Dr Graham Exelby March 2025
Introduction to POTS Comorbidities
Postural Orthostatic Tachycardia Syndrome (POTS) exists not as an isolated disorder, but as a clinical phenotype emerging from a convergence of systemic dysfunctions. Increasingly, it is understood that POTS frequently coexists with a broad spectrum of comorbidities—ranging from chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME), mast cell activation syndrome (MCAS), Ehlers-Danlos syndrome (EDS), mitochondrial disease, and intracranial hypertension, to neuroimmune disorders, autoimmune diseases, and mechanical abnormalities such as Chiari malformation and tethered cord. The high prevalence of these overlapping conditions is unlikely to be coincidental. Instead, these associations point to a shared network of pathophysiological disturbances that underpin not only POTS, but a wider syndromic constellation of dysautonomia-driven diseases.
The comorbidities associated with POTS frequently align with four recurring domains of dysfunction: immune dysregulation, autonomic instability, metabolic insufficiency, and mechanical or vascular obstruction. These axes intersect through key signalling pathways—most notably TLR4/NF-κB/RAGE activation, mitochondrial impairment (particularly at the level of pyruvate dehydrogenase), and disruption of neurovascular and glymphatic homeostasis. Immune triggers, whether infectious, autoimmune, or environmental, initiate a cascade involving chronic inflammation, mast cell activation, oxidative stress, and endothelial damage. In parallel, mechanical impediments—such as intracranial hypertension or pelvic venous congestion—compound cerebral hypoperfusion and autonomic dysregulation, perpetuating symptoms like fatigue, cognitive impairment, and orthostatic intolerance.
Central to many of these comorbidities is the theme of metabolic crisis, often manifesting as impaired energy generation (via PDH dysfunction), aberrant amino acid utilization (e.g., aspartate, GABA, glutamate), and disrupted phospholipid and neurotransmitter synthesis. These disruptions not only reflect but also exacerbate immune signalling abnormalities and autonomic instability. Similarly, structural abnormalities—whether due to connective tissue fragility in EDS, cerebrospinal fluid dysregulation in Chiari malformation, or venous hypertension in pelvic congestion—converge on shared outcomes: reduced cerebral perfusion, impaired baroreflex, and energy-deficient neuronal signalling.
This section explores the diverse and complex comorbidities of POTS through this unified lens. By detailing the immunologic, autonomic, metabolic, and mechanical contributions to each condition, we aim to reframe POTS as a systems disorder—a final common pathway of multiple upstream disruptions. Recognizing and categorizing these comorbidities not as separate syndromes but as reflections of core underlying dysfunction is essential for developing integrated diagnostic frameworks and precision treatment approaches.
Full paper to follow
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