Plasma epoxyeicosatrienoic acids and diabetes-related cardiovascular disease: The cardiovascular health study
Rozenn N. Lemaitre,
Paul N. Jensen,
Maxwell Zeigler,
Amanda M. Fretts,
Jason G. Umans,
Barbara V. Howard,
Colleen M. Sitlani,
Barbara McKnight,
Sina A. Gharib,
Irena B. King,
David S. Siscovick,
Bruce M. Psaty,
Nona Sotoodehnia,
Rheem A. Totah
Affiliations
Rozenn N. Lemaitre
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA; Corresponding author at: Cardiovascular Health Research Unit, University of Washington, 1360 Minor Ave, Seattle WA 98101, USA.
Paul N. Jensen
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA
Maxwell Zeigler
Department of Medicinal Chemistry, University of Washington, Seattle, WA, USA
Amanda M. Fretts
Cardiovascular Health Research Unit, Department of Epidemiology, University of Washington, Seattle, WA, USA
Jason G. Umans
MedStar Health Research Institute, Hyattsville, MD, USA
Barbara V. Howard
MedStar Health Research Institute, Hyattsville, MD, USA; Georgetown and Howard Universities Center for Translational Science, Washington DC, USA
Colleen M. Sitlani
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA
Barbara McKnight
Department of Biostatistics, University of Washington, Seattle, WA, USA
Sina A. Gharib
Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of Washington, Seattle, WA, USA
Irena B. King
Department of Internal Medicine, University of New Mexico, Albuquerque, NM, USA
David S. Siscovick
New York Academy of Medicine, New York, NY, USA
Bruce M. Psaty
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA; Cardiovascular Health Research Unit, Department of Epidemiology, University of Washington, Seattle, WA, USA; Kaiser Permanente Washington Health Research Institute, Seattle, WA
Nona Sotoodehnia
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA; Division of Cardiology, Department of Medicine, University of Washington, Seattle, WA, USA
Rheem A. Totah
Department of Medicinal Chemistry, University of Washington, Seattle, WA, USA
Summary: Background: Epoxyeicosatrienoic acids (EETs) are metabolites of arachidonic acid that may impact atherosclerosis, and animal experimental studies suggest EETs protect cardiac function. Plasma EETs are mostly esterified to phospholipids and part of an active pool. To address the limited information about EETs and CVD in humans, we conducted a prospective study of total plasma EETs (free + esterified) and diabetes-related CVD in the Cardiovascular Health Study (CHS). Methods: We measured 4 EET species and their metabolites, dihydroxyepoxyeicosatrienoic acids (DHETs), in plasma samples from 892 CHS participants with type 2 diabetes. We determined the association of EETs and DHETs with incident myocardial infarction (MI) and ischemic stroke using Cox regression. Findings: During follow-up (median 7.5 years), we identified 150 MI and 134 ischemic strokes. In primary, multivariable analyses, elevated levels of each EET species were associated with non-significant lower risk of incident MI (for example, hazard ratio for 1 SD higher 14,15-EET: 0.86, 95% CI: 0.72–1.02; p=0.08). The EETs-MI associations became significant in analyses further adjusted for DHETs (hazard ratio for 1 SD higher 14,15-EET adjusted for 14,15-DHET: 0.76, 95% CI: 0.63–0.91; p=0.004). Elevated EET levels were associated with higher risk of ischemic stroke in primary but not secondary analyses. Three DHET species were associated with higher risk of ischemic stroke in all analyses. Interpretation: Findings from this prospective study complement the extensive studies in animal models showing EETs protect cardiac function and provide new information in humans. Replication is needed to confirm the associations. Funding: US National Institutes of Health.
