Lipoprotein(a) Elevation: A New Diagnostic Code with Relevance to Service Members and Veterans

CVD Risk Predictive Value

There are a large number of studies demonstrating that Lp(a) elevations are an independent predictor of adverse cardiovascular outcomes including MI, sudden death, strokes, calcific aortic valve stenosis and peripheral vascular disease (Table 3). The Copenhagen City Heart Study and Copenhagen General Population Study are well known prospective population- based cohort studies that track outcomes through national patient registries. ⁹⁵ These studies demonstrate increased risk for MI, CHD, CAVS, and heart failure when subjects with very high Lp(a) levels (50-115 mg/dL) are compared with subjects with very low Lp(a) levels (< 5 mg/dL). ^96-100 Subjects with less extreme Lp(a) elevations (> 30 mg/dL) also show increased risk of CVD when they have comorbid LDLC elevations. ¹⁰¹ However, the Copenhagen studies are composed exclusively of white subjects and the effects of Lp(a) are known to vary with race or ethnicity.

The Multi-Ethnic Study of Atherosclerosis (MESA) recruited an ethnically diverse sample of > 6,000 Americans, aged 45 to 84 years, without CVD, into an ongoing prospective cohort study. Research using subjects from this study has found consistently increased risk of CHD, heart failure, subclinical aortic valve calcification, and more severe CAVS in white subjects with elevated Lp(a). ^60,102,103 Black subjects with elevated Lp(a) had increased risk of CHD and more severe CAVS and Hispanic subjects with Lp(a) elevation were at higher risk for CHD. ^60,102 So far, no studies of MESA subjects have identified a relationship between Lp(a) elevation and CVD events for Asian-Americans subjects (predominantly of Chinese descent). There is a need for ongoing research to more precisely define relevant cut-off levels by race, ethnicity and sex.

The Atherosclerosis Risk in Communities (ARIC) Study was a prospective multiethnic cohort study including > 15,000 US adults, aged 45 to 64 years. ¹⁰³ Lp(a) elevations in this cohort were associated with greater risks for first CVD events, heart failure, and recurrent CVD events. ^61,64,105 The risk of stroke for subjects with elevated Lp(a) was greater for black and white women, and for black men. ^61,106 However, a meta-analysis of case-control studies showed increased ischemic stroke risk in both men and women with elevated Lp(a). ⁵⁷

A recent European meta-analysis collected blood samples and outcome data from > 50,000 subjects in 7 prospective cohort studies. Using a central laboratory to standardize Lp(a) measurements, researchers found increased risk of major coronary events and new CVD in subjects with Lp(a) > 50 mg/dL compared to those below that threshold. ¹⁰⁷

Although many of these studies show modest increases in risk of CVD events with Lp(a) elevation, it should be noted that other studies do not demonstrate such consistent associations. This is particularly true in studies of women and nonwhite ethnic groups. ^103,108-112 The variability of study results may be due to other confounding factors such as autoantibodies that either upregulate or downregulate atherogenicity of LDLC and potentially other lipoproteins. This is particularly relevant to women who have an increased risk for autoimmune disease.

Lp(a) has significant genetic heritability—75% in Europeans and 85% in African Americans. ¹¹³ In whites, the LPA gene on chromosome 6p26- 27 with the polymorphism genetic variants rs10455872 and rs3798220 is consistently associated with elevated Lp(a) levels. ^63,100,113 However, the degree of Lp(a) elevation associated with these specific genetic variants varies by ethnicity. ^78,113,115