Genetic predisposition to elevated LDL tied to aortic valve calcium, aortic stenosis

New research provides evidence of a causal association between LDL and aortic valve disease. Researchers found that genetic predisposition to elevated LDL was associated with the presence of aortic valve calcium and the incidence of aortic stenosis.

The data were published in JAMA to coincide with a presentation at the Canadian Cardiovascular Congress by George Thanassoulis, MD, from the department of preventive and genomic cardiology at McGill University Health Center and Research Institute, Montreal.

George Thanassoulis

The researchers investigated whether genetic data were consistent with an association between LDL, HDL or triglycerides and aortic valve disease. They used a Mendelian randomization study design to determine whether weighted genetic risk scores were associated with aortic valve disease. Participants were from four community based-cohorts: the Framingham Heart Study (n=1,295), the Multi-Ethnic Study of Atherosclerosis (n=2,527), the Age Gene/Environment Study (n=3,120) and the Malmö Diet and Cancer Study (n=28,461). The primary outcome was incident aortic stenosis for participants in the Malmö Diet and Cancer Study and aortic valve calcium quantified by CT for participants in the other studies.

During a median follow-up of 16.1 years in the Malmö Diet and Cancer Study, aortic stenosis developed in 17 per 1,000 participants (n=473) and aortic valve replacement for aortic stenosis was required in seven per 1,000 participants (n=205). Among participants in the other studies, the prevalence of aortic valve calcium was 32% (n=2,245), according to the researchers.

In the subgroup of the Malmö Diet and Cancer Study in which lipid fractions were measured (n=5,269), plasma LDL was associated with incident aortic stenosis (lowest LDL quartile, 1.3%; highest LDL quartile, 2.4%; HR per mmol/L=1.28; 95% CI, 1.04-1.57), but plasma HDL and plasma triglycerides had no association with aortic stenosis.

LDL genetic risk score was associated with presence of aortic valve calcium (OR per genetic risk score increment=1.38; 95% CI, 1.09-1.74) in the other three groups, and with incident aortic stenosis in the Malmö Diet and Cancer Study subgroup (lowest genetic risk score quartile, 1.9%; highest genetic risk score quartile, 2.6%; OR per genetic risk score increment=2.78; 95% CI, 1.22-6.37). The researchers did not observe similar associations for HDL genetic risk score or triglycerides genetic risk score.

A sensitivity analysis excluding variants that were weakly associated with HDL or triglycerides revealed that the LDL genetic risk score remained associated with aortic valve calcium (P=.03) and aortic stenosis (P=.009).

When the researchers conducted an instrumental variable analysis, LDL was associated with an increase in risk for incident aortic stenosis (HR per mmol/L=1.51; 95% CI, 1.07-2.14).

“Our findings link a genetically mediated increase in plasma LDL with early subclinical valve disease, as measured by aortic valve calcium, and incident clinical aortic stenosis, providing supportive evidence for a causal role of LDL in the development of aortic stenosis,” J. Gustav Smith, MD, from the department of cardiology at Lund University in Sweden, and colleagues wrote in the JAMA study. “These data suggest that, in addition to the established risk for [MI] and other vascular diseases, increases in LDL are associated with increased risk for aortic stenosis. Whether earlier investigation to reduce LDL could prevent aortic valve disease merits further investigation.”

The presentation won the Young Investigator Award – Clinical Science at the Canadian Cardiovascular Congress.

For more information:

Smith JG. JAMA. 2014;doi:10.1001/jama.2014.13959.

Thanassoulis G. Abstract #395. Presented at: Canadian Cardiovascular Congress; Oct. 25-28, 2014; Vancouver, British Columbia.

Disclosure: Thanassoulis reports receiving speaker fees from Servier Canada. Another researcher reports receiving funding from Boston Heart Diagnostics.