While many of us know our cholesterol (including both good [HDL] and the bad [LDL] levels), I bet that very few can say the same about Lipoprotein(a), also known as “Lp(a)”, even though we’ve long known how dangerous high levels can be. In fact, my longstanding friend and colleague, Dr. Tom Pearson referred to Lp(a) as the “Heart Attack Maker” more than 30 years ago!
So why has Lp(a) been left out of the spotlight, especially when compared to LDL and other well-established promoters of cardiovascular disease? The simple answer is that until recently, we did not have powerful or effective Lp(a) lowering therapies. Secondly, and equally important is that we still don’t know whether lowering Lp(a) will translate into a reduced risk of a future heart attack or stroke. With more effective therapies available or in clinical trial testing, we should now, more than ever, know our Lp(a) level. Here’s why:
- Lp(a) increases risk of cardiovascular disease: One might consider Lp(a) as “the bad cholesterol” on steroids. That’s because Lp(a) consists of LDL plus the protein, apo(a), that is chemically similar to the clot buster, plasminogen. By binding to specific chemical (lysine) sites normally activated by plasminogen, apo(a) inhibits this process. As a result, blood clotting increases rather than decreases. In other words, Lp(a) not only promotes cholesterol plaque buildup in the coronary arteries (as mediated by LDL) but also sets up a blood clotting environment that is ripe for the so-called “coronary thrombosis”, a medical term for a heart attack composed of clotted blood that overlies a cholesterol plaque and obstructs blood flow in a coronary artery. A normal level of Lp(a) is less than 75 nmol/L (or 30 mg/dL). The 2018 Cholesterol Guidelines published by the American Heart Association/American College of Cardiology defines high risk levels as 125 nmol/L (50 mg/dL) and greater. The risk of heart attack, stroke and valve disease (aortic stenosis) increases 2-4 fold in those with very high compared to normal Lp(a) levels.
- Lp(a) increases the risk of premature heart disease: A group at particularly high risk of premature heart disease due to high Lp(a) are South Asians (ancestral origins from India, Pakistan, Bangladesh and Sri Lanka) where ~1 in 4 has levels exceeding 125 nmol/L and where the risk of heart attack or stroke is collectively higher than in European White populations. Similarly, Black Americans have ~2-4 fold higher Lp(a) levels than White Americans with elevated levels associated with an increased risk of cardiovascular disease. In some instances, high Lp(a) levels are only discovered after premature heart disease has set in. A case in point is a young patient I evaluated a number of years ago. She was in her 20s when she suffered a heart attack and had coronary bypass surgery. In my experience, women who have experienced a heart attack under the age of 40 have been heavy cigarette smokers (at least a pack a day), smoked cigarettes and used birth control pills, were drug users (cocaine), had extremely high LDL (see below) or had diabetes for at least 10 years. My patient had none of these risk factors. However, when we checked her Lp(a) levels, they were in the 500 nmole/L range- more than 4 times the normal range! (you can read about her case here)
- The combination of high Lp(a) and high LDL is very worrisome:While having a high Lp(a) or a high LDL cholesterol will each raise the risk of heart disease, the combination of high/high markedly accelerates risk. I evaluated a woman in her early 30s who came to see me after her brother, a college track star died suddenly. His autopsy revealed a near total occlusion of his left main coronary artery. While they both had elevated LDL (in the 200-300 mg/dL range), Lp(a) levels had never been assessed. As it turns out, her Lp(a) was also very high (~250 nmol/L). There are only a few conditions where severe coronary disease occurs in such a young person. With respect to cholesterol, genetic conditions include 1) homozygous familial hypercholesterolemia (FH) (LDL ~600-800 mg/dL) or extremely high Lp(a) [as our case illustrated above] and 2) heterozygous FH (LDL ~300-400 mg/dL) plus a 2nd risk factor (high Lp(a), smoking and diabetes). Needless to say, anyone with a family history of premature heart disease should have their Lp(a) levels assessed. The good news is that Lp(a) levels are relatively stable and in the absence of treatment (see below) do not change significantly over time.
- Lp(a) can be lowered by new treatments: What can you do to lower high Lp(a) levels? Although lifestyle therapy is the cornerstone in the prevention and management of heart disease, Lp(a) levels are stubbornly resilient to these measures. Even cholesterol lowering medications such as statins are ineffective for lowering an elevated Lp(a). However, the newer and powerful class of non-statin cholesterol lowering medications referred to as “PCSK9 inhibitors” can lower Lp(a) levels upwards of 30%. A highly effective method for lowering Lp(a) is through plasma exchange or “lipoprotein apheresis”. However, while a single session lowers Lp(a) levels ~50-75%, the process needs to be repeated ~every 2 weeks with a sizeable time commitment depending upon the location of the medical center conducting this procedure. The big question that remains is does lowering high levels of Lp(a) reduce cardiovascular events, such as heart attacks and strokes. Fortunately, a new (once monthly injectable) therapy will be studying this question. Known as “Lp(a) antisense therapy”, genetic material [single-stranded DNA antisense oligonucleotide binds to apo(a) mRNA) blocks production of the Lp(a) protein; the result is a dramatic reduction in Lp(a) levels upwards of 80%! An international clinical trial is currently underway to test whether lowering Lp(a) will indeed reduce risk of future cardiovascular events. You may qualify for the HORIZON study, if your Lp(a) level is at least 175 nmol/L (70 mg/dL) and have experienced a heart attack or stroke within the past 10 years. The University of Maryland School of Medicine is a site for this trial; if you are interested and live in/around the Baltimore region, contact us at 410 328-8790 to set up a screening visit.
Michael Miller, MD is Professor of Cardiovascular Medicine at the University of Maryland School of Medicine. Check out his HeartHealth Tip of the Day on Twitter @mmillermd1 and book “Heal Your Heart…” available online, at your library or bookstore.