Submitted to: Journal of the American Heart Association
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/12/2012
Publication Date: 2/19/2013
Citation: Matthan, N., Lichtenstein, A., Zhu, L., D'Agnostino, R., Schaefer, E., Pencina, M. 2013. Sex specific differences in the predictive value of cholesterol homeostasis markers and 10-Year CVD event rate in Framingham Offspring Study participants. Journal of the American Heart Association. 2(1):e005066. Interpretive Summary: Data is limited on factors influencing cholesterol homeostasis, (balance between cholesterol absorbed and synthesized in the body) and their value in predicting subsequent cardiovascular disease (CVD) events. To address this, we measured the concentration of specific compounds in the blood that have been validated as surrogate measures of cholesterol absorption (campesterol, sitosterol, cholestanol) and synthesis (squalene, desmosterol, lathosterol), respectively. The study population included 2616 subjects enrolled in the Framingham Offspring Study. We found significant differences in the concentrations of these markers by sex, age, body mass index, blood pressure and smoking status. Women and men with lower cholesterol absorption had higher triglyceride and lower HDL-C concentrations, and those with lower cholesterol synthesis had higher LDL-C concentrations. Additionally, we found that one of the cholesterol synthesis markers (squalene) was associated with lower risk of death and myocardial infarction (heart attack) in women but with a higher risk in men. This could have implications in the management of CVD risk and choice of lipid lowering therapy, including newer agents such as the squalene synthase inhibitors.
Technical Abstract: Available data are inconsistent on factors influencing plasma cholesterol homeostasis marker concentrations and their value in predicting subsequent cardiovascular disease (CVD) events. To address this issue the relationship between markers of cholesterol absorption (campesterol, sitosterol, cholestanol) and synthesis (squalene, desmosterol, lathosterol), and 10-year CVD incidence was assessed in Framingham Offspring Study participants (cycle 6) without CVD at baseline and not taking lipid lowering medications (N=2616). The primary endpoint was “hard” coronary heart disease (HCHD; coronary death and myocardial infarction), and secondary endpoint was full CVD (HCHD plus stroke, coronary insufficiency, angina pectoris, peripheral artery disease and congestive heart failure). In cross-sectional analysis, significant differences by sex, age, body mass index, blood pressure and smoking status were observed. In both women and men, lower cholesterol absorption was associated with higher triglyceride and lower HDL-C concentrations, while lower cholesterol synthesis was associated with higher LDL-C concentrations(p for trend<0.05). In women only, lower cholesterol synthesis and absorption were associated with higher non-HDL-C concentrations. Using Cox proportional hazards model adjusting for standard CVD risk factors, squalene concentrations were associated with lower HCHD in women (HR=0.70 [0.5-0.9]). In contrast, squalene (HR=1.40 [1.1-1.8]) concentrations were associated with higher HCHD in men (p<0.0001 for interaction). The cholesterol absorption markers were not predictive of HCHD or full CVD in either women or men.These data suggest significant sex differences in the 10-year prognostic value of cholesterol synthesis markers and HCHD, specifically coronary death and incidence of myocardial infarction.