In medical school nearly 40 years ago I was taught that heart disease is mainly due to smoking, hypertension, diabetes, cholesterol disorders, and a family history of early heart events (Framingham risk factors). Most patients are still evaluated by obtaining information regarding these 5 factors. Missing from this approach are major advances in understanding the development of coronary artery disease (CAD).
What is Lipoprotein(a) Cholesterol?
One of the most important advances is the recognition that a type of lipid (cholesterol) particle that is inherited on a genetic basis is both common and causes a large number of tragic cardiac events, even deaths. This particle is called Lipoprotein(a) or Lp(a) and can be easily measured in a blood sample at most laboratories. A recent case at the Kahn Center for Cardiac Longevity was striking for the role of Lp(a) in causing early and severe CAD.
Case Study
In 2009, a 34-year old man with no known cardiac disease began training for a half-marathon running event. He had no known heart disease, never smoked, was on no medications, and did not have a history of premature CAD. He developed jaw pain while training and scheduled a medical evaluation leading to a stress test. Due to abnormalities found on the treadmill test, he had a coronary angiogram showing a severe narrowing in his left main coronary artery (LMCA), the largest artery to the heart. After various opinions, he was treated with a single coronary stent. He had complete resolution of his exertional jaw pain and has never required additional invasive procedures or hospitalizations. He was maintained on cholesterol lowering therapy after his procedure along with aspirin.
When seen at my clinic in 2020, he brought older laboratory testing that identified that his Lp(a) level in 2014 was severely elevated at 431 nmol/L, with a normal of <75 nmol/L. In 2019 his total cholesterol was 152 mg/dl, HDL 35, LDL 85 and triglycerides were 153. He never had been diagnosed with hypertension or diabetes. He was maintained on rosuvastatin 20 mg, ezetimibe 10 mg, fenofibrate 140 mg, aspirin 81 mg, and clopidogrel 75 mg daily since his stent.
A recent laboratory evaluation in 2020 revealed a HgbA1C of 5.3%, normal liver and thyroid studies, a total cholesterol of 132 mg/dl, triglycerides of 185, HDL cholesterol of 42, apoB of 92, a hs-CRP of 1.0, and a Lp(a) level of 539 nmol/L.
Currently he has switched his fenofibrate to prescription omega-3, is scheduled for a stress echocardiogram, has adopted a whole-food plant diet, and has been referred to the HORIZON study of an investigational pharmacologic agent to lower Lp(a).
Discussion
It is rare to identify advanced coronary artery disease in someone in their mid 30’s, particularly a severe lesion of the LMCA. Fortunately, the stent he received has performed well for a decade even though it was a novel therapy at the time. In the absence of a smoking habit, diabetes mellitus, and hypertension, abnormalities of cholesterol are the most likely cause of his premature CAD. Although his cholesterol panel did identify a low HDL cholesterol and mildly elevated triglycerides, the most striking finding was the extreme elevation of Lp(a), one of the highest I have encountered.
Why does Lipoprotein(a) cholesterol matter?
Lp(a) is a complex cholesterol molecule whose presence in the blood is determined by genetic inheritance. Lp(a) is composed of an LDL-cholesterol particle, a sulfur bridge, and another particle called apolipoprotein(a). In the approximate 25% of individuals that inherit Lp(a), levels in the blood will reach a plateau at around age two and remain high through adulthood. It is the most common inherited risk for developing premature cardiovascular disease. Many studies have acknowledged the importance of elevated levels of Lp(a) since its identification by Norwegian researchers in 1963. According to a National Heart, Lung, and Blood Institute report published in 2018, an estimated 1.4 billion people globally have elevated Lp(a) levels.
What Diseases can Lipoprotein(a) Cholesterol Cause?
Lp(a) can cause several types of coronary heart disease, such as heart attack, stroke, peripheral arterial disease, aortic valve disease, and heart failure. Certainly, the risk of heart disease from elevated Lp(a) will be even higher in the presence of smoking, hypertension, and type 2 diabetes.
As one example, the Canadian-led INTERHEART study of 2004 found that people with high Lp(a) levels had a risk of heart attacks that was about 1.5 times greater than for people with lower Lp(a) levels even after factoring in other known risk factors. A study that combined research done from 1970 through 2009 showed that the rates of heart disease in people whose Lp(a) values were in the top third of those measured were 5.6 times higher than those in people with levels in the lowest third. Another analysis published in 2019 indicated that elevated Lp(a) levels were independently associated with an increased risk of overall cardiac events in heart disease patients. The researchers concluded that measurement of the lipoprotein(a) level has the potential to help people with heart disease—and their health-care providers—determine their level of risk.
How Do You Measure Lipoprotein(a) Cholesterol?
Although measurement of Lp(a) is widely available, it is not yet considered a routine lab test in most clinics in the USA. In my preventive clinic, levels of Lp(a) have been drawn routinely for over a decade and encompass thousands of patients. In 2019 the European Society of Cardiology recommended drawing a level of Lp(a) once in a person’s lifetime. Furthermore, a clinical trial of a novel pharmacological therapy that requires injection is currently randomizing over 7,500 patients and the results are anticipated in 4-5 years.
This Case of Lipoprotein(a) Cholesterol in Perspective
This dramatic case study of a patient recently seen emphasizes the importance of Lp(a) to cause CAD even at an early age. Strategies to lower it need to be proven for safety, efficacy and reduction of clinical events. Until then, checking Lp(a) levels in patients with CAD and aortic valve disease is recommended. The approach recommended of checking the level of Lp(a) at least once in a person’s lifetime will be more pressing when a definitive therapy is available. More information on Lp(a) is available in my new book.
