Lp(a) Levels Linked to Aortic Valve Calcification, Not Progression

(UPDATED) Lipoprotein(a) is associated with the development of aortic valve calcification (AVC), but the atherogenic lipoprotein does not appear to be linked to the progression of calcification over long-term follow-up, according to a new analysis.

The new findings, say investigators, suggest there are two distinct disease stages in the pathophysiology of aortic valve stenosis: the first an initiation phase triggered by traditional cardiovascular risk markers, including Lp(a), and the second a propagation phase seemingly unrelated to these risk factors.

“We still think Lp(a) is a very good target to prevent aortic valve stenosis, but not necessarily treat it once calcium deposits have been established within the valve,” lead investigator Yannick Kaiser, MD (University Medical Center Rotterdam, the Netherlands), told TCTMD.

Given that Lp(a) does not appear to drive AVC once it begins, the findings could have consequences for the investigational Lp(a)-lowering agents that have been posited as a treatment for calcific aortic valve stenosis. In patients with AVC, even potent Lp(a)-lowering strategies might not be enough to slow calcification once it starts, say investigators.

Clinical trials testing Lp(a) in aortic valve disease would likely need to include patients at high risk for calcific aortic stenosis rather than those who had already developed it. Additionally, rather than assess a traditional outcome measure such as the need for aortic valve replacement, a better endpoint might be the onset of new aortic valve calcification on cardiac CT, said Kaiser.

“Nevertheless, the jury’s still out whether Lp(a)-lowering can slow down progression of calcification, but we’re quite sure it won’t regress the disease,” he said.  

Rishi Puri, MBBS, PhD (Cleveland Clinic, OH), who wasn’t involved in the study, said that medical interventions to alter the natural progression of aortic valve disease have been largely failures. For example, statins have been ineffective in preventing the progression of aortic stenosis, including in the ASTRONOMER study. In the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial, treatment had no impact on the progression of aortic valve stenosis as measured by the need for aortic valve replacement or by echocardiography.

The reason, said Puri, is likely because these treatments are started too late in the disease process. “You need to target at-risk patients very early,” he told TCTMD. “Once you have calcification, then it’s perhaps a different pathogenesis that may be more accelerated as opposed to the precalcification molecular changes that are occurring.”

The new study was recently published in the European Heart Journal.

Initiation, Not Progression

Lp(a) is a genetically determined low-density lipoprotein that has been tied to atherosclerosis, coronary artery disease, stroke, and aortic stenosis. Right now, the European Society of Cardiology/European Atherosclerosis Society guidelines recommend measuring Lp(a) at least once during a person’s lifetime to identify high-risk patients. The American College of Cardiology/American Heart Association guidelines say that Lp(a) is a “risk-enhancing” factor to be considered when making decisions about treatment. 

We still think Lp(a) is a very good target to prevent aortic valve stenosis, but not necessarily treat it once calcium deposits have been established within the valve. Yannick Kaiser

A number of companies are developing therapies to target Lp(a) and there is already one large-scale, cardiovascular outcomes trial launched. That study, known as the Lp(a)HORIZON trial, is testing whether an mRNA-based antisense oligonucleotide, pelacarsen (Ionis Pharmaceuticals/Novartis), can reduce major adverse cardiovascular events in more than 8,000 patients with established atherosclerotic cardiovascular disease and Lp(a) levels ≥ 70 mg/dL. Other companies are also on the hunt, including Amgen and Silence Therapeutics, both of whom are developing and testing small-interfering RNA (siRNA) molecules to lower Lp(a).  

At the moment, no randomized, controlled trials testing Lp(a)-lowering agents in aortic valve disease have been started.

In the new analysis, Kaiser and colleagues studied 922 individuals (mean age 66 years; 47.7% men) with two cardiac CT examinations from the ongoing, population-based Rotterdam Study. Of these, AVC was present in 23.9% of participants, who as a group were older, more often men, and who had higher Lp(a) and creatinine levels. They also had lower HDL-cholesterol levels and were more likely to be using lipid-lowering medications.

The median time from baseline to the follow-up CT scan was 14.0 years. Of the 702 people without calcification at baseline, 59.1% had AVC on the follow-up scan. Again, these participants tended to be older, were more likely to be men, had a higher body mass index, higher Lp(a) and creatinine levels, lower HDL cholesterol levels, and were more likely to be on lipid-lowering therapy. 

In multivariate-adjusted modeling, Lp(a) was significantly associated with baseline AVC (OR 1.43 per 50 mg/dL higher Lp(a); 95% CI 1.15-1.79). Lp(a) also was significantly associated with new-onset AVC on follow-up CT, with the effect size similar (OR 1.30 per 50 mg/dL higher Lp(a); 95% CI 1.02-1.65). However, Lp(a) was not associated with the progression of AVC, nor were any traditional cardiovascular risk factors. Instead, only baseline AVC scores were linked to disease progression.

To TCTMD, Kaiser said two previously published small, post hoc analyses have suggested that Lp(a) accelerates the progression of calcific aortic valve stenosis. However, it’s possible that the type of aortic valve disease in those analyses—more fibrosis than calcification—differed from the disease of the healthy patients in the Rotterdam Study. Also, follow-up in those studies was considerably shorter at just 2 years.

“These factors may have led to the different results we observed,” he said.

Sotirios Tsimikas, MD, PhD (University of California San Diego), who is a vice president at Ionis Pharmaceuticals, said the new analysis adds to the increasing awareness of Lp(a) in aortic valve disease, but added that the results should be considered hypothesis-generating rather than definitive. In an email, he pointed out that just one-third of patients had a follow-up CT scan, which may have led to some selection bias. He also noted that previous studies have shown Lp(a) was associated with hemodynamic changes on echocardiography and was “clearly associated with progression in mild, moderate, and severe aortic stenosis.”

Similarly, Tsimikas said that the relationship between AVC with clinical disease requires more validation “as often there is fibrosis and other components of the valve that lead to clinical sequelae that might not be captured by aortic valve calcium.”

More Advanced Imaging Studied Needed

Puri pointed out that the uptake of 18F-sodium fluoride (18F-NaF) on positron emission tomography has been shown to be a more-sensitive assessment of subclinical valve degeneration than traditional imaging and could be used to assess early calcification in patients at risk for aortic stenosis. 

“I’m a big fan of surrogate imaging endpoints that give us a snapshot of what is happening at a mechanistic level,” he said. “Sodium-fluoride has been validated as a way to home in on the earliest manifestations of microcalcification. It would allow you to assess not only the natural history [of aortic stenosis] but also how medications, such as those that lower Lp(a), could potentially reverse the earliest processes that drive calcification.”

In the coronary artery disease setting, for example, researchers at the Cleveland Clinic and elsewhere have shown IVUS is an effective surrogate to assess different medications targeting atherosclerosis. If these treatments failed to regress CAD, or even attenuate progression, then they are unlikely to reduce clinical events, said Puri.

“Here, it’s a parallel scenario,” said Puri. “We now have imaging tools to look at the earliest disease manifestations of aortic stenosis and we have therapies that mechanistically make sense and we need to prove whether they work.”

Advanced imaging, he added, can provide investigators with confidence that different investigational treatments targeting aortic valve disease can be effective at the earliest stages. With 18F-NaF, for example, they’d be able to look for the onset of microcalcification and this would provide researchers with greater clarity when launching larger-scale trials. Puri said he’s lobbied different pharmaceutical companies for research grants to study different investigational agents, including Lp(a)-lowering therapies and PCSK9 inhibitors, in patients who have just undergone TAVI or surgical valve replacement. So far, such pitches have fallen on deaf ears.

“We put these valves in and say they’ll last 10 years,” said Puri. “Sometimes longer, sometimes less, but we have no way of protecting these valves. We know that Lp(a) and PCSK9 levels drive valve degeneration—both native and prosthetic—so now is the time for us to do these trials and to use the right tools so that we can get an answer within 1, 2, or 3 years, at least mechanistically.”   

In their paper, Kaiser and colleagues say that delaying the onset of AVC may be able to prevent end-stage aortic valve stenosis from occurring, a notion supported by the observation that not a single participant in the study without AVC on the first scan underwent aortic valve replacement during 14 years of follow-up. Past studies have suggested that as many as one in five people with Lp(a) > 50 mg/dL develop AVC between 50 and 60 years of age, they note.