Dysautonomia in hypermobile Ehlers–Danlos syndrome and hypermobility spectrum disorders is associated with exercise intolerance and cardiac atrophy

Abstract

Dysautonomia is a recognized manifestation in patients with joint hypermobility (JH) disorders. Symptoms can be highly debilitating and commonly include physical deconditioning and poor aerobic fitness. In this study, the prevalence of dysautonomia, range of associated symptoms, patient-reported physical activity levels, and echocardiographic features were assessed retrospectively in a cohort of 144 patients (94% female) with hypermobile Ehlers-Danlos syndrome (hEDS) or hypermobility spectrum disorder (HSD). Echocardiographic parameters of left ventricular size and function were compared between patients with and without dysautonomia as well as to reported values from healthy controls. Dysautonomia was identified in 65% of female and 44% of male subjects and was associated with a high burden of symptomatology, most commonly exercise intolerance (78%). Exercise capacity was limited by dysautonomia, often postural symptoms, in half of all patients. We observed a reduction in physical activity following the onset or significant flare of hEDS/HSD, most strikingly noting the proportion of dysautonomic patients with sedentary lifestyle, which increased from 44% to 85%. JH-related dysautonomia was associated with smaller cardiac chamber sizes, consistent with the previous reports in positional orthostatic tachycardia syndrome. Dysautonomia is prevalent in patients with hEDS/HSD, and exercise intolerance is a key feature and leads to drastic decline in physical activity. Unfavorable cardiac geometry may underlie dysautonomia symptoms and may be due to cardiac atrophy in the setting of aerobic deconditioning.

Looking back and beyond the 2017 diagnostic criteria for hypermobile Ehlers‐Danlos syndrome: A retrospective cross‐sectional study from an Italian reference center

“…Regarding other comorbidities such as chronic fatigue, dysautonomia (e.g., orthostatic intolerance, POTS), psychological distress (e.g., anxiety, sleep disturbances, impaired memory/concentration, depression), functional gastrointestinal and bladder disorders, and allergic/atopic features, we found that, with a few exceptions, the presence of individual comorbid features was no more or less frequent in hEDS and HSD, in line with other reports (Brock et al, 2021;Celletti et al, 2020;Hakim et al, 2021;Lam et al, 2021;Mathias et al, 2021;McGillis et al, 2020;Ruiz Maya et al, 2021;Wasim et al, 2019). In addition, many of these comorbidities are also frequently observed in other EDS forms, such as classical and vascular EDS, as well as rarer types (Malfait et al, 2020;Ritelli, Rovati, et al, 2020;, and in other chronic pain and fatigue conditions (Hakim et al, 2021).…”

“…Dysautonomia is also common and can impact pain and fatigue levels. Autonomic dysfunction may underlie both musculoskeletal pain and fatigue (Mathias et al, 2021; Ruiz Maya et al, 2021). Psychiatric and psychological comorbidities like depression and anxiety also frequently co‐occur and can worsen physical symptoms (Baeza‐Velasco et al, 2021; Bulbena‐Cabré et al, 2021).…”

“…However, shortly after the updated diagnostic criteria were introduced, several authors raised concerns about their limits, since they neither effectively recognize the more severely affected patients nor account for the numerous extra‐musculoskeletal manifestations of hEDS (Aubry‐Rozier et al, 2021; Castori, 2021; Copetti et al, 2019; Hakim, 2019; Hakim et al, 2021; Martinez et al, 2021; Morlino et al, 2019; Williams, 2019; Yew et al, 2021). These associated conditions are nowadays recognized, with varying levels of evidence, as JHM‐associated comorbidities and include chronic fatigue, pelvic floor problems, bladder dysfunction, various dysautonomic features (e.g., orthostatic decompensation, unstable cardiac rhythms and rates, postural orthostatic tachycardia syndrome [POTS], and gastrointestinal dysfunction), neurological involvement, behavioral disturbances, psychological distress, and immune system alterations such as mast cell disorders (Atwell et al, 2021; Brock et al, 2021; Castori et al, 2017; Celletti et al, 2020; Fernandez et al, 2022; Lam et al, 2021; Malfait et al, 2017; Malfait et al, 2020; Mathias et al, 2021; Pietri‐Toro et al, 2023; Rashed et al, 2022; Ruiz Maya et al, 2021; Thwaites et al, 2022; Tinkle et al, 2017; Vermeulen et al, 2022; Wasim et al, 2019). These comorbidities are common not only in hEDS but also in HSD, although their exact incidence has not been extensively documented thus far.…”

Characterization of small fiber neuropathy in hypermobile Ehlers Danlos Syndrome

“…Yet, none of the classification systems categorizing hypermobility syndromes, whether by Villefranche, Brighton or Malfait 2017, appears to stratify successfully patients according to severity [72]. Indeed, many experts in the field combine these conditions into a single phenotype termed hEDS/HSD [5,[72][73][74][75][76].…”

Evaluation and Management of Dyspnea in Hypermobile Ehlers-Danlos Syndrome and Generalized Hypermobility Spectrum Disorder: Protocol for a Pilot and Feasibility Randomized Controlled Trial

“…Individuals with EDS or G-HSD experienced increased dyspnea while walking on a flat level compared with healthy controls [ 12 ]. Furthermore, a study investigating physical activity levels between patients with hEDS or G-HSD with autonomic dysfunction and those without autonomic dysfunction observed that autonomic dysfunction was associated with exercise intolerance, which is often attributed to increased symptoms of dyspnea and chest pain [ 14 ]. Postural orthostatic tachycardia syndrome, a more severe form of autonomic dysfunction, has also been observed to be associated with dyspnea, chest pain, and impairments in HRQL [ 15 , 16 ].…”