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From the Townsend Letter
June 2013

Metabolic Syndrome and Cardiovascular Disease: Testing and Treatment
Part 2: Quantifying Risk and Review of Treatment Options
by Gary Huber, DO, AOBEM
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The reduction of any and all threats to the endothelium is the key to halting plaque formation and reversing the risk of myocardial infarction. The testing noted above, along with a good history, should easily highlight those at risk. The key is to not wait until visible evidence of plaque appears but rather to start early to redirect biochemistry, shift cytokine physiology, and reduce inflammation from all causes.

Treatment needs to include anything that reverses this process:
1. Lifestyle habits need to be addressed, since sleep and stress patterns are a significant factor, as discussed in part 1 of this article.
• Assess sleep with Epworth questionnaire and refer for sleep study if indicated.
• Meditation and prayer are avenues to balance sympathetic and parasympathetic drive.
• Exercise restores endothelial function and prevents decline.73
• Adaptogen use and management of HPA axis to restore normal cortisol patterns will reduce the inflammatory process.

2. Nutritional guidance and blood glucose response need to be optimized to reduce oxidative stress on the endothelial lining. Dietary guidance is key with movement toward a low-glycemic, Paleolithic-type diet.

3. Employ herbal and nutraceutical therapy to alter oxidative stress and tissue response, thus enhancing nitric oxide production. Discussed in detail below.

4. Correct hyperlipidemia, LDL particle size and number, and pertinent related lipid markers as noted above. The benefits of statins are well documented but they are not a panacea. Statins can reduce LDL-particle number and size as well as CRP but have the disadvantage of increasing risk for diabetes, depleting coenzyme Q10 levels, and reducing testosterone levels, which adversely increase cardiovascular risk.

5. Inhibition of the renin-angiotensin system with an ACE inhibitor or angiotensin-I receptor blocker if appropriate to address hypertension has been shown via flow mediated vasodilatation studies to improve endothelial health and function.74,75

6. Hormone replacement or balance of hormones as indicated will increase the synthesis and release of nitric oxide. Ample data exist detailing the benefits of estrogen and testosterone on blood glucose, lipids, and cardiovascular health.76-78

Herbal and Nutraceutical therapy
There is strong literature support for the use of these agents in the correction of endothelial dysfunction. They favorably alter inflammatory pathophysiology that extends far beyond the endothelium, affecting multiple organ systems, and carry a very low risk profile. Here is a list, including the common daily dosage range, to consider as you formulate a plan:

• omega-3 fatty acids: DHA in doses of 1000 to 2000 mg
• alpha-lipoic acid: 600 to 1200 mg
• arginine: 2 to 3 grams
• vitamin E: mixed tocopherol 400 to 800 IU daily (avoid alpha-tocopherol "only" supplements)
• grape-seed extract (oligomeric proanthocyanidin) 100 to 300 mg
• curcumin: (preferably in phytosome form): 750 to 1500 mg
• aged garlic extracts: 1200 to 2400 mg
• berberine: 1000 mg
• N-acetylcysteine: 1500 mg
• coenzyme Q10: 50 mg of monglyceride base or 200 mg of an oil base
• resveratrol: 30 to 100 mg daily
• vitamin C, folic acid, and other antioxidants in general.

Omega-3 fatty acids reduce the production of IL-1 β, TNF-α, and IL-6 and reduce granulocyte and macrophage colony-stimulating factor by peripheral mononuclear cells. DHA has been shown to inhibit in vitro human endothelial cell production of IL-6, while conversely the consumption of hydrogenated fat increases production of IL-6 and TNF-α.79,80 This reduction in endothelial inflammation lowers the vascular risk seen with diabetes and metabolic syndrome.81,82

Alpha-lipoic acid is a strong antioxidant that reduces endothelial dysfunction but also affects cytokines and blood sugar. Alpha-lipoic acid stimulates glucose uptake in insulin resistant cells and improves insulin sensitivity in patients with type 2 diabetes.74,83,84, Alpha-lipoic acid also affects thyroid and metal detoxification, and enhances beneficial PGC-1a, which improves mitochondrial biogenesis.

L-arginine increases NO, thus reducing endothelial injury.85-87 It also lowers plasma endothelin concentrations, resulting in a reduction of blood pressure. Arginine administration increased apoptosis of vascular cells in intimal lesions, leading to regression of atherosclerosis and prevention of the progression of atherosclerotic plaques.88-90 Impaired NO pathways are seen in diabetes, hypertension, and coronary artery disease patients. Heavy salt intake impairs NO production in patients with hypertension.

The ugly side of NO was reported in the VINTAGE MI study, wherein 9 grams of L-arginine was given daily for 6 months post myocardial infarction.91 This treatment arm increased mortality rate by 8%. NO is a free radical with an unpaired electron, so an excess will react with superoxide to produce peroxynitrites. The problem here was that the arginine administration produced a wave of reactive nitrogen species, which would normally be absorbed by gamma-tocopherol in a healthy body. As this mechanism was overwhelmed with large doses of arginine in a vascular system that was already exceeding oxidative stress limits post infarction, the reactive species were free to cause ongoing damage.

Vitamin E, in the form of gamma- and delta-tocopherol, specifically scavenges reactive nitrogen species. Giving large doses of arginine may deplete gamma-tocopherol and increase the cardiovascular risk of damage from arginine/NO. Thus arginine is not recommended immediately after an infarction for this very reason. I would recommend the use of mixed tocopherol, specifically one with a large percentage of gamma- and delta-tocopherol, for cardiovascular patients. We need also remember that large doses of alpha-tocopherol will compete with gamma-tocopherol for absorption, thus leading to depleted gamma levels and increased risk of adverse events. Most suboptimal vitamin E supplements in the marketplace are "d-alpha-tocopherol only" and should be avoided. Proper tocopherol supplementation will reduce CRP, deoxidize the oxidized LDL, and improves endothelial function. Tocotrienols are an important topic as well but beyond our scope here.

Grape-seed extract (proantho­cyani­dins) improve vascular endo­thelial function and blood pressure.92-94 The endothelial benefit serves to reduce blood pressure by increasing eNOS activity and also has a mild effect of reducing oxidized LDL.

Curcumin has a strong ability to reduce inflammation by downregulating the activity of COX-2, LOX, and iNOS enzymes. It can inhibit production of TNF-a, as well as interleukin (IL) -1, -2, -6, -8, and -12. Its suppression of NFkappaB activation blocks cytokine gene expression and inhibits monocyte chemoattractant protein.95-97

Aged garlic extracts have more than 600 clinical studies demonstrating their benefits over traditional garlic.98,99 When you think of AGEs (advanced glycation end products), think about AGE (aged garlic extracts). Aged garlic has been shown to lower LDL cholesterol and oxidized LDL, reduce triglycerides, elevate HDL levels, and lower CRP measures, also to improve blood flow in humans by increasing bioavailable NO metabolites derived from eNOS, thus improving endothelial function.100-106 It has been shown to greatly reduce the progression of coronary calcification in patients on statin therapy.107

Berberine has multiple beneficial effects, including: increases insulin receptor sensitivity; lowers Hgb-A1C; increases AMPK, which contributes to eNOS function and production; reduces chemokines and cytokines, including IL-1b, IL-8, and NfkappaB; and improves left ventricular function.108 Its broad impact on multiple aspects of vascular health make this a strong choice for inclusion in any program.

NAC can potentiate the activity of NO and may promote scavenging of free radicals. One study of 16 patients with atherosclerosis found that NAC supplements improved coronary and peripheral endothelium-dependent vasodilation.109

Coenzyme Q10
The very drugs that are commonly used to treat metabolic syndrome and cardiovascular disease such as statins, beta blockers, sulfonylureas, and hydrochlorthiazide all deplete coenzyme Q10. A reduction in available coenzyme Q10 can weaken the myocyte and contribute to congestive heart failure, hypertension, and endothelial dysfunction. A meta-analysis in 2012 demonstrated that coenzyme Q10 significantly improves endothelial function, and other studies have demonstrated its abilty to reduce blood pressure.110,111

Resveratrol has impact beyond its role as an antioxidant. It affects SIRT1 and PGC1alpha regulation, resulting in enhanced endothelial nitric oxide synthase activity, thus elevating levels of nitric oxide.112-115

Vitamin C and methylated folic acid have been shown to reduce endothelial dysfunction by reducing oxidative stress and preventing the degradation of nitric oxide.116,117

Direct Treatment of Abnormal Myeloperoxidase Levels
Managing an elevated myeloperoxidase level is important as we have discussed its ability to reverse the benefits of HDL and adversely alter LDL. Several natural elements have been shown to have benefit.
Resveratrol has demonstrated strong inhibitory influence on the peroxidasic activity of MPO.118 In fact resveratrol has shown a strong inhibitory effect on all phases of the inflammatory response: reducing recruitment of neutrophils, reduced production of MPO, and performance as a competitive electron donor for MPO reduction.119

Quercetin is a potent inhibitor of MPO action and is directly able to scavenge hypochlorous acid generated by MPO.93,120 Dietary flavonoids of all types but particularly quercetin have been shown to act as a substrate for MPO reaction, thereby acting as a competitive inhibitor and neutralizing its harmful effects on LDL and other substrates.121

Cocoa acts as substrate for MPO as well as a potent inhibitor of the lipid peroxidation of LDL by MPO or peroxynitrate. Cocoa acts as a scavenger of NO2 radicals and favorably modulates the metabolism of NO.122

This topic is broad with many avenues unexplored in this brief overview. But clearly we have many excellent tools at our disposal. The key is to look for inflammatory disease in all of its varied forms as early as possible. Identify risky behavior and follow this with in-depth evaluation that truly uncovers treatable markers. Heart disease starts in our 20s as evidenced by the autopsies of Korean War victims.122 Targeting endothelial repair early is the truest path to health.

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