An overlooked but important cardiovascular risk factor

By Naveed Saleh, MD, MS
Published November 1, 2021

Key Takeaways

When it comes to cardiovascular risk factors, research has left little doubt that elevated lipoprotein(a), or Lp(a), is an important biomarker for adverse outcomes in heart disease. Yet, its exact physiological role is poorly understood, and challenges exist with regard to screening, diagnosis, and management.

But now, experts are recommending screening for this risk factor—even with a paucity of randomized controlled data—citing growing evidence that lowering Lp(a) levels can decrease the risk of cardiovascular symptoms and improve symptoms.

Here’s a closer look at this underappreciated—and not routinely tested—biomarker of cardiovascular disease.

What is it?

Lp(a) is a low-density lipoprotein (LDL)-like particle produced by the liver that transports cholesterol in the blood, and remains high in patients who experienced cardiovascular events regardless of optimal lipid management.

The plasma lipoprotein Lp(a) is genetically determined and composed of a cholesterol-rich LDL particle with one molecule of apolipoprotein B100 and an additional protein, apolipoprotein(a), attached by means of a disulfide bond. It is proatherogenic and prothrombotic by means of numerous mechanisms. Ultimately, Lp(a) harbors atherothrombotic traits of apoB, which are derived from LDL, and apoA, which involve thrombo-inflammatory aspects.

Lp(a) levels are usually tested via immunoassays with polyclonal antibodies against apoA. These assays vary greatly, however, which can be confusing for researchers and clinicians. Intriguingly, research has demonstrated that variations in apolipoprotein(a) [apo(a)] size affect the outcome of the immunochemical methods that are used to measure Lp(a). Moreover, inaccuracy of Lp(a) values via methods influenced by apo(a) size compromise the determination of individual risk status for coronary artery disease, according to the authors of a review published in Global Cardiology & Science Practice.

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Clinical significance

The authors of the aforementioned review stated that the results of “large epidemiological studies have erased any doubt that elevated Lp(a) represents a significant independent cardiovascular risk factor.” 

The relative risk of coronary heart disease per 3.5-fold higher Lp(a) level increment was 1.16 and 1.13 for age and sex, respectively, after compensating for systolic blood pressure, smoking, history of diabetes, and total cholesterol. These findings indicate that the association between Lp(a) and coronary heart disease was only minimally confounded by conventional risk factors.

The authors also presented results from a prospective study that showed the association between Lp(a) levels and coronary heart disease did not rely on other cardiovascular disease risk factors such as LDL levels. Levels of Lp(a) were related to future peripheral artery disease and coronary artery disease.

In a review published in the Circulation Journal, the authors noted that Mendelian randomization studies have demonstrated that Lp(a) concentrations are causal for different types of heart disease, including coronary artery disease, calcified aortic valve disease, stroke, and heart failure. The causality persists regardless of optimal LDL cholesterol.


According to the authors of the aforementioned review, statin, niacin, and cholesterol transfer protein have not been shown to reduce Lp(a) levels. Proprotein convertase subtilisin-kexin type 9 inhibitors (PCSK9 inhibitors) or antisense oligonucleotide technology may be able to effectively lower Lp(a), according to emerging research. Although cumbersome and costly, lipoprotein apheresis has been shown to decrease levels of Lp(a) by 60%-75%, “and is increasingly recognized as the gold standard of treatment for elevated Lp(a)."

Who should be screened?

“One may argue that we should only screen for a condition if we are prepared to treat it and certainly challenges remain in terms of available therapies for raised Lp(a),” according to the authors of the review in Global Cardiology & Science Practice. 

Despite such reservations, the authors go on to cite guidance recommending testing for Lp(a) in the patient populations with premature CVD, a family history of premature CVD with or without elevated Lp(a), and recurrent CVD regardless of statin treatment, among other risk factors.

The US National Library of Medicine added that individuals with heart disease despite normal results on other lipid tests receive screening for Lp(a), as well as those with high cholesterol despite a healthy diet. In patients with high levels, eating a healthy diet, weight control, smoking cessation, decreasing blood pressure/LDL cholesterol, reducing stress, and exercising more may be options.

Bottom line

Although no great options for lowering Lp(a) levels currently exist—with emerging treatments on the horizon—this biomarker should likely be tested for in populations at high risk for heart disease. In these patients, lifestyle modifications and medication management for blood pressure and LDL cholesterol could be prudent.

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