Published: Oct 27, 2014
By Crystal Phend, Senior Staff Writer, MedPage Today
Image from Medpagetoday.com
High LDL cholesterol appears to cause aortic stenosis, even though lipid-lowering trials in established valve disease haven’t worked, a genetic study suggested.
In the Mendelian randomization study — using genetic allocation conferred at conception akin to trial randomization — weighted genetic risk scores forpredisposition to high LDL cholesterol were linked to 28% higher incident aortic stenosis risk per mmol/L LDL and 2.78-fold higher incidence per genetic risk score increment (both P=0.02). (Each mmol/L of LDL cholesterol equals about 39 mg/dL.)
Genetic risk scores for HDL and triglycerides held no such link, George Thanassoulis, MD, of McGill University Health Center and Research Institute in Montreal, and colleagues reported.
The findings appeared online in theJournal of the American Medical Association to coincide with a presentation at the Canadian Cardiovascular Congress in Vancouver.
“Low-density lipoprotein cholesterol is an important risk factor for aortic valve disease in epidemiologic studies,” they wrote, “however, large randomized trials of LDL-cholesterol-lowering therapy in patients with advanced aortic stenosis have failed to demonstrate effectiveness in reducing disease progression.
“Nonetheless, if LDL-C plays a causal role in the earlier stages of aortic valve disease, this could have important implications for prevention.”
These genetic predisposition results now provide the evidence to support a causal association between LDL and aortic valve disease, Thanassoulis’ group concluded. They previously found a link with a common variant in lipoprotein(a) as well.
“Based on the known biology of valve calcification and the failure of prior randomized trials targeting advanced disease, our results suggest that early lipid lowering, prior to the development of even mild forms of aortic stenosis, may be required to prevent aortic valve disease,” they suggested, though cautioning that “this hypothesis remains to be tested in a randomized trial.”
Their analysis assigned weighted genetic risk scores (based on single-nucleotide polymorphisms identified in genome-wide association studies for plasma lipids associated with aortic valve disease) to individuals in community-based cohorts in the CHARGE consortium.
Those included the Framingham Heart Study, the Multi-Ethnic Study of Atherosclerosis, Age Gene/Environment Study-Reykjavik, and the Malmö Diet and Cancer Study, which together had more than 28,000 participants with more than 15 years of follow-up for aortic stenosis incidence.
Among the 6,942 participants with subclinical data on aortic valve calcium, the prevalence of aortic valve calcium across those cohorts was 32%.
The LDL cholesterol genetic risk score was significantly associated with presence of aortic valve calcium across the cohorts, with an odds ratio per risk score increment of 1.38 (P=0.007).
The incidence of aortic stenosis was 2.4% in the highest LDL quartile versus 1.3% in the lowest quartile of one cohort; it was 1.9% and 2.6% in the lowest and highest genetic risk score quartiles, respectively.
In sensitivity analyses excluding genetic variants that were weakly associated with HDL cholesterol or triglycerides, the LDL cholesterol genetic risk score remained associated with aortic valve calcium (P=0.03) and aortic stenosis (P=0.009), the researchers noted.
An instrumental variable analysis also confirmed a 51% increase in the risk of incident aortic stenosis per mmol/L LDL cholesterol (P=0.02).
Limitations included use of summary-level data that didn’t allow for adjustment for many potential covariates, inability to exclude non-LDL-related mechanisms as an explanation for the link, and inclusion of only participants of European descent.
Thanassoulis was supported by the Fonds de la Recherche du Québec–Santé, the RI-MUHC/Merck Research Competition, and the Canadian Institutes of Health Research
He disclosed relationships with Servier Canada.
From the American Heart Association: