A Multi-Marker Approach to Identify Coronary Artery Disease

JANUARY 17, 2019
Simon Murray, MD
Simon Murray, MDCoronary artery disease is generally caused by atherosclerosis, a process of thickening of the artery wall due a buildup of plaque consisting of cholesterol, fatty substances, cellular waste products, calcium, and fibrin (a clotting material in the blood). The process generally slowly progresses and can eventually lead to coronary artery disease, stroke, and peripheral artery disease.

Since the 1960s, the rate of death due to coronary artery disease has dropped about 50%, but recently has begun to rise slowly. We have done well at identifying and treating many of those at risk, but we have missed half of the at-risk population, many of whom may be treatable. In recent years scientists have identified new ways to evaluate patients who are asymptomatic in addition to the traditional risk factors. The hope is that by looking at new and innovative tools, more lives can be saved, since coronary artery disease still remains the number one killer of Americans.

Through our understanding of the pathogenesis of atherosclerosis we have developed tools to evaluate patients who may be at risk at an earlier stage than we were previously able to do. Using a multi-marker approach, we can better stratify cardiovascular risk.

High-sensitivity C Reactive Protein

The Jupiter trial was the first major trial to incorporate a multi-marker approach to identify and stratify individuals at risk, using inflammatory markers as well as LDL cholesterol. This trial used high-sensitivity C-reactive protein (hsCRP) combined with LDL cholesterol to decide who to treat with the cholesterol-lowering drug Rosuvastatin. The study used an inexpensive marker for inflammation—hsCRP—to stratify risk.

Several other large studies, including the Physician’s Health Study and the Women’s Health Initiative, established that hsCRP was a better predictor for coronary disease than LDL cholesterol. Patients with elevated hsCRP are 4 times more likely to have CAD than those with elevated LDL cholesterol.


Myeloperoxidase (MPO) is a white cell derived inflammatory enzyme that measures disease from the luminal aspect of the artery. Elevated MPO predicts future risk in individuals otherwise considered low-risk. It is a specific marker for vascular inflammation, so not likely to be influenced by inflammation caused by rheumatologic conditions. Elevated MPO doubles a patients’ risk for coronary artery disease.

LDL & HDL Cholesterol

Lipoprotein measurements are the gold standard when evaluating the effects of serum cholesterol on vascular health. For years treatments targeted LDL concentration. Then it was thought that LDL size was more predictive than concentration. Now, we believe that LDL particle number is actually the driver of LDL damage to blood vessels.

There is a cohort of patients from the Framingham heart study with very high LDL who lived well into their nineties because they had low particle number. Initially this was felt to be due to LDL particle size, since it appeared logical that large LDL would have a more difficult time passing through the endothelial wall. Actually, the difference in size between large and small LDL is nonconsequential and many large LDL particles are just as dangerous as lots of small LDL particles. We now think it is the gradient of LDL particles that is the principal driver of LDL penetration into arteries.
HDL, the second major lipoprotein, was once believed to be protective against coronary artery disease. Four large drug trials using medications to raise HDL all failed to show any meaningful outcome benefit. One study published in The Lancet used a database of genetic information to find that patients who were genetically prone to have high HDL had no less risk than those who didn’t have the genetic predisposition. They actually reported that patients with lower HDL as well as low LDL were at lower risk. It is theorized that HDL develops proinflammatory properties when exposed to dietary intake of saturated fat and thus become harmful. HDL also transfers cholesterol to LDL lipoproteins rather than eliminating it through the liver in certain cases.

Lipoprotein(a)—or Lp(a)—is a type of LDL which is genetically determined and is known to be associated with increased risk for coronary disease. Even though it can’t be modified, it can be measured to help assess risk. Lp(a) is widely available and should be done at least once in the assessment of cardiac risk.
An ideal LDL particle number for most patients is less than 1000. For those with heart disease, less than 850 is ideal. Particle number doesn’t always correlate with LDL concentration. In the presence of insulin resistance there will often be a marked discordance between the concentration and number of LDL particles. Statins will reduce LDL particle number in most patients but may not be enough to reduce them in insulin resistant patients. In those cases, treating the insulin resistance reduces particle numbers.

Insulin Resistance

Insulin resistance is a major player in driving atherosclerosis and knowing about it can help assess risk at an early stage. Insulin levels measured several times over a period of weeks can predict insulin resistance. HgA1c and fasting glucose levels that are minimally elevated
indicate insulin resistance.

Cleveland Heart Lab has compiled a risk score for insulin resistance using 6 of the lipoprotein tests they routinely perform to come up with a risk score called the LPIR score. High scores predict insulin resistance and can even predict the future risk of developing diabetes. Other markers for insulin resistance are having large sized VLDL particles, and elevated triglycerides.

TAMO is a protein made by gut bacteria and predicts insulin resistance. High levels should prompt a provider to recommend dietary changes to reduce insulin resistance. That would include following a low carbohydrate diet, avoidance of white carbohydrates (especially white sugar, flour, pasta, bread, and rice), reducing calories, and increasing exercise.

Carotid Intimal Thickness

Measurement of carotid intimal thickness can predict the health of arteries long before the lumen of the artery is blocked. The test can measure how much plaque exists in the artery wall, and whether or not that plaque is vulnerable to rupture. The test can show changes to the artery wall long before traditional ultrasound demonstrates luminal narrowing and velocity changes.

These changes occur relatively late in the course of the illness when it is more likely advanced. Carotid artery intimal thickness is a well-recognized measure of risk, is inexpensive and noninvasive.

Other Red Flags

Lastly, knowing some simple red flags can alert us to the possibility that a patient may be at risk for vascular disease. Some of these include vertical ear lobe creases, hyperuricemia and gout, gallstones, kidney stones, rheumatoid arthritis, psoriasis, and many other inflammatory disorders. These are not cause and effect but rather are proven associations and can prompt us to look for atherosclerotic disease in otherwise asymptomatic patients. In doing so we may be able to reach some of the millions of patients who now die prematurely of coronary artery disease.
Simon Murray, MD, is an internist based in Princeton, NJ. The piece reflects his views, not necessarily those of the publication.

Healthcare professionals and researchers interested in responding to this piece or contributing to MD Magazine® can reach the editorial staff here.

Related Coverage >>>
Copyright© MD Magazine 2006-2018 Intellisphere, LLC. All Rights Reserved.