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Returning to the discussion of microvascular glycation related stiffening or lack of pulsatile ability of vascular tissue, pulsation of the microcirculation turns out to be critical for all major organ health. This is the simple reason that scientific medicine has not yet developed an effective implantable artificial heart. Pulsatile flow is something that is required in normal physiology. Any experimental animal that is put on a heart bypass pump that uses nonpulsatile or laminar flow dies within days of progressive, multiple organ (kidney, heart, brain) failure due to progressive microvascular dysfunction – called scientifically increased peripheral vascular resistance.147 Our best technological engineers can make pumps smaller than a dime that can operate in climates as alien as the Martian surface, but they have not yet mastered the essential, life-sustaining properties of biologically imperative pulsatile flow. The main physiologic cause of pathological microvascular stiffness is glucotoxicity.139 Clinical counterparts of this "laboratory" phenomenon of increased organ microcirculatory stiffness are commonly encountered, but just as commonly, the causal underlying mechanism (microvascular stiffening due to glycocalyx/endothelial caramelization) is usually not clinically recognized and thus crude, noncurative symptomatic drug or surgical therapy follows. One commonly missed clinical example of this phenomenon may be heart and peripheral arterial vascular stunning and hibernation.148,149 Integrative medicine employing chelation therapy has demonstrated clinical effectiveness in reversing stunning and hibernation, in both entire organs (heartmicrocirculation) and extremities (leg macrocirculation/vasa vasorum).148,149 The actual cause of the phenomenon of stunning and hibernation is "unknown" in evidence-based medicine, but glucotoxicity of the microcirculation in the corresponding capillary bed of the heart muscle or the vasa vasorum (or microcirculation) of the macrovessel arterial wall may be involved.
Another clinical "symptom pattern" manifestation of insulin resistance is polycystic ovary syndrome (PCOS). The currently accepted treatment for PCOS is either using synthetic hormone birth control pharmaceuticals (BCP) or the off-label use of the antidiabetic drug metformin.150,151 Interestingly, birth control helps PCOS symptomatically, although it is known to cause weight gain and high blood sugar, and, more importantly, increase vascular resistance.152 It appears that while improving the clinical picture BCPs seem to be making the manifestations of endothelial dysfunction worse. The clinical and laboratory effects of metformin in PCOS were found to be clinically superior to BCPs.153 It is also possible that other chronic degenerative diseases may be related to underlying microvascular pathology. For example, osteoarthritis, which is really osteoarthrosis, since no true inflammation ("-itis") is involved, may be related to reduced microcirculation to the associated joint and cartilage tissue. This could explain why the simple clinical methods of heat, massage, and injecting ozone (prolozone therapy) into the affected joint and/or periarticular tissue results in reduction and elimination of pain by increasing microcirculation. Chronic unexplained pelvic pain in both sexes may be related to regional microvascular disease. Localized "trigger points" in muscles may also be due to localized microcirculatory disturbance. Much like the phenomenon of localized compromise of microcirculation in the brain (dementia), heart (diastolic heart failure), or kidney (hypertension) leads to different clinical patterns resulting from the same underlying pathology, perhaps other degenerative conditions will be found to be related to reduced microcirculation to an affected organ or anatomic/physiologic area.
Since the 1960s, cholesterol has been the focus of medical science regarding the major cause of cardiovascular disease. This model was based on research demonstrating a statistical connection between elevated blood levels of cholesterol and finding cholesterol products within arterial plaque. While not all patients with sudden vascular accidents (heart attack, stroke) demonstrated elevated levels of blood cholesterol, the cholesterol model was very successful in treating disease in males from the 1960s through the 1990s. The advent of "statin drugs" (HMG-CoA reductase inhibitors) seemed to advance the cholesterol theory of vascular disease to the zenith of scientific medicine.154-158 Their effects were initially thought to be produced by lowering cholesterol blood levels; further research began to show additional benefits of statin agents, including marked reduction of inflammation among others. This led to the "routine" use of these pharmaceutical agents in all vascular disease patients, whether or not the blood cholesterol level was elevated. Despite this change in approach, the decline in the level of vascular disease in males leveled off. Also, during the 1990s despite dramatic declines in vascular disease in males, heart disease among women correspondingly and dramatically increased despite application of the same medical model used in males (bypass surgery, arterial angioplasty and drug cocktails including statins, beta-blockers, ACE inhibitors, ARBs, and aspirin). This "cookbook approach" was far less effective in women, which led some to begin questioning the accuracy of the cholesterol model of cardiovascular disease.
Several facts seem to bolster this questioning. A major one is the fact that many women having heart attacks had "normal" cholesterol blood levels. In addition, many men and women with high cholesterol never develop cardiovascular disease. Finally, the erratic way that plaque appeared throughout the circulation, with one artery being affected and others seemingly escaping disease ("skip lesions"), strongly suggested that other mechanisms were at play. In the scientistic and media frenzy about cholesterol and vascular disease for the past 60 years, many overlooked the fact that cholesterol was simply a theory – not a proven fact. Other theories for the cause of vascular disease, including systemic vascular inflammation, occult infection, various immune mechanisms, sugar toxicity, trans fats, and free radical damage, were proposed, but never received the attention (research money, scientific inquiry, etc.) that cholesterol commanded. With the increasing incidence of disease occurring in women beginning in the 1990s, these other theories began to take on more significance. The toxicity of sugar and its recognized relationship to obesity, diabetes, and micro- and macrovascular disease began to challenge and displace the cholesterol theory as a fundamental cause of these common vascular disease syndromes. For example, microcirculatory (capillary) disease involving the microcirculation of the arterial wall (vasa vasorum) can easily explain the phenomenon of atherosclerotic "skip lesions." In addition, the presence of tissue scarring (wall motion abnormality in the heart and leukoaraiosis of the brain) in the absence of corresponding hemodynamically significant macrovascular disease can be explained by local microvascular compromise.
At the present time old recommendations of reducing dietary cholesterol are being challenged as not useful.159,160 In addition, the actual "beneficial effects" of statin drugs is being seriously questioned.161 It appears that statistical manipulation and corporate profiteering may have played a large hand in the now questioned widespread use of statin drugs. Interestingly, diabetes, blood sugar elevation, liver and muscle damage, and heart failure are known, common, and usually limiting side effects of statin drug use. Recent research suggests that statin drugs may actually cause atherosclerosis ("arteriosclerosis?") and congestive heart failure.162 While this research needs to be confirmed, it should prompt serious clinical questioning of the widespread use of statin drugs, especially for "primary prevention," where no vascular event has actually occurred and the drug is being prescribed based exclusively on an elevated level of blood cholesterol in the absence of evidence of significant arterial plaque formation or symptoms. As with the phenomenon of elevated triglycerides, now recognized as a marker of insulin resistance/metabolic syndrome, it appears that cholesterol may be an effect of the underlying glucose/insulin receptor metabolic dysfunction rather than a cause.
Like all other steroid hormones, vitamin D (a hormone, not a vitamin) is made in the body from cholesterol. This unfortunate confusion of terms is the root the new scientific interest in the "sunlight vitamin."163-175 The basic concept of "hormone" is a substance made in one area of the body that enters the circulation to have its physiologic effect on another organ or area of the body. Vitamin D3 is naturally made from cholesterol in several steps, beginning with a specific frequency of ultraviolet light from the sun interacting with cholesterol in the skin to form a precursor of provitamin D. This provitamin travels through the blood to the liver and is converted into a second provitamin (25-hydroxy vitamin D3), which is again secreted into blood to be transported to the kidney and converted into the final, metabolically active vitamin D3 (1,25-dihydroxyvitamin D3 or cholecalciferol). In addition to bone and intestine where calcium is absorbed, cellular vitamin D receptors are found in all neural, endocrine, and immune cells, indicating the extreme metabolic and regulatory importance of vitamin D in the optimal function of the neuroendocrine-immune system. Due to the past focus on vitamin D for calcium/bone metabolism, medical science is only recently discovering the widespread effects and physiological disturbances related to low or suboptimal vitamin D levels. Inflammation, and symptoms related to chronic inflammation have been shown to be related to vitamin D function.176-178 Low vitamin D has also been implicated in some cases of depression, as well as cardiovascular diseases, cardiometabolic disorders, cancer , and more directly related to glucotoxicity and Microvascular disease, cognitive decline, diabetes/metabolic syndrome, and hypertension.179-197
There are two active forms of vitamin D commonly used medically. Vitamin D3 is the bioidentical form of the hormone normally found in humans and other mammals. Given current research results, this is the only form humans should be taking.192-200 Vitamin D2, which is made from ergosterol converted into ergocalciferol, is found in third-kingdom organisms (yeast, algae) and should not be taken by humans. While both forms have similar effects on calcium metabolism and bone (D2 is said to be about 40% the "potency" of D3), they have different effects on the immune system.198 Vitamin D3 activates human immune precursor cells, while vitamin D2 caused these cells to enter a state of hydrogen peroxide induced cellular apoptosis (programmed cell death).199 In addition, low vitamin D levels have been shown to affect delayed hypersensitivity response to skin test antigens.200 Unfortunately, vitamin D2 is what the food industry has been "enriching" in processed foods for decades. Most processed and/or "vitamin D enriched" foods should be avoided or minimized. A vitamin D supplement will be labeled as to which type (D2 or D3) is in the product, but if just the term vitamin D is on the label, it is vitamin D2 (FDA "standard of identity"). The large body of research demonstrating vitamin D's effects on inflammation , blood sugar and blood pressure, and other manifestations of metabolic syndrome/sugar toxicity suggest that one hormonal effect of vitamin D3 may involve enhancing the activity of the cellular insulin receptor.176-178,194-197 Similar to the concept of insulin receptor resistivity (insulin resistance/metabolic syndrome), vitamin D also works through activating the vitamin D receptor inside each cell. By optimizing vitamin D3 blood levels to between 50 and 60 ng/dl many clinical manifestations of insulin resistance commonly improve, indicating that vitamin D deficiency/insufficiency is part of the widespread epidemic of metabolic syndrome, insulin resistance, diabetes, hypertension, leukoaraiosis, and obesity.180-184,189-197
An interesting concept in the new thinking regarding "low" vitamin D blood levels and chronic disease involves the Marshall protocol. In some chronic inflammatory diseases, such as post (chronic) Lyme syndrome, fibromyalgia, sarcoidosis, multiple chemical sensitivity syndrome, lupus, and rheumatoid arthritis, the blood levels of the provitamin D (25-hydroxy-vitamin D) is found to be low while the level of the active 1,25-dihydroxyvitamin D will be found to be high-normal to high. Marshall believes that this situation is caused by L-form bacteria and other intracellular infectious agents disrupting the function of the intracellular vitamin D receptor which disrupts the innate immune system's ability to find and destroy the infected cells.201-204 Patients with chronic inflammatory diseases in addition to metabolic syndrome/insulin resistance problems may benefit from having both 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D blood levels measured together to evaluate for a metabolic disturbance of Vitamin D metabolism. If this situation is found the Marshall protocol advises that vitamin D not be given or supplemented and the vitamin D receptor be "reactivated" using the drug olmesartan (Benicar) and others specific protocol recommendations.201-204 Since this concept and its clinical application is "anecdotal," the patient and treating physician should evaluate the information in light of the underlying clinical reality of each individual patient. Simultaneously evaluating the level of both 25-hydroxy- and 1,25-dihydroxyvitamin D may serve as a biochemical marker that may distinguish pathologic inflammation or chronic infection from chronic degenerative structural/functional microvascular disease.
The formal definition of metabolic syndrome requires a patient to manifest a minimum of four of the following criteria: centralized obesity, hypertension, elevated fasting blood sugar, fasting insulin level, and/or blood triglyceride level, low HDL cholesterol level and/or high LDL cholesterol. The clinical difficulty with diagnosing metabolic syndrome/sugar toxicity by definition is that by the time one fulfills the "formal" criteria for academic recognition of sugar toxicity, the process has progressed to a point of clinical disease. The "real world" diagnosis of preclinical sugar toxicity depends on a number of factors. There is no single physical finding or test that can accurately "diagnose" sugar toxicity. Pathologic Maillard/sugar toxicity reactions, like free radical chemistry, are fundamental processes in human physiology. There is a biological, biochemical, and pathophysiologic continuum from birth through aging, disease, and ultimately death. Once this fact is acknowledged, it logically follows that the earlier the clinical detection of abnormal protein glycation/sugar toxicity, the more effective intervention will be. Relying on laboratory "normal reference values" and late symptomatic pathological pattern recognition after disease is present is inferior medical practice. The earlier dysmetabolic and microvascular manifestations can be detected, the sooner remedial diet/lifestyle measures can be recommended and/or treatment applied.
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