POTS

Example of Systemic Dysfunction
Hypothesis

POTS – When Fibrin amyloids Reduce Oxygen Delivery and Prevent Energy Recovery

Fibrin amyloids have been proposed to significantly contribute to POTS symptoms associated with Long COVID and potentially other syndromes (Kell et al., 2024).

Fibrin amyloids restrict microvascular oxygen delivery, reducing aerobic ATP production and slowing the restoration of cellular energy stores. Ordinary activities can therefore consume ATP and phosphocreatine faster than they can be regenerated. When new activity begins before recovery is complete, the energy deficit accumulates and symptoms may continue to worsen for hours after the activity has ended.

Standing Increases the Demand on an Already Oxygen-Limited Circulation

When a person stands up, gravity naturally pulls blood downward. In a healthy body, vascular constriction, the skeletal-muscle pump, and venous valves help maintain blood return to the heart and sufficient oxygen delivery to tissues.

If persistent Fibrin amyloids already obstruct the microcirculation, oxygen delivery is limited before the person even stands. Moving upright adds a new circulatory demand to a system that is already operating with reduced tissue oxygen availability.

Blood Pooling Further Reduces an Already Limited Oxygen Supply

When transitioning to an upright position, blood pooling in the lower body reduces venous return and stroke volume. At the same time, Fibrin amyloids continue to restrict red-blood-cell passage through the smallest vessels.

The combined effect is a further reduction in oxygen delivery to tissues and the brain.The autonomic nervous system attempts to compensate by increasing heart rate and vascular tone to maintain cardiac output and cerebral circulation.

Standing Uses Energy Faster Than It Can Be Restored

Cells continuously use ATP and must continuously regenerate it. Efficient ATP regeneration depends on sufficient oxygen reaching the tissues and being available for aerobic energy production. When Fibrin amyloids restrict oxygen delivery, ATP cannot be restored as efficiently as it is being consumed. Standing increases energy demand at the same time that oxygen availability remains limited.

Microvascular obstruction → reduced oxygen delivery → impaired ATP regeneration → standing increases ATP demand → available energy falls faster than it can be restored

As long as the person remains upright, the energy deficit can continue to deepen because the cells cannot adequately replenish what they are using.

The Energy Reserve Can Collapse While Upright

The resulting problem is not simply that standing “uses more energy.” The body is trying to maintain circulation, blood pressure, cerebral oxygen delivery, and basic cellular function while the oxygen required to continuously restore cellular energy remains insufficient.

The longer the person remains upright, the greater the mismatch can become between energy being consumed and energy being regenerated. This can eventually produce a functional collapse in which sitting or standing becomes increasingly difficult until the circulatory and energy demand is reduced again.

Why Tachycardia Fails to Fix the Problem

Faster Heart Rate Does Not Guarantee Oxygen Delivery

In POTS, the heart can beat at 120 beats per minute simply while washing dishes in the kitchen. One might assume that this rapid heart rate would pump blood and oxygen into tissues efficiently, but this does not happen.

Microvascular Barriers Prevent Tissue Oxygenation

If there is a functional barrier within the capillaries and microcirculation—such as persistent Fibrin amyloids, localized vasospasm, or abnormal flow patterns—A higher heart rate does not correct impaired microvascular flow. Blood flow can remain uneven, and some tissue regions continue to receive too little oxygen despite maintained pressure in the larger vessels.

The Tachycardia Paradox: The heart works overtime consuming myocardial energy, but blood shunts past critical tissue zones due to microvascular barriers.

The Heart Compensates But The Problem Remains

The rapid heart rate in POTS represents an emergency compensatory response. The heart performs additional work and consumes more energy, yet tissue oxygen availability remains limited when the underlying microvascular obstruction persists.

Fibrin amyloids > The Forced Shift to Glycolysis

Oxygen Shortage Forces a Survival Shift

When fibrinaloid structures restrict oxygen delivery, the cells rely more heavily on glycolysis, producing energy from glucose in the cytoplasm. However, glycolysis is highly inefficient—producing a mere 2 ATP energy molecules per glucose molecule, whereas the optimal mitochondrial pathway would yield over 30 ATP molecules. The cell is left in a state of continuous, relative energy starvation, and lactate production increases while hydrogen ions accumulate, contributing to local tissue acidification.

Standing Rapidly Increases Energy Demand

When a POTS patient stands up, the dynamic physical load causes cellular energy and oxygen demands to skyrocket. Inefficient glycolysis can no longer cover this sudden energy crisis, increasing reliance on phosphocreatine as a rapid energy buffer.

The system desperately attempts to generate immediate energy and fill the deficit left by glycolysis by transferring phosphate groups from creatine directly to reform ATP. It tries to initiate its internal recovery and recharging mechanism—the creatine phosphate shuttle—to rapidly produce the missing energy.

The Oxygen Lock Prevents Energy Recovery

This is where the cellular catastrophe occurs: persistent microclots and microvascular barriers severely impair oxygen delivery to the tissues. For the phosphocreatine system to restore depleted energy reserves, it depends entirely on aerobic ATP production inside the mitochondria. 

When oxygen delivery becomes insufficient, ATP production slows and phosphocreatine stores cannot recharge normally. Phosphocreatine attempts to perform its role, but it runs directly into an oxygen lock created by impaired oxygen delivery. The system cannot generate energy out of thin air without oxygen.

Spectroscopy shows that cellular energy stores cannot recharge without continuous mitochondrial oxygen availability.

Phosphocreatine recovery after exertion is abnormally delayed. This delay appears to persist over time rather than normalize spontaneously, suggesting that the underlying problem remains present as long as oxygen delivery remains impaired.

The problem appears to be systemic rather than limited to skeletal muscle, since delayed phosphocreatine recovery correlates directly with reduced myocardial energy reserves as well.

Phosphocreatine recovery depends entirely on oxygen availability. The mitochondria themselves remain structurally intact, but persistent microclots impair tissue oxygen delivery and prevent normal restoration of cellular energy stores.

Low-level CO exposures become catastrophic

Loss of Buffering Capacity

A person already living at the absolute limit of their recovery capacity loses the ability to buffer even minor additional disruptions. The primary issue is not necessarily the absolute magnitude of the exposure itself, but the complete lack of physiological reserve. An exposure level that causes zero symptoms in a healthy person becomes highly significant when the body’s capacity for recovery is already critically limited.

These routine scenarios include sitting in heavy traffic, spending time near idling vehicles, everyday exposure to combustion products from wood-burning stoves, saunas, fireplaces, barbecues, gas stoves, gas ovens, and gas heating systems, and poorly ventilated spaces where combustion products accumulate.

Carbon Monoxide Targets Two Critical Systems

When carbon monoxide enters the system, it strikes directly at two vulnerable mechanisms. First, it binds to hemoglobin, further reducing an already compromised blood oxygen-carrying capacity. Second, it binds directly to cytochrome c oxidase within the mitochondria, completely blocking the minimal aerobic energy production that the mitochondria were still managing to sustain.

As a result, the kinetics of cellular respiration and the recovery speed of energy stores grind to a near-total halt. The system enters an acute cellular energy emergency, triggering a severe crash with an intense need for prolonged rest or sleep. Reduced activity lowers energy demand while CO clears and energy recovery gradually resumes. Sleep serves as the body’s ultimate protective mechanism—a state where energy expenditure is driven down so low that even a minimal, baseline recovery can slowly begin once the exposure subsides.

Summary

POTS and its resulting orthostatic intolerance are the direct consequence of severely slowed systemic oxygen delivery kinetics. The central problem is impaired oxygen delivery caused by persistent fibrin amyloid microclots, which progressively limit both aerobic energy production and the restoration of energy reserves.

POTS is not merely a wild, runaway heart rate; it is the body’s desperate, macro-level mechanical attempt to compensate for a micro-level lack of oxygen. It is entirely a relationship between physiological load and the body’s buffering capacity. The burden imposed by persistent microclots and impaired oxygen delivery becomes so severe that even minor dynamic changes, such as gravity, completely overwhelm the system’s ability to transport oxygen and generate energy efficiently.

Each new metabolic demand arrives before the previous recovery process has had the chance to finish. The body therefore operates not within a single, acute energy failure, but under the constant weight of an accumulating recovery deficit.

Sources