WHAT IS HOMOCYSTEINE?

Transcription

1 CARDIO BENEFITS

2 Efforts to support healthy cardiovascular function are routinely pigeon-holed: take care of cholesterol to solve this problem, begin blood pressure medication to address that one. But there are such intricate connections between each area of cardiovascular focus that these types of regimens may not provide the whole-system cardiovascular support your patients are searching for. This paper will outline a method for diversifying supportive efforts and will include overviews of the physiology of cardiovascular health, the many connections within it, and the nutrients that may provide support for each. HOMOCYSTEINE Let s begin with a discussion of a certain amino acid that greatly impacts cardiovascular health, despite the fact that many of our conversations about the system may not include mention of its name. WHAT IS HOMOCYSTEINE? Homocysteine is a non-protein amino acid. Our bodies can recycle homocysteine into methionine or convert it to cysteine when aided by specific B vitamins. Homocysteine is biosynthesized from methionine, not taken into the body via nutrients in the diet. In the biosynthesis process, things get a bit complicated, beginning with methionine. First, it must receive an adenosine group from ATP (otherwise known as the energy molecule). That reaction is catalyzed by S-adenosyl-methionine synthetase, a protein enzyme. SAM, or S-adenosylmethionine, is the product of that reaction. SAM transfers a methyl group to an acceptor molecule. At that point, hydrolysis occurs, yielding l-homocysteine, which can be then converted back into l-methionine or into l-cysteine. That s a lot to take in, but the recycling process is a very important action in our bodies, and it s important to understand if we are to understand homocysteine s impact on health. NORMAL HOMOCYSTEINE CONVERSION When focusing on the conversion of homocysteine to lesser damaging metabolites, one needed look any further than three key nutrients. This process exists within very well established methylation biochemistry cycles including the Folate, Biopterin, Neurotransmitter and Homocysteine Cycles. When homocysteine enters this process, adequate B12 levels are necessary to stimulate the conversion to methionine. Trimethylglycine (TMG) is also required for this critical process. (Incidentally, upon the conversion of TMG to dimethylglycine [DMG], this newly formed glycine with two methyl donors drives the methylfolate cycle). From here methionine converts to SAMe which feeds the methylation pathways and supports numerous processes such as detoxification and mood. In losing its methyl group, SAMe becomes SAH (S Adenosyl Homocysteine), which is then converted to homocysteine, at which point pyridoxine-linked enzymes involved in amino acid metabolism, specifically the cystathinione synthase enzyme, drive the conversion to cystathione and ultimiately to cysteine. This step becomes critical for cellular health when cysteine is combined with glutamate and glycine to form one of the body s master nutrients, glutathione. 1

3 HOW IS HOMOCYSTEINE RELATED TO HEART HEALTH? The recycling of this amino acid is instrumental to maintaining a healthy cardiovascular system. According to the National Institutes of Health Office of Dietary Supplements, Elevated homocysteine levels are thought to promote thrombogenesis, impair endothelial vasomotor function, promote lipid peroxidation, and induce vascular smooth muscle proliferation ( Dietary supplement fact sheet: vitamin B12 health professional fact sheet, 2011). A high blood level of homocysteine, known as hyperhomocysteinemia, makes us more vulnerable to injury of the endothelial cells, which can lead to a compromise to blood vessels and, eventually long term implications. The coronary arteries supply the heart with necessary oxygenated blood. When that blood flow is blocked by plaque, the disease occurs. Some theories suggest that homocysteine may destroy endothelial cells, leading to the idea that plaque may attempt to fill in the damaged areas of the arteries once damage has occurred. Other theories suggest that homocysteine may itself oxidize low-density lipoproteins, promoting buildup of cholesterol along the walls. Both theories, along with several others, describe reasoning for the correlation between arterial aging and elevated homocysteine levels. We aren t sure, still, if high levels of homocysteine are independent risk factors for blood clots, strokes and heart attacks. But we are sure that high levels of homocysteine and cardiovascular health are linked, as are aging and increased homocysteine levels, making support for this aspect of the cardiovascular system ever more important for patients after the age of 40 (Wierzbicki, 2007). BLOOD PRESSURE Because homocysteine can drive the cholesterol s deposit along the walls, homocysteine and blood pressure are also linked, indicating a need for a broad approach to cardiovascular system support. Also identified as potential underlying causes for the need for blood pressure support are elevated cortisol levels and nutrient depletion, often derived from medication. Cortisol has quickly become a problematic hormone for numerous systems in the body when unchecked. And when there are elevated levels of cortisol in the blood, the pressure within the vascular system can be negatively impacted. One study performed by Litchfield and colleagues found elevated urinary free cortisol excretion in 153 white patients exhibiting essential hypertension than 18 normotensive controls. The authors of the Four Corners Study published in 1992 observed 50 young people with high blood pressure and high parental blood pressure with higher plasma cortisol concentrations as compared with similar numbers of people with lower pressure. Morning plasma cortisol concentrations were elevated in untreated male hypertensives selected from the Paris Prospective Study (total cohort n = 6424) (Filipovsky et al, 1996). 2

4 Interestingly enough, males have been implicated more than females when it comes to this correlation of higher cortisol levels and elevated blood pressure according to Walker et al (2000). The study examined 226 Swedish subjects in a cross-sectional study and found higher plasma cortisol was independently associated with higher diastolic blood pressure in men, but not women. This is far from conclusive that men are at greater risk, however, it highlights a commonly overlooked underlying risk factor for males exhibiting elevated blood pressure levels. Another factor implicated in blood pressure impact is nutrient levels. In clinical practice it is quite common that patients present with a need for specific nutrient support, there are times when drug induced nutrient depletion is a driving factor. One such nutrient is Coenzyme Q10, often depleted with statin drugs as well as blood pressure medications. Both preliminary trials and double blind trials have concluded that supplementing with CoQ10 may lead to significant levels of support for blood pressure. Much of the research has focused on doses of 100 mg/day for at least 2-3 months. (Folkers K, et al. Res Commun Chem Pathol Pharmacol 1984, Langsjoen P,et al. Mol Aspects Med 1994, Digiesi V, et al Molec Aspects Med 1994, Digiesi V, et al. Curr Ther Res 1990, Singh RB, et al. J Hum Hypertens 1999.) In fact, several studies have linked plasma homocysteine levels to blood pressure. Observations of homocysteine-lowering therapies being followed by decreases in blood pressure may suggest that it s possible for homocysteine s role in blood pressure to be causal, but the evidence for mechanisms that can explain that relationship (homocysteine-induced arteriolar constriction, renal dysfunction and increased sodium reabsorption, and increased arterial stiffness) is still circumstantial. Therefore, while we know blood pressure and homocysteine are linked, we should consider a causal relationship as yet unproven (Stehouwer & Guldener, 2003). Certain health factors support healthy blood pressure, such as an abundance of vessel-specific nutrients, normal weight, structural integrity of the vessels, hormonal balance and a healthy stress response. CHOLESTEROL Cholesterol is among the most misunderstood and demonized physiologic components. It has many vital functions that indicate that it is far from the maniacal villain it has been painted as. In fact, it happens to be a foundational compound with structural roles as well as neuroendocrine. Cholesterol is an important component of the cell membranes, including organelle membranes inside the cell. The right proportion of phospholipids, fatty acids and cholesterol in cell membranes allows them to be flexible while still holding their shape and supports permeability. When it comes to the supportive role it plays in vascular health and the structural support it provides to the tunica intima, it becomes clear that we re not looking at an enemy but need to embrace cholesterol as a friend. As it has been stated in Know Your Fats, Cholesterol is used by the body as raw material for the healing process. This is the reason the injured areas in the arteries have cholesterol along 3

5 with several other components (such as calcium and collagen) in the scar tissue that is formed to heal the wound (Enig, Know Your Fats, 2000). Further, cholesterol is key in vitamin D synthesis via 7-dehydrocholesterol, which has the potential to provide support to the blood pressure, insulin resistance and the cardiac tissue itself (see Vitamin D Studies in subsequent section of this writing). Beyond cardiovascular support, the endocrine system relies heavily on the production and distribution of adequate cholesterol. Adrenal and gonadal hormones are made from cholesterol. These are the stress handling, energy producing and reproductive hormones. (This explains the connection between elevated levels of stress and subsequent elevated serum cholesterol during prolonged stress.) From a digestive standpoint, cholesterol is converted into bile salts in the liver which are needed to break down and emulsify fats. Optimal levels of this function creates a cycle by which cholesterol is metabolized most effectively. These processes are also driven by beneficial bacteria and thrive with adequate flora population in the gut (J Cardiovasc Dis Res Oct-Dec; 1(4): ). Based on the understanding relating to the multifaceted nature of cholesterol, functional elevation in the serum should lead to an exploration of the underlying cause for the elevation rather than strictly a cholesterol lowering strategy. HOW CAN CARDIO BENEFITS PROVIDE SUPPORT? While none of the studies below were performed with the Cardio Benefits formula, each was used for inspiration for the formulation of the product. The following studies provide a rationale for the inclusion of each of the nutrients in this comprehensive formula. Vitamin D: A 2009 review in American Journal of Medical Science examines the epidemiologic and clinical evidence for vitamin D deficiency as a cardiovascular risk factor and explores potential mechanisms for the cardioprotective effect of vitamin D. In this review the National Health and Nutritional Examination Surveys (NHANES) ( , ) conducted in the United States have provided a means to explore cross-sectional associations between vitamin D status and cardiovascular health. Kendrick, et al, reported that individuals surveyed in NHANES with vitamin D deficiency (25(OH)D <20 ng/ml) had higher prevalence of self-reported angina, myocardial infarction, and heart failure compared with individuals with higher levels of vitamin D. During another 10-year follow-up period, men in the Health Professionals Follow-up Study without previous CVD and vitamin D deficiency (25(OH)D <15 ng/ml) exhibited a 2-fold increased rate of myocardial infarction. The proposed mechanisms of action are not fully elucidated, however three primary mechanisms have emerged as making the most physiological sense. The first is that vitamin D has the potential to support the renin-angiotensin-aldosterone system. The next focuses on the potential role on insulin sensitivity due to the presence of the VDR on the pancreas. And the last is the impact that vitamin D has directly on vascular tissue. One study demonstrated that matrix metalloproteinases, proteins that contribute to aberrant cardiomyocyte remodeling in response to injury and atherosclerosis, were supported in VDR animal models. (Judd, & Tangpricha, 2009). 4

6 Vitamin K2: The form of Vitamin K2 has become as important as the dosage recommended. Mena Q7 Crystals are currently the gold standard boasting a multi-step process of purification, condensation, and crystallization of naturally derived vitamin K2. This innovative process leads to an end product that is more than 96% pure natural all-trans MK-7. Further, as Crystals is manufactured using Bacillus licheniformis, MenaQ7 is free of soy products and all known allergens. Over the past decade many studies have been publishing extolling the virtues and clinical impact K2 has on both bone health and cardiovascular health. The most recent looked at a double-blind, randomized, intervention study of 244 postmenopausal women given either 180 mcg of Vitamin K2 as MK-7 (as MenaQ7 ) or a placebo daily for 3 years. Using ultrasound and pulse-wave velocity measurements (recognized as standard measurements for cardiovascular health), researchers determined that carotid artery distensibility was significantly improved for a 3-year period in the MenaQ7 group as compared with that of a placebo group. Also, pulse-wave velocity showed a statistically significantly decrease after 3 years for the Vitamin K2 (MK- 7) group, but not for the placebo group, demonstrating an increase in the elasticity and reduction in age-related arterial stiffening, especially in women having high arterial stiffness. B6, Folate and B12: One of the most significant findings in terms of B vitamins and homocysteine was actually brought to light through a meta-analysis of the clinical trials involving B6, folic acid and B12 relating to homocysteine levels. This analysis extracted information from a range of databases, including Embase, Pubmed, Ovid, Biosis, China National Knowledge Infra-structure (CNKI), Wanfang Data, VIP Database for Chinese Technical Periodical (VIP), Chinese Biomedical Literature Database (CMB), were searched to identify random control trials between February 1994 to February 2014 on the effect of folic acid, vitamin B(6) and B(12) supplementation on plasma homocysteine level. The findings were clinically significant in terms of the functional impact on homocysteine levels through these three B vitamins. The conclusion stated Folic aicd combined with vitamin B(6) and B(12) treatment significantly reduced plasma homocysteine levels. The review went on to conclude that this supportive mechanism did not, however, diminish the risk for developing cardiovascular disease. Nevertheless, 12 studies looking at patients and finding that the mean homocysteine levels were significantly lower with folic acid, vitamin B(6) and B(12) therapy compared with placebo during follow-up is worth noting from a functional perspective (Li, Li, Qi, & Shen, 2015). B12 is essential for heart health because it functions as a cofactor for methionine synthase, which catalyzes the homocysteine-to-methionine conversion ( Dietary supplement fact sheet: vitamin B12 health professional fact sheet, 2011). When B12 is insufficient, homocysteine levels can rise due to inadequate methionine synthase function (Clarke et. al, 2014). 5

7 In terms of the form of B12 used for optimal clinical outcomes, MecobalActive, a form of methylcobalamin, which is made with a patented sustainable green process versus toxic or pollutant for the others has emerged as the foremost option. Another differentiating factor is the lower moisture content which averages 4% versus up to 12%. The last factor would be that MecobalActive has a very low impurity profile. Since this ingredient crosses the brain barrier, purity is of the utmost importance. Magnesium helps to maintain proper smooth muscle function in the blood vessels. Magnesium supplementation has even been found to have a modest effect on CHD risk in males (Mathers & Beckstrand, 2009). Clinical results have shown that higher intake of dietary magnesium supports normal blood pressure in women, and that increased magnesium intake may improve serum lipid profiles (Champagne, 2008), ( Magnesium University of Maryland Medical Center, 2015). Magnesium can also support cellular homeostasis through supporting the proper shuttling of nutrients into and out of cells.* L-Carnitine s mechanism of action has been brought to light in Food and Function Journal. This particular study started by outlining the role that impaired lipid metabolism has on the development of chronic disease. The role of L-Carnitine in supporting these metabolic challenges has secured this amino acid as one of the top nutrients to apply to patients for cardiometabolic support. The results of the experiment showed L-Carnitine supplementation attenuated high-carbohydrate, highfat diet-induced changes, together with modifications in lipid metabolism including the inhibition of stearoyl-coa desaturase-1 activity, reduced storage of short-chain monounsaturated fatty acids in the tissues with decreased linoleic acid content and trans fatty acids stored in retroperitoneal fat. This mechanism demonstrates another avenue for nutritive support for cardiovascular health and successfully supports the case for L-Carnitine to be included in any cardiometabolic approach (Panchal, Poudyal, Ward, Waanders, & Brown, 2015). Trimethylglycine has long been associated with supporting homocysteine levels and this was demonstrated in a study published in the Journal of Nutrition. It was stated that Betaine and 5-methyltetrahydrofolate can remethylate homocysteine into methionine via independent reactions. We determined the effect of daily betaine supplementation, compared with both folic acid and placebo, on plasma concentrations of total homocysteine after an overnight fast and after methionine loading in men and women with mildly elevated homocysteine. It was found that betaine not only supported healthier fasting homocysteine levels but also provided ongoing support when challenged with the methionine loading dose far better than that of the placebo and folic acid groups. The conclusion did not clearly state that there was any broad support of cardiovascular health, however, the data on homocysteine levels was clearly defined (Steenge, Verhoef, & Katan, 2003). 6

8 CoQ10 is highest in concentration in organs that demand energy, such as the heart muscle, because it participates in the generation of ATP. There is strong scientific evidence that a deficiency of CoQ10, which is made naturally in the body, can cause symptoms such as heart failure, high blood pressure and chest pain ( Coenzyme Q10 evidence - Mayo Clinic, 2015). Coenzyme Q10 is also known to be depleted by traditional CV medications like statins. Write Mortensen et. al, Although HMG-CoA reductase inhibitors are safe and effective within a limited time horizon, continued vigilance of a possible adverse consequence from coenzyme Q10 lowering seems important during long-term therapy (Mortensen, Leth, Agner, & Rohde, 1997). WHY DIVERSIFY? Each piece of the cardiovascular system affects the others. The best way to support healthy levels of the three main components of cardiovascular health (homocysteine, blood pressure and cholesterol) is to diversify efforts, such that each component receives the nutrient support your patient s body demands. SUPPLEMENT FACTS Serving Size 3 Capsule Servings Per Container 30 Amount Per Serving % Daily Value Vitamin D3 (as Cholecalciferol) 1,000 IU 250% Vitamin K2 (as Mena Q7 ) 150 mcg 188% Vitamin B6 (as Pyridoxal 5-Phosphate) 30 mg 1,500% Folate (as [6S]-5-methyltetrahydrofolic acid from 1,600 mcg of Quatrefolic [6S]-5-methyltetrahydrofolic acid, glucosamine salt) 800 mcg 200% Vitamin B12 (as MecobalActive ) 1,000 mcg 16,667% Magnesium (as Mg Citrate) 150 mg 38% L-Carnitine 500 mg * Trimethylglycine (Betaine Anhydrous) 500 mg * Coenzyme Q mg * *Daily Value not established. Other ingredients: hypromellose (caspule), microcrystalline cellulose, vegetarian leucine. MenaQ7 is a trademark of Nattopharma, Norway; Patented in the United States and Canada. US Patent Number: 8,354,129; Canada Patent Number: 2,347,387. Quatrefolic is a registered trademark of Gnosis S.p.A. Corporation. U.S. Patent No. 7,947,662 Mecobalactive is a trademark of INTERQUIM, S.A. 7

9 REFERENCES Champagne, C. M. (2008). Magnesium in hypertension, cardiovascular disease, metabolic syndrome, and other conditions: a review. Nutrition in Clinical Practice, 23(2), doi: / Clarke, R., Bennett, D., Parish, S., Lewington, S., Skeaff, M., Eussen, S. J., on behalf of the B-Vitamin Treatment Trialists Collaboration. (2014). Effects of homocysteine lowering with B vitamins on cognitive aging: meta-analysis of 11 trials with cognitive data on 22,000 individuals. The American Journal of Clinical Nutrition, 100(2), ajcn Cleveland Clinic. (2014, June). Estrogen & hormones Health & Prevention Heart & Vascular Institute Cleveland Clinic. Retrieved from Coenzyme Q10 evidence - Mayo Clinic. (2015). Retrieved September 8, 2015, from Dietary supplement fact sheet: vitamin B12 health professional fact sheet. (2011, June 24). Retrieved from od.nih.gov/factsheets/vitaminb12-healthprofessional/ Grundy, S. M., & Griffin, A. C. (1959). Effects of periodic mental stress on serum cholesterol levels. Circulation, 19, doi: /01.CIR Judd, S. E., & Tangpricha, V. (2009). Vitamin D deficiency and risk for cardiovascular disease.the American Journal of the Medical Sciences, 338(1), doi: /maj.0b013e3181aaee91 J. Y., Kim, T. S., Cai, J., Kim, J., Kim, Y., Shin, K.,... Kim, K. (2013). Nattokinase improves blood flow by inhibiting platelet aggregation and thrombus formation. Lab Anim Res, 29(4), doi: /lar Kolodgie, F. D., Burke, A. P., Nakazawa, G., & Virmani, R. (2007). Is pathologic intimal thickening the key to understanding early plaque progression in human atherosclerotic disease? Arteriosclerosis Thrombosis and Vascular Biology, 27, doi: /atvbaha Li, J., Li, B., Qi, J., & Shen, B. (2015). Meta-analysis of clinical trials of folic acid, vitamin B12 and B6 supplementation on plasma homocysteine level and risk of cardiovascular disease. Zhonghua Xin Xue Guan Bing Za Zhi, 43(6), Magnesium University of Maryland Medical Center. (2015, August 6). Retrieved from altmed/supplement/magnesium Mathers, T. W., & Beckstrand, R. L. (2009). Oral magnesium supplementation in adults with coronary heart disease or coronary heart disease risk. Journal of The American Academy of Nurse Practitioners, 21(12), doi: /j x Mortensen, S. A., Leth, A., Agner, E., & Rohde, M. (1997). Dose-related decrease of serum coenzyme Q 10 during treatment with HMG-CoA reductase inhibitors.molecular Aspects of Medicine, 18, 18 Suppl:S doi: /s (97) Panchal, S. K., Poudyal, H., Ward, L. C., Waanders, J., & Brown, L. (2015). Modulation of tissue fatty acids by l -carnitine attenuates metabolic syndrome in diet-induced obese rats. Food Funct, 6(8), doi: /c5fo00480b Steenge, G. R., Verhoef, P., & Katan, M. B. (2003). Betaine supplementation lowers plasma homocysteine in healthy men and women. J Nutr, 133(5), Retrieved from Stehouwer, C. D., & Guldener, C. V. (2003). Does homocysteine cause hypertension?clinical Chemistry and Laboratory Medicine, 41(11), doi: /cclm Sumi, H., Hamada, H., Nakanishi, K., & Hiratani, H. (1990). Enhancement of the fibrinolytic activity in plasma by oral administration of nattokinases. Acta Haematologica, 84(3), doi: / Suzuki, Y., Kondo, K., Ichise, H., Tsukamoto, Y., Urano, T., & Umemura, K. (2003). Dietary supplementation with fermented soybeans suppresses intimal thickening.nutrition, 19(3), doi: /s (02) What causes high blood cholesterol? - NHLBI, NIH. (2012, September 19). Retrieved from health-topics/topics/hbc/causes Wierzbicki, A. S. (2007). Homocysteine and cardiovascular disease: a review of the evidence. Diab Vasc Dis Res, 4(2), Retrieved from 8