An Important New Test – Beyond Routine Cholesterol Testing

By Paul E. Lemanski, MD, MS, FACP

Editor’s Note: This is the 107th in a series on optimal diet and lifestyle to help prevent and treat disease. Any planned change in diet, exercise or treatment should be discussed with and approved by your personal physician before implementation. The help of a registered dietitian in the implementation of dietary changes is strongly recommended.

Medicines are a mainstay of American life and the healthcare system not only because they are perceived to work by the individuals taking them, but also because their benefit may be shown by the objective assessment of scientific study. Clinical research trials have shown that some of the medicines of Western science may reduce the risk of heart attacks, strokes and cardiovascular death.

In the first 106 installments of the Non-Medicated Life, certain dietary practices and a healthy lifestyle have been shown to accomplish naturally for the majority of individuals most of the benefits of medications in the prevention and treatment of chronic medical conditions such as hypertension, high cholesterol, pre-diabetes, and diabetes that increase the risk for cardiovascular disease and death. High levels of cholesterol increase risk and, specifically, the higher the “bad” cholesterol or LDL the higher the risk, and the lower the LDL the lower the risk. Moreover, lowering LDL cholesterol by dietary change and medications will lower risk for cardiovascular disease. However, there are sub-populations of patients whose risk may not be adequately defined by LDL cholesterol alone. One such population are those with an elevation of a marker called Lp little a, or Lp(a). Moreover, knowing if your Lp(a) is elevated may alter strategy for risk reduction, as it appears to be an independent risk factor that lifestyle change and some medications do not appear to effect.

Lp(a) is a lipoprotein with a unique structure. Lp(a) is made up, in part, of a protein (apo a) with an amino acid sequence identical to plasminogen. Plasminogen is a protein the body uses to dissolve blood clots. Clotting of blood is required to prevent bleeding to death from wounds and the prevention of uncontrolled bleeding into tissues with even minor trauma. However, to have blood only possess the ability to clot would put us at risk for the cessation of blood flow to tissues and the risk of death of that tissue. Thus, the ability to break up or “lyse” clots is equally important to normal tissue function. Normally there is a fine balance maintained between clot formation and clot lysis. Plasminogen is intimately involved in clot lysis and thus the process of maintaining such a balance.

The other part of Lp(a) is an LDL particle. Low Density Lipoprotein or LDL exist in the blood stream as spherical particles of various sizes. They are made up of cholesterol, cholesterol ester, and triglycerides, (collectively making up the fat portion of LDL) and protein ( Apo B) that serves as a scaffolding for the fat portion and the means by which the body may identify the particle. When found in excess, LDL in the blood may penetrate the walls of arteries to form a plaque that is the necessary precondition for a heart attack to occur. For Lp(a) an LDL particle is chemically bonded to apo a. 

However, in Lp(a), this amino acid sequence identical to plasminogen is non-functional, meaning it does not lyse clots. In fact, because it is what is called a competitive inhibitor of plasminogen, Lp(a) may increase the tendency to clot. It, literally, may get in the way of active plasminogen and prevent some element of clot lysis from occurring. There is also evidence that Lp(a) binds to white blood cells called macrophages that may lead to increased intracellular accumulation of LDL cholesterol within macrophages with adverse consequences on plaque structure, as described below.

What does this mean for cardiovascular risk? The mechanism of a heart attack is a plaque disruption. A short digression is necessary to understand this mechanism and how elevated Lp(a) increases risk. Plaque accumulates in the artery wall one cell layer beneath the blood flow. This overlying cell layer is made up of plate-like cells called endothelial cells. Envision a pipe, the inner aspect of which is lined by octagonal bathroom tile. In this analogy, the pipe wall is the artery wall and the tile represent the endothelial cells. These endothelial cells abut one another separated by a thin “grout” line. This junction between endothelial cells may be one point of entry of LDL to the space beneath. When plaque forms in an artery, it forms just beneath the endothelial cells. Over time with continued deposition of LDL the plaque may grow in size, so as to push the overlying endothelial cell layer out, partially obstructing the blood flow above the plaque.

Plaque disruption occurs in a series of steps. First the LDL in the plaque is oxidized (ox-LDL). The ox-LDL then is recognized as non-self and is attacked by the immune system. The type of white blood cells called macrophages are the body’s sentries to find and kill invading organisms like bacteria. If a bacterium were to gain entrance to the arterial wall macrophages would enter the wall and engulf (eat) the bacterium and then digestive enzymes within the macrophage would destroy it. Ox-LDL within plaque is treated in a similar manner, with the macrophage engulfing the ox-LDL and trying to digest it. Unfortunately, the enzymatic machinery that will digest bacteria does not work on ox-LDL. 

Consequently, in step two of plaque disruption, the macrophage continues to engulf ox-LDL until the macrophage literally bursts and releases its enzymatic machinery – elastase and collagenase – into the plaque. Once there, these enzymes digest the physical connection between the plaque and arterial wall, undermining the physical integrity of the plaque/artery connection. 

Finally, in step three, the force of red blood cells flowing down the artery (pushing on the plaque before going over it) results in a shear force that along with the physical weakening of the plaque, may cause a small tear in the wall of the artery. A blood clot then forms on the surface of the plaque to plug what the body perceives as a hole in the wall. If the clot is large, it can completely obstruct the flow of blood above the plaque, cutting off oxygen and nutrients and resulting in the death of tissue downstream from the plaque. If this occurs in the heart it is a heart attack, in the brain it is a stroke.

If Lp(a) inhibits the bodies clot lysis system, and increases the risk that plaque disruption by a tear in the artery wall will result in a large artery obstructing clot, then elevated Lp(a) may result in increased risk for heart attack and stroke, independent of LDL cholesterol level. Moreover, neither lifestyle nor most cholesterol medications reduce Lp(a). While both niacin and a group of injectable cholesterol lowering drugs called PCSK9 inhibitors do reduce Lp(a) up to 25%, it is not clear at the present time that such reductions will reduce the rate of heart attacks and strokes. 

While waiting for the results of clinical trial, most experts suggest for those at risk using a low saturated fat diet and medications to maximally reduce the LDL cholesterol to less than 50 mg/dl. In this regard, measurement of Lp(a) is an important first step in refining an assessment of an individual’s cardiovascular risk and suggesting a strategy for risk reduction.

Paul E. Lemanski, MD, MS, FACP (plemanski3@gmail.com) is a board-certified internist practicing internal medicine and lifestyle medicine in Albany. Paul has a master’s degree in human nutrition, he’s an assistant clinical professor of medicine at Albany Medical College, and a fellow of the American College of Physicians.