Extreme Lipoprotein(a) Levels and Improved Cardiovascular Risk Prediction

Study Questions:

Do extreme lipoprotein(a) [Lp(a)] levels and/or corresponding Lp(a) risk genotypes improve myocardial infarction (MI) and coronary heart disease (CHD) risk prediction beyond conventional risk factors?

Methods:

A total of 8,720 Danish persons, ages 20 to 80+ years, participated in a general population study from 1991 to 1994 through 2011. Using predefined cut points for extreme Lp(a) levels and/or corresponding Lp(a) risk genotypes (kringle IV type 2 [KIV-2]) repeat polymorphism, rs3798220, and rs10455872 single nucleotide polymorphisms), net reclassification risk strata included <10% to 10-19.9% to ≥20% absolute 10-year MI and CHD risk. Standard risk factors included age, sex, total cholesterol, high-density lipoprotein cholesterol (HDL-C), systolic blood pressure, smoking, and diabetes mellitus.

Results:

At baseline, 57% of the 8,720 persons were women, and mean age was 59 years. Mean values for lipids included cholesterol 235 mg/dl, HDL-C 58 mg/dl, and Lp(a) 17 mg/dl; mean systolic blood pressure was 136 mm Hg; 49% were smokers, and 4% were diabetics. Seven-hundred and thirty MIs and 1,683 CHD first-time events occurred during 17 years of follow-up. For individuals with Lp(a) levels ≥80th percentile (≥47 mg/dl), 23% (p < 0.001) of MI events and 12% (p < 0.001) of CHD events were reclassified correctly, whereas no events were reclassified incorrectly for either endpoint. As some incorrect reclassification of individuals with no events occurred, addition of Lp(a) levels ≥80th percentile overall yielded net reclassification indices of +16% (95% confidence interval [CI], 8-24%) and +3% (-1% to 8%) for MI and CHD, respectively. Corresponding net reclassification indices for number of KIV-2 repeats ≤21st percentile were +12% and +4%, for rs3798220 carrier status +15% and +10%, and for rs10455872 carrier status +16% and +2%. Considering only individuals at 10-19.9% absolute 10-year MI and CHD risk, addition of extreme Lp(a) levels or corresponding Lp(a) risk genotypes improved risk prediction even further.

Conclusions:

The authors concluded that extreme Lp(a) levels or corresponding Lp (a) KIV-2/rs10455872 risk genotypes substantially improved MI and CHD risk prediction.

Perspective:

An elevated Lp (a) is the most common lipid abnormality in persons with premature coronary disease, a variable not considered in this study. That reclassification for MI with an extreme level of Lp (a) was nearly twofold that for CHD is consistent with the increased thrombotic risk superimposed on the atherosclerotic risk. The modest incremental risk prediction for Lp(a) above the 80th percentile or approximately 50 mg/dl in the Danish study is similar to other studies. The unique contribution is the genetic studies, which have little clinical application considering their cost and rarity. It is not clear why the authors chose to use the term 'extreme' rather than 'high' for 80th percentile. It is important to recognize that while Lp(a) may be a lipid risk marker, there is no evidence it is a modifiable risk factor, and its importance may be considerably less in patients on statins and/or antiplatelets agents.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Advanced Lipid Testing, Lipid Metabolism, Nonstatins, Smoking

Keywords: Myocardial Infarction, Kringles, Lipoprotein(a), Polymorphism, Single Nucleotide, Biological Markers, Coronary Disease, Cholesterol, HDL, Genotype, Diabetes Mellitus, Smoking


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