The Trifecta

How POTS, MCAS, and EDS Are Connected—and Why It Matters

Introduction
You’ve likely heard of POTS, MCAS, and EDS separately, but what if I told you they often show up together—and it’s not a coincidence? This trio is part of a complex and under-recognized cluster of conditions affecting many people, especially women, often for years before a diagnosis. Understanding how they’re connected can shed light on symptoms that don’t seem to fit into any one box—and offer a roadmap toward more effective care.

What Is POTS?

POTS (Postural Orthostatic Tachycardia Syndrome) is a form of dysautonomia, meaning the autonomic nervous system (which controls involuntary functions like heart rate and blood pressure) isn’t working properly. People with POTS experience a rapid increase in heart rate—by 30 beats per minute or more—when standing up, along with symptoms like:

• Dizziness or lightheadedness

• Fatigue

• Palpitations

• Brain fog

• Heat intolerance

What Is MCAS?

MCAS (Mast Cell Activation Syndrome) occurs when mast cells—the immune cells responsible for allergic and inflammatory responses—are overly sensitive and release mediators (like histamine) inappropriately. This can cause a range of unpredictable symptoms, including:

• Hives or skin flushing

• GI issues (bloating, diarrhea, nausea)

• Shortness of breath

• Headaches

• Swelling or anaphylaxis in extreme cases

What Is EDS?

Ehlers-Danlos Syndrome is a group of genetic connective tissue disorders. The most common type—Hypermobile EDS (hEDS)—affects collagen, making joints overly flexible and tissues fragile. Common features include:

• Joint hypermobility

• Frequent joint dislocations or subluxations

• Chronic pain

• Digestive issues

• Easy bruising or stretchy skin

How Are They Connected?

1. Shared Underlying Physiology
All three conditions involve systemic dysregulation:

• EDS affects connective tissue integrity throughout the body—including in blood vessels, gut lining, and the nervous system.

• This fragility can contribute to the poor vascular tone seen in POTS.

• It may also impair the stability of mast cells, predisposing people to MCAS symptoms.

2. Dysautonomia as a Common Denominator
POTS and MCAS both involve the autonomic nervous system. In EDS patients, lax connective tissues can stretch and irritate nerves, disrupting autonomic signaling. Many patients with hEDS also develop POTS—some estimates say up to 78% of POTS patients meet criteria for hEDS.

3. Inflammation and Immune Dysregulation
MCAS releases inflammatory mediators that worsen both POTS symptoms (by dilating blood vessels and dropping blood pressure) and pain levels in EDS (by increasing nerve sensitization and inflammation).

4. Hormonal and Environmental Triggers
All three conditions are more common in women and tend to worsen around puberty, menstruation, pregnancy, or significant stress. Environmental triggers like heat, infections, or certain foods can also affect symptoms across the board.

Living with the Trifecta

Patients with one of these diagnoses should be screened for the others, especially when symptoms seem out of proportion or treatment isn’t working. Here’s what an integrated management plan might include:

• Compression garments, salt loading, and beta blockers for POTS

• Antihistamines, mast cell stabilizers, and low-histamine diets for MCAS

• Physical therapy and joint stabilization strategies for EDS

• Nervous system support, such as vagal nerve stimulation, trauma-informed care, and pacing

Why This Connection Matters

Recognizing the overlap between POTS, MCAS, and EDS can:

• Prevent misdiagnosis or dismissal as anxiety or psychosomatic illness

• Validate the lived experience of complex, chronic symptoms

• Improve quality of life through targeted, holistic treatment

• Help clinicians approach care from a systems biology perspective

Final Thoughts

These three conditions don’t always travel alone, but when they do, they create a web of symptoms that can feel overwhelming without the right context. If you suspect you or someone you love may be dealing with this trifecta, know that you're not imagining it—and you're not alone. Advocacy, education, and integrative care can change the game.