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Intensive Cardiovascular Risk Reduction Induces Sustainable Changes in Expression of Genes and Pathways Important to Vascular Function.

Abstract

BACKGROUND:

-Healthy lifestyle changes are believed to mediate cardiovascular disease (CVD) risk through pathways affecting endothelial function and progression of atherosclerosis; however, the extent, persistence, and clinical significance of molecular change during lifestyle modification are not well known. We examined the impact of a rigorous CVD risk reduction program on peripheral blood gene expression profiles in 63 participants and 63 matched controls to characterize molecular responses and identify regulatory pathways important to cardiovascular health.

METHODS AND RESULTS:

-Dramatic changes in dietary fat intake (-61%, P<0.001 versus controls) and physical fitness (+34%, P<0.001) led to significant improvements in CVD risk factors. ANOVA with FDR-correction for multiple testing (P<0.05) identified 26 genes after 12 weeks and 143 genes after 52 weeks that were differentially-expressed from baseline in participants. Controls showed little change in CVD risk factors or gene expression. Quantitative RT-PCR validated differential expression for selected transcripts. Lifestyle modification effectively reduced expression of proinflammatory genes associated with neutrophil activation and molecular pathways important to vascular function, including cytokine production, carbohydrate metabolism, and steroid hormones. Prescription medications did not significantly affect changes in gene expression.

CONCLUSIONS:

-Successful and sustained modulation of gene expression through lifestyle changes may have beneficial effects on the vascular system not apparent from traditional risk factors. Healthy lifestyles may restore homeostasis to the leukocyte transcriptome by down-regulating lactoferrin and other genes important in the pathogenesis of atherosclerosis. Clinical Trial Registration-www.clinicaltrials.gov.; Unique identifier: NCT01805492.

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