Lipoprotein(a) has long been thought to be a potential marker of aortic valve disease, and the population-based Rotterdam Study in the Netherlands has reported that Lp(a) has a strong association with new-onset aortic valve calcium (AVC), but not necessarily with progression of aortic valve disease.
Reporting in the European Heart Journal, the study authors analyzed data on 922 participants in the Rotterdam Study whose Lp(a) was measured along with a computed tomography scan upon enrollment, followed by CT scan 14 years later. At baseline, 702 participants didn’t have AVC, but the follow-up scan identified new-onset AVC in 415 (59.1%).
Dr. Daniel Bos
The investigators found an association between Lp(a) concentration and baseline AVC, with an odds ratio of 1.43 for each 50 mg/dL higher Lp(a) (95% confidence interval, 1.15-1.79), as well as new-onset AVC, with an OR of 1.30 for each 50 mg/dL increase in Lp(a) (95% CI, 1.02-1.65). However, the study found no association between rising Lp(a) levels and AVC progression; it found only an association between baseline AVC score and progression (P < .001).
‘Trigger’ for calcification but not progression
“This suggests that Lp(a) is an important trigger in the initiation of aortic valve calcification, but once the valve is calcified, disease progression may be primarily driven by other factors such as the baseline calcium burden of the valve and likely other unknown factors,” senior study author Daniel Bos, MD, PhD, said in e-mailed comments.
Dr. Bos and coauthors claim this is the first study to show that even minor AVC progresses independently of Lp(a).
“There are previous studies that showed a possible relationship between Lp(a) [and] progression of aortic valve calcium,” he said. “Our study suggests that the most meaningful benefit of Lp(a) lowering may actually be prior to the onset of aortic valve calcification.”
While no treatments have been approved for lowering Lp(a), the study findings could be meaningful if trials, including the ongoing phase 3 Lp(a) HORIZON trial of the investigational antisense agent pelacarsen (NCT04023552), show promising results, Dr. Bos said. Citing Lp(a) HORIZON, he said, “If the study shows Lp(a) lowering leads to a reduction in incident cardiovascular disease, similar strategies may be applied to prevent, rather than slow down, progression of aortic valve calcification.”
Dr. Bos called the Rotterdam Study results “an important first pointer into that direction.” He added, “We will need randomized trials to provide a definitive answer to the question whether Lp(a) lowering may prevent aortic valve calcium.”
Focus on AVC is study ‘weakness’
The study findings raise a key question for clinical trials of investigative Lp(a)-lowering therapies as well as how to use those therapies to treat aortic valve disease, said Christie Ballantyne, MD, chief of cardiology at Baylor College of Medicine in Houston.
Dr. Christie M. Ballantyne
The findings could be “problematic” for these clinical trials, he said. “This study is just looking at calcium progression,” Dr. Ballantyne noted. “What we want to know about clinically is the progression to aortic stenosis, and then in particular to progression from mild disease to moderate or severe disease, because once you get into more severe disease, one has to do an intervention with either surgery or TAVR [transcatheter aortic valve replacement].”
He considered the study’s focus on AVC rather than aortic valve function a weakness and noted that only 14 study participants had TAVR. “We’re going to need much bigger numbers to look into this question of progression, including progression to severe diseases,” he said.
However, the Rotterdam Study showed the importance of CT in evaluating AVC, which can easily be done in other trials to further explore the association between Lp(a) and AVC, Dr. Ballantyne said.
Dr. Bos has no relevant disclosures. Study coauthors disclosed relationships with Amgen, Sanofi, Reservlogix, Athera, Experio, Novartis and Ionis Pharmaceuticals. Dr. Ballantyne disclosed relationships with Amgen and Novartis.