Risk Factors For Coronary Artery Disease (Part 2)

Novel Risk Factors

By: Samuel J. Stagg III, M.D., F.A.C.C., F.A.C.P.
Heart disease and stroke are the leading causes of death in the United States. We have already discussed the factors that are well known as causatives in vascular disease, but now we will look at what we call “the novel risk factors.” These are the ones that have come from continued research into this deadly disease, and most of them look at the level of “inflammation” inside the blood vessel as a principal etiologic factor.

As a reminder, the traditional risk factors that we are aware of and are exceedingly important in cardiovascular risk are:

  1. Family history
  2. Age
  3. Sex
  4. Race
  5. Hypertension
  6. High blood cholesterol
  7. Cigarette smoking
  8. Diabetes mellitus
  9. Obesity
  10. Lack of exercise
  11. Metabolic syndrome
  12. Mental stress and depression

Non-traditional or Novel Risk Factors1

Increased levels of any of these novel risk factors increase the risk of coronary artery disease:

  1. Homocysteine – Increased levels identify people at increased risk and may also indicate folic acid deficiency.
  2. ApoB – There is an ApoB molecule attached to every molecule containing LDL (low-density lipoprotein), IDL (intermediate-densitylipoprotein), VLDL (very low-density lipoprotein), bad cholesterol.
  3. PLAC®-Lp-PLA2 – Increased levels of Lp-PLA2 (lipoprotein-associated phospholipase A2) indicate increased risk of stroke in particular or impending cardiovascular event.
  4. Crp (C-reactive protein) – High levels are indicative of high levels of intravascular inflammation and increased cardiac risk.
  5. Lp(a) – Increased levels are indicative of increased cardiovascula
  6. Small dense LDL particles – Indicative of increased risk with increased levels.
  7. Fibrinogen – Indicative of increased vascular inflammation.
  8. Testosterone – Low levels indicative of increased cardiovascular risk in patients with coronary artery disease.
  9. Myeloperoxidase – Increased levels indicative of increase cardiovascular disease and events.
  10. Vitamin D – Nutritional deficiency associated with increased cardiovascular risk.



 Homocysteine is the byproduct of methionine metabolism. Increased levels have been shown to indicate increased risk of coronary artery disease. Folic acid replacement can help to lower levels but there is little data supportive of clinical benefit of folic acid treatment.


ApoB is a atherogenic lipoprotein attached to every VLDL-LDL-IDL (bad cholesterol) molecule, and levels above 79 indicate increased risk of coronary disease. Statins have been shown to decrease levels of this molecule.

PLAC®-Lp-PLA2 (Lipoprotein-associated phospholipase A2)

The PLAC test measures levels of Lp-PLA2, an enzyme in the blood produced inside plaque when the artery is inflamed, and the inflamed plaque is much more likely to rupture. Increased levels of Lp-PLA2 indicate an increased risk of myocardial infarction and stroke. Levels above 200 are worrisome.

Crp (C-reactive protein)

Crp is a blood-bound protein indicative of vascular inflammation. This inflammation is involved in plaque formation and in plaque instability and rupture. Plaque rupture is often the precipitating event in myocardial infarction (heart attack) and stroke. The JUPITER Trial showed that healthy people without elevated lipids but with an elevated Crp treated with the statin drug Rosuvastatin had a significant decrease in the risk of major cardiovascular events.2

Lp(a) (lipoprotein a)

People with increased levels of Lp(a) have an increased risk of myocardial infarction developing from coronary artery disease. There is currently, however, a lack of effective agents available for lowering Lp(a). Niacin (Vitamin B3) has shown some effect here.

Small dense LDL

LDL particle size has been shown to differentiate risk of cardiovascular disease. People with increased levels of small dense LDL particles have an increased risk of coronary disease compared to people with large “fluffy” LDL particles.


Fibrinogen levels in the blood increase during an inflammatory response. It mediates the final step in clot formation. Increased levels of fibrinogen have been shown to increase the risk of cardiovascular events.3

Low testosterone

Men with “low T” levels may have a worse prognosis if they have coronary disease.4 The study by Malkin showed an association between low testosterone levels in patients with coronary artery disease having increased cardiovascular events. The therapy and therapeutic benefits of replacing testosterone in patients with coronary disease is not confirmed at this point.


Myeloperoxidase is a peroxidase enzyme found in the human, often found in the white blood cell neutrophils. It has been found to be important in many inflammatory functions. Recent studies have reported an association between elevated levels of myeloperoxidase and the severity of coronary artery disease.6 There has also been an association found between elevated levels of myeloperoxidase and cardiovascular mortality rate.7

Vitamin D

Vitamin D deficiency has been associated with increased myocardial infarction (heart attack) and mortality7 There were studies published this year8 showing evidence that Vitamin D protects against major diseases. Adults with low levels of Vitamin D had a 35% increased risk of death from heart disease and a 14% increased risk of death from cancer. All-cause mortality was also increased in people with low levels of Vitamin D.

They also found supplementation with Vitamin D3 reduced all-cause mortality by 11%.



Almost all of these emerging markers or novel markers have a role in indicating the body’s level of intravascular inflammation. With abnormal levels, the person is not in a stable steady state, and he or she is at increased risk of cardiovascular events secondary to this heightened inflammatory state.

Check the levels of Crp, homocysteine, Lp(a), Lp-PLA2, ApoB, myeloperoxidase, LDL particle size, fibrinogen, testosterone, and Vitamin D can help assess one’s level of vascular inflammation and cardiovascular risk.

These should be used with your healthcare provider in some high-risk patients as part of a routine cardiovascular workup and in patient’s with minimal risk as add-on assessment where indicated.

These factors should all be used along with the conventional risk factors to fully assess one’s cardiovascular status.

Using the conventional as well as emerging cardiac risk factors is a way we as physicians can help make an early diagnosis as well as use them to guide treatment for vascular disease. As individual people, these are all ways that we can assess our own cardiovascular risk and help guide our own treatment to maintaining heart and vascular health.