Continuing from the previous part, this article continues to examine the 7M damage patterns. The body text, figures, and citations follow the original manuscript.
[Figure 4] 3M Coating & Blocking: Representative Clinical Distribution
| Place | Representative clinical | Microscopic-dimension event |
|---|---|---|
| Pancreatic and muscle insulin signal | Insulin resistance, type 2 diabetes | Microcalcification of insulin receptors and insulin signal pathways |
| Thyroid and endocrine glands | Some forms of hypothyroidism, secretory-signal desensitization | Microcalcification of secretory-signal pathways |
| Vascular endothelium | Endothelial functional decline, pre-hypertension stage | Calcium-protein particles damage the endothelial nitric oxide signal |
| Cardiac electrical signal | Some forms of arrhythmia | Micro-calcium deposition in the myocardial electrical-conduction signal |
| Blood lipid and calcium metabolism | Hyperlipidemia, hypercalcemia | Desensitization of lipid and calcium signal homeostasis |
If 3M is the pattern of signal cutoff, the 4M of the following article is the pattern of hardening. From the signal dimension to the structural dimension, from the blockade of molecular signals to the hardening of tissue, the pattern moves over.
4M Hardening: Hardens
4M Hardening is the pattern in which the tissues of the human body (vessel walls, organ parenchyma, connective tissue, skin) lose the elasticity they originally had and harden. Unraveled into Korean, it is the event of hardening. The English name expresses together hardening, stiffening, and loss of elasticity, and it is an integrated pattern that gathers in one place the clinical phenomena that existing pathology has handled separately as fibrosis, sclerosis, and atherosclerosis.
This pattern is also the most commonly observed pattern in aging and chronic disease. 4M appears in almost all fields that specialty medicine has handled. Cardiology handles atherosclerosis and high blood pressure. Nephrology handles the renal sclerosis of chronic renal failure. Gastroenterology handles cirrhosis and hepatic fibrosis. Rheumatology handles the stiffening of ankylosing spondylitis and rheumatoid arthritis. Dermatology handles scleroderma and systemic sclerosis. Pulmonology handles idiopathic pulmonary fibrosis. They are different diagnostic names by specialty, but when looked at closely they are all manifestations of one event at different places. It is the event in which collagen piles up excessively in the extracellular matrix of the tissue, microcalcification deposits together at that spot, and the tissue loses its original elasticity and hardens.
The reason different diagnostic names are bound into the same one pattern also lies in setting out from the same molecular-dimension event. When microcalcification deposits in the microvasculature and the flow declines, chronic hypoxia is made at that spot. A cell exposed to chronic hypoxia secretes collagen as a protective reaction, and that collagen accumulates within the tissue. At the same time, as the same microcalcification expands into the macroscopic dimension, the tissue hardens. Only the clinical name differs depending on at which place this one mechanism occurs. In the artery it surfaces as atherosclerosis, in the kidney as renal sclerosis, in the liver as cirrhosis, in the spine as ankylosing spondylitis, and in the skin as scleroderma.
A comprehensive review published by the Chen, Zhao, and Wu research group of the University of Alabama in the United States in an American atherosclerosis-medicine journal organized one decisive fact. It is that vascular calcification and arterial stiffness are not simply two separate events observed together, but two faces of the same event connected by one molecular mechanism. The mechanism that review organized is this. When vascular smooth muscle cells are exposed to oxidative stress, high blood sugar, and disturbance of calcium-phosphorus homeostasis, they change their identity and begin to behave like bone-forming cells. The molecules that cell secretes are no longer molecules that maintain the elasticity of the vessel but molecules that make bone. So microcalcification accumulates on the vessel wall, and at the same time that wall gradually hardens. It is that atherosclerosis, diabetes, and chronic renal failure all surface as 4M Hardening through the same one mechanism (bone-forming conversion).
A comprehensive review published in the English-language journal of the Korean Society of Clinical Hypertension made clear the clinical consequence of 4M Hardening. When an artery hardens, one clinical event occurs at that spot. The rise of systolic blood pressure. A normal artery stretches elastically when blood is ejected from the heart and absorbs the shock of the pressure. But a hardened artery cannot stretch, and transmits the ejection pressure as it is. As a result, systolic blood pressure rises. The fact that review made clear is even more decisive. The raised systolic blood pressure again damages the arterial wall, and at that damaged site inflammation and microcalcification accumulate further so that the artery hardens more, forming a vicious cycle. Arterial stiffness and systolic hypertension are not a one-directional causal relationship but a bidirectional vicious cycle. It confirmed with clinical data that the two clinical events we have seen separately in specialty medicine (atherosclerosis and high blood pressure) are essentially two faces of the same one event.
When the two materials are placed in one place, the fact becomes even clearer. The clinical events diagnosed in specialty medicine as atherosclerosis, high blood pressure, cirrhosis, renal sclerosis, scleroderma, ankylosing spondylitis, and pulmonary fibrosis are, in their underlying reality, all manifestations of one event. It is the event in which microvascular microcalcification makes chronic hypoxia, that chronic hypoxia induces collagen over-accumulation, and microcalcification accumulates into the macroscopic dimension at the same spot so that the tissue hardens. 4M Hardening is the pattern in which the microcalcification dual blockade surfaces most commonly at the tissue dimension.
Organizing the representative clinical diseases belonging to the 4M pattern gives the following. A large part of the chronic diseases most frequently encountered in the clinic is gathered within this one pattern.
[Figure 5] 4M Hardening: Representative Clinical Distribution
| Place | Representative clinical | Microscopic-dimension event |
|---|---|---|
| Artery and vessels | Arteriosclerosis, atherosclerosis, high blood pressure, systolic hypertension | Bone-forming conversion of vascular smooth muscle cells + microcalcification |
| Kidney | Chronic renal failure, renal sclerosis, diabetic nephropathy | Renal microvascular calcification + glomerular fibrosis |
| Liver | Cirrhosis, hepatic fibrosis, non-alcoholic fatty liver | Hepatic microvascular calcification + collagen over-accumulation |
| Spine and joints | Ankylosing spondylitis, the stiffening of rheumatoid arthritis | Joint and spinal connective-tissue microcalcification |
| Skin and connective tissue | Scleroderma, systemic sclerosis | Skin and connective-tissue microcalcification |
| Lung | Idiopathic pulmonary fibrosis, some chronic obstructive pulmonary disease | Pulmonary microvascular calcification + alveolar collagen over-accumulation |
The clinical importance of 4M Hardening lies in its frequency. Wherever the microcalcification dual blockade occurs, if time accumulates sufficiently, that spot progresses in the direction of hardening. So the majority of aging and chronic disease finally comes to have the form of 4M Hardening. The vessels of an atherosclerosis patient, the kidney of a chronic renal failure patient, and the liver of a cirrhosis patient are all tissues that have lost their original elasticity and hardened. 4M is the most common form of the result of the microcalcification dual blockade accumulated along time, and so this pattern is the pattern most frequently diagnosed in the clinic.
If 4M is the pattern of hardening, the 5M of the following article is the pattern of overflowing and bursting. From hardening to overflow, from stiffening at the tissue dimension to overload at the cellular dimension, the pattern moves over.
5M Overflow & Burst: Overflows and Bursts
5M Overflow & Burst is the pattern in which calcium flows into the cell more than the originally permitted amount so that the signal turns on excessively, and as a result the cell hypertrophies, hyperproliferates, or dies. Unraveled into Korean, it is the event of overflowing and bursting. The English name expresses together the flooding, overload, and bursting of calcium, and it is an integrated pattern that gathers in one place the clinical phenomena that existing pathology has handled separately as tumor, hypertrophy, and apoptosis.
The mechanism of 5M Overflow & Burst is essentially different from the preceding patterns. If the occlusion of 1M, the movement-dulling of 2M, the signal cutoff of 3M, and the hardening of 4M are all in the direction of decline of flow and function, 5M is, to the exact contrary, the excess of the signal. A normal cell precisely regulates the calcium concentration inside the cell within a very narrow range. When calcium is too little, or too much, the cell cannot maintain normal function. But when, for some reason, the calcium inside the cell comes in more than the originally permitted amount, that cell stands at two forking roads. It either hypertrophies abnormally or hyperproliferates, or it enters the road of death. Whichever road it goes, the result is a clinical event.
This pattern has been diagnosed in specialty medicine under very powerful but separated clinical names. Oncology handles hepatocellular carcinoma, breast cancer, prostate cancer, and multiple myeloma. Gynecology handles uterine fibroids. Urology handles prostatic hypertrophy. Cardiology handles some of myocardial hypertrophy and heart failure. They are different diagnostic names by specialty, but all are one molecular-dimension event surfacing at different places. It is the event in which the calcium signal inside the cell turns on excessively, and the cell that received that signal splits into hypertrophy, hyperproliferation, and death.
The reason different diagnostic names are bound into the same one pattern is that they all set out from the same molecular event of calcium overload. The calcium signal is a core signal that regulates growth and division even in a normal cell. But when that signal loses its precise regulation and becomes chronically excessive, the cell begins to hypertrophy or hyperproliferate beyond the normal growth limit. Only the clinical name differs depending on at which place it occurs. When it occurs in hepatocytes, it surfaces as hepatocellular carcinoma; in breast epithelial cells, as breast cancer; in prostate cells, as prostate cancer or prostatic hypertrophy; and in myocardial cells, as myocardial hypertrophy.
A comprehensive review published by the Ali, Rychkov, and Barritt research group of Flinders University in Adelaide, Australia, in an international cancer-medicine journal made this integration clear. That review organized that about 20 calcium signaling proteins play a decisive role in every stage of the initiation, progression, and metastasis of hepatocellular carcinoma (clinical name HCC). The proteins that regulate the calcium concentration inside the cytoplasm, the endoplasmic reticulum, and the mitochondria govern the growth, migration, and death of liver cancer cells. The fact that review made clear is even more decisive. It is that a change in the calcium signal inside the cell can send the same cell down both the road of hyperproliferation and the road of death. Depending on the intensity and duration of the calcium signal, the same cell becomes a tumor cell or becomes a dying cell. It is that the same molecular event makes two branches of clinical results.
A molecular-biology study published by the Molkentin, Lu, Antos, and Olson research group of the University of Texas Southwestern Medical Center in the United States in the American life-science journal Cell made clear, at the molecular dimension, the form in which the same event is manifested in the heart. That study showed that when some stimulus is applied to myocardial cells and the calcium inside the cell comes in excessively, a calcium-dependent enzyme called calcineurin is activated and moves two transcription factors, NF-AT3 and GATA4, into the nucleus, and as a result the gene program by which the myocardial cell hypertrophies turns on. When calcineurin is blocked with a drug, myocardial hypertrophy is blocked. That is, the hypertrophy of the myocardial cell is not simply the passive result of pressure or volume overload but a molecular program that the calcium excess inside the cell actively turns on. This discovery made clear that myocardial hypertrophy occurs by the same molecular mechanism as the hypertrophy of tumor cells (the excessive activation of the calcium signal).
When the tumor of the hepatocyte and the hypertrophy of the myocardial cell are placed in one place, the fact becomes clear. The clinical events diagnosed in oncology, gynecology, and urology as liver cancer, breast cancer, prostate cancer, uterine fibroids, and multiple myeloma, and the clinical event diagnosed in cardiology as myocardial hypertrophy, are, in their underlying reality, all manifestations of one event. It is the event in which the calcium signal inside the cell turns on excessively, and that cell goes in the direction of hypertrophy and hyperproliferation. 5M Overflow & Burst is the pattern in which the microcalcification dual blockade surfaces as signal excess at the cellular dimension.
Organizing the clinical diseases frequently encountered in the 5M pattern by place gives the following.
[Figure 6] 5M Overflow & Burst: Representative Clinical Distribution
| Place | Representative clinical | Microscopic-dimension event |
|---|---|---|
| Liver | Hepatocellular carcinoma | Hepatocyte calcium signal excess → tumor-cell conversion |
| Breast and female reproductive organs | Breast cancer, uterine fibroids | Epithelial and smooth-muscle cell calcium signal excess |
| Prostate | Prostate cancer, prostatic hypertrophy | Prostate cell calcium signal excess |
| Blood and bone marrow | Multiple myeloma | Plasma cell calcium signal excess |
| Myocardium | Myocardial hypertrophy, some heart failure | Calcineurin activation → hypertrophy gene program |
The branching of 5M is in two directions. Depending on within which cellular environment the same calcium excess occurs, it splits on one side into the road of hyperproliferation (tumor and hypertrophy), and on the other side into the road of death. The 6M we will see in the following article is, even among the roads of death, the pattern of disconnection-type death directly connected to microcalcification. If the death of 5M is direct death caused by calcium overload itself, the death of 6M is circuit-type death caused by the disconnection of the pathway. The two patterns are similar only in their result; the event of the underlying reality is clearly different.
If 5M is the pattern of overflowing and bursting, the 6M of the following article is the pattern of being cut off and disconnected. From overflow to cutoff, from the explosion of signal excess to the severance of pathway disconnection, the pattern moves over.
6M Disconnection: Cut Off and Disconnected
6M Disconnection is the pattern in which the microvasculature is occluded by microcalcification, so that the tissue or nerve circuit that vessel supplied is cut off from the supply of nutrition and oxygen and dies or loses function. Unraveled into Korean, it is the event of being cut off and disconnected. The English name expresses together circuit disconnection, pathway blocking, and loss of connection, and it is an integrated pattern that gathers in one place the clinical phenomena that existing pathology has handled separately as ischemic necrosis, micro-infarction, and vascular dementia.
The difference between 6M Disconnection and the 5M Overflow & Burst seen earlier is clear. If the death of 5M is death that calcium overload itself directly causes inside the cell, the death of 6M is circuit-type death that occurs because the pathway going to that cell is blocked and the supply of nutrition and oxygen is cut off. If 5M is an event inside the cell, 6M is an event outside the cell, that is, of the microvascular pathway leading to that cell. The result can be similar, but they are two patterns whose molecular-dimension starting points differ.
This pattern, too, is scattered under very various clinical names in specialty medicine. Nephrology and dermatology handle calcinosis (in medical terms, calciphylaxis). Neurology handles vascular dementia, multiple cerebral infarction, and lacunar infarction. Vascular surgery handles the late stage of peripheral vascular disease, that is, the gangrene of toes or fingers. Emergency medicine handles acute ischemic necrosis. Ophthalmology handles the loss of vision due to retinal vessel occlusion. They are different diagnostic names by specialty, but all are manifestations of one event at different places. It is the event in which a small vessel is blocked by microcalcification, so that the tissue beyond that vessel is cut off from the supply of nutrition and oxygen.
The reason different diagnostic names are bound into the same one pattern lies in setting out all from the same molecular event of microvascular occlusion. If the occlusion of a large vessel makes 1M Obstruction & Rupture, the occlusion of the microvasculature (that is, arterioles and capillaries) makes 6M Disconnection. In both patterns occlusion is the start, but only the size of the place where the occlusion occurs differs and the clinical form of its result differs; the event of the underlying reality sets out from the same microscopic-dimension calcium deposition.
The calciphylaxis entry of the StatPearls medical information database operated by the U.S. National Library of Medicine organized the clearest clinical case of 6M Disconnection. Calciphylaxis is the event in which calcium deposits in the medial layer of the arterioles and capillaries of the skin so that those vessels are occluded, and the skin and subcutaneous tissue those vessels supplied are cut off from the supply of nutrition and oxygen and progress to pain, ulcer, and necrosis. The fact that material made clear is decisive. It is so fatal that the one-year mortality exceeds 50 percent, and most of the causes of death are sepsis that begins from infection of the necrotic site. That is, a microscopic-dimension event of the microvasculature surfaces, in the clinic, as the most fatal result. It is the clear form of the event in which a small calcium crystal deposited on a small vessel takes a person's life. Calciphylaxis is the most blatant clinical specimen of 6M Disconnection.
A comprehensive review published by the Inoue, Shue, and Kanekiyo research group of the Mayo Clinic in the United States in a molecular-neurodegeneration journal organized the form in which the same event is manifested in the brain. The fact that review organized is decisive. It is that vascular dementia and Alzheimer's are not two events that progress separately, but the same event that both set out from the microvascular damage of the brain. When the small arteries and capillaries of the brain are damaged so that the nerve circuit those vessels supplied is cut off from the supply of nutrition and oxygen, the nerve cells of that circuit gradually die. The result is lacunar infarction, white-matter degeneration, and micro-hemorrhage, and when accumulated it becomes the molecular-dimension foundation of vascular dementia and Alzheimer's. That review organized that cerebral small-vessel disease directly explains about 20 percent of all dementia, and the rate at which it accompanies Alzheimer's and accelerates cognitive decline is far higher than that. That is, the neurodegenerative diseases we have seen separately in specialty medicine set out, in their underlying reality, from the same one event (the disconnection of the brain's microvasculature).
When the cases of skin and brain are placed together, the fact is clear. The clinical events diagnosed in specialty medicine as calciphylaxis of the skin, vascular dementia of the brain, gangrene of the limbs, and vessel occlusion of the retina are, in their underlying reality, all manifestations of one event. It is the event in which the microcalcification deposited on the microvasculature occludes that vessel, so that the tissue or nerve circuit beyond that vessel is disconnected. 6M Disconnection is the pattern in which the microcalcification dual blockade surfaces most fatally at the pathway dimension.
Organizing by place how the 6M pattern surfaces in the clinic gives the following.
[Figure 7] 6M Disconnection: Representative Clinical Distribution
| Place | Representative clinical | Microscopic-dimension event |
|---|---|---|
| Skin and subcutaneous tissue | Calciphylaxis, chronic ulcer, some pressure ulcers | Skin arteriole microcalcification → occlusion → tissue necrosis |
| Brain | Vascular dementia, lacunar infarction, multiple cerebral infarction, white-matter degeneration | Brain microvascular microcalcification → occlusion → nerve-circuit disconnection |
| Limbs | Late peripheral vascular disease, gangrene, diabetic foot | Limb microvascular microcalcification → occlusion → tissue necrosis |
| Retina | Retinal vessel occlusion, some vision loss | Retinal microvascular microcalcification → occlusion |
| Organ microvasculature | Organ micro-infarction, local ischemic damage | Organ microvascular microcalcification → occlusion |
If 6M is the pattern of being cut off and disconnected, the 7M of the following article is the pattern of collapsing. From cutoff to collapse, from the circuit-type death of pathway disconnection to the structural breakdown caused by the negative mineral balance of bone and tooth, the pattern moves over.
7M Collapse: Collapses
7M Collapse is the pattern in which the mineral balance of the hard tissue of the human body, that is, bone and tooth and spine, tilts in the negative (陰) direction so that the structure itself is physically weakened and collapses. Unraveled into Korean, it is the event of collapsing. The English name expresses together structural failure and negative mineral balance, and it is an integrated pattern that gathers in one place the clinical phenomena that existing pathology has handled separately as osteoporosis, osteomalacia, spondylolysis, dental caries, and periodontitis.
7M Collapse is an event in the exact opposite direction from the preceding six patterns. 1M Obstruction & Rupture, 2M Dysfunction, 3M Coating & Blocking, 4M Hardening, 5M Overflow & Burst, and 6M Disconnection all had one thing in common. They are events in which calcium has piled up in a place where it should not be, that is, on the surfaces of vessels, soft tissue, and signaling molecules. But 7M is the exact opposite. It is the event in which calcium leaves the place where it should be, that is, bone and tooth. It is a contradictory event in which, inside the body of the same one person, calcium piles up in the wrong place on one side and leaves the place where it ought to be on the other side, so that a reversed flow progresses simultaneously. But this contradiction is resolved at once when the movement of the physical entity is traced. That calcium that left the bone piles up in the vessels and soft tissue of the same patient. 7M is the opposite end of the same event as the patterns from 1M to 6M.
This pattern, too, has been diagnosed in specialty medicine under very separated clinical names. Orthopedics handles osteoporosis and osteomalacia, spondylolysis and spondylolisthesis, and scoliosis. Dentistry handles dental caries and periodontitis, and alveolar bone resorption. These two specialty medicines have different treatment spaces, different patient complaints, and different imaging equipment. But seen from the viewpoint of 7M, all these clinical names are the surfacing of one event at different places. It is the event in which calcium and phosphorus leave a mineralized macroscopic structure, so that the mineral balance of that place tilts negative, and finally that structure is physically weakened and collapses.
The clinical meaning of 7M touches closest to the integrated message of this whole book. The two events specialty medicine has seen separately, that is, osteoporosis and vascular calcification, are essentially not separate diseases but two faces of one event. It means it is the event in which the calcium that left the bone of a patient piles up in the vessels of the same patient. The fact that at the very time osteoporosis is diagnosed in an orthopedic patient, coronary artery calcification is progressing in the cardiology examination of the same patient is no coincidence. The two events are accompanying events that surface simultaneously at the two ends of the same one calcium movement. In medicine this is called the calcium paradox, or the polarization of the bone-vascular axis.
The parathyroid hormone physiology entry of the StatPearls medical information database operated by the U.S. National Library of Medicine clearly organized the molecular mechanism of 7M Collapse. According to that material, when the blood calcium concentration drops, the parathyroid gland in the front of the neck senses that signal and secretes parathyroid hormone (PTH). PTH binds to the osteocytes inside the bone and increases the expression of a signaling molecule called RANKL, and this signal in turn activates the bone-resorbing cells and breaks down the bone. From the broken-down bone, the calcium of the hydroxyapatite crystal is released into the blood, and the blood calcium concentration recovers to normal. This mechanism is, in itself, a normal device for maintaining calcium homeostasis. But the fact that material made clear is decisive. When this mechanism operates chronically, that is, when the bone is repeatedly mobilized as a calcium storehouse, the result is that a dangerous amount of calcium leaves the bone and is released into the blood, and an early transition to osteoporosis and an increase of fracture susceptibility occur. It is the event in which a normal homeostatic mechanism becomes chronic and turns into the underlying reality of pathology.
A comprehensive review published by the Abou Neel et al. multinational research group of the UCL Eastman Dental Institute in the United Kingdom in an international nanomedicine journal organized how the same event unfolds at the molecular dimension. That review made clear one decisive fact. It is that bone and tooth are the same kind of hard tissue made of the same mineral, that is, hydroxyapatite (Ca₁₀(OH)₂(PO₄)₆) crystals. The two tissues have differences in their degree of hardness and the arrangement of the crystals. The crystals of tooth enamel are larger and more aligned than the crystals of bone, forming the hardest tissue in the human body. But both tissues are, throughout life, within a dynamic balance of mineralization and demineralization, and when this balance tilts in the negative direction, both places weaken. The fact that review made clear is even more decisive. It is that the osteoporosis of orthopedics and the dental caries and periodontitis of dentistry are classified as completely different diseases in specialty medicine, but at the molecular dimension they are the same one event, that is, the negative-balance event of the hydroxyapatite crystal.
When the two materials are placed in one place, the fact is clear. The clinical events diagnosed in specialty medicine as osteoporosis, osteomalacia, spondylolysis, dental caries, and periodontitis are, in their underlying reality, all manifestations of one event. It is the event in which the mineral of hard tissue (bone, tooth, spine) tilts in the negative direction. And that departed mineral piles up in the vessels and soft tissue of the same patient and surfaces as the patterns from 1M to 6M. 7M Collapse is the pattern in which the microcalcification dual blockade surfaces at the hard-tissue dimension, and at the same time it is the opposite end of the same event as all the patterns from 1M to 6M.
Organizing under which clinical names the 7M pattern surfaces in specialty medicine gives the following.