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Discovery of Lp(a) as risk factor for aortic stenosis generates more questions than answers
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In the quest for preventing CVDs, researchers have discovered a gene associated with a form of cholesterol that increases the risk for developing aortic stenosis by more than 60%.
“Genetic variation in the LPA locus, mediated by lipoprotein(a) levels, is associated with aortic valve calcification across multiple ethnic groups and with incident clinical aortic stenosis,” George Thanassoulis, MD, and researchers for the CHARGE Extracoronary Calcium Working Group wrote in The New England Journal of Medicine in February.
Currently, no treatments are approved to prevent aortic stenosis or reduce the need for aortic valve replacement.
George Thanassoulis, MD, and colleagues have studied lipoprotein(a) as a causal risk factor for CVDs.
Photo provided by: George Thanassoulis, MD; reprinted with permission
Although the association with aortic valve disease is a new discovery, lipoprotein(a) — or Lp(a) — has been a research focus for years. Increasing evidence suggests Lp(a) is a potential causal, genetic and independent risk factor for CHD, atherosclerosis, thrombosis and stroke.
Sotirios Tsimikas
“High Lp(a) in the blood is a common abnormality,” Sotirios Tsimikas, MD, director of vascular medicine at University of San Diego, said in an interview. High Lp(a) is typically defined as levels >25 mg/dL.
“In the United States, there are probably an estimated 100 million people who have high Lp(a) levels. Extrapolated globally, there are likely a billion people who have elevated Lp(a).”
The NEJM genetics study and other recent studies linking Lp(a) and CV risk factors have “put Lp(a) back on the map again,” according to Robert Roberts, MD, professor of medicine at University of Ottawa Heart Institute and Cardiology Today Editorial Board member.
Genetic link to aortic stenosis established
Robert Roberts
Using CT scanning, Thanassoulis and colleagues determined genome-wide associations with the presence of aortic valve calcification in 6,942 participants and mitral annular calcification in 3,795 participants. The analysis included participants of white European ancestry.
Study results indicate a strong association with the single nucleotide polymorphism (SNP) rs10455872 in the LPA locus and presence of aortic valve calcification (OR per allele=2.05). This finding was replicated in additional cohorts of white European, African American and Hispanic American descent (P<.05 for all). Aortic valve calcification was also associated with genetically determined Lp(a) levels, predicted by LPA genotype.
In prospective analyses, the LPA genotype was linked to incident aortic stenosis (HR per allele=1.68; 95% CI, 1.32-2.15) and aortic valve replacement (HR=1.54; 95% CI, 1.05-2.27) in a large Swedish cohort, and the link with incident aortic stenosis was replicated in an independent Danish cohort. Genome-wide significance for mitral annular calcification was achieved with two SNPs — rs17659543 and rs13415097 — near the pro-inflammatory gene IL1F9. However, researchers noted these findings were not consistently replicated.
According to Thanassoulis, previous studies did not differentiate whether Lp(a) was a cause or a marker of valve disease.
“Through Mendelian randomization, we know that Lp(a) is actually a causal factor. We don’t know many causal factors in CVD; we know risk factors,” Thanassoulis said. “Our results strongly suggest a causal link and add to mounting evidence that Lp(a) may be an important drug target for cardiovascular diseases.”
Wendy S. Post, MD, researcher, cardiologist, and associate professor of medicine and epidemiology at Johns Hopkins University School of Medicine, said these data provide an “important step forward in understanding the biology of the development of aortic stenosis and how this common genetic variant, found in 13% of the general population, contributes to that risk.
“Advancing age is a major risk factor for aortic stenosis and, with the aging of the population, this will become an even bigger health concern,” Post said.
Debate to screen, not screen
Plasma levels of Lp(a) are similar in men and women. It is estimated that one in five people have Lp(a) levels >50 mg/dL.
Experts Cardiology Today interviewed said data continue to accumulate that screening for Lp(a) could become routine practice in the future. However, debate about universal screening persists.
The European Atherosclerosis Society Consensus Panel in 2010 suggested screening for elevated Lp(a) in individuals at moderate to high risk for CVD/CHD, on the basis of extensive epidemiological and genetic evidence. Desirable Lp(a) levels <50 mg/dL are the recommended treatment priority. The panel also recommended niacin (nicotinic acid, 1-3 g/day) as the primary treatment for Lp(a) risk reduction. In 2011, the National Lipid Association convened a panel of experts and issued a consensus document with similar recommendations to screen moderate- or high-risk individuals for elevated Lp(a).
“To not measure Lp(a) in patients at risk would be like putting your head in the sand,” Joseph L. Witztum, MD, professor of medicine at University of California, San Diego, said in an interview. “It would be foolish, in my opinion, with our present state of knowledge.”
Joseph L. Witztum
According to Roberts, the issue with screening everyone for Lp(a), like LDL, is the lack of clear-cut data to support the next step in terms of treatment or lifestyle changes. “We don’t currently have an [approved] drug or answers about which diet or exercise may be best for Lp(a). Until we do, it is fairly prudent to say, ‘Don’t screen everyone,’” Roberts said.
“It isn’t clear what to do with the results once we do find elevated Lp(a),” Thanassoulis added.
In an interview, Tsimikas said he views selective screening as a more proactive approach. For example, screening patients at risk for developing aortic stenosis.
Available therapies
Randomized clinical trials providing evidence that lowering Lp(a) levels leads to improved clinical outcomes have not been performed. In addition, it may not be feasible to test this hypothesis without development of a novel Lp(a)-lowering agent because there is a lack of specific, effective agents that do not affect other lipoproteins, Tsimikas and Jennifer L. Hall, PhD, wrote in a viewpoint article published in the Journal of the American College of Cardiology in 2012.
Carl J. Pepine
It is known that niacin and estrogens can lower Lp(a) by up to 30%. Carl J. Pepine, MD, Chief Medical Editor of Cardiology Today, noted that clinically important aortic valve stenosis, either postinflammatory or associated with calcification of a congenital bicuspid valve, is much more frequent in adult men than women, yet the pathologic genotype for Lp(a) is similarly distributed among men and women. “So perhaps estrogens, by keeping Lp(a) low, protect women in their premenopausal years,” he said. “It is important to note that aortic stenosis of a tricuspid valve not associated with commissural fusion, calcific aortic stenosis of the elderly, has no clear sex dominance, so perhaps lowering Lp(a) could benefit both sexes later in life.”
Varying results with statins, however, show an increase, a decrease or no effect on Lp(a) levels. Other studies indicate that cholesterol ester transport protein (CETP) inhibitors, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, aspirin, thyroid mimetics and mipomersen may reduce Lp(a). However, in studies to date, these agents lowered Lp(a) levels in conjunction with changes in other lipoproteins, according to background information in the viewpoint article.
Use of niacin for Lp(a) risk reduction remains controversial. Evidence is based on retrospective analyses — the proper target for Lp(a) levels has not been established — and recent trials such as HPS2-THRIVE and AIM-HIGH have shown no benefit and possibly harmful effects of niacin in patients with vascular disease.
“I do not believe anyone is ready to recommend niacin for Lp(a) at the moment, as they may have 5 to 10 years ago,” Roberts said.
At present, without an approved therapy, Witztum said his primary therapy is to lower LDL maximally and pay attention to all risk factors.
“We use what is available, whether it is high-dose statins to lower LDL or niacin in patients who can tolerate it,” Thanassoulis said.
Next phases of development
Once effective therapies are achieved to lower Lp(a), the next phase is a clinical trial, Witztum said.
“Ultimately, we need to conduct a randomized controlled trial with a Lp(a)-lowering drug vs. placebo to determine whether reducing levels affects aortic stenosis progression or cardiovascular events,” Tsimikas said.
Isis Pharmaceuticals announced in April the initiation of phase 1 clinical trials for ISIS-APOA(Rx), an antisense drug targeting Lp(a) for the treatment of atherosclerosis. The blinded, placebo-controlled, dose-escalation study will enroll 56 healthy participants to assess the safety, tolerability and pharmacokinetics of single and multiple doses of ISIS-APOA(Rx).
In addition, another obstacle will be to achieve a standardized method to measure Lp(a) that all health care professionals agree on, Thanassoulis added.
“The journey of Lp(a) as a clinically relevant lipoprotein over the last 50 years has evolved from an antigenetic determinant in blood type, to a putative cardiovascular risk factor, to an independent, genetic risk marker of CVD,” Tsimikas and Hall wrote in their viewpoint. “The next phase is to test causality as a risk factor by improved understanding of its biological functions and the development of novel and specific targeted therapies to assess reduction of cardiovascular outcomes and residual risk. We urge increased efforts to study the atherogenicity of Lp(a).”
Disclosure: Pepine reports no relevant financial disclosures. Roberts reports receiving consulting fees from Celera Corporation and Cumberland Pharmaceuticals. Thanassoulis reports serving on the speakers’ bureau for Servier Canada. Tsimikas reports consulting for Genzyme, Isis Pharmaceuticals and Quest Pharmaceuticals; he has received investigator-initiated grants from Merck and Pfizer. Witztum reports consulting for Isis Pharmaceuticals.