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Cardiac Heart Rate Dependence on Mitochondrial Deuterium 2H Content
Abstract
Mitochondrial cardiac ATP production efficiency in beef hearts has been known to decrease with increasing systemic deuterium 2H levels since the 1980’s. Recently ketogenic diets which are known to decrease deuterium levels in humans were found to decrease both the resting and exercise heart rates in a volunteer. Furthermore, resting heart rates were found to systematically vary with the deuterium content from the previous meal consumed by six volunteers. A cardiac model is proposed showing extreme sensitivity of heart rate on the deuterium loading of the ATP synthase nanomotors. A predicted increase in heart rate by 28% is expected with a 5% decrease in ATP production. This finding strongly suggests that high deuterium levels in the fatty acids contribute to the diastolic dysfunction in heart failure not already attributed to direct structural damage, i.e., heart failure with preserved ejection fraction.
... but the mechanism remained elusive until the discovery of the ATP nanomotor and different binding energies for the protium and deuterium nuclei acting on these nanomotors [5][6]. A detailed summary of the effect of deuterium on the mitochondria energy production is published in open-source literature elsewhere [7][8]. ...
... More recently, the deuterium content in food was shown to impact the cardiac stroke volume leading to inotropic changes in the heart rate [7][8]. The deuterium in the fatty acids which is known to disrupt the ATP nanomotors located in the mitochondria was found to decrease the cardiac stroke volume leading to increased heart rates [7]. ...
... More recently, the deuterium content in food was shown to impact the cardiac stroke volume leading to inotropic changes in the heart rate [7][8]. The deuterium in the fatty acids which is known to disrupt the ATP nanomotors located in the mitochondria was found to decrease the cardiac stroke volume leading to increased heart rates [7]. When the heart rate reaches the point that further compensation cannot occur, heart failure with preserved ejection fraction (HFpEF) occurs [8]. ...
The deuterium concentration in the fattyacids of food consumed was recently shownto impact the maximal rate of ATP production effecting the resting heart rates in six volunteers. One of these volunteers had three echocardiocardiograms to evaluate an intermittent systolic ejection murmur that first appeared after adopting a ketogenic diet and this murmur became more pronounced following a low deuterium cold water sea food diet. The echocardiograms revealed that the aortic ejectionvelocity and aortic pressuregradients systematically increasewith decreasing deuteriumlevels in the diet. These findings reveal that the meals consumed do have a significant impact on the parameters determined from echocardiography likely due to changes in the ventricular contractility. The aorticpressure gradients extrapolate to zero as the deuterium content approaches 155.9 ppm.
... Detrimental changes to the cardiac structure occur in coronary artery disease, myocardial infarction, cardiomyopathy from substances/infections, chronic uncontrolled hypertension, chronic uncontrolled diabetes, cardiac birth defects, valvular damage, and high output demand from obesity [2]. In cases of relatively preserved structural integrity, the etiology has been attributed to a decrease in ATP production within the mitochondria from previous research studies [3]. These are frequently termed heart failure with reduced ejection fraction (HFrEF) when structural integrity is compromised and heart failure with preserved ejection fraction (HFpEF) when ATP production is slowed [4][5][6][7][8]. ...
... More recently, it was discovered that the heavy isotope of hydrogen 2 H, deuterium, jams the ATP nanomotors at the end of the electron transport chain, decreasing the maximal rate of ATP production [9]. The level of deuterium found in food and water also varies and is systematically linked to the heart rate [3]. ...
... More recently, the rates of remission from deuterium depletion have been studied in the lung [19], rare childhood [20], renal cell [21], and colorectal [22] cancers. Furthermore, the effect of deuterium levels on depression [23], diabetes mellitus [24,25], and heart rate [3] has also been studied. Deuterium is also known to stabilize viral proteins and RNA to enhance their thermostability [26]. ...
Heart failure results from the loss of structural integrity of the heart and/or a decrease in the rate of maximal ATP production. In cases of relatively preserved structural integrity, a decrease in ATP production in the mitochondria leads to a decrease in the cardiac stroke volume, thereby increasing the heart rate required to maintain the cardiac output. For many years, the exact location of this defect in the metabolic energy cycle remained elusive. Evidence is presented here to show that it is not a single metabolic substrate involved but rather the heavy isotope of hydrogen 2H, deuterium, that is jamming the ATP nanomotors slowing the rate of ATP production. During the digestion of a meal, the cardiac heart rate is shown to be very sensitive to the level of deuterium contained in the fatty acids recently consumed. During strenuous exercise in the fasting state, the enzyme adipose triglyceride lipase (ATGL) is found to mobilize the highest deuterium triglycerides more rapidly than the healthier lower deuterium triglycerides, converting the adipose tissue into a deuterium-depleted energy pool. This is believed to contribute to the low resting heart rates frequently observed in athletes. In vulnerable individuals, i.e., those weakened by disease(s) or space explorers in a weightless environment, the decreased ability to perform strenuous exercise leads to higher deuterium levels in their adipose tissue compromising their ATP production. In these individuals, maintaining healthy deuterium levels is best achieved by an increased intake of lower deuterium-containing foods.
Introduction
This review addresses metabolic diversities after grain feeding of cattle using artificial total mixed ration (TMR), in place of pasture-based feeding.
Objectives
To determine how grain feeding impairs the deuterium-depleting functions of the anaplerotic mitochondrial matrix during milk and meat production.
Methods
Based on published data we herein evaluate how grain-fed animals essentially follow a branched-chain amino acid and odd-chain fatty acid-based reductive carboxylation-dependent feedstock, which is also one of the mitochondrial deuterium-accumulating dysfunctions in human cancer.
Results
It is now evident that food-based intracellular deuterium exchange reactions, especially that of glycogenic substrate oxidation, are significant sources of deuterium-enriched ( ² H; D) metabolic water with a significant impact on animal and human health. The burning of high deuterium nutritional dairy products into metabolic water upon oxidation in the human body may contribute to similar metabolic conditions and diseases as described in state-of-the-art articles for cows. Grain feeding also limits oxygen delivery to mitochondria for efficient deuterium-depleted metabolic water production by glyphosate herbicide exposure used in genetically modified crops of TMR constituents.
Conclusion
Developments in medical metabolomics, biochemistry and deutenomics, which is the science of biological deuterium fractionation and discrimination warrant urgent critical reviews in order to control the epidemiological scale of population diseases such as diabetes, obesity and cancer by a thorough understanding of how the compromised metabolic health of grain-fed dairy cows impacts human consumers.
An emerging hallmark of cancer is metabolic reprogramming, which presents opportunities for cancer diagnosis and treatment based on metabolism. We performed a comprehensive metabolic network analysis of major renal cell carcinoma (RCC) subtypes including clear cell, papillary and chromophobe by integrating transcriptomic data with the human genome-scale metabolic model to understand the coordination of metabolic pathways in cancer cells. We identified metabolic alterations of each subtype with respect to tumor-adjacent normal samples and compared them to understand the differences between subtypes. We found that genes of amino acid metabolism and redox homeostasis are significantly altered in RCC subtypes. Chromophobe showed metabolic divergence compared to other subtypes with upregulation of genes involved in glutamine anaplerosis and aspartate biosynthesis. A difference in transcriptional regulation involving HIF1A is observed between subtypes. We identified E2F1 and FOXM1 as other major transcriptional activators of metabolic genes in RCC. Further, the co-expression pattern of metabolic genes in each patient showed the variations in metabolism within RCC subtypes. We also found that co-expression modules of each subtype have tumor stage-specific behavior, which may have clinical implications.
The effects of deuterium depletion on the human organism have been, except for the antitumor action, seldom investigated by now and the available data are scarce. In oncological patients who also suffered from diabetes and were treated with deuterium-depleted water (DDW), an improvement of glucose metabolism was observed, and rat studies also proved the efficacy of DDW to reduce blood sugar level. In the present work, 30 volunteers with pre- or manifest diabetes were enrolled to a clinical study. The patients received 1.5 L of water with reduced deuterium content (104 ppm instead of 145 ppm, equivalent 12 mmol/L in human) daily for 90 days. The effects on fasting glucose and insulin level, on peripheral glucose disposal, and other metabolic parameters were investigated. Fasting insulin and glucose decreased, and insulin reaction on glucose load improved, in 15 subjects, while in the other 15 the changes were opposite. Peripheral glucose disposal was improved in 11 of the subjects. In the majority of the subjects, substantial increase of serum high-density lipoprotein (HDL) cholesterol and significant decrease of serum Na⁺ concentration were also seen—the latter possibly due to activation of a Na⁺/H⁺ antiporter by the decreased intracellular deuterium level. The results support the possible beneficial role of DDW in disorders of glucose metabolism but leave questions open, requiring further studies.
Accumulating evidence suggests that metabolic reprogramming has a critical role in carcinogenesis and tumor progression. The usefulness of formalin-fixed paraffin-embedded (FFPE) tissue material for metabolomics analysis as compared with fresh frozen tissue material remains unclear. LC/MS-MS–based metabolomics analysis was performed on 11 pairs of matched tumor and normal tissues in both FFPE and fresh frozen tissue materials from patients with colorectal carcinoma. Permutation t test was applied to identify metabolites with differential abundance between tumor and normal tissues. A total of 200 metabolites were detected in the FFPE samples and 536 in the fresh frozen samples. The preservation of metabolites in FFPE samples was diverse according to classes and chemical characteristics, ranging from 78% (energy) to 0% (peptides). Compared with the normal tissues, 34 (17%) and 174 (32%) metabolites were either accumulated or depleted in the tumor tissues derived from FFPE and fresh frozen samples, respectively. Among them, 15 metabolites were common in both FFPE and fresh frozen samples. Notably, branched chain amino acids were highly accumulated in tumor tissues. Using KEGG pathway analyses, glyoxylate and dicarboxylate metabolism, arginine and proline, glycerophospholipid, and glycine, serine, and threonine metabolism pathways distinguishing tumor from normal tissues were found in both FFPE and fresh frozen samples. This study demonstrates that informative data of metabolic profiles can be retrieved from FFPE tissue materials.
Implications
Our findings suggest potential value of metabolic profiling using FFPE tumor tissues and may help to shape future translational studies through developing treatment strategies targeting metabolites.
The present study examined the acute effect of alcohol and its cues on autonomic and cardiovascular physiology, as indexed by changes in heart rate (HR), in a relatively large sample of healthy young adult men and women. Participants (27-31 years old, final N = 145) were administered an alcoholic beverage (n = 88; 52 women) or a placebo beverage (n = 57; 35 women) in a simulated bar. Target breath alcohol concentration (BrAC) was .08 g%. HR was recorded while participants were seated alone during an initial baseline assessment in a lab room; seated with others during preparation and administration of 2 beverages in a simulated bar; and seated alone in the lab room at ascending, peak, and descending BrAC. HR increased over time for participants in both beverage groups during beverage preparation. During beverage consumption, HR decreased over time in those who drank placebo whereas HR increased over time in those who drank alcohol, increasing at a faster rate in women compared to men. HR remained elevated at the ascending, peak, and descending limb assessments only in participants who drank alcohol with HR increasing over time at ascending BrAC in the women but not men. Sex differences in HR under alcohol were not explained by sex differences in body mass index, BrAC, recent alcohol use, or subjective stimulation. Our findings suggest that women may be more sensitive to alcohol-induced increases in HR, especially in environments where alcohol cues are abundant. This may have implications for cardiovascular risks associated with alcohol. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
We present a novel approach to a personalized therapeutic concept for solid tumors. We illustrate this on a rare childhood tumor for which only a generalized treatment concept exists using carbonic anhydrase IX and aquaporin 1 inhibitors. The use of microcalorimetry as a refined in vitro method for evaluation of drug susceptibility in organotypic slice culture has not previously been established. Rapid microcalorimetric drug response assessment can refine a general treatment concept when it is applied in cases in which tumors do not respond to conventional chemo-radiation treatment. For solid tumors, which do not respond to classical treatment, and especially for rare tumors without an established protocol rapid microcalorimetric drug response testing presents an elegant novel approach to test alternative therapeutic approaches. While improved treatment concepts have led to improved outcome over the past decades, the prognosis of high risk disease is still poor and rethinking of clinical trial design is necessary. A small patient population combined with the necessity to assess experimental therapies for rare solid tumors rather at the time of diagnosis than in relapsed or refractory patients provides great challenges. The possibility to rapidly compare established protocols with innovative therapeutics presents an elegant novel approach to refine and personalize treatment.
A case report is presented in which a type-II diabetic patient significantly improved his dysfunctional β -islet cells using a combination of a strenuous exercise program, cyclical ketogenic diet, and oral GABA/probiotic supplementation. The patient was diagnosed with type-II diabetes at the age of 41 which then progressed through a typical series of treatment changes over 14 years. Treatment periods consisted of metformin therapy alone for 4 years followed by a metformin/glyburide combination therapy for 6 years, and eventually an insulin/metformin combination therapy for 4 years. One year after the initiation of insulin, the patient increased the level of strenuous physical activity (hiking and weight lifting) and adopted a ketogenic diet. Oral GABA and probiotic supplementation were also initiated at the age of 52.7. By the age of 55, the patient no longer required any insulin and is currently being managed with metformin alone. C-peptide values indicate a functional improvement of the β -islet cells during the time of insulin/GABA/probiotic treatment.
Mitochondrial dysfunction has been implicated in the development of heart failure. Oxidative metabolism in mitochondria is the main energy source of the heart, and the inability to generate and transfer energy has long been considered the primary mechanism linking mitochondrial dysfunction and contractile failure. However, the role of mitochondria in heart failure is now increasingly recognized to be beyond that of a failed power plant. In this Review, we summarize recent evidence demonstrating vicious cycles of pathophysiological mechanisms during the pathological remodeling of the heart that drive mitochondrial contributions from being compensatory to being a suicide mission. These mechanisms include bottlenecks of metabolic flux, redox imbalance, protein modification, ROS-induced ROS generation, impaired mitochondrial Ca2+ homeostasis, and inflammation. The interpretation of these findings will lead us to novel avenues for disease mechanisms and therapy.
Key points:
Otto Warburg observed a peculiar phenomenon in 1924, unknowingly laying the foundation for the field of cancer metabolism. While his contemporaries hypothesized that tumor cells derived the energy required for uncontrolled replication from proteolysis and lipolysis, Warburg instead found them to rapidly consume glucose, converting it to lactate [1]. The significance of this finding, later termed the Warburg effect, went unnoticed by the larger scientific community at that time. The field of cancer metabolism lay dormant for almost a century awaiting advances in molecular biology and genetics which would later open the doors to new cancer therapies.
Cardiac muscle contraction is a strictly regulated process which conjugates a series of electrophysiological, biochemical and mechanic events, resulting in the pumping of blood to all bodily tissues. These phenomena require a very high energetic demand both for generating the necessary mechanical force, and for maintaining cellular homeostasis during the process. In the myocardium, fatty acids (FA) represent the main energy substrate, although other secondary substrates, such as glucose and ketone bodies, may also be used. Nevertheless, under certain conditions such as heart failure or myocardial ischemia, FA metabolism may become deleterious via mechanisms such as oxidative stress and arrhythmogenesis. In an ischemic milieu, various metabolic changes occur as a consequence of hypoxia, favoring cell necrosis, ventricular arrhythmias, and death. Major events in this context include an increase in extracellular K⁺, a decrease in pH, and accumulation of intracellular calcium. This review includes a detailed description of the molecular basis underlying myocardial contraction and energetic metabolism in cardiomyocytes, aiming to promote an integral understanding of the pathophysiology of heart ischemia. This in turn may aid in the development of future, more satisfactory alternative treatments in the management of acute coronary ischemia episodes.
Lung cancer causes more deaths in men and women than any other cancer related disease. Currently, few effective strategies exist to predict how patients will respond to treatment. We evaluated the serum metabolomic profiles of 25 lung cancer patients undergoing chemotherapy ± radiation to evaluate the feasibility of metabolites as temporal biomarkers of clinical outcomes. Serial serum specimens collected prospectively from lung cancer patients were analyzed using both nuclear magnetic resonance (¹H-NMR) spectroscopy and gas chromatography mass spectrometry (GC–MS). Multivariate statistical analysis consisted of unsupervised principal component analysis or orthogonal partial least squares discriminant analysis with significance assessed using a cross-validated ANOVA. The metabolite profiles were reflective of the temporal distinction between patient samples before during and after receiving therapy (¹H-NMR, p < 0.001: and GC–MS p < 0.01). Disease progression and survival were strongly correlative with the GC–MS metabolite data whereas stage and cancer type were associated with ¹H-NMR data. Metabolites such as hydroxylamine, tridecan-1-ol, octadecan-1-ol, were indicative of survival (GC–MS p < 0.05) and metabolites such as tagatose, hydroxylamine, glucopyranose, and threonine that were reflective of progression (GC–MS p < 0.05). Metabolite profiles have the potential to act as prognostic markers of clinical outcomes for lung cancer patients. Serial ¹H-NMR measurements appear to detect metabolites diagnostic of tumor pathology, while GC–MS provided data better related to prognostic clinical outcomes, possibility due to physiochemical bias related to specific biochemical pathways. These results warrant further study in a larger cohort and with various treatment options.
Electronic supplementary material
The online version of this article (doi:10.1007/s11306-016-0961-5) contains supplementary material, which is available to authorized users.
Heart failure (HF) is a systemic and multiorgan syndrome with metabolic failure as fundamental mechanism. As a consequence of its impaired metabolism, other processes are activated in the failing heart, further exacerbating the progression of HF.
Metabolic agents are a relatively new class of drugs that act through optimisation of cardiac substrate metabolism. Among the metabolic modulators, Trimetazidine (TMZ) and perhexiline are the only two agents with proven anti-ischaemic effect currently available. However, due to its major side effects, perhexiline is not yet approved in the US or Europe.
Clinical trials have demonstrated that the adjunct of TMZ to optimal medical therapy improves symptoms and prognosis of HF without exerting negative hemodynamic effects. Due to its anti-ischaemic/anti-anginal effect and excellent tolerability, the modulation of cardiac metabolism with TMZ represents a promising approach for the treatment of patients with HF.
A systematic study was done examining the steady state kinetics of F1-catalyzed nucleotide hydrolysis in the presence of various activating divalent metal cations. Values of Km and kcat were obtained from Lineweaver-Burk plots, and kcat/Km values were calculated. With some exceptions, kcat/Km was shown to be independent of the metal present for F1-catalyzed ATP hydrolysis, independent of the nucleotide hydrolyzed with magnesium as the metal cation present, and independent of temperature with most activating metal cations. An average value for kcat/Km of 2.62 X 10(5) M-1 S-1 is calculated as the lower limit to the second order rate constant for binding substrate to enzyme. Changes in steady state kinetic parameters with temperature were also studied. The Ki value for ADP inhibition of F1-catalyzed ATP hydrolysis with magnesium as divalent cation present was found to be temperature-independent. Plots of log kcat versus 1/T showed either abrupt breaks or straight line dependencies depending on the metal ion present. These results may indicate that different rate-limiting steps in the reaction sequence can be operative at different temperatures depending on the divalent cation present.
The role of tyrosine in the catalytic mechanism of nucleoside triphosphate hydrolysis by beef heart mitochondrial ATPase is explored. We compare the rates of the ATPase reaction by both nitrated and native F1 at both pH 8 and pH 6. The pH-activity profile of nitrated F1 is compared to the pH-activity profile of the unmodified enzyme. These data indicate that the phenolic group of an active-site tyrosine must be protonated during the hydrolysis reaction. Deuterium oxide is used in the reaction buffer to explore the role of protons in the ATPase reaction. Kinetic constants of the nucleoside triphosphates are obtained at various levels of D2O using both the nitrated and native forms of F1. Several nucleoside diphosphates are used as inhibitors of F1-catalyzed ITP hydrolysis. Dissociation constants of these inhibitors are obtained at both low and high concentrations of D2O for both the nitrated and native F1. We explore the possibility that a tyrosine and an arginine lie in close proximity in the F1 active site by studying the effects of sequential modification of arginine and tyrosine. These results are interpreted in terms of possible ATP hydrolysis mechanisms. Two possible roles for tyrosine in the hydrolysis of nucleoside triphosphates by F1 are suggested.
Background
In nature, deuterium/hydrogen ratio is ~1/6600, therefore one of ~3300 water (H2O) molecules is deuterated (HOD + D2O). In body fluids the ratio of deuterons to protons is ~1/15000 because of the lower ionization constant of heavy water. The probability of deuteronation rather than protonation of Asp 61 on the subunit c of F0 part of ATP synthase is also ~1/15000. The contribution of deuteronation to the pKa of Asp 61 is 0.35.
Theory and Discussion
In mitochondria, the release of a deuteron into the matrix side half-channel of F0 is likely to be slower than that of a proton. As another example, deuteronation may slow down electron transfer in the electron transport chain (ETC) by interfering with proton coupled electron transport reactions (PCET), and increase free radical production through the leakage of temporarily accumulated electrons at the downstream complexes.
Conclusion
Deuteronation, as exemplified by ATP synthase and the ETC, may interfere with the conformations and functions of many macromolecules and contribute to some pathologies like heavy water toxicity and aging.
A 59-year-old patient with a 18-year history of type-II diabetes is presented who showed dramatic improvements to glucose tolerance tests and increased fasting hepatic glucose production with systemic deuterium depletion. Deuterium, which is well known to decrease the efficiency of the ATP syntheses nanomotors, is likely the mechanism leading to the systemic changes to both insulin and hepatic glucose production in the pancreas and liver, respectively. Systemic deuterium depletion occurs with consumption of low carbohydrate (keto) diets and deuterium depleted water.
We carried out a prospective case study in a high-level amateur natural male bodybuilder throughout preparation for 4 competitions and during the ensuing post-contest recovery period. Laboratory testing was conducted monthly over a 1-year period, which included the following assessments: B-mode ultrasound evaluation of muscle thickness (MT), multi-frequency bioelectrical impedance analysis (MF-BIA), blood pressure (BP) and heart rate (HR) assessment, resting metabolic rate (RMR) via indirect calorimetry, skinfold testing, vertical jump height, isometric lower body strength testing, and a 3-factor eating questionnaire. Blood work (including testosterone, thyroid hormone, sex hormone binding globulin, glomerular filtration rate, blood urea nitrogen, aspartate aminotransferase, alanine aminotransferase, white blood count, albumin/globulin ratio, and lipoprotein A) was obtained separately from an outside lab at 4 timepoints. We also assessed the effectiveness of a carb deplete/carb load peaking strategy employed immediately prior to competition. The participant employed a high-volume, high-frequency, whole-body training program throughout the study period. Average daily nutritional intakes ranged from 1,953 to 3,415 kilocalories; 104 to 386 g carbohydrate; 253 to 263 g protein, and; 57 to 95 g lipid. Body fat was reduced to very low levels (~5%) immediately prior to competition, but this corresponded with a loss of lean mass. Alterations in metabolism, hormonal status, explosive strength, and psychological aspects of eating were observed during pre-contest preparation; however, all of these variables recovered quickly post-competition. The implementation of a carb deplete/carb load peaking strategy acutely increased muscle thickness, and thus may be a viable pre-contest approach to maximize muscular aesthetics.
Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome with an increasingly recognized heterogeneity in pathophysiology. Exercise intolerance is the hallmark of HFpEF and appears to be caused by both cardiac and peripheral abnormalities in the arterial tree and skeletal muscle. Mitochondrial abnormalities can significantly contribute to impaired oxygen utilization and the resulting exercise intolerance in HFpEF. We review key aspects of the complex biology of this organelle, the clinical relevance of mitochondrial function, the methods that are currently available to assess mitochondrial function in humans, and the evidence supporting a role for mitochondrial dysfunction in the pathophysiology of HFpEF. We also discuss the role of mitochondrial function as a therapeutic target, some key considerations for the design of early-phase clinical trials using agents that specifically target mitochondrial function to improve symptoms in patients with HFpEF, and ongoing trials with mitochondrial agents in HFpEF.
Assessment of heart rate has been used for millennia as a marker of health. Several studies have indicated that low resting heart rate (RHR) is associated with health and longevity, and conversely, a high resting heart to be associated with disease and adverse events. Longitudinal studies have shown a clear association between increase in heart rate over time and adverse events. RHR is a fundamental clinical characteristic and several trials have assessed the effectiveness of heart rate lowering medication, for instance beta-blockers and selective sinus node inhibition. Advances in technology have provided new insights into genetic factors related to RHR as well as insights into whether elevated RHR is a risk factor or risk marker. Recent animal research has suggested that heart rate lowering with sinus node inhibition is associated with increased lifespan. Furthermore, genome-wide association studies in the general population using Mendelian randomization have demonstrated a causal link between heart rate at rest and longevity. Furthermore, the development in personal digital devices such as mobile phones, fitness trackers and eHealth applications has made heart rate information and knowledge in this field as important as ever for the public as well as the clinicians. It should therefore be expected that clinicians and health care providers will be met by relevant questions and need of advice regarding heart rate information from patients and the public. The present review provides an overview of the current knowledge in the field of heart rate and health.
Diabetes mellitus (DM) is a major cause of heart failure in the western world, either secondary to coronary artery disease or from a distinct entity known as “diabetic cardiomyopathy”. Furthermore, Heart Failure with Preserved Ejection Fraction (HFpEF) is emerging as a significant clinical problem for patients with DM. Current clinical data suggests that between 30-40% of patients with HFpEF suffer from DM. The typical structural phenotype of the HFpEF heart consists of endothelial dysfunction, increased interstitial and perivascular fibrosis, cardiomyocyte stiffness and hypertrophy along with advanced glycated end products deposition (AGE). There is a myriad of mechanisms that result in the phenotypical HFpEF heart including impaired cardiac metabolism and substrate utilization, altered insulin signaling leading to protein kinase C activation, AGE deposition, pro-sclerotic cytokine activation e.g. transforming growth factor-β activation, along with impaired nitric oxide production from the endothelium. Moreover, recent investigations have focused on the role of endothelial-myocyte interactions. Despite intense research, current therapeutic strategies have had little effect on improving morbidity and mortality in patients with DM and HFpEF. Possible explanations for this include a limited understanding of the role that direct cell-cell communication or indirect cell-cell paracrine signaling plays in the pathogenesis of DM and HFpEF. Additionally, integrins remain another important mediator of signals from the extracellular matrix to cells within the failing heart and may play a significant role in cell-cell crosstalk. This review discusses the characteristics and mechanisms of DM and HFpEF to stimulate potential future research for patients with this common, and morbid condition.
At ~1 deuterium/6600 protons natural abundance the ATP synthase protein nanomotor may break down in every few seconds without effective deuterium depleting biochemical processes through glycolysis and the TCA cycle. This talk explains how deuterons damage mitochondrial ATP synthase nano-mechanics by severely compromising proton on-off loading onto the Asp61 C-protein residue of the FO rapidly (9000/min) rotating nano-motor subunit. This is based on the ~1500 proton/second transfer velocity of the rotating protein. Alike, there are deuterium-induced isotope effects caused by its low dissociation constant from asparagine and its high mass to co-regulate the TCA cycle by malate dehydrogenase during oxaloacetate formation. This is because in malate dehydrogenase there are also Asp168 and several arginine residues that participate in proton binding, stabilization and transfer reactions. The inherent complexities of glycolysis and the TCA cycle is explained by their primary role in deuterium depletion, as well as multiple exchanges with metabolic water in the cytoplasm coming from the mitochondrial matrix. In simple terms glycolysis acts as a metabolic “dryer” to rip off all extracellular and extramitochondrial deuterium and hydrogen atoms from glucose, while the TCA cycle acts as a metabolic “washer” by adding hydrogen atoms back from low deuterium metabolic matrix water to specific carbons to be oxidized in the TCA cycle. Therefore, natural ketogenic substrate oxidation via deuterium depleted matrix water production becomes a critical resource for mitochondrial health. On the other hand, the Warburg effect and serine oxidation with glycine cleavage (SOGC) are deuterium loading alternative energy producing pathways and are the result of excessive deuteronation of the mitochondrial matrix and intermembrane space. In conclusion, excessive deuterium loading is involved in isotopic breakdowns of ATP synthase, malate dehydrogenase and thus TCA cycle nanomechanics, which require mitochondrial repairs with important adaptive changes in cellular metabolism. These may produce the Warburg effect for lactate efflux due to insufficient pyruvic acid oxidation, even in the presence of oxygen at intolerable deuterium levels in diseased mammalian cells. The talk offers mechanisms how deuterium becomes an oncoisotope and how global warming, for example, may be a contributor to increased cancer incidence worldwide due to limited deuterium fractionation during water cycling in Nature. Talk: https://youtu.be/6P8gqB4zLGQ
Unlabelled:
Bodybuilding is a sport in which competitors are judged on muscular appearance. This case study tracked a drug-free male bodybuilder (age 26-27 y) for the 6 mo before and after a competition.
Purpose:
The aim of this study was to provide the most comprehensive physiological profile of bodybuilding competition preparation and recovery ever compiled.
Methods:
Cardiovascular parameters, body composition, strength, aerobic capacity, critical power, mood state, resting energy expenditure, and hormonal and other blood parameters were evaluated.
Results:
Heart rate decreased from 53 to 27 beats/min during preparation and increased to 46 beats/min within 1 mo after competition. Brachial blood pressure dropped from 132/69 to 104/56 mmHg during preparation and returned to 116/64 mmHg at 6 mo after competition. Percent body fat declined from 14.8% to 4.5% during preparation and returned to 14.6% during recovery. Strength decreased during preparation and did not fully recover during 6 months of recovery. Testosterone declined from 9.22 to 2.27 ng/mL during preparation and returned back to the baseline level, 9.91 ng/mL, after competition. Total mood disturbance increased from 6 to 43 units during preparation and recovered to 4 units 6 mo after competition.
Conclusions:
This case study provides a thorough documentation of the physiological changes that occurred during natural bodybuilding competition and recovery.
D, deuterium
δD(NMR), chemical shift axis in a deuterium NMR spectrum
F6P, fructose-6-phosphate
G6P, glucose-6-phosphate
IRMS, isotope ratio mass spectrometry
NMR, nuclear magnetic resonance
PGI, phosphoglucose isomerase
Intramolecular deuterium distributions of the carbon-bound hydrogens of glucose were measured using deuterium nuclear magnetic resonance. Glucose isolated from leaf starch of common bean (Phaseolus vulgaris cv. Linden) or spinach (Spinacia oleracea cv. Giant nobel) was depleted in deuterium in the C(2) position, compared with glucose isolated from leaf sucrose or bean endosperm starch. In beans, the depletion of C(2) was independent of the light intensity during growth (150 or 700 μmol photons s–1 m–2). The ratio of glucose-6-phosphate to fructose-6-phosphate ([G6P]/[F6P]) in bean chloroplasts was 0·9 in high light, indicating that the phosphoglucose isomerase reaction was not in equilibrium ([G6P]/[F6P]) ≈ 3). This implies that the kinetic isotope effect of phosphoglucose isomerase depleted deuterium in the C(2) position of G6P. Because the depletion was the same, the chloroplastic ([G6P]/[F6P]) ratio was in disequilibrium irrespective of the light intensity. If the ([G6P]/[F6P]) ratio was in equilibrium, a large chloroplastic pool of G6P would be unavailable for regeneration of ribulose-1,5-bisphospate. We argue that chloroplast phosphoglucose isomerase activity is regulated to avoid this. The deuterium depletion of C(2) explains the known low overall deuterium abundance of leaf starch. This example shows that measurements of intramolecular deuterium distributions can be essential to understand overall deuterium abundances of plant material.
To determine the cardio-protective effect of heavy water on the ischemic myocardium, a thoracotomy was performed on 18 mongrel dogs. The animals were connected to the extracorporeal circulation in a standardized experimental procedure. Following total cardiopulmonary bypass, 2,000 ml of a standard cardioplegic solution (LK 352) was infused at the aortic root of 10 dogs, which served as controls (group I), and the same solution containing 20% of 99.8% deuterium oxide was given at the aortic root of the remaining animals (group II). At the end of 60 minutes of ischemia, 1,000 ml of the solutions was again administered at the aortic root of the corresponding animals. Myocardial biopsies were taken from the apex of the left ventricle of each dog before cardiopulmonary bypass, immediately after the infusion of the cardioplegic solutions, following 90 minutes of ischemia, and after 30 minutes of reperfusion, and studied ultrastructurally. Whereas the ultrastructure of the myocardium of group I was well preserved at the end of the ischemic period, deuterium-oxide-treated hearts showed extensive focal and global myofilamentolysis and lysis of whole myocytes. Structural damage to glycogen, nuclear chromatin dispersal, severe intracellular edema and complete rupture of the intercalated discs were characteristic findings. At the end of ischemia, all the hearts of group I could be resuscitated. During the ischemia, all the hearts of group II developed into stone hearts. Biochemical studies on a second series showed a higher ATP depletion and a significantly higher lactate accumulation in group II than in group I.(ABSTRACT TRUNCATED AT 250 WORDS)
A study was done examining the steady-state kinetics of F1-catalyzed ATP and ITP hydrolyses in the presence or absence of D2O as a function of temperature. The steady-state kinetic parameters kcat and kcat/Km were obtained. For ATP hydrolysis, kcat/Km was independent of temperature in the presence or absence of D2O, while kcat/Km for ITP hydrolysis increased in both cases. The relative magnitudes of change of kcat and kcat/Km in the presence and absence of D2O over the temperature range studied were much different for the cases of ATP and ITP hydrolysis. A normal isotope effect was observed in plots of kcat H2O/kcat D2O versus temperature for ATP hydrolysis, which increased then leveled off as temperature increased. An inverse isotope effect at low temperatures changed to a normal isotope effect and increased dramatically as temperature increased during ITP hydrolysis. The results are discussed in terms of the nature and location of the rate-limiting steps in the reaction mechanisms.
Mice fed for 15 days with Deuterium-Depleted Water (30 ppm deuterium) had a statistically significant increased survival rate compared with control groups fed with normal distilled water (150 ppm deuterium), after 8.5 Gy irradiation (61% survival in the test group versus 25% in the control group). The hematological picture showed that normal WBC, RBC and platelet counts were maintained in the test groups. Immunological parameters (serum opsonic and bactericidal capacity, bactericidal capacity of the peritoneal macrophages) showed a marked increase in the test groups compared to a severe decrease in the control groups. Auxiliary tests using chemical radiomimetics (hydrochloric embihine) and immunosuppressors (cyclophosphamide) showed a strong protective effect of deuterium-depleted water against the decrease of the leukocyte counts and other immunologic parameters. In conditions of experimental inflammation induced with subcutaneous-implanted pellets, deuterium-depleted water feeding resulted in a statistically significant increase of the inflammatory response, demonstrated by increased percentages of PMN and lymphocytes in the peripheral blood and the increased phagocytic capacity of the peripheral blood PMN. Experimental infections induced with K. pneumoniae 506 and S. pneumoniae 558 in mice irradiated or treated with cyclophosphamide showed increased, non-specific immunity parameters. All results show a marked intensification of the immune defenses and increased proliferation of the peripheral blood cells, probably accounting for the radioprotective effects.
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