Heat and Cold Intolerance

Dr Graham Exelby December 2024 (with AI assistance)

Temperature intolerance is a common symptom in Postural Orthostatic Tachycardia Syndrome (POTS) and often manifests as heat intolerance, cold sensitivity, or unpredictable thermoregulatory responses. This phenomenon is likely driven by a complex interplay between mast cell dysfunction, neurotransmitter imbalances (aspartate/glutamate dysregulation), and autonomic instability.

1. Mast Cell Dysfunction and Temperature Intolerance

Mast cells, as part of the immune system, are involved in regulating vascular permeability, inflammation, and local tissue responses to environmental changes, including temperature.  Mast cell activation syndrome (MCAS) has been increasingly recognized as a comorbid condition in some POTS patients, contributing to temperature regulation issues.

a. Temperature as a Mast Cell Trigger

• Heat and cold can directly activate mast cells, leading to degranulation and the release of vasoactive and inflammatory mediators such as:

  • Histamine: Increases vascular permeability, causing flushing, swelling, or urticaria.

  • Prostaglandins and leukotrienes: Mediate vasodilation and contribute to the vascular dysregulation seen in POTS.

  • CCL2 and TNF-α: Promote chronic inflammation, which may sensitize thermoregulatory pathways in the CNS.

b. Impaired Vasomotor Responses

• Mast cell-derived mediators disrupt smooth muscle tone in blood vessels, impairing vasoconstriction and vasodilation.

• This dysregulation may lead to orthostatic pooling and delayed thermal adjustments, resulting in symptoms like:

  • Feeling excessively cold in normal conditions.

  • Heat intolerance due to inadequate dissipation of heat.

2. Aspartate/Glutamate Dysregulation and Central Thermoregulation

Aspartate and glutamate are critical excitatory neurotransmitters that regulate neuronal activity in thermoregulatory centres, particularly the hypothalamus.

a. Aspartate/Glutamate Imbalance

• Aspartate depletion and glutamate accumulation, often observed in POTS and related conditions, disrupt the excitatory-inhibitory balance in the CNS.

• Excessive glutamate can overstimulate NMDA receptors, leading to:

  • Dysfunctional signalling in the hypothalamus and brainstem regions responsible for thermoregulation.

  • Heightened sensitivity to external temperature changes.

b. Links to Neuroinflammation

• Mast cell degranulation near the blood-brain barrier can release mediators that cross into the CNS, amplifying neuroinflammation.

• Neuroinflammation further destabilizes glutamate regulation and impairs thermoregulatory circuits.

c. Role in Autonomic Dysregulation

• Aspartate/glutamate dysregulation in the brainstem may impair the autonomic nervous system’s (ANS) control of temperature responses by disrupting:

  • Sweating mechanisms for heat dissipation.

  • Peripheral vasoconstriction to retain heat.

3. Autonomic Instability in POTS and Thermoregulation

The ANS, particularly the sympathetic nervous system (SNS), plays a critical role in temperature regulation by modulating blood flow and sweat production.

a. SNS Overactivity

• POTS patients often exhibit sympathetic hyperactivity, which can lead to:

  • Inappropriate vasoconstriction or vasodilation in response to temperature changes.

  • Overactive sweat glands, exacerbating heat intolerance.

b. Baroreceptor Dysregulation

• Impaired baroreceptor signalling, as described in POTS pathophysiology, leads to inadequate compensation for blood pressure and temperature changes, amplifying symptoms.

c. Peripheral Dysregulation

• Peripheral vascular dysfunction, influenced by mast cell activity and inflammatory cytokines (e.g., IL-6, CCL2), may impair heat dissipation and lead to regional pooling of blood, further complicating temperature adaptation.

4. Integrated Mechanisms of Temperature Intolerance

1. Mast Cell Dysfunction:

   • Direct activation by temperature extremes exacerbates vascular dysregulation and inflammation.

2. Aspartate/Glutamate Imbalance:

   • Neurotransmitter dysregulation contributes to hypothalamic dysfunction and altered central thermoregulatory responses.

3. Autonomic Instability:

   • Impaired SNS and ANS responses fail to adapt appropriately to temperature changes, worsening symptoms of heat and cold intolerance.

5. Potential Management Strategies

a. Mast Cell Stabilization

• Cromolyn sodium or H1/H2 blockers (e.g., famotidine) to reduce mast cell activation and mitigate inflammatory mediator release.   While mast cells are primarily regulated by H1 and H4 receptors, H2 blockade with agents like famotidine can stabilize mast cell activity indirectly by reducing systemic histamine levels, inhibiting pro-inflammatory cytokine and chemokine production, and modulating histamine-mediated feedback loops.   Cromolyn and Famotidine have both been identified as CCL2 modulators, potentially providing an important management option in the important TLR4/ NFKB/CCL2 activation process that is a vital part of Long COVID.

• Low-dose naltrexone (LDN): Modulates neuroinflammation and immune dysregulation, targeting central and peripheral effects of mast cell dysfunction via H4 blockade.

b. Aspartate/Glutamate Balance Restoration

• Aspartic acid supplementation: dietary or supplementation may support neurotransmitter balance and mitochondrial function, but indiscriminate supplementation with aspartic acid is not recommended as the body's regulation of amino acid levels is tightly controlled, and supplementation could disrupt this balance, potentially leading to adverse effects.   At present management may be better targeted at managing the causes of the underlying dysfunction.

• NMDA receptor antagonists (e.g., magnesium): Reduces glutamate-mediated excitotoxicity and central sensitization.

c. Autonomic Regulation

• Beta-blockers or ivabradine may manage sympathetic overactivity and improve blood flow regulation.

• Compression garments reduce/prevent orthostatic pooling and improve temperature stability through enhanced circulation.

d. Anti-Inflammatory Interventions

• PPAR-γ agonists (e.g., telmisartan): Address neuroinflammation and autonomic dysregulation.   This is at research level only at this stage.

• Antioxidants: Reduce oxidative stress contributing to neuroinflammation and autonomic instability.

Conclusion

Temperature change instability in POTS is a multifactorial phenomenon involving mast cell dysfunction, aspartate/glutamate imbalances, and autonomic instability. These interconnected mechanisms disrupt thermoregulation, leading to symptoms of heat intolerance, cold sensitivity, and unpredictable responses to environmental changes. A combination of targeted therapies addressing mast cell activation, neurotransmitter dysregulation, and autonomic instability may provide effective symptom management.