This article is the front part of Chapter 6 of The Declaration of the Age of Physical Medicine (Yoon Jong-won). It is an academic exposition presenting the author's hypothesis of physical medicine, and the body text, figures, and citations follow the original manuscript.
There are stifling moments that everyone has experienced at least once. When the sink drain is clogged and the water does not go down. When the road is jammed at commuting time and one can neither enter nor leave. When breathing becomes gradually more stifling in a cramped room whose ventilation fan has broken down. These moments have one thing in common. Coming-in and going-out stop simultaneously. Only one path is blocked, yet the flows on both sides are cut off together. And this stifling deepens as time passes.
The same event happens inside our body. Every cell needs two things in order to live. Oxygen and nutrition and hormones must come in, and carbon dioxide and waste and toxins must go out. Coming-in (IN) and going-out (OUT). Only when this bidirectional flow continues without being cut off can the cell stay alive. The place where this flow occurs is the microvasculature. The microvasculature is not a simple pathway but a bidirectional exchange station where coming-in and going-out occur simultaneously at the same spot.
So when something happens in the microvasculature, not one event but two events occur simultaneously. When the pathway narrows, the road by which oxygen and nutrition come in is blocked, and at the same time the road by which waste goes out is also blocked. The event in which what should come in cannot come in, and what should go out cannot go out, occurs all at once at the same spot. This is the event this book calls the dual blockade. If only one path were blocked, the human body could recover by compensation. But when the two paths are blocked simultaneously, recovery mode ends and it converts to survival mode. And that conversion is irreversible.
This event is, before any abnormality of molecular signals, a physical event. It is a structural event in which the road narrows, the flow stops, and the pathway is blocked. Just as the essence of that stifling we already know from everyday life (the clogged drain, the jammed road, the stifling room) is the physical cutoff of flow, the dual blockade that occurs inside our body is the same kind of event. This is the reason this book bears the name physical medicine. It is because the underlying reality of aging and chronic disease is, before any abnormality of molecular signals, an event in which flow and pathway and structure are physically deformed.
At the end of the previous chapter we saw one important fact. The fact that when deficiency, inflammation, acidosis, and hypoxia are pulled all at once, the human body activates the same emergency prescription and releases calcium from the bone. The fact that the DIAH triggers are the starting point of aging and chronic disease, and the DIAH four gateways are the last pathway toward every death. And the fact that calcium is the central medium of the metabolism of life, mobilized first in every crisis of the human body. One question remained. Where does the calcium that leaves like that go? In a normal environment it is recovered back into the bone within a short time. But in an environment where the DIAH triggers are pulled chronically, the recovery cannot keep up. The calcium that is not recovered settles into a new place inside the human body. That place is precisely the wall of the microvasculature.
This chapter is the story of that settling. It unravels, in turn, where in the microvascular wall calcium settles, what event begins there, and why, once it has begun, recovery is difficult. Cardiovascular medicine handles atherosclerosis, renal medicine handles chronic renal failure, endocrine medicine handles diabetic complications, and orthopedic medicine handles osteoporosis. Specialty medicine diagnoses these four separately and treats them separately. But when the main bodies of those events are gathered in one place and looked at, they all converge into one and the same event. It is the event in which the leaked calcium settles on the microvascular wall and blocks the two flows of coming-in and going-out simultaneously. The manifestations of aging and chronic disease that specialty medicine has seen separately are, at the physical dimension of microvascular flow, one.
At the end of the previous chapter we received the promise of one path. It is the five-stage integrated pathway in which the determining factor settles in, the trigger is pulled, the dual blockade is made, the damage is manifested, and it finally leads to collapse. Binding the English initials of these five stages, we call it DTDMC. Determinants, Trigger, Dual blockade, Manifestation, Collapse. The various branches of scenery we have seen so far (that is, the empty layer of medicine, the human body's flow and microvasculature, the gradient as a universal law of nature, the ambivalence of calcium, and the work of gathering the DIAH triggers into one place) are precisely this path of DTDMC. This chapter unravels the front four stages among those five, that is, the path of the underlying reality from the determining factor to the manifestation of damage. The final stage, collapse, and its seven patterns of clinical manifestation, are handled in the following chapter.
Microcalcification Dual Blockade: The Underlying Reality That Imaging Cannot Catch
The large plaque, the reduced kidney function, and the raised blood sugar that appear on the outside are the faces of the result. Beneath them, the flow collapse in which the supply and discharge of the microvasculature narrow simultaneously has long been accumulating. The underlying reality of aging and chronic disease is in a smaller place, a spot not caught by standard imaging. It is the microvasculature.
There are two kinds of blood vessel in the human body. The large vessels we commonly recall (the aorta, the cardiac arteries, the cerebral arteries, the renal arteries) and the almost invisible microvasculature: the arterioles, capillaries, and venules of diameter 100 micrometers or less. If the lengths of all the blood vessels of the human body are added together, it reaches about one hundred thousand kilometers, and most of that is microvasculature. Every cell of the human body is in direct contact not with the large vessels but with the microvasculature. Oxygen, nutrition, hormones, and immune cells all reach the cell only through the microvasculature.
It is precisely on this microvascular wall that the leaked calcium finds its place of settling. The calcium ion meets the phosphate ion and combines to form a minute mineral crystal. A microcrystal whose diameter reaches from nanometers to tens of micrometers. This is microvascular microcalcification. This microcalcification, positioned on the microvascular wall, not only narrows the flow at the pathway dimension but also, at the same spot, shakes together the signal dimension that the cell receives. A blockade that occurs simultaneously in the two dimensions of pathway and signal: the event pointed to as the underlying reality of this whole book is precisely this, and this book calls this underlying-reality event the microcalcification dual blockade.
The most decisive characteristic of microcalcification is that it is not detected by standard imaging. The standard resolution of the computed tomography used in clinical practice is about 0.5 millimeters, and even using fine high-precision imaging, the limit is about 0.2 millimeters. But the size of microvascular microcalcification is far smaller than that. It is not visible on standard imaging.
A comprehensive review published by the Demer and Tintut research group of the University of California, Los Angeles (UCLA) in the American cardiovascular journal Circulation organized that vascular calcification is not a mere product of aging but an active mineralization process. That review showed, with molecular- and cellular-level evidence, that the event in which calcium and phosphorus combine on the vessel wall and crystal formation begins progresses long before clinical symptoms are manifested, and that the microscopic stage that standard imaging cannot catch is the starting point of the underlying reality. The period when the patient does not yet feel any symptom, and the doctor does not find any abnormality on imaging, but the calcium-phosphate crystal has already begun to deposit on the microvascular wall. This period is called the clinically asymptomatic latent period.
Another comprehensive review published by the Lanzer et al. multinational research group of Germany in a European cardiovascular journal made clear one more decisive fact of this event. It is that the medial calcification occurring in the microvasculature is a separate event clearly distinguished from the general atherosclerosis that begins in the intima of the large arteries. Medial calcification accumulates slowly and clinically asymptomatically, and is hard to catch with standard imaging, but it has a decisive influence on microvascular flow. The place we must look at in aging and chronic disease is not the plaque of the large arteries but the medial calcification that occurs at a far smaller place.
[Figure 1] Comparison of Macrocalcification and Microcalcification
| Item | Microvascular microcalcification | Macrocalcification |
|---|---|---|
| Size | Nanometers to tens of micrometers | Millimeters to centimeters |
| Location | Wall of arterioles, capillaries, venules | Large vessels, tissues, organs |
| Imaging detection | Not detected by standard CT (resolution 0.5mm) | Visible on imaging (object of clinical diagnosis) |
| Clinical | Latent period before symptom manifestation | Already in progressed stage at the time of diagnosis |
| Time order | Progresses first | Becomes visible later |
The reason the microcalcification dual blockade is pointed to as the underlying reality of aging and chronic disease is not merely that it is invisible. The very fact that it occurs in the microvasculature is decisive. The following article unravels that reason.
The Two Roads of the Microvasculature: Supply and Discharge
The microvasculature is not a simple pathway. It is a bidirectional exchange system that performs two tasks simultaneously.
In one direction, everything the cell needs in order to live comes in. Oxygen, glucose, amino acids, lipids, vitamins, minerals, hormones, immune cells, drugs. This is supply. In the other direction, everything the cell has made goes out. Carbon dioxide, metabolic waste, lactate, uric acid, toxins, excess inflammatory substances. This is discharge. Across the microvascular wall (a single layer of endothelial cells), bidirectional exchange is occurring ceaselessly.
When supply is blocked the cell starves, and when discharge is blocked the cell is submerged in its own waste. If either one of the two roads is blocked, the cell immediately falls into crisis. But the human body has an intricate system in which, even if one side is partially blocked, the other side is activated and compensates. When one road narrows, the other road opens more, and the cell endures up to a certain point.
[Figure 2] The Two Functions of the Microvasculature: Supply and Discharge
| Direction | Role | Main substances | Event upon blockade |
|---|---|---|---|
| Supply (IN) | Cell entry | Oxygen, glucose, amino acids, hormones, immune cells, drugs | Energy deficiency, functional halt, failure of drug delivery |
| Discharge (OUT) | Cell exit | Carbon dioxide, metabolic waste, lactate, uric acid, toxins, inflammatory substances | Self-intoxication, acidification, inflammation accumulation, cell death |
The problem is that the two roads meet at the same spot (the same microvascular wall). When microcalcification deposits on the microvascular wall, the bidirectional exchange that passes through this wall is all affected. The supply signal weakens, and the discharge pathway narrows. The two roads begin to be blocked simultaneously.
If we render into plain expression the event in which the two roads weaken simultaneously, it becomes this. The cell comes to receive less nutrition and oxygen, and at the same time comes to discharge less waste. Starvation and intoxication begin simultaneously. But here there is one point to make precise. Both supply and discharge are events of material transport through the microvascular pathway. This blockade at the pathway dimension is called, in this book, pathway blockade, abbreviated DLT. But the event that makes the true underlying reality of aging and chronic disease is not completed by the pathway dimension alone. Only when another dimension different from the pathway dimension, that is, the dimension of the signal that the cell must receive in order to operate its own function, is blocked together does recovery come to an end. The following article unravels precisely the identity of the two dimensions and their combination.
Dual Blockade: When Channel Blockade (DLT) and Signal Blockade (CAM) Operate Together
The cells of the human body live while depending simultaneously on two dimensions. The first is the physical-transport dimension. Through the microvasculature, oxygen and glucose and amino acids come in, and carbon dioxide and waste and toxins go out. When this bidirectional material flow is blocked, the cell starves and is intoxicated. The second is the signal dimension. The cell operates its own function by accurately receiving the various signals it receives from outside: hormones, growth factors, immune signals, and, most crucially, the calcium second-messenger signal inside the cell. All of these operations (the contraction of muscle, the transmission of nerves, the secretion of hormones, and the regulation of cellular differentiation and death) depend on the signal dimension.
A blockade can occur in each of these two dimensions. When microvascular microcalcification narrows the inner diameter of the microvasculature, material transport declines. Oxygen supply decreases and waste discharge is blocked. This event is pathway blockade (DLT). Meanwhile, when the same calcium fluctuates repeatedly in the blood, the stability of the calcium second-messenger signal inside the cell is disturbed. The cell cannot accurately interpret the external signal and loses the precision of its functional operation. This event is signal blockade (CAM).
The fact to note is that both blockades set out from the same one event. The calcium leaked from the bone. When that calcium deposits as a solid on the microvascular wall, pathway blockade is made, and when the same calcium causes concentration fluctuation in the blood, signal blockade is made. One substance advances two blockades simultaneously.
Here is the decisive fact. The human body is very strong against a single blockade. In the case where only pathway blockade (DLT) is activated, that is, even if the microvascular flow narrows, if the signal is normal, the cell accurately operates the hypoxia-adaptation mechanism. The hypoxia-inducible factor is activated and it converts to fermentative metabolism, autophagy operates and recycles the cell's resources, and the apoptosis circuit is also precisely regulated. There remains a road to buy time and recover. In the case where only signal blockade (CAM) is activated, that is, even if the calcium signal is unstable, if the pathway is normal, the cell absorbs the signal fluctuation to a certain degree through the compensation of external hormones and homeostatic mechanisms. Some forms of arrhythmia or transient spasm do occur, but system-level compensation operates. In both cases, the one remaining dimension makes the recovery of the system possible.
But the moment the two blockades are activated simultaneously, the moment DLT and CAM operate together, the compensation pathway itself disappears. While the signal dimension is shaken so that the cell cannot accurately operate the compensation mechanism, the pathway dimension is blocked so that the energy and materials needed for compensation are not supplied either. There is neither the signal to operate compensation nor the resource to operate it. Recovery mode ends, and the human body converts to survival mode. This is the dual blockade.
The dual blockade is not simply the sum of two blockades. Because the compensation pathways of the two dimensions depend on each other's operation, the moment one dimension is blocked, the recovery of the other dimension also stops together. The two events that occur at the same spot on the microvascular wall, that is, the stenosis of the pathway (DLT) and the fluctuation of the signal (CAM), combine to make the irreversible underlying reality of aging and chronic disease. So this book defines the common underlying reality of aging and chronic disease, which specialty medicine has seen separately, as the dual blockade, the combination of pathway blockade and signal blockade.
The intensity of the dual blockade is expressed exactly by the product of the two blockade indices. If the signal-blockade index is called CAM and the pathway-blockade index is called DLT, the product of the two indices is the dual-blockade index (B*). Written as a formula, it is as follows.
B* = CAM × DLT
The moment this index exceeds the threshold point, the human body converts from recovery mode to survival mode. The following article clearly unravels why it must be multiplication, not addition, and the reason for it.
[Figure 3] The Difference Between Single Blockade and Dual Blockade
| State | Signal blockade (CAM) | Pathway blockade (DLT) | Compensation mechanism | Possibility of recovery |
|---|---|---|---|---|
| CAM single blockade | Activated | Normal | Hormonal and homeostatic compensation | Recovery possible |
| DLT single blockade | Normal | Activated | HIF, anaerobic metabolism, autophagy compensation | Recovery possible |
| Dual blockade | Activated | Activated | Compensation pathway itself disappears | Irreversible |
Why Multiplication
There are three clear reasons why the dual-blockade event that occurs inside a person's body must be expressed as a multiplicative formula. It is not an arbitrary choice of formula; physical law requires it so.
First, if one side is alive, the whole is alive
Let us think of the case where the signal dimension is completely normal. If signal blockade (CAM) is near 0, then even if pathway blockade (DLT) is partially activated, the cell can endure. Likewise, if the pathway dimension is completely normal, then even if signal blockade (CAM) is partially activated, the cell can endure. If either side is normal, the human body operates in recovery mode.
Rendering this into mathematics makes it clear. If the blockade index of either axis is 0, then the product of the two axes is also 0. If only one axis is alive, the total blockade index becomes 0. That is, it becomes a state in which the blockade is not established. Only multiplication expresses this fact accurately. This is precisely what the human body's compensation system does. As long as one axis is alive, the total flow does not stop.
Second, addition cannot distinguish single blockade from dual blockade
Suppose we assume we express the two blockade indices as a sum. Then even in a state where signal blockade (CAM) is very seriously activated and pathway blockade (DLT) is normal, the summed value exceeds the blockade threshold. That is, a single blockade is misdiagnosed as a dual blockade. But clinical reality is not so. A patient in whom only one axis is activated endures and recovers through the compensation of the other axis. Only the dual-blockade patient progresses to an irreversible event.
The multiplicative formula reflects this reality accurately. In the same situation, the product is 0. It is accurately judged as a single blockade. Addition creates the structural possibility of a diagnostic error, but multiplication blocks that error at the source.
Third, Poiseuille's law says so
The most basic physical law describing the flow rate of a viscous fluid flowing inside a tube is Poiseuille's law. This law, discovered by the French physician Poiseuille in 1846, is written as follows.
Q = (π × ΔP × r⁴) / (8 × μ × L)
Here Q is the flow rate (the amount flowing), ΔP is the pressure difference (the gradient that makes the flow), r is the radius of the pathway, μ is the viscosity, and L is the length. The core of this formula is the fact that the flow rate is determined by the product of the pressure gradient and the fourth power of the radius. It is multiplication, not addition.
When this law is mapped onto the dual blockade of the microvasculature, exactly the same structure is revealed. The event in which the pressure gradient weakens corresponds to the blockade of the signal dimension (CAM), and the event in which the radius of the pathway narrows corresponds to the blockade of the physical pathway (DLT). When the two events occur simultaneously, the flow rate changes as the product of the two changes. Multiplication is not a formula we chose arbitrarily but the original structure of the physical event called flow.
This fact touches the very core of this whole book. Aging and chronic disease are not chemical-reaction events at the molecular level but physical events at the flow level. So atherosclerosis, renal failure, diabetic complications, and osteoporosis, which specialty medicine has seen separately only at the molecular level, converge into one and the same event at the physical dimension of flow. The dual blockade that occurs in the microvasculature. That is the physical underlying reality of aging and chronic disease.
[Figure 4] The Three Scenarios of the Dual-Blockade Index B*
| Scenario | Signal blockade (CAM) | Pathway blockade (DLT) | Dual-blockade index (B*) | Judgment |
|---|---|---|---|---|
| A. CAM single blockade | 0.9 | 0.1 | 0.09 | Safe, compensation possible |
| B. Partial dual blockade | 0.5 | 0.5 | 0.25 | Borderline, in progress |
| C. Severe dual blockade | 0.8 | 0.8 | 0.64 | Dual blockade established, irreversible |
In scenario A, even though signal blockade (CAM) is very seriously activated at 0.9, if pathway blockade (DLT) is near normal at 0.1, the dual-blockade index stays at 0.09. The system still operates. Scenario C is the exact opposite. When the two dimensions are simultaneously activated at the level of 0.8 each, the product is 0.64 and exceeds the blockade threshold point. If one axis is alive the whole lives, and if the two axes weaken simultaneously the whole dies. Within the simple operation of multiplication, the human body's recovery system and its limit are accurately contained.
This multiplicative structure also has a direct implication for the recovery strategy. Even if only one dimension is recovered, the product is recovered in proportion to that dimension. If the two dimensions are recovered together, the product is recovered as the product of the two recovery amounts. The clinical observation that the effect of a single-dimension intervention is limited, and that a multi-dimensional integrated intervention creates an effect more than proportional, is exactly the result of the same multiplicative structure. Although it is hard to stop the progression of chronic disease with only one drug or one change of lifestyle habit, an integrated intervention that recovers the signal axis and the pathway axis simultaneously makes the effect explode in the form of a product. The mathematical reason we must pursue, when handling chronic disease, not a single-dimension intervention but an integrated intervention of several dimensions lies here.
Calcification Acceleration: Why Some People Harden Faster
Even when the same amount of calcium has leaked, some people's microvasculature hardens rapidly, and some people's microvasculature hardens slowly. Even with the same dietary life, one person progresses to atherosclerosis in their 50s, while another person's microvasculature stays clean until their 80s. What is the variable that determines the speed of calcification?
A comprehensive review published by the Hofbauer et al. research group of the Dresden University of Technology in Germany in an international osteoporosis journal organized one decisive fact. It is that osteoporosis and vascular calcification are not two separately progressing events, but progress simultaneously within the same patient and share the same molecular mechanism. The fact that the event in which calcium leaves the bone and the event in which calcium deposits on the vessel are connected by the same trigger signal. This makes clear that the two diseases we have seen separately in specialty medicine are essentially two faces of one event. That review and the studies that followed showed that the decisive variables of microvascular calcification acceleration are organized into three.
The first variable is the supersaturation state of calcium and phosphorus. The leaked calcium combines with phosphate to make a crystal. The higher the concentrations of calcium and phosphorus in the blood, the faster crystal formation becomes. Here lies the reason microvascular calcification explodes in chronic renal failure patients. When the human body loses the balance of calcium and phosphorus, the chemical starting point of crystal formation is made.
The second variable is the identity conversion of the vessel-wall cell. In the normal microvascular wall there exists a cell called the vascular smooth muscle cell. This cell is originally in charge of the contraction and relaxation of the vessel. But when inflammation or oxidative stress, high blood sugar, and aging products act chronically, this cell begins to change its identity. A study published by the Reynolds et al. research group of the University of Cambridge in the United Kingdom in a journal of the American Society of Nephrology showed that when the vascular smooth muscle cell is exposed to changes in the concentration of calcium and phosphorus, the minute vesicles inside the cell directly begin crystal formation. Another molecular-biology study published by the Speer et al. research group of the United States in an American cardiovascular research journal traced, stage by stage, the conversion in which the same cell begins to behave like a bone-forming cell. The fact that those two studies showed together is clear. Once this conversion occurs, the microvascular wall actively begins to make calcium crystals. It is active calcification beyond simple deposition.
The third variable is the decrease of the calcification-inhibiting factors the human body has. The human body has an intricate defense system to prevent calcification. Three molecules (Matrix GLA protein, Fetuin-A, and pyrophosphate) actively block crystal formation on the microvascular wall. But when aging, vitamin K deficiency, chronic renal failure, and chronic inflammation accumulate, these inhibiting factors weaken. Matrix GLA protein must have vitamin K to be activated, and in chronic deficiency its activity decreases meaningfully. When the defense weakens, crystals are formed more easily.