or chronic fatigue syndrome].

In this review, we discuss the myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), which is characterised by extreme mental and physical fatigue with associated symptoms of pain, disturbed sleep, cognitive and autonomic dysfunction, as well as post-exertional malaise. This con-dition is often preceded by an infection, severe physiological and/or psychological strain. Over the last decades, research has demonstrated mitochondrial, neuroendocrine, immuno-logical, and metabolic perturbations in patients with ME/CFS, giving hope for the development of new biomarkers and new treatment modalities.

Correction to: Autonomic dysfunction and HPV immunization: an overview.

In the recently published paper, "Autonomic dysfunction and HPV immunization: an overview", the last name of the lead author is listed incorrectly. The author's name is Svetlana Blitshteyn.

Autonomic dysfunction and HPV immunization: an overview.

This article reviews the case series reported from several countries describing patients with suspected severe side effects to the HPV vaccines. The described symptom clusters are remarkably similar and include disabling fatigue, headache, widespread pain, fainting, gastrointestinal dysmotility, limb weakness, memory impairment episodes of altered awareness, and abnormal movements. This constellation of symptoms and signs has been labeled with different diagnoses such as complex regional pain syndrome (CRPS), postural orthostatic tachycardia syndrome (POTS), small fiber neuropathy (SFN), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), or fibromyalgia. It is known that autoimmunity and autoantibodies are present in a subset of patients with CRPS, POTS, SFN, ME/CFS, and fibromyalgia. This article proposes that vaccine-triggered, immune-mediated autonomic dysfunction could lead to the development of de novo post-HPV vaccination syndrome possibly in genetically susceptible individuals. Being cognizant that a temporal relationship between vaccination and symptom onset does not necessarily equate to causality, mounting evidence of case series calls for well-designed case-control studies to determine the prevalence and possible causation between these symptom clusters and HPV vaccines. Since personalized medicine is gaining momentum, the use of adversomics and pharmacogenetics may eventually help identify individuals who are predisposed to HPV vaccine adverse events.

Type 1 narcolepsy is not present in 29 HPV-vaccinated individuals with subjective sleep complaints.

INTRODUCTION: Human papilloma virus (HPV) vaccine uptake in girls and women is dropping markedly in some countries. Concern about the presumed side effects is the commonest reason why. Reports about side effects include specific sleep complaints such as excessive daytime sleepiness, altered dream activity and periods of muscle weakness. These symptoms are commonly seen in individuals with narcolepsy type 1. We aimed to evaluate whether HPV vaccination was associated with the development of hypocretin-deficient narcolepsy. METHODS: We report the evaluation for sleep disorders, including narcolepsy, in 29 HPV-vaccinated girls and women who were submitted for evaluation of narcolepsy. All were evaluated by polysomnography and the Multiple Sleep Latency Test, and 18 individuals were also evaluated by measures of cerebrospinal fluid hypocretin-1 concentration. RESULTS: None of the 29 girls and women showed signs of narcolepsy type 1. CONCLUSION: Our results do not suggest that an association exists between HPV vaccination and the development of narcolepsy type 1. FUNDING: none. TRIAL REGISTRATION: not relevant.

[Postural orthostatic tachycardia syndrome].

Postural orthostatic tachycardia syndrome is a hetero-geneous condition of dysautonomia and suspected autoimmunity characterised by abnormal increments in heart rate upon assumption of the upright posture accompanied by symptoms of cerebral hypoperfusion and sympathoexcitation. An increase in heart rate equal to or greater than 30 bpm or to levels higher than 120 bpm during a head-up tilt test is the main diagnostic criterion. Manage-ment includes both non-pharmacological and pharma-cological treatment focusing on stress management, volume expansion and heart rate control.

Postural Orthostatic Tachycardia Syndrome (POTS) in Denmark: Increasingly recognized or new epidemic?

AIMS: The incidence of Postural Orthostatic Tachycardia Syndrome (POTS) has grown in recent years. Whether this is an emerging epidemic or increasing recognition is unclear. METHODS: We retrospectively examined 8790 tilt-table tests (HUT) performed between 1997 and 2014 in patients with orthostatic intolerance and/or suspected syncope. Tests were reclassified according to the current diagnostic criteria for POTS. The number of POTS diagnoses in proportion to the number of tilt tests performed per year was calculated. The number of papers published with the term "Postural Orthostatic Tachycardia Syndrome" 1997-2014 was retrieved from PubMed and related to yearly POTS incidence. RESULTS: Eight-hundred-and-seventy-five tests with suspected POTS were thoroughly evaluated. The reclassification of test results yielded 243 POTS diagnoses (age, 27.0 ±â€¯11.8 years). An increase in total number of POTS diagnoses was observed but the proportion of POTS-positive tests per year was relatively constant (≈2-3%) except for the period 2013-2014 (≈7%). The increase in POTS diagnoses was preceded by an increase in number of POTS-related papers in PubMed. CONCLUSION: The proportion of POTS diagnoses among patients investigated for suspected syncope and/or orthostatic intolerance was relatively constant 1997-2012. The growing number of POTS-related publications in PubMed preceded the steep increase in diagnostic rate of POTS observed after 2012.