Statins for Aortic Calcification? Imaging Study Reopens Debate Over LDL’s Role in Aortic Valve Disease

New insights into the prevalence of aortic valve calcification—and its progression—among carriers of a common genetic mutation may reopen a long-simmering debate about the role of statins in preventing the development of aortic valve stenosis.

Authors of the study, published early online in the Journal of the American College of Cardiology, say that LDL cholesterol and its metabolism likely play a critical role in the development of aortic valve calcification in patients with heterozygous familial hypercholesterolemia (FH). Moreover, their findings may have implications for patients with very high LDL who are not carriers of this disease.

An inherited disorder, heterozygous FH was once thought to be relatively rare but is now believed to affect approximately 1 in 250 Caucasians, and its prevalence may be even higher in specific groups, Jeanine Roeters van Lennep, MD, PhD, of Erasmus Medical Centre (Rotterdam, the Netherlands), told TCTMD.

“We all know that patients with heterozygous FH have an increased risk of cardiovascular disease, and we already knew that in patients with homozygous FH, which is very rare, that not only CVD but also aortic valve disease is a problem,” she said. “Until now, it was not known whether aortic valve disease was also a problem in heterozygous FH.”

That is partly because, until the statin era, most people with heterozygous FH developed severe CVD at such a young age that physicians “were not even bothering to consider” aortic valve disease, since it is something not seen until much later in life, she added.

“Now these patients are surviving longer and elderly FH patients are something we see in the clinic [and] we’re finding that they might have another problem, which is aortic valve disease, and that’s new,” Roeters van Lennep noted. “We’ve never screened heterozygous FH patients for aortic valve disease; this study shows that maybe we should.”

Prevalence of Aortic Valve Calcification Doubled

Roeters van Lennep and colleagues compared prevalence and aortic valve calcium score, based on CT imaging, between 145 patients with asymptomatic heterozygous FH and 131 hypercholesterolemic controls who were not carriers of the FH mutations. They found that prevalence of aortic valve calcification was nearly double among the heterozygous FH patients, at 41%, than in the controls, at 21% (P < .001). Age, untreated maximum LDL cholesterol, and diastolic blood pressure all were independent predictors of aortic valve calcification, whereas treated LDL-C was not predictive.

Of note, while FH is caused by mutations in the LDL receptor gene, the apolipoprotein B (APOB) gene, or the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene, it was the LDL receptor gene mutations that were most strongly associated with prevalence and extent of aortic valve disease in the present study. This is important, the authors note, since it underscores the role of LDL metabolism in the development of aortic valve disease.

Revisiting Statins for Aortic Valve Disease?

Nalini Rajamannan, MD, of Most Sacred Heart of Jesus Cardiology and Valvular Institute, (Sheboygan, WI) and the Mayo Clinic (Rochester, MN), who wrote an editorial accompanying the study, reminded TCTMD that the key trials attempting to lower LDL cholesterol with statins in order to prevent or mitigate aortic valve disease—SALTIRE, ASTRONOMER, and SEAS—all failed to show a benefit.

“That may be because of the potentially different genetics in the patients studied or it may be that the timing of the treatment [was too late],” she suggested. “If you start the statins early in the patients that have a very high LDL cholesterol level and you start to modify those levels, there may be a chance to slow progression of aortic valve disease.”

Roeters van Lennep agreed. Following the negative statin trials, she explained, people abandoned the theory that LDL lowering could play a role reducing the risk of in aortic valve disease. But she said their study, however, hints that aortic valve disease is a “2-step disease”: an early atherosclerotic process related to high LDL cholesterol and a secondary calcification process, wherein statins are no longer effective “and it’s too late to turn the tables on the disease.”

Implications for Patient Care

The implications for patient care are important, if subtle. In many centers, patients identified as carriers of heterozygous FH and who have high LDL levels are likely already being prescribed statins in order to prevent cardiovascular disease. These new data, however, provide an additional rationale for aggressive LDL management, said Roeters van Lennep. She gave the example of parents with FH who are worried about early testing and treatment of their children who are also carriers of the mutations: “Some patients will say, well, is it really necessary to measure the lipids in my children? One of the reasons [to do so] is to prevent CVD, however we also have reason to believe that there is another disease that we really need to treat, starting at a very early age.”

Rajamannan, for her part, pointed out that young patients—even those in their early 40s—may not already on be on aggressive statin therapy or, for that matter, even “on the radar” as having FH.

One clue, she said, may be the early murmur of aortic valve sclerosis. “It’s really easy to hear, we hear it in the clinic all the time. And we used to think, well, okay, that’s a functional murmur but really, what we know now is that it may be a precursor to atherosclerosis,” Rajamannan explained, adding, “This is really an area where the primary care and family practice physicians are going to play a huge role, because if they hear that murmur and they see an increasing LDL level, that’s where they’re going to want to try to monitor and modify [cholesterol] levels.”

There is currently no indication for using statins in the setting of aortic valve disease in American College of Cardiology/American Heart Association guidelines, “and I really think we need to think through this again,” Rajamannan said, specifically with regards to patients with LDL receptor mutations and high LDL. “To me, the biology is there.”

Both Roeters van Lennep and Rajamannan pointed out that the prospect of delaying or modifying the progression of aortic valve disease with statin therapy in heterozygous FH patients may also justify an expanded indication for cardiac echo. Currently, only homozygous FH patients undergo routine cardiac ultrasound. “This may be a reason to perform regular screening in heterozygous FH as well,” said Roeters van Lennep.

She also does not rule out the potential for a LDL-aortic valve disease link in patients who do not have FH but have dysfunctional LDL metabolism. “There are other patients who do not have FH, but who also have a high cholesterol; so the cholesterol is the driving force,” she concluded.

Sources: 
1. ten Kate G-JR, Bos S, Dedic A, et al. Increased aortic valve calcification in familial hypercholesterolemia: prevalence, extent, and associated risk factors. J Am Coll Cardiol. 2015;66:2687-2695.
2. Rajamannan NM. Calcific aortic valve disease in familial hypercholesterolemia: the LDL-density-gene effect [editorial]. J Am Coll Cardiol. 2015;66:2696-2698.

Disclosures:

• The Dutch Heart Foundation and the Interuniversitair Cardiologisch Instituut Nederland supported the study.
• Roeters van Lennep reports no relevant conflicts of interest.
• Rajamannan discloses being the inventor of a patent for methods to slow progression of aortic valve disease, owned by the Mayo Clinic, for which she receives no royalty payments.