What causes dyspnea in patients with hypermobile Ehlers-Danlos Syndrome (hEDS)?

Mechanisms of Dyspnea in Hypermobile Ehlers-Danlos Syndrome

Dyspnea in hEDS is primarily caused by respiratory muscle weakness, which is present in approximately 77% of patients, combined with structural airway abnormalities and autonomic dysfunction. 1, 2

Primary Respiratory Mechanisms

Inspiratory Muscle Weakness

• Reduced inspiratory muscle strength (SNIP <80% predicted) occurs in 77% of hEDS patients and is the predominant cause of exertional dyspnea. 2
• Inspiratory muscle weakness leads to blunted tidal volume expansion during exercise, which is the primary mechanism of dyspnea perception rather than indices of inspiratory effort. 3
• The connective tissue abnormalities in hEDS—specifically softer, less stiff connective tissue with altered collagen fibril structure—likely compromise the structural integrity of respiratory muscles and their fascial attachments. 3, 4

Airway Structural Abnormalities

• Upper and lower airway collapse occurs due to connective tissue laxity affecting the trachea and bronchi, contributing to dyspnea during exertion. 5, 6
• Tracheobronchomalacia is a recognized structural manifestation that causes dynamic airway collapse during breathing. 7
• Chest wall abnormalities including pectus deformities, scoliosis, and recurrent rib subluxations create mechanical constraints on ventilation. 7

Abnormal Lung Volumes

• Despite normal baseline lung function, 24% of hEDS patients demonstrate higher-than-normal forced vital capacity (FVC) and 12% have elevated total lung capacity (TLC), suggesting altered chest wall compliance. 2
• These volume abnormalities may reflect the generalized tissue laxity characteristic of hEDS affecting thoracic structures. 2

Secondary Contributing Factors

Autonomic Dysfunction (POTS)

• Patients with hEDS and coexisting POTS experience more severe dyspnea due to orthostatic intolerance and altered cardiovascular responses to exercise. 3
• The vascular laxity in hEDS may predispose to POTS through impaired venous return and peripheral pooling, exacerbating exercise intolerance. 3
• Approximately 37.5% of hEDS patients report a diagnosis of POTS, which compounds respiratory symptoms through cardiovascular deconditioning. 3

Mast Cell Activation

• MCAS occurs in a subset of hEDS patients and can cause bronchospasm and respiratory symptoms through histamine release and inflammatory mediator effects on airways. 3
• Mast cells migrate into connective tissue including respiratory mucosa, where excessive degranulation can trigger asthma-like symptoms. 8
• However, MCAS should only be suspected when multisystem symptoms are present, not for isolated dyspnea. 3

Breathing Pattern Disorders

• Inducible laryngeal obstruction and exercise-induced hyperventilation may be misdiagnosed as asthma in hEDS patients. 7, 3
• Dysfunctional breathing patterns with increased respiratory frequency and reduced tidal volume occur due to mechanical constraints. 3

Differential Considerations

Distinguishing from Other Causes

• True asthma coexists in some hEDS patients and should be evaluated with standard spirometry and bronchoprovocation testing. 5, 6
• Gastroesophageal reflux disease is common in hEDS (reported in over 60% of patients with GI symptoms) and can contribute to respiratory symptoms through aspiration or reflex bronchoconstriction. 3, 7
• Sleep apnea has high prevalence in non-vascular EDS types and contributes to daytime dyspnea through sleep fragmentation and nocturnal hypoxemia. 5

Critical Pitfall

• Do not assume dyspnea in hEDS is purely deconditioning or anxiety-related without objective assessment of respiratory muscle strength using SNIP measurements. 2 The high prevalence of measurable inspiratory muscle weakness (77%) means this is a treatable organic cause that should not be missed. 2

Clinical Assessment Approach

Measure sniff nasal inspiratory pressure (SNIP) in all hEDS patients with dyspnea, as this identifies the 77% with respiratory muscle weakness who will benefit from targeted inspiratory muscle training. 2

• Perform standard spirometry to assess for obstructive or restrictive patterns, though baseline values are often normal. 2
• Evaluate for chest wall deformities, scoliosis, and rib subluxations on physical examination. 7
• Assess for POTS using postural vital signs if orthostatic symptoms accompany dyspnea. 3
• Consider laryngoscopy if inspiratory stridor or voice changes suggest laryngeal involvement. 7