There is much evidence that the common indulgence of empty calories, particularly those derived from simple carbohydrates and processed fats, is producing pathophysiologic brain effects due to what has been termed high calorie malnutrition. This form of malnutrition is totally different from that produced by starvation, the traditional form of malnutrition. Although the concentration of thiamine in the blood may be considered to be normal, it is only normal in the presence of a healthy diet. The excess of empty calories results in a high calorie/thiamine ratio that overwhelms the normal oxidative capacity associated with the presence of thiamine.
Patients suffering from high calorie malnutrition represent the “walking sick” of America. In its early stages it results in a polysymptomatic disease that defies our present concept of diagnosis. Traditional laboratory results may be quite normal or nonspecifically abnormal and the symptoms “written off” as psychosomatic. It may well be that some cases of hypertension, affecting millions, is part of the clinical effect produced by the dysautonomia of thiamine deficiency. The text that follows provides support for this hypothesis. It may also be true that failure to recognize the true etiology may lead over time to chronic brain disease in the untreated patient.
Autonomic Control of Blood Pressure
It has been well documented that the autonomic nervous system plays a key role in controlling blood pressure values. The hypothesis has been put forward that the origin, progression, and outcome of human hypertension are related to dysfunctional autonomic cardiovascular control, especially to abnormal activation of the sympathetic division. There is a consistent association between hypertension and pro-inflammatory cytokines of the innate and adaptive immune system. The sympathetic nervous system, a major determinant of hypertension, is pro-inflammatory, whereas the parasympathetic nerve activity dampens the inflammatory response through α7-nicotinic acetylcholine receptors. In the Goldblatt model of renal hypertension and the use of renal denervation in the treatment of drug-resistant hypertensive patients, autonomic mechanisms underpin the maintenance of this hypertension. Autonomic mechanisms initiate the development and maintenance of renal vascular hypertension. Obesity-associated overnutrition leads to neural inflammatory molecular changes, particularly in the hypothalamus, leading to elements of the metabolic syndrome. Increased sympathetic activation is a critical mediator.
Children, Hypertension, and Obesity
There are an increasing number of children diagnosed with primary hypertension, mainly in association with obesity. One of the factors considered is dysregulation of the autonomic nervous system. Emerging evidence suggests that the sympathetic branch plays a much broader role in the regulation of blood pressure, including the development and maintenance of sustained hypertension by a chronically elevated central sympathetic tone. A recent study examined the relationship between the autonomic nervous system dysfunction, anxiety and depression in hypertension. The sympathetic nervous system and arterial baroreceptor reflex control of renal sympathetic nerve activity has been proposed to play a role in long-term control of arterial pressure.
Abundant evidence supports the role of the sympathetic nervous system in the pathogenesis of obesity -related hypertension. The mechanisms are incompletely understood. A study supports the concept that increased renal sympathetic activity is the critical mechanism by which increased central sympathetic outflow initiates and maintains reductions in renal excretion function, resulting in obesity hypertension. Hypertension and obesity are risk factors for coronary heart disease in adults. Childhood weight problems and high blood pressure increase the risk of subsequent obesity and hypertension as an adult.
The Role of Hypoxia in Blood Pressure Regulation
Obstructive sleep apnea is one of the most common causes of hypertension in Western societies, causing chronic intermittent hypoxia. The normal homeostatic balance between HIF-1α-dependent pro-oxidant and HIF-2α dependent antioxidant enzymes is disrupted. Hypertension affects one in three United States adults and involves the integration of the actions of multiple organ systems, including the central nervous system, driving enhanced sympathetic outflow and increased blood pressure. There is increased understanding of hypothalamic activity in hypertension. Changes in the baroreflex and chemoreflex may contribute to the development of chronic hypertension observed in obstructive sleep apnea patients. Animal studies have identified induced hypoxic hypertension, but this is still conjectural in humans.
Thiamine Deficiency and Pseudo-hypoxia
Because mild to moderate thiamine deficiency results in pseudo-hypoxia in the limbic system and brainstem, emotional and stress reflexes of the autonomic nervous system are stimulated and exaggerated. Like chronic intermittent hypoxia that activates HIF-1 and suppresses HIF-2-mediated transcription, thiamine deficiency induces HIF-1α mediated gene expression similar to that observed in hypoxic stress. Thiamine deficiency induces an early, functionally significant central muscarinic cholinergic lesion that may be at least part of the reason for sympathetic overdrive. Details of the genetic determination in hypertension are poorly understood. A novel blood pressure locus that encodes a previously uncharacterized thiamine transporter has been reported, again perhaps emphasizing the importance of thiamine deficiency in hypertension. Evidence supports the likelihood that an increased cytosolic ratio of NADH/NAD+, caused by hyperglycemia, results in playing an important role in the pathogenesis of diabetic complications. Thiamine deficiency occurs in individuals with diabetes, leading to hyperglycemic-induced damage and oxidative stress. The potential benefit of long-term replacement is not yet known but may well reduce the cardiovascular risk and angioplasty complications. Thiamine deficiency should be considered in all patients with pulmonary hypertension of unknown origin.
Maternal hypertension is the most common medical disorder of pregnancy, varying from 4 to 6% of all pregnancies. The daily dose of 100 mg of thiamine has been given to over 1000 non-selected prenatals starting in the second and third trimesters. The expected number of toxemia patients in this group was well over 150, but the actual occurrence was zero.
Hypertension and High Calorie Malnutrition
Optimum nutrition is the level of intake that should promote the highest level of health. A deficit in nutrition may result in tissue depletion of essential nutrients that can lead to biochemical changes and eventually to clinical signs and symptoms. Adverse conditions prenatally increase the risk of cardiovascular disease, including hypertension. Obstructive sleep apnea increases over the course of pregnancy and is common during the third trimester. These adverse conditions have reportedly been completely prevented by the use of 100 mg of thiamine beginning even before pregnancy is confirmed. Thiamine deficiency, resulting in impaired oxidative metabolism, leads to a multifactorial cascade of events in the brain that include focal decreases in energy status, oxidative stress, blood-brain barrier disruption, glutamate-mediated excitotoxicity, amyloid deposition, immediate-early gene induction and inflammation.
Thiamine Tetrahydrofurfuryl Disulfide and Hypertension
This disulfide derivative of thiamine is the synthetic counterpart of allithiamine that occurs naturally in garlic. Allithiamine was discovered in Japan in 1951 and extensively researched by Japanese scientists. Experimental work in animals and human subjects revealed that its metabolic effect was much more powerful than the thiamine from which it was derived. Almost unknown in America, its therapeutic actions have been reviewed.
SHR rats are widely studied as a model of hypertension, exhibiting metabolic abnormalities that share features with the human metabolic syndrome. The SHR rat becomes hypertensive early in life and blood pressure continues to increase with age, often resulting in a cardiovascular event. Over the course of four months, blood pressure and body weight of two groups of SHR rats were monitored. The control group was fed normally and the TTFD group was given increasing doses of TTFD from 5 to 15 mg. There was a statistically significant reducing effect on the treated rats as compared with the controls. Of the 13 TTFD-supplemented rats, five showed a definite response with no rise in the expected blood pressure measurements, while the control group showed a 20 to 25 mm Hg increase in blood pressure across the experiment. The results showed that TTFD has a preventive effect on blood pressure in these genetically abnormal rats.
Thiamine Deficiency > Hypoxia > Hypertension
It has been shown in the above text that hypoxia and pseudo-hypoxia have virtually identical effects in the area of the brain that is peculiarly sensitive to thiamine deficiency. Since any phenomenon that causes inefficient oxygen consumption is dangerous to the organism, activation of the fight-or-flight reflex seems to be entirely logical. Repeated hypoxia in sleep apnea syndrome induces persistent chronic sympathetic dominance and is obviously an abnormal state of metabolism. It is possible that sleep apnea represents a combination of brainstem thiamine deficiency and recurrent obstructive hypoxia. Lonsdale and Marrs have published evidence that thiamine deficiency is widespread in the American population and that its effects in the brain are diverse and the resulting morbidity prolonged. Evidence could be accumulated by proving thiamine deficiency and attempting clinical trials with TTFD.
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