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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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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 is 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 60%.

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 apoA1 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.


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