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Metabolic syndrome and cardiovascular disease: testing and treatment: part 2: quantifying risk and review of treatment options.

As discussed in part 1 of this article, metabolic syndrome and the cardiovascular disease that it creates is a problem of lifestyle habits that generate inflammation. That inflammatory process leads to endothelial dysfunction, which results in vascular plaque formation. Part 2 will focus on the integrative solutions that directly target endothelial health and repair.

So how are we to evaluate and quantitate an individual's risk? A discussion of lifestyle that includes overall balance, assessment of workload and stress, sleep quality, food quality, toxic exposures (both chronic and ongoing), heavy metal content, quality of water, EMF exposure and grounding (Earthing), dental health, exercise patterns, meditation, and more are all important topics that are beyond the scope of this presentation. It is assumed that integrative clinicians are exploring these topics for areas of weakness. This article will discuss the labs that aid our assessment and the potential treatment options that are available to the integrative care physician. Treatment will focus on the use of bioactive compounds that improve function and repair of the endothelial lining where plaque occurs.

Evaluating Cardiovascular Risk

Lipids are not the sole cause of heart disease. If the majority of myocardial infarctions occur in the face of normal lipid levels as current research has shown, then we must look at inflammatory markers as our true guide to avoid vessel damage and the chronic development of plaque. To truly assess cardiovascular risk we need to look at markers of inflammation in light of family history and lifestyle habits.

In my view, these first tier tests should be ordered in all general evaluations of cardiac status. The second tier can be reserved for more in-depth investigation when needed based on clinical history, family history, or as suspicion dictates.

Tier 1 testing: Applies to any initial evaluation regardless of history or lifestyle. All of these numbers can be acquired from a traditional lab service and include a nuclear magnetic resonance lipid panel, glucose, insulin, Hgb-A1C, CRP-hs, homocysteine.

1. LDL particle number: desired level is <1000. If there is no family history or suspicious indicators, then a level 1300 might be acceptable but suboptimal.

* This is a strong predictor of risk and is easily obtained. Given its low cost and ease of access, this marker is quickly becoming the standard for any physician serious about health assessment.

2. LDL particle size: greater than 20.5 (type A)

3. Triglycerides: desired measure is <100

* Reflects the status of glycemic control and insulin level, so treatment should be geared toward weight loss, diet change, and addressing insulin resistance.

4. Glucose, insulin, and Hgb-A1C: primary driver of inflammation

* Fasting glucose is ideally <85, or 2 hour postprandial is <100

* Insulin is best tested as 2 hour postprandial, desired is <20 at 2HPP

* Hgb-A1C desired to be <5.5

5. CRP-hs: desired level is <1.0

* Anything above this reflects the presence of inflammation as discussed in part 1 of this topic.

6. Homocysteine: desired level is <10.0

* If elevated then consider checking MTHFR and address B vitamin status.

* Elevated homocycsteine associated with increased intima-media thickness and lower nitric oxide levels. (57), (58)

7. LDL/HDL ratio: desired ratio is 2:1 or less

8. HDL: desired level is >45, optimal is 60-80

* Caveat: if level rises above 80 then suspicion for an elevated myeloperoxidase (discussed below) must be evaluated. An HDL >80 may in fact reflect abnormal or dysfunctional HDL.

9. Total cholesterol: desired is <200

* Total cholesterol is only included in this list to be complete. A healthy HDL will elevate this marker, making it misleading. This is clearly the least significant marker in the list and recent studies have gone as far as to state that total cholesterol does not predict heart disease risk. (59) Its inclusion in the Framingham criteria reflects an outdated paradigm.

Tier 2: a deeper look at the patient's physiology, applies to anyone with a strong family history of cardiovascular disease, risky lifestyle or inflammatory habits, or if tier 1 testing showed abnormalities requiring further investigation. All of these tests can be acquired through traditional lab services and do not require specialty peripheral lab work.

10. Oxidized LDL: optimal is <45 U/L

* Currently one of the best predictors of cardiovascular risk but is not widely employed. If you are serious about stratifying cardiovascular risk, this test needs to be included in your evaluation.

* Measures: moderate risk 45-59, high risk 60-79, very high risk >79.

11. Oxidized LDL/HDL ratio: desired is <1.0

* At this time, an established "standard" does not exist. Ideally we simply want to see an optimal HDL relative to the optimal oxidized LDL, which ideally is less than 1.

* Study by Johnston showed Ox-LDL/HDL ratio was a far superior as a predictor of heart disease when compared with traditional standards. (59) Haung showed similar findings recommending Ox-LDL/TC ratio as superior to any traditional lipid markers. (60)

12. Fibrinogen: desired is <370

* Broad marker of inflammation, acute phase reactant.

* Predicts risk for cardiovascular events. (61)

13. Myeloperoxidase: quantitative (not antibody). The desired level is 75th percentile or less of the established range.

* There are multiple labs performing this test and each has its own range of normal depending on their process. We are simply seeking to be near the midrange and avoid high normal or abnormal readings.

* Abnormality here is a great predictor of future events. (62)

14. Microalbuminuria/creatinine ratio: any amount is abnormal.

* Do not wait for this to elevate above 30 before taking action.

* Offers a quick noninvasive assessment of endothelial health.

15. Lp(a): desired level is <25

* Not highly amenable to change but there are some therapeutic approaches that can be tried.

16. ApoE gene: desired is 3/3. Any other result suggests adversely altered lipid transport potential.

* Becomes more important if there is a strong family history of CAD, as this may represent the genetic link. This genetic alteration will have significant consequences on your dietary recommendations. A patient with an abnormal ApoE gene will have difficulty properly processing even healthful fats and his/her overall fat intake needs to be restricted.

17. MTHFR single nucleotide polymorphism: both A1298C and C677T

* Don't rely on homocysteine result to dictate your need for this test.

* Having one SNP confers a rough approximation of 30% reduction in ability to methylate folic acid. A second SNP further reduces methylation by roughly 6001o.

We don't live an ideal world and so may not have the luxury of exploring all of these parameters. If cost, lack of insurance, or a patient's unwillingness to comply becomes a limiting issue, then identify the few parameters that you are most comfortable with and become an expert with them. If limited, then I would rely on a thorough glucose evaluation, CRP-hs, the nuclear magnetic resonance (NMR) test of lipids to evaluate LDL particle number and size, and an oxidized LDL. These tests are easily obtained, affordable, highly reliable, and predictive.

Discussion of Some of These Less Familiar Markers

Oxidized LDL: This test has become available through traditional testing facilities and is very affordable. It has greater predictive power than any of the traditional markers and is superior to Lp-PLA2 for discriminating patients with coronary artery disease from healthy patients. Given its tremendous predictive power and ease of availability, you may want this in your first-tier approach. Studies by Johnston and Huang demonstrate the superiority of this test. (59), (60)

Microalbuminuria/creatinine ratio: This test evaluates integrity of the endothelial lining. Albumin is never a normal finding in the urine, and any lab that reports a measure of <30 as normal is falsely optimistic. Any presence of albumin is reflective of disease and dysfunction and inflammation of the endothelial lining. The inflammatory process that causes leaky gut (dysbiosis) that we are so familiar with is the same model of inflammation that affects the endothelial lining. Inflammation involving the immune system leads to endothelial separation and an opportunity for albumin to leak via the kidney into the urine. This is a valuable noninvasive tool for evaluating endothelial status.

Myeloperoxidase: Neutrophils produce the enzyme myeloperoxidase (MPO) in response to infections. MPO converts hydrogen peroxide into hydrochlorous acid, which is cytotoxic and kills pathogens. Current evidence shows that MPO-derived oxidants play a role outside their important immune function, as they contribute to tissue damage and the initiation and propagation of acute and chronic vascular inflammatory disease. MPO is proatherogenic and present at high levels in human atheroma, rendering plaque unstable. (63) MPO will oxidize and modify LDL and promote a local inflammatory process that contributes to the development of atheromatous plaque. (64) Serum elevations of MPO have been shown to predict risk for major cardiac events. (62)

The hypochlorous acid generated by the action of myeloperoxidase regulates the activity of matrix metalloproteinase-7 (MMP-7, matrilysin), thus activating MMPs in the artery wall. Both MMP-7 and myeloperoxidase have been localized to lipid-laden macrophages in human atherosclerotic lesions contributing to plaque rupture. (63)

In the study by Brennan, MPO was positive in the face of acute MI but also was able to predict subacute events, coronary syndrome, and remote events. In patients reporting chest pain that showed a negative troponin T level, MPO measures were consistently elevated in those who went on to experience a major cardiac event in the next 6 months. It is a sensitive predictor of the presence of vulnerable plaque. Subsequent significant cardiovascular event risk was 4.7-fold higher for those in the highest quartile of MPO and proved more predictive than CRP. (62) This is clearly a marker of inflammation that is strongly predictive of bad outcomes and affords us a warning that if heeded could prevent cardiac events. (62)

HDL typically exerts an anti-inflammatory effect by decreasing monocyte chemotaxis, thus reducing progression of plaque. (65) It also promotes nitric oxide (NO) production. But the apoAl protein of HDL is a target for MPO which then gets altered, rendering the HDL dysfunctional and even pro-inflammatory. (66-71) HDL loses its ability to activate lecithin cholesterol acyl transferase (LCAT) and induces the expression of VCAM-1 in endothelial cells, thus promoting atherosclerosis. (66), (72)

The bottom line here is that if HDL appears elevated beyond what we consider a normal healthy level (>80), we need to evaluate whether MPO is present at abnormally high levels leading to altered, dysfunctional HDL that is creating vascular inflammation.

Treatment

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 [beta], TNF-[alpha], 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-[alpha]. (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-la, 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. (89-90) 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 prtein. (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 SIRTI and PGel alpha 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 MP0. (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)

Conclusion

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.

Notes

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by Gary Huber, DO, AOBEM

Dr. Gary Huber is president of the LaValle Metabolic Institute. He spent 20 years as an emergency medicine physician before joining Jim LaValle in the practice of integrative medicine at LMI. Dr. Huber is an adjunct professor teaching integrative medicine practice at the University of Cincinnati College of Pharmacy as well as a clinical preceptor for pharmacy students. Dr. Huber also lectures on hormone replacement therapies and integrative care for the American Academy of Anti-Aging Medicine for the University of South Florida. He has developed the Metabolic Code Professional Weight Loss Program that has proved very beneficial in reversing metabolic syndrome issues. Dr. Huber has a long held interest in nutrition and human physiology as it relates to wellness and longevity. He has served as medical director for the Flying Pig Marathon and is presently on the board of directors for Loveland's Amazing Race, a local charity event.
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Author:Huber, Gary
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Geographic Code:1USA
Date:Jun 1, 2013
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