Ancient Chinese philosophy defines two basic types of error: "Near-error," characterized by a myopic focus on what is closest at hand to the exclusion of the bigger picture and; "Far-error," an obsession with the horizon at the expense of what is in proximity.
In our efforts to deal with heart disease, we physicians have been guilty of both.
The near-error viewpoint is evidenced by our over-reliance on single biomarkers to predict risk status. Consider the following:
- Lipids: 50% of heart attacks and strokes occur in patients with normal cholesterol values. No longer can we provide reassurance to patients when their lipid values are "normal." (Ridker PM et al. N Engl J Med. 2002; 347: 1557-1565). Clinical emphasis on reducing cholesterol with statins may have the unintended effect of decreasing motivation to improve lifestyle. A recent study in JAMA showed that over a ten-year period, patients prescribed statins increased their caloric intake by nearly 10% and their fat intake by 14% as compared to statin non-users, who showed no such changes (Sugiyama T, et al, JAMA Intern Med, 2014)
- HsCRP: High-sensitivity C-reactive protein is involved in generalized inflammation and associated with atheroma and increased cardiovascular risk. However, there is no definitive evidence that it is a causative factor in atherothrombosis. (Yousuf O et al. J Am Coll Cardiol. 2013 Jul 30;62(5):397-408). Approximately 40% of the population has an elevated hsCRP, making it a poor stand-alone predictor of CVD risk.
- Homocysteine: While moderate homocysteine elevations are a strong predictor of CVD independent of other atherothrombotic risk factors, several large intervention trials with B vitamins showed no benefit from lowering homocysteine in high-risk patients (Smulders YM and Blom HJ. J Inherit Metab Dis. Feb 2011; 34(1): 93-99). Proponents for B vitamin therapy argue that the studies may have been underpowered or the subjects not followed long enough.
At any rate, it is clear that the "silver bullet" risk marker is more a myth than a reality.
On the other side, the far-error is rooted in erroneous pragmatism and the mindset that, "These tests don't really matter. Inflammation is inflammation. I can assume that all my at-risk patients have it—and put them on statins, low-dose aspirin, a low-inflammation diet, and inflammation-regulating supplements. Why spend the time/money on tests? Why does it make sense to quantify the inflammation process?"
While there are grains of truth in both approaches, the "middle way" clearly has the greatest advantages. In the context of CVD prevention, this middle way is found in a multi-marker risk assessment comprised of urine and blood tests. Taking a multi-marker approach offers the following advantages:
• Reassurance that you have not overlooked one of the less obvious causes of inflammation.
• Identification of those patients at more emergent near-term risk, often due to the presence of vulnerable arterial plaque; these patients require much closer monitoring and/or referral to specialists.
• Ability to monitor and adjust your therapy over time and identify non-adherence.
• Positive feedback and reinforcement for the patient engaged in a lifestyle approach and/or therapeutic regimen.
A multi-marker approach also takes into account the multi-factorial nature of vascular disease.
In 1976, Russell Ross, PhD, at the University of Washington, published a sentinel paper entitled, "The Pathogenesis of Atherosclerosis," that clearly outlined two components of thrombotic disease: an injury and a response to that injury (Ross R and Glomset JA. N Engl J Med. 295: 369-377 and 420-425).
Inflammation, the response to the injury, is the real culprit.
Oxidized LDL is but one of many independent factors that can damage the body's 60,000 miles of blood vessels. Others include dental bacteria, smoking, sleep apnea, insulin resistance and stress.
The latter is a biggie. Stress-related activation of the sympathetic nervous system, the hypothalamic-pituitary axis, and the renin-angiotensin system increases catecholamines, corticosteroids, glucagon, growth hormone, renin, and homocysteine. By some estimates, stress may account for the approximately 40% of atherosclerosis cases in people with no other known risk factors. (Black, PH & Garbutt LD. J Psychosom Res. 2002 Jan;52(1):1-23.)
Advanced Biomarkers for Inflammation
A comprehensive, multi-marker array of inflammation measures is now available from Cleveland HeartLab (CHL), a CLIA-certified, CAP-accredited national clinical reference laboratory that serves thousands of the most sophisticated prevention-oriented clinicians in the United States.
While offering traditional laboratory panels, CHL specializes in advanced cardiovascular and inflammatory biomarkers; some of these tests have been licensed exclusively from the Cleveland Clinic. CHL's Inflammation Testing panel allows practitioners to assess CVD along a severity and time-phased continuum that includes:
• Oxidative damage and risk of disease (long-term)
• Presence of disease (mid-term risk)
• Activity of disease (near-term risk)
Gauging the Cardiovascular "Heat"
"Inflammation testing is a critical part of managing cardiovascular risk. We have evidence that inflammation is the cause of atherothrombotic disease from inception, through progression, to culmination in a cardiovascular event," says Bradley Bale, MD, co-founder of the Bale-Doneen method, and medical director of the heart health program at Grace Clinic, Lubbock, TX. "The Bale-Doreen method rests upon maintaining the arteries in a non-inflamed state, so we routinely monitor our at-risk patients every three months."
Along with co-author Amy Doneen, Dr. Bale is the author of Beat the Heart Attack Gene: A Revolutionary Plan to Prevent Heart Disease, Stroke, and Diabetes. The book outlines his approach to treating arterial disease.
Dr. Bale routinely uses the inflammation panel to gauge the "heat" of the arteries. He routinely evaluates F2-Isoprostanes (F2-IsoPs), a biomarker formed from arachidonic acid that is considered the "gold standard" for assessing oxidative stress as it relates to lifestyle choices.
The more oxidized a patient is, the higher the F2-IsoPs, and the more likely they are to form clots. Elevated urinary F2-IsoPs levels are associated with a high intake of red meat, lack of exercise, poor sleep and smoking. (Morrow JD et al. N Engl J Med. 1995; 332: 1198-1203; Tappel A. Med Hypotheses. 2007; 68: 562-564; Shi M et al. Prev Med. 2007; 12: 202-208.). The good news is that isoprostane can be lowered through lifestyle improvements.
Dr. Bale routinely uses the F2-IsoPs marker to track compliance with lifestyle change. "When asked how they are doing on their program, many patients reflexively answer 'fine.' When their F2-IsoPs come back high and we confront them with this, we get a more accurate history. I've had one patient remark, 'I can't get away with anything with you'".
OxLDL, another component in CHL's IT panel, measures the amount of LDL oxidation, an early warning sign of vessel damage. High OxLDL levels predict metabolic syndrome and are closely associated with risk of heart disease in seemingly healthy individuals (Holvoet P et al. JAMA. 2008; 299: 2287-2293. Holvoet P et al. Arterioscler Thromb Vasc Biol. 2001; 21: 844-848.)
Dr. Bale utilizes three additional tests to assess endothelial function: hsCRP and fibrinogen, along with the microalbumin/creatinine ratio.
Regarding the latter, he cites the Framingham study. "We know from these data that the microalbumin/creatine ratio was an independent predictor of heart attack. Most conventional labs put the cut off point at a value of 30, which is the point of end stage renal disease. When the ratio was above 4 in men and above 7.5 in women, the risk of a cardiovascular event in the next six years was three times greater."
Going to the (Arterial) Wall
In his work with at risk patients, Dr. Bale uses two tests that specifically assess inflammation in the arterial walls. Lipoprotein-associated phospholipase-A2 (Lp-PLA2; AKA "the PLAC® Test") is a vascular-specific inflammatory enzyme that binds to LDL cholesterol and releases a chemical inside the artery wall.
The PLAC® test measures vessel wall inflammation beneath the collagen cap. Recent data indicate that Lp-PLA2 is not just a marker in the wall, but also a factor in the disease process itself. (Serruys PW et al. Circulation. 2008; 118: 1172-1182.)
Myeloperoxidase (MPO) identifies the body's inflammatory response to vascular damage due to vulnerable plaque, cellular erosions, and cracks in the artery wall. Because it is a marker of plaque instability MPO is an indicator of near-term risk. It is also important for predicting risk in apparently healthy people who may not otherwise have been identified with conventional tests (Meuwese MC et al. J Am Coll Cardiol. 2007; 50: 159-165).
Serial management of inflammatory biomarkers is critical for optimal management of the at-risk cardiovascular patient.
According to Dr. Bale, "Numerous pathologies can cause arterial inflammation and some can be occult in nature. We use these markers to follow the patient with known arterial disease to make sure nothing is rekindling. This happens more frequently than we'd like."
He points to the prevalence of occult dental infection, either periodontal disease or dental caries. Both are strongly linked to vessel inflammation. Dr. Bale reminds clinicians that periodontal disease is the most chronic disease in the world. "By age 30, half of all people have evidence of periodontitis. At age 65, the incidence of periodontal disease climbs to 70%. Bacteria and bacterial DNA have been found in arterial plaque."
Validating the Multi-Marker Approach
The value of the multi-marker approach was recently validated in a large-scale study by Marc Penn MD, PhD, FACC, Chief Medical Officer of Cleveland HeartLab, and Andrea Klemes, DO, Chief Medical Officer of MDVIP.
The study compared the multi-marker approach with conventional lipid screening for identification of hidden risk in a large cohort of otherwise healthy people. Based on a lipid-only panel, approximately 30% of patients were deemed "at risk" for CVD. Based on a multi-marker panel, 70% of patients were found to be at risk, with 40% having more than one elevated risk marker."
"The addition of vascular specific markers, Lp-PLA2 and MPO, can help identify the patients we need to be worried about and for whom a near-term event might be more likely," said Dr. Penn.
The Lynchpin of CVD
Inflammation is the lynchpin of CVD, and the key to reducing risk, according to Mimi Guarneri, MD, formerly director of the Scripps Center for Integrative Medicine, and currently senior advisor at the Atlantic Health Center for Well Being, Morristown, NJ.
"Inflammation is linked to diet, food sensitivities, obesity, toxins and other injurious agents. It is a final common pathway for disease. With regard to markers, we know that hsCRP is the tip of the iceberg in that it is a non- specific inflammatory marker. Other markers such as MPO, Lppla2, TNF, IL6, IL18, and others also reflect levels of inflammation."
She added that it is very important to take into account individual variations when assessing inflammation and CVD risk. "We also need to be increasingly aware of the emerging role of genomics in personalized medicine. For example, the MTHFR SNP is most likely a better predictor of who needs B vitamins and activated forms of methyl folate. This is not looked at in most studies."
Dr. Guarneri believes markers of inflammation have an important role to play in validating the impact of holistic therapeutic approaches. "A growing body of evidence is accumulating documenting the efficacy of techniques such as meditation, yoga, the practice of gratitude and forgiveness, and mindfulness."