👤 Omar Chehab

Lp(a) (lipoprotein[a]) is a known cardiovascular risk factor; however, its role in cardiac remodeling and functional changes over time across diverse racial and ethnic groups remains underexplored. MESA is a prospective multi-ethnic cohort study of individuals without a history of cardiovascular disease on enrollment (2000-2002), conducted across 6 sites in the United States. Participants with baseline Lp(a) measurements and cardiac magnetic resonance imaging at both baseline and 10-year follow-up exam were included. Lp(a) was treated as both a log-transformed continuous variable (per SD log) and a categorical variable based on data-driven Lp(a) terciles. Multivariable regression models adjusted for sociodemographic, and cardiovascular risk factors, including coronary artery calcium and interim myocardial infarction, were used to assess associations between Lp(a) and longitudinal changes in left ventricular and atrial structure and function over a decade across different racial/ethnic groups. A total of 2366 participants were included. The average age at baseline was 60±9 with 53% women, 43% White, 24% Black, 21% Hispanic, and 12% Chinese. Each 1-SD increase in log-transformed Lp(a) was associated with an increase in left ventricular end-systolic volume index (β, 0.60 [95% CI, 0.02-1.18]), and left atrial minimum volume index (β, 0.81 [95% CI, 0.09-1.52]), and a decline in left ventricular ejection fraction (β, -0.75 [95% CI, -1.34 to -0.17]), and total left atrial emptying fraction (β, -1.17 [95% CI, -2.09 to -0.24]) in Hispanic subjects over a decade. No significant associations were seen in White, Black, or Chinese participants. The observed findings persisted after adjusting for coronary artery calcium, interim myocardial infarction, and atrioventricular decoupling, and when Lp(a) was treated as a categorical variable with race-specific terciles. Elevated Lp(a) levels were independently associated with maladaptive left ventricular and left atrial remodeling in Hispanic adults over a decade, while no statistically significant relationships were observed in White, Black, and Chinese participants. This suggests a unique susceptibility of Hispanic individuals to Lp(a)-mediated cardiovascular remodeling, independent of ischemic pathways. Show less

The Forkhead transcription factors FoxO1, FoxO3a, and FoxO4 play a prominent role in regulating cell survival and cell cycle. Whereas FOXO1 was shown to mediate insulin sensitivity and adipocyte differentiation, the role of the transcription factor FoxO4 in metabolism remains ill defined. To uncover the effects of FoxO4, we generated a cellular model of stable FoxO4 overexpression and subjected it to microarray-based gene expression profiling. While pathway analysis revealed a disruption of cholesterol biosynthesis gene expression, biochemical studies revealed an inhibition of cholesterol biosynthesis, which was coupled with decreased mRNA levels of lanosterol 14alpha demethylase (CYP51). FoxO4-mediated repression of CYP51 led to the accumulation of 24,25 dihydrolano-sterol (DHL), which independently and unlike lanosterol inhibited cholesterol biosynthesis. Furthermore, FoxO4-overexpressing cells accumulated lipid droplets and triacylglycerols and had an increase in basal glucose uptake. Recapitulation of these effects was obtained following treatment with CYP51 inhibitors, which also induce DHL buildup. Moreover, DHL but not lanosterol strongly stimulated liver X receptor alpha (LXRalpha) activity, suggesting that DHL and LXRalpha mediate the downstream effects initiated by FoxO4. Together, these studies suggest that FoxO4 acts on CYP51 to regulate the late steps of cholesterol biosynthesis. Show less