Lipoprotein(a) and Family History Predict CV Disease Risk

Quick Takes

  • In ARIC, an Lp(a) level ≥50 mg/dl (considered elevated) was seen in only 2.5%.
  • Elevated Lp(a) and premature family history (FHx) was associated with >2-fold risk for ASCVD and CHD events, which was much higher in the Dallas Heart Study.
  • The 10-year cumulative ASCVD incidence in ARIC with both elevated Lp(a) and FHx (or premature FHx) was about 10%, which is higher than the ACC/AHA statin initiation threshold of 7.5%. We do not know the appropriate age to use the data.

Study Questions:

What is the independent and joint association of lipoprotein(a) [Lp(a)] and family history (FHx) with atherosclerotic cardiovascular disease (ASCVD) and coronary heart disease (CHD) among asymptomatic subjects?

Methods:

Plasma Lp(a) was measured and FHx was ascertained in two cohorts (Atherosclerosis Risk in Communities [ARIC] and the Dallas Heart Study [DHS]). Elevated Lp(a) was defined as the highest race-specific quintile for the models and ≥50 mg/dl for clinical discussion. Independent and joint associations of Lp(a) and FHx with CV risk were determined using Cox regression models adjusted for CV risk factors including age, sex, race, diabetes, smoking, systolic blood pressure (sBP), antihypertensive use, total cholesterol, high-density lipoprotein cholesterol (HDL-C), triglycerides, body mass index, and statin use at baseline.

Results:

Among 12,149 ARIC participants (mean age 54 years, 56% women, 23% black, 44% with FHx), 3,114 ASCVD events were observed during 21 years of follow-up. In ARIC, the mean sBP was 120 mm Hg, antihypertensive use was 25%, total cholesterol 215 mg/dl, HDL-C 52 mg/dl, triglycerides 108 mg/dl, low-density lipoprotein cholesterol (LDL-C) 137 mg/dl, statin use 0.5%, and Lp(a) 7.7 mg/dl. FHx and elevated Lp(a) were independently associated with ASCVD (hazard ratio [HR], 1.17; 95% confidence interval [CI], 1.09-1.26, and HR, 1.25; 95% CI, 1.12-1.40, respectively), and no Lp(a)-by-FHx interaction was noted (p = 0.75). Compared with subjects without FHx and nonelevated Lp(a), those with either elevated Lp(a) or FHx were at a higher ASCVD risk, while those with both had the highest risk (HR,1.43; 95% CI, 1.27-1.62). Similar findings were observed for CHD risk in ARIC, in analyses stratified by premature FHx, and in an independent cohort, the DHS. Presence of both elevated Lp(a) and FHx resulted in greater improvement in ASCVD and CHD risk reclassification and discrimination indexes than either marker alone.

Conclusions:

Elevated plasma Lp(a) and FHx have independent and additive joint associations with CV risk and may be useful concurrently for guiding primary prevention therapy decisions.

Perspective:

Lp(a) is a small highly atherogenic lipoprotein formed in the liver composed of an LDL-like particle with a glycoprotein, apolipoprotein(a) (apo[a]), linked to a molecule of apoB. In addition to CHD and the complexity and extent of plaque, it is associated with strokes, venous thromboembolism, and occlusion of vascular stents and coronary bypass grafts. This study adds to the literature of the importance of both Lp(a) and family history of premature CHD and CHD at any age. This was a very low-risk cohort, mean Lp(a) was very low with no difference in levels in those with and without a FHx of CHD or premature CHD, and the analysis was limited to highest versus lowest quintile of Lp(a). Further studies are needed to inform to what degree FHx of CHD (which may not be accurate in the clinical setting) and plasma levels of Lp(a) should influence ASCVD prevention.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Hypertriglyceridemia, Lipid Metabolism, Nonstatins

Keywords: Antihypertensive Agents, Apolipoproteins A, Atherosclerosis, Blood Pressure, Body Mass Index, Cholesterol, HDL, Cholesterol, LDL, Coronary Disease, Dyslipidemias, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Lipoproteins, Primary Prevention, Risk Factors, Triglycerides, Vascular Diseases


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