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From the Townsend Letter
May 2017

Beyond Cholesterol
by Chris D. Meletis, ND and Kimberly Wilkes
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An Often-Neglected Aspect of Cardiovascular Health
When physicians evaluate cardiac risk factors in their patients, one aspect of cardiovascular health that is often neglected is testing nitric oxide levels. Maintaining optimal levels of nitric oxide is crucial for the health of the cardiovascular system. Lower levels of nitric oxide are associated with many cardiovascular diseases including hypertension, atherosclerosis, stroke, and heart failure.41 Scientists believe that increased levels of ROS are to blame for decreased nitric oxide absorption.41
L-Citrulline and beetroot juice both have a lot of research backing up their ability to raise nitric oxide levels. Heart failure is characterized by increased activity of angiotensin–converting enzyme and reduced peripheral blood flow, both of which reduce the generation of nitric oxide.42 L-Citrulline has improved dilation of the blood vessels of stable systolic heart failure patients.42 Studies also have shown that L-citrulline can reduce arterial stiffness in middle-aged men and postmenopausal women43,44 and that it can reduce postoperative pulmonary hypertension.45 L-Citrulline is especially effective when combined with the antioxidant glutathione, since glutathione prevents the oxidative damage to nitric oxide caused by exposure to ROS.46
Beetroot juice works in a manner similar to L-citrulline in that is raises levels of nitric oxide.47 In peripheral arterial disease, not enough blood reaches tissues resulting in intermittent claudication pain during walking. In peripheral arterial disease patients, beetroot juice increased nitric oxide levels and improved peripheral tissue oxygenation in areas of hypoxia (low oxygen).48 It also increased exercise tolerance, and patients given beetroot juice walked for 17% longer compared to people taking a placebo.48 In addition, studies have shown beetroot juice enhances vascular function in people with high cholesterol49 and improves muscle power in individuals with systolic heart failure.50

A Good Night's Sleep Equals a Healthy Heart
During obstructive sleep apnea, a person stops breathing intermittently throughout the night. Sleep apnea can mirror peripheral ischemia as sleep apnea literally is low oxygen  levels due to nighttime desaturation. When asking a patient about how they are sleeping, a doctor recognizes it is just as much about how much oxygen the person is receiving as it is about insomnia.
CoreBioticThere is a strong link between sleep apnea and daytime hypertension and it may also be associated with pulmonary hypertension, stroke, coronary artery disease, and cardiac arrhythmias.51 One study ofHispanics found that sleep apnea increases the risk of peripheral artery disease.52 People with sleep apnea also have increased carotid and aortic wall thickness and high-risk carotid atherosclerosis plaques.53
Proper sleep in a dark room also allows the body to secrete healthy amounts of melatonin, a hormone that acts like an antioxidant. Melatonin is important in maintaining the endothelium, the lining of the blood vessels.54 An analogy can be made between a healthy blood vessel (the circulatory system) and a non-stick pan. It is not until there is damage to the non-stick coating that there is an issue with the frying pan and food begins to stick. Yet, it's not the item that is sticking to the pan that caused the problem in the first place. It was the problem with the non-stick coating. The endothelium lining of the blood vessel walls is like that non-stick coating. Therefore, we must address issues that are occurring in the endothelium, otherwise it will do no good to lower cholesterol.
Melatonin is an important ally in keeping the endothelium strong and healthy.54 To study the effect of melatonin on the endothelial cells lining the blood vessels, researchers evaluated this hormone's effects on intercellular adhesion molecule (ICAM), vascular cell adhesion molecule (VCAM), CRP, and nitric oxide in patients with three-vessel coronary disease.54 The study participants were given either 10 mg oral melatonin one hour before sleeping for one month or a placebo. After one month, people taking the melatonin experienced a significant drop in levels of ICAM, VCAM, and CRP while people taking the placebo experienced an increase in VCAM. Nitric oxide levels also increased in the melatonin group, whereas they decreased in the placebo group.
According to the researchers, "The results of this study suggested that melatonin may have beneficial effects on endothelial oxidative stress even in patients with severe and advanced atherosclerosis."

Genetic Risk Factors
Folate is critical for cardiovascular health. Yet, due to a genetic mutation in the gene for methylenetetrahydrofolate reductase (MTHFR), many people lack the ability to convert the folic acid found in supplements and fortified foods into the biologically active form of folate known as L-5-Methyltetrahydrofolate (L-5-MTHF). Functional medicine providers often look for this genetic risk factor, specifically the MTHFR 1298 mutation and C677T mutation. When these mutations are not adequately compensated for, it's common for homocysteine levels to also be elevated.55 Homocysteine is an amino acid linked to cardiovascular disease.
Often one of the first clues that a person has a MTHF mutation is that their mean corpuscular volume (MCV) is starting to creep above 90. The average red blood cell lives 90 to 120 days and can serve as the proverbial coal miner's canary in regards to vitamin B12 and folate deficiency. It is important that anyone with these MTHF mutations supplement with L-5-MTHF rather than folic acid.

Cholesterol Isn't the Only Lipid To Be Worried About
Besides LDL cholesterol, there are several other lipid risk factors for coronary heart disease and stroke, yet these risk factors are usually ignored in conventional medicine settings. One of these lipid risk factors is lipoprotein-associated phospholipase A2 (Lp-PLA2), an enzyme that serves as a marker for vascular inflammation and rupture-prone plaque.56 Most heart attacks and strokes are caused by ruptured plaque rather than blocked blood vessels. Higher Lp-PLA2 activity is associated with a greater risk for fatal and nonfatal coronary heart disease events.57 Because Lp-PLA2 is vascular specific, testing for it can be more beneficial than testing for CRP,58 which is a marker for systemic inflammation and can be elevated for other reasons besides heart disease. 
Another lipid-related cardiovascular risk factor is small dense low-density lipoprotein particles, which are especially prone to triggering atherosclerosis and are much more harmful than larger particle LDL. This is why only testing total and LDL cholesterol levels does not present a complete picture of a person's coronary health. One study found that eating a Mediterranean diet supplemented with nuts increased the LDL particle size.59 
Finally, it's also important to monitor levels of lipoprotein(a) and apolipoprotein B (ApoB), components of lipids involved in atherosclerosis and cardiovascular disease. Niacin is one supplement known to lower lipoprotein(a) levels60 while omega-3 fatty acids have lowered ApoB.61

Other Cardiovascular-Supporting Supplements
In addition to the dietary supplements already discussed in this article, other nutrients show promise in enhancing circulatory health. Berberine is a botanical that has anti-inflammatory, antioxidant, and heart-protective properties.62 In patients with congestive heart failure, 1.2 to 2 grams/day of berberine decreased ventricular premature complexes and reduced mortality.63 Berberine also improves insulin resistance, which is another way in which it improves cardiovascular health.64
Another important addition to a cardiovascular health regimen is vitamin D. Low levels of vitamin D are linked to peripheral artery disease65 and an increased risk of heart attacks.66 Vitamin D combined with gamma-tocopherol, vitamin C, and tetrahydrobiopterin (BH4) was effective in blocking atherogenesis and formation of plaques.67 Vitamin E reduces the risk of venous thromboembolism68 while B vitamin deficiency may increase the risk of venous thrombosis.69

Cholesterol is only one piece of the cardiovascular disease puzzle. Other, possibly even more important, risk factors for heart disease and stroke include fibrinogen, CRP, mitochondrial dysfunction, nitric oxide levels, sleep apnea, the MTHFR genetic mutation, Lp-PLA2, small dense low-density lipoprotein particles, lipoprotein(a), and ApoB. The most effective regimens for supporting cardiovascular health address all of these risk factors.

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References .pdf

Chris Meletis


Dr. Chris D. Meletis is an educator, international author, and lecturer. His personal mission is "Changing America's Health One Person at a Time." He believes that when people become educated about their bodies, that is the moment when true change and wellness begin. Dr. Meletis served as dean of naturopathic medicine and chief medical officer for 7 years at National College of Natural Medicine (NCNM) and was awarded the 2003 Physician of the Year award by the American Association of Naturopathic Physicians.

Kimberly Wilkes


Kimberly Wilkes is a freelance writer specializing in health, science, nutrition, and complementary medicine. She has written more than 300 articles covering a variety of topics from the dangers of homocysteine to sugar's damaging effects on the heart. She is the editor of Complementary Prescriptions Journal and enjoys scouring the medical literature to find the latest health-related science.


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