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Cardiac Biomarkers: A Well Validated Clinical Management Tool.

Introduction

Cardiovascular disease (CVD) is the leading cause of mortality in the United States. (1) Physicians recommend the classic lipid panel, which is certainly a valid predictor of cardiac risk in general. However, it does not give information about real-time events in the lining (intima and more precisely the "endothelium") of the inside of the artery. Most patients don't know of any other possible way to predict risk. Many will never be told by their physician that a relatively inexpensive panel can provide information about shorter term risk and that the rate and stability of the plaques are a sign but not the root cause of cardiovascular disease.

Atherosclerosis is an inflammatory disease, and it is critical for prevention oriented physicians to obtain information about the state of arterial inflammation and stability of focal plaques of their patients. (2) There are new tools to track this inflammation and the impact on the inner lining of our arteries and these are collectively known as cardiac biomarkers. In understanding how inflammatory biomarkers are indicative of cardiovascular risk, healthcare practitioners can better inform their patients of the potential risks they may face and prevent cardiac events from occurring. (3)

The use of advanced cardiac biomarkers is an emerging, yet, well-validated clinical tool that may be a better predictor of short-term risk than the classic lipid panel. (3) Half of all patients who have experienced a cardiac event had cholesterol within proper guidelines at the time. (4) As evidenced in the JUPITER trial, statin drugs such as Rosuvastatin lower C-reactive protein; thus, this function may be as important as their total effect on circulating lipid levels. (5)

Unlike the traditional lipid panel, cardiac biomarker testing provides information about inflammation. Let's examine a few of the many biomarkers that have had very extensive research behind them. Note that obtaining this information does not and should not preclude the annual lipid panel, and these authors stress the importance of patients sitting with their physician and calculating their risk including family history, body mass index, diet etc. Some of the biomarkers we'll explore here tell us about oxidative stress within the endothelium, oxidized LDL (OxLDL), C-reactive protein (CRP), and plaque (atherosclerotic) growth and stability.

A Brief Gallery of Cardiac Biomarkers

[F.sub.2]-lsoprostanes (IsoPs) are a measure of lipid peroxidation (whereby oxygen and other molecules render a fat damaged, rancid essentially) due to the metabolism of arachidonic acid, (an extremely common compound necessary for mediating basic bodily functions, such as building muscle tissue). In a number of clinical trials, this inexpensive marker that comes from a urine test can tell very precisely how much free radical activity is going on in the artery. (6) IsoPs have since become recognized as one of the most reliable biomarkers for lipid peroxidation and how it corresponds to disease. They've been linked to hypertension and tend to rise when other signs of inflammation rise. People whose hearts are aging and who take time to recover from states of lower oxygen (like during snow shoveling or running) have significantly elevated IsoPs. (7) Individuals with the highest IsoP levels have a thirty-fold increased risk for developing coronary heart disease (CHD). (8,9) An increase in IsoPs has been associated with increased intake of red meat, smoking, burnt foods and extreme (think marathon runner) exercise. (10) IsoPs not only indicate an increase in arterial oxidative stress, they also tighten up arteries and encourage blood clots. (6,7)

Oxidized LDL (OxLDL) measures LDL cholesterol that has been attacked and damaged by reactive oxygen species. OxLDL is the perfect weapon to damage the arteries, and it can kick off the vascular inflammation that will lead to long-term damage. It has been associated with an increased risk of atherosclerotic coronary heart disease, metabolic syndrome, cardiovascular disease, and worsening complications of diabetes mellitus. (6,11) Individuals who have increased levels of OxLDL are four times more likely to develop metabolic syndrome, the pre-diabetic condition that so many people suffer from; and in healthy middle-aged males, high OxLDL relates to a four times greater risk for developing coronary heart disease. It seems that the higher the OxLDL, the more severe the cardiovascular disease progression. (9,12)

C-reactive protein (CRP or hsCRP, named after the test method) is an acute phase protein released by the liver during inflammation and plays a major role in the innate human immune response; in other words, it is a natural event when the body is challenged. Thanks to decades of research it is well associated with heart disease because it gets released within diseased atherosclerotic arteries in smooth muscle cells and is an indicator for low-grade systemic inflammation. (13) Remember that inflammation is driving this damage, with many local events helping to keep the inflammation going. Elevated levels of hsCRP may indicate an increased risk for plaque growth in the arteries; and for someone who already has established coronary artery disease and angina pectoris (pain in the chest and elsewhere from bursts of low oxygen to the heart), a high hsCRP test spells trouble. It means they are in danger of near-term cardiovascular events, in other words, a myocardial infraction or ischemic stroke. (6) hsCRP has also been relevant in the use of primary prevention; future stroke, myocardial infarction, incident peripheral arterial disease, and cardiovascular death have been predicted independently by baseline hsCRP levels in two studies. (14,15) Many MD family practitioners, internists, and cardiologists are beginning to simply order this routinely. Naturopathic doctors are acutely interested in these kinds of early detection methods and have been including this in their patients' care for years. (9)

Urinary microalbumin measures very small amounts of albumin that leaks into the urine; albumin is the most common protein in the blood. In persons with an increased risk for cardiovascular events, such as those with hypertension or diabetes mellitus, microalbuminuria (the presence of very small amounts of this protein in the urine) is an established risk factor for cardiovascular disease and death, as well as end-stage renal disease. (16,17) This test shows vascular damage in the kidneys and essentially aging of the vascular system (the kidney has a large amount of blood vessel network), and microalbumin tests have been suggested as a marker for increased risk of all-cause and CVD mortality and elevated incidence of coronary heart disease events. (16,17) The higher the microalbumin level, the higher the risk for heart attack, stroke, and death. (9,16)

Myeloperoxidase (MPO) is secreted by white blood cells when arteries are under attack due to the inflammatory events that create atherosclerosis. Evidence suggests MPO may play a role in plaque vulnerability, an increased risk for cardiovascular disease, coronary heart disease, and possibly heart attack. (6,18) By plaque vulnerability we mean the risk for a plaque that is partially blocking an artery to grow weak and then suddenly rupture. That event, like all wounds, leads to a blood clot, which spells trouble for the heart. One study showed that MPO was literally found "at the scene of the crime" by being plentiful at plaque rupture sites in human atherosclerotic plaques taken from patients with sudden cardiac death. (19) In another study, patients who came to the hospital with heart symptoms but whose standard blood work didn't look too bad, had a greater risk for future cardiovascular events upon six-month follow-up due to MPO prediction. If someone has both a high MPO and hsCRP and they have proven plaques in their arteries, their chances of dying from this condition are significantly higher. (6) In spite of the fact that MPO can go up due to things like gum disease, it is still a specific marker of vascular inflammation and vulnerable plaque, erosions, or fissures. (9)

Lipoprotein associated phospholipase [A.sub.2] (Lp-PL[A.sub.2]) is an inflammatory enzyme that can turn a normal molecule in the body that comprises the cell membrane into two dangerous particles. For those with established CVD, Lp-PL[A.sub.2] can predict the risk of future adverse events. (6) In one study, both Lp-PL[A.sub.2] and CRP were independently and significantly associated with CHD in patients who had LDL cholesterol levels that seemed safe, below 130 mg/dL. (6) A separate study showed elevated Lp-PL[A.sub.2] levels were predictive for hard coronary events in a 14-year follow-up of middle-aged men who had elevated choleserol. (6) Lp-PL[A.sub.2] has also been suggested as an independent predictor of incident type 2 diabetes due to its positive association with insulin resistance among older adults. (9,20)

Relevance to Patients

The question remains, how relevant is this practice both for the naturopathic medicine field of the authors, and for medical practice in general? If the lifestyle measures that patients need to embark on are obvious, and the medical alternatives are clear, what is the need for these tests? The answer is fourfold:

1. The biomarkers can predict risk in the short-term and while still very important, the standard lipid panel speaks to long-term risk, even decades.

2. The biomarkers provide vastly more information about actual events than a standard lipid panel, including inflammation, endothelial dysfunction, changes to apoA on LDL particles, immune activation, and plaque progression and plaque instability; therefore, they can help us target what physiological processes are dysfunctional and what needs to be changed with plant extracts, nutritional therapy, and other intervention.

3. The biomarkers can be used for patient education; for instance, a young patient with high F2-isoprostanes can see that they have oxidative stress in their arteries, or a 13-year-old with dysfunctional HDL due to high myeloperoxidase can be shown to be at a significant risk for metabolic syndrome.

4. Of paramount importance, we can gauge if nutritional, herbal, lifestyle, and other approaches are working. Is there a change in inflammation? Is that patient's risk of a cardiac event actually decreasing? These questions can be given clear answers by the testing outlined in this article.

What can people do in general? Eating a diet with a high amount of plant foods, fiber, health fats like omega-3s, and very low amounts of damaged (think store-bought vegetable oil and deep fryer oil) polyunsaturated fats, trans fats, burnt foods, and sugars. Obtaining sufficient vitamin C (which a plant-based diet should provide and possibly with supplementation) is a good idea as the late and great Linus Pauling showed us with his research. Dark chocolate, preferable organic and ethically harvested, has been shown to lower the MPO enzyme mentioned above. We hope to share a heart and vascular system support protocol in future articles; but knowing your risk, beyond the basic lipid panel, is of the utmost importance for millions of people.

References

(1.) U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Health Statistics. Health, United States, 2016. DHHS Publication. May 2017; No. 2017-1232.

(2.) Ross R. Atherosclerosis - An inflammatory disease. N Engl J Med. 1999; 340:115-126.

(3.) Ikonomidis I, et al. Multimarker approach in cardiovascular risk prediction. Dis Markers. 2009; 26: 273-285.

(4.) Sachdeva A, et al. Lipid levels in patients hospitalized with coronary artery disease: An analysis of 136,905 hospitalizations in Get With The Guidelines. American Heart Journal. 2009; 157(1): 111-117.

(5.) Ridker PM, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. Yearbook of Vascular Surgery. 2008; 359: 2195-2207.

(6.) Tsimikas S, Willerson JT, Ridker PM. C-reactive protein and other emerging blood biomarkers to optimize risk stratification of vulnerable patients. Journal of the American College of Cardiology. 2006; 47(8): C19-C31.

(7.) Davies SS, Roberts LJ 2nd. F2-Isoprostanes as an indicator and risk factor for coronary heart disease. Free Radic Biol Med. 2011; 50: 559-566.

(8.) Schwedhelm E, et al. Urinary 8-iso-prostaglandin F2alpha as a risk marker in patients with coronary heart disease: a matched case-control study. Circulation. 2004 Feb 24; 109(7): 843-848.

(9.) Cleveland HeartLab. Test Menu. Available at: http://www.clevelandheartlab.com. Accessibility verified October 30, 2017.

(10.) Meyer KA, et al. Dietary patterns are associated with plasma F2-isoprostanes in an observational cohort study of adults. Free Radical Biology and Medicine. 2013; 57: 201-209.

(11.) Taleb A, Witztum JL, Tsimikas S. Oxidized phospholipids on apoB-100-containing lipoproteins: a biomarker predicting cardiovascular disease and cardiovascular events. Biomarkers in Medicine. 2011; 5(5): 673-694.

(12.) Holvoet P, Keyzer DD, Jacobs DRJ Jr. Oxidized LDL and the metabolic syndrome. Future Lipidology. 2008; 3(6): 637-649.

(13.) Du Clos TW. Function of C-reactive protein. Ann Med. 2000; 32(4): 274-278.

(14.) Ridker PM, Stampfer MJ, Rifai N. Novel risk factors for systemic atherosclerosis: a comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein(a), and standard cholesterol screening as predictors of peripheral arterial disease. JAMA 2001; 285: 2481-2485.

(15.) Ridker PM. Clinical application of C-reactive protein for cardiovascular disease detection and prevention. Circulation 2003; 107: 363-369.

(16.) Arnlov J. Low-grade albuminuria and incidence of cardiovascular disease events in nonhypertensive and nondiabetic individuals: the framingham heart study. Circulation. 2005; 112(7): 969-975.

(17.) Toyama T, et al. The impacts of albuminuria and low eGFR on the risk of cardiovascular death, all-cause mortality, and renal events in diabetic patients: meta-analysis. PLoS ONE. 2013; 8(8): e71810

(18.) Karakas M, et al. Myeloperoxidase is associated with incident coronary heart disease independently of traditional risk factors: results from the MONICA/KORA Augsburg study. Journal of Internal Medicine. 2011; 271(1): 43-50.

(19.) Sugiyama S, et al. Macrophage myeloperoxidase regulation by granulocyte macrophage colony-stimulating factor in human atherosclerosis and implications in acute coronary syndromes. Am J Pathol 2001; 158: 879-891.

(20.) Nelson TL, et al. Lipoprotein-associated phospholipase A2(Lp-PLA2) and future risk of type 2 diabetes: results from the cardiovascular Health study. The Journal of Clinical Endocrinology & Metabolism. 2012; 97(5): 1695-1701

by Fraser Smith, ND, and Jocelyn Faydenko

Jocelyn Faydenko is a fourth-year naturopathic and chiropractic medical student at the National University of Health Sciences (NUHS) in Lombard, Illinois. Her research interests involve cardiovascular disease as well as pharmacognosy (specifically medical ethnobotany) and how that can be implemented in the treatment of autoimmune conditions. Jocelyn currently works as an assistant to Dr. Fraser Smith for a pilot study investigating the use of inflammatory biomarker testing in determining cardiovascular health. She has been published in the Naturopathic Doctor News and Reviews and is taking an active role in helping NUHS create a naturopathic research agenda.

Dr. Fraser Smith is the assistant dean of naturopathic medicine and professor at NUHS in Lombard, Illinois. Prior to working at NUHS, he served as dean of naturopathic medicine at the Canadian College of Naturopathic Medicine (CCNM) in Toronto, Ontario. Dr. Smith is a licensed naturopathic physician (VT) and graduate of CCNM. He is author of the textbook Introduction to Principles and Practices of Naturopathic Medicine, and several books for the public with Robert Rose Publications such as Keep Your Brain Young: A Health and Diet Program for Your Brain, Including 150 Recipes.
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Author:Smith, Fraser; Faydenko, Jocelyn
Publication:Townsend Letter
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Geographic Code:1USA
Date:May 1, 2019
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