Elevated LDL-C gene linked to narrowing of the aortic valve.

In an analysis that included approximately 35,000 participants, researchers from Lund University linked the genetic predisposition to elevated low-density lipoprotein cholesterol (LDL-C) to aortic valve calcium and narrowing of the aortic valve.  The findings support a causal association between low-density lipoprotein cholesterol and aortic valve disease, according to a study appearing in JAMA. The study is being released to coincide with its presentation at the Canadian Cardiovascular Congress.

Aortic valve disease remains the most common form of heart valve disease in Europe and North America and is the most common indication for valve replacement. Despite the heavy disease burden, no medical treatments are known to stop or slow disease progression.

Plasma low-density lipoprotein cholesterol has been associated with aortic stenosis (narrowing) in observational studies; however, randomized trials with cholesterol-lowering therapies in individuals with established valve disease have failed to demonstrate reduced disease progression. If low-density lipoprotein cholesterol plays a causal role in the earlier stages of aortic valve disease, this could have important implications for prevention, according to background information on the article.

Because of the random allocation of genetic information that occurs at conception, genetic variation can be used as an effective tool to distinguish potentially causal from noncausal biomarkers. Termed ‘Mendelian randomization,’ this approach has been successfully applied to assess for causality of several biomarkers with various clinical end points.

Using this approach the team evaluated whether weighted genetic risk scores (GRSs), a measure of the genetic predisposition to elevations in plasma lipids, were associated with aortic valve disease. The researchers included community-based cohorts participating in the CHARGE consortium of 6,942 patients, including the 1,295 patient Framingham Heart Study running from 1971-to-2013, the 2,527 patient Multi-Ethnic Study of Atherosclerosis running from 2000-to-2012, the 3,120 patient Age Gene/Environment Study–Reykjavik running from 2000-to-2012, and the 28,461 patient Malmö Diet and Cancer Study (MDCS) running from 1991-to-2010.

Aortic valve calcium was quantified by computed tomography; prevalent and new diagnoses of aortic stenosis and aortic valve replacement were identified by record linkage with nationwide registers on hospitalizations and causes of death.

The researchers found that in the 5,269 patient subgroup of the Malmö Diet and Cancer Study (MDCS) where lipid fractions were measured, baseline low-density lipoprotein cholesterol, but not high-density lipoprotein cholesterol or triglycerides levels, were significantly associated with new aortic stenosis.

Also, the low-density lipoprotein cholesterol genetic risk scores (GRS), but not high-density lipoprotein cholesterol or triglycerides GRS, was significantly associated with presence of aortic valve calcium in CHARGE and with new aortic stenosis in MDCS.

The team state that the findings link a genetically mediated increase in plasma low-density lipoprotein cholesterol with early subclinical valve disease, as measured by aortic valve calcium, and incident clinical aortic stenosis, providing supportive evidence for a causal role of low-density lipoprotein cholesterol in the development of aortic stenosis.

These data suggest that, in addition to the established risks for myocardial infarction and other vascular diseases, increases in low-density lipoprotein cholesterol are also associated with increased risk for aortic stenosis.

Whether earlier intervention to reduce low-density lipoprotein cholesterol could prevent aortic valve disease merits further investigation.

Source:  American Medical Association