- This analysis of the CASABLANCA study examined the extent to which coronary atherosclerosis, as well as incident cardiovascular disease events, are attributable to lipoprotein(a) [Lp(a)] concentrations and oxidized phospholipids (OxPLs)
- Lp(a) and OxPLs were not predicted by traditional lipid parameters and were not correlated with traditional cardiovascular risk factors
- Elevated Lp(a) and OxPLs were associated with multiple coronary stenoses on baseline coronary angiography and the risk of clinical cardiovascular events—such as myocardial infarction and cardiovascular death—during follow-up. These associations were sustained even after controlling for cardiovascular risk factors
- Lp(a) and OxPLs were associated with multivessel coronary artery disease
- Medications for lowering Lp(a) are in late-stage development. These therapies may complement statin therapy for primary and secondary prevention in patients with elevated Lp(a)
Abundant preclinical evidence supports elevated lipoprotein [Lp(a)] as an important risk factor for first and recurrent coronary artery disease (CAD) events. A major proposed mechanism is through oxidized phospholipids (OxPLs), which are principally carried by Lp(a) and can be bound to either apolipoprotein [OxPL-apo(a)] or apolipoprotein B100 (OxPL-apoB).
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In studies conducted more than 25 years ago, both Lp(a) plasma concentrations and OxPL-apoB were positively associated with peripheral atherosclerosis progression, prevalent symptomatic atherosclerotic cardiovascular disease, and coronary atherosclerosis among patients presenting for coronary angiography.
Now, Massachusetts General Hospital researchers have found the same in a modern cohort. Pradeep Natarajan, MD, MMSc, director of the Cardiovascular Disease Prevention Center, Thomas C. Gilliland, MD, a cardiology fellow, and colleagues present the details in the Journal of the American College of Cardiology.
Between 2008 and 2011 at Mass General, 1,098 patients were enrolled in the CASABLANCA study and underwent coronary angiography. The study was designed to identify circulating biomarkers that predict short and long-term adverse events, and the median follow-up was four years.
For this analysis, the researchers quantified Lp(a) in first-thaw samples of pre-procedure blood from CASABLANCA participants using a novel isoform-independent assay that yields Lp(a) particle number rather than Lp(a) mass. They also separately measured OxPLs associated with apo(a) or apoB.
The angiographic outcomes were:
- Any CAD (≥70% stenosis in at least one of the following: left anterior descending, left circumflex, or right coronary arteries; or left main artery stenosis ≥50%)
- Multivessel CAD (≥70% stenoses in at least two of the left anterior descending [LAD], left circumflex [LCx], or right coronary artery [RCA]; or left main coronary artery [LM] stenosis ≥50% plus any number of ≥70% stenoses in the LAD, LCx, or RCA)
The primary outcome was major adverse cardiovascular events (MACEs), defined as the composite of cardiovascular death, nonfatal myocardial infarction (MI), nonfatal stroke, or need for coronary revascularization.
71% of the participants were male, their mean age was 66, and 93% were white. 20% underwent angiography because of an acute coronary syndrome (acute MI or unstable angina). At baseline, CAD had been diagnosed in 52% of participants, and statins were prescribed for 73%.
The novel assay showed 32% of participants had Lp(a) greater than the customary clinical risk threshold of 30 mg/dL, and 16% had Lp(a) ≥70 mg/dL.
Lp(a) Biomarkers and Standard Risk Factors
The three Lp(a)-related biomarkers were highly correlated with each other:
- Lp(a) and OxPL-apo(a): r=0.95
- Lp(a) and OxPL-apoB: r=0.91
- OxPL-apo(a) and OxPL-apoB: r=0.93
In contrast, there was a minimal correlation between the biomarkers and traditional lipid parameters.
No significant association was observed between any biomarker and traditional risk factors for atherosclerotic cardiovascular disease, such as smoking or diabetes.
Lp(a) Biomarkers and Atherosclerosis
None of the Lp(a) biomarkers were associated with the presence of any CAD.
However, Lp(a) and OxPL-apoB were significantly associated with multivessel CAD. For doubling of these biomarkers in analyses adjusted for LDL-C and other predictors of CAD:
- Lp(a): OR 1.10 (P=0.006)
- OxPL-apoB: OR 1.18 (P=0.01)
- OxPL-apo(a): OR 1.07 (P=0.07)
Lp(a) Biomarkers and MACEs
The risk of MACEs was also significantly higher with elevated Lp(a) biomarkers:
- Lp(a): OR 1.08 (P=0.001)
- OxPL-apoB: OR 1.15 (P=0.004)
- OxPL-apo(a): OR 1.07 (P=0.02)
MACE risk did not depend on whether individuals had established CAD at baseline or whether percutaneous coronary intervention was performed during index angiography.
Toward Clinical Translation
Medications for lowering Lp(a) are in late-stage development, with randomized clinical trials prospectively testing whether Lp(a) lowering reduces cardiovascular risk in patients with established CAD. In the future, routine screening for elevated Lp(a) may identify individuals who would benefit from Lp(a)-lowering therapies to complement statin therapy.
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