Oxidized Phospholipids and Lp(a) Strongly Associated With MACE: CASABLANCA

Lipoprotein(a) as well as two oxidized phospholipids (OxPLs) are all associated with multivessel coronary artery disease detected on angiography and also linked to a higher risk of major adverse cardiovascular events, according to results from the CASABLANCA study.

Although Lp(a), OxPL-apoB, and OxPL-apo(a) were strongly correlated, the association with prevalent CAD and major adverse cardiovascular events appeared to be a little stronger for OxPL-apoB, raising the possibility that it might be a future target to lower the residual risk of patients treated with Lp(a)-lowering therapies.

“What’s interesting is that the oxidized phospholipids linked to all apoB lipoproteins seemed to show a stronger signal than Lp(a), and this is adjusting for things like LDL cholesterol,” senior investigator Pradeep Natarajan, MD (Massachusetts General Hospital, Boston, MA), told TCTMD. “This suggests that oxidized phospholipids are enriched in Lp(a), but it’s not only in Lp(a). As we think about the next generation of lipid-modulating therapies, which have focused on both changes and concentrations of lipoproteins, there might be a focus on specific components within these lipoproteins.”

Lp(a) is now widely regarded as an important risk factor for atherosclerotic cardiovascular disease (ASCVD) and recurrent CAD, with higher levels shown to be associated with increased risk. Graded, dose-dependent associations between Lp(a) and clinical outcomes have been seen in numerous observational studies. Several agents to lower Lp(a) are currently in development, the furthest advanced being pelacarsen (Ionis Pharmaceuticals/Novartis) in the Lp(a)HORIZON trial.

Despite the vast interest, researchers aren’t entirely sure how Lp(a) influences cardiovascular risk, said Natarajan. It’s been hypothesized it may be mediated via OxPLs, he said.

Robert Rosenson, MD (Icahn School of Medicine at Mount Sinai, New York), who wasn’t involved in the study, said that while Lp(a), OxPL-apoB, and OxPL-apo(a) were highly correlated, the findings do hint at potential differences between the OxPLs worth exploring down the road.

“It really serves as a basis for future studies to delve into mechanisms whereby Lp(a) mediates risk through the oxidized phospholipids,” Rosenson told TCTMD. “The strength of the association was higher for OxPL-apoB than it was for Lp(a) and OxPL-apo(a), but it’s difficult to know if those differences are meaningful because they are so highly correlated. Still, what it shows is that perhaps lowering Lp(a) alone might not be sufficient and looking at the bioactive molecules on the Lp(a)—the oxidized phospholipids—may be an important consideration in clinical trials of Lp(a)-lowering therapy.”

It’s been exciting for us to reprise this tantalizing hypothesis that’s been out there for a number of years. Pradeep Natarajan

Michael Boffa, PhD (Robarts Research Institute/University of Western Ontario, Canada), who has studied the adverse cardiovascular effects of elevated Lp(a), said high levels of Lp(a) are clearly associated with a higher risk of ASCVD events. Working out the mechanism is important, he added, because it has implications for whom to treat (and when) with Lp(a)-lowering therapy.   

“These questions are all wrapped up in it,” he said. “The problem is that the structure of Lp(a) is uniquely complicated. It has two facets to it: it can promote atherosclerosis, the underlying vessel-wall disease, and it can also potentially contribute to thromboses, the inappropriate blood clots that cause the clinical manifestations of heart attack and stroke.” 

OxPLs, said Boffa, serve as a “danger signal” and can provoke a series of inflammatory events, a trait that has led to them being fingered as the bad actor of Lp(a).

“Oxidized phospholipids trigger cell responses that contribute to the atherosclerotic process,” he told TCTMD. “They promote inflammation within the vessel wall, they activate inflammatory cells to get into the vessel wall, and they can damage the endothelial cells lining the vessel wall. It initiates and promotes the atherosclerotic process. We know a lot about these molecules and what they can do quite apart from whether they’re associated with Lp(a) or not.”

CASABLANCA Study

OxPLs are created when phospholipid molecules containing polyunsaturated fatty acids are oxidized, typically in areas where there is oxidative stress. These proatherogenic particles, which promote a proinflammatory cascade, have a large affinity for Lp(a). Studies have shown that approximately 85% of plasma OxPLs are found in association with apo(a), which is bound to the LDL-like portion of Lp(a). The relative roles of Lp(a) plasma concentrations compared with OxPLs in CAD and risk prediction, however, are not well known, according to the researchers.

The new analysis, published this week in the Journal of the American College of Cardiology, is based on a contemporary cohort of patients enrolled in the CASABLANCA study who underwent coronary angiography at Massachusetts General Hospital between 2008 and 2011. Using blood samples from the preprocedural period, collected from a centrally inserted arterial femoral or radial artery catheter, the researchers measured isoform-independent Lp(a) particle number, OxPL-apoB, and OxPL-apo(a) in 1,098 patients (mean age 66.3 years; 70.9% male). The most common indication for coronary catheterization was an abnormal stress test.

Overall, Lp(a) was highly correlated with both OxPL-apoB and OxPL-apo(a), with respective R values of 0.91 and 0.95, respectively (P < 0.001). The two OxPLs were also highly correlated with each other (R = 0.93; P < 0.001). On the other hand, there was little correlation with any Lp(a)-mediated biomarker and traditional lipid measures. There were also no statistically significant associations between Lp(a), OxPL-apoB, or OxPL-apo(a) and any traditional risk factor for ASCVD.   

In an adjusted regression model, there was no statistically significant association between any of the Lp(a) biomarkers and the presence of any CAD. However, there was a significant association with Lp(a) and OxPL-apoB with multivessel CAD, as well as a borderline association with OxPL-apo(a) and multivessel CAD. When Lp(a) and OxPL-apoB values were doubled, there was significant 10% and 18% higher odds of multivessel disease on angiography. A doubling of OxPL-apo(a) levels was associated with a 7% nonsignificant higher risk of multivessel CAD.

With respect to hard clinical endpoints, which were assessed after a median 4.2 years of follow-up, doubling of Lp(a), OxPL-apoB, and OxPL-apo(a) levels was associated with an 8%, 15%, and 7% higher odds of major adverse cardiovascular events, with all three associations statistically significant. In sensitivity analyses that looked at the association with each component of the primary endpoint, the results were most consistent for revascularization and cerebrovascular accident, say researchers.

To TCTMD, Natarajan said understanding whether or not OxPLs, particularly OxPL-apoB, will have a clinical role in the future will require more work.

“The data sets so far have been pretty small,” he said. “As the landscape evolves over the next 5 or 10 years when we have Lp(a)-lowering medicines, whether this will be a residual marker of risk among people who are treated with Lp(a)-lowering therapy needs to be determined. The fact that there is a stronger signal for OxPL-apoB suggests there might actually be residual risk for some patients, even with Lp(a) being addressed, but that’s really going to require more study. But it’s evolving, and it’s been exciting for us to reprise this tantalizing hypothesis that’s been out there for a number of years.”

Important Patient Population

Identifying an association between the OxPLs and ASCVD events hints at a way of fine-tuning the risk attributable to Lp(a), said Boffa. However, “from all the studies that I’ve ever seen, and you can see it here, the OxPL measurements track extremely well with the Lp(a) measurements,” he said. “There’s rarely any difference in the predictive value of Lp(a) versus OxPL.”

From a physician’s perspective, Lp(a) provides all the information necessary for clinical decision-making, he said.

Nonetheless, the new research is valuable given the patient population, he said. Many studies with Lp(a) and OxPL are derived from older cohorts where the management of cardiac patients wasn’t as rigorous as it is today. LDL cholesterol levels, for one, are much lower now than in previous eras. In the present study, 73% were treated with statins and the baseline LDL cholesterol level was 83.4 mg/dL. Despite this, Lp(a) was still associated with a significantly higher risk of major adverse cardiovascular events.

“That means it’s still worth targeting therapeutically,” said Boffa. “It’s still worth measuring to assess somebody’s risk.”

What it shows is that perhaps lowering Lp(a) alone might not be sufficient and looking at the bioactive molecules on the Lp(a)—the oxidized phospholipids—may be an important consideration in clinical trials of Lp(a)-lowering therapy. Robert Rosenson

In the CASABLANCA cohort, one in three patients had Lp(a) levels greater than 30 mg/dL and one in six had levels exceeding 70 mg/dL, the latter being the cutoff for inclusion in the Lp(a)HORIZON trial. Boffa noted that the trial enrolled patients with preexisting CAD, making half of the CASABLANCA cohort ineligible for that outcomes trial.

“They wouldn’t be eligible for the trial and Lp(a) won’t be indicated for them if the trial is successful,” he said. “To show that Lp(a) is a risk factor for this particular high-risk, primary-prevention population is an important finding.”

In an editorial, Daniel Rader, MD, and Archna Bajaj, MD (University of Pennsylvania, Philadelphia, PA), point out that pelacarsen reduced OxPL-apoB and OxPL-apo(a) levels by 88% and 70%, respectively, in phase II studies. Researchers testing olpasiran (Amgen), which recently showed impressive Lp(a) reductions in the phase II OCEAN(a)-DOSE study, have not yet published any data on OxPLs. Rader and Bajaj also point out there are preclinical animal data suggesting that targeting OxPLs, independent of Lp(a) lowering, could inhibit atherosclerosis.

“As novel Lp(a)-lowering therapies advance in clinical development, it will be interesting to note whether they reduce cardiovascular outcomes in part through lowering OxPL levels,” they write.