ObjectiveLipid peroxides and their reactive aldehyde derivatives (LPPs) have been linked to obesity-related pathologies, but whether they have a causal role has remained unclear. Glutathione peroxidase 4 (GPx4) is a selenoenzyme that selectively neutralizes lipid hydroperoxides, and human gpx4 gene variants have been associated with obesity and cardiovascular disease in epidemiological studies. This study tested the hypothesis that LPPs underlie cardio-metabolic derangements in obesity using a high fat, high sucrose (HFHS) diet in gpx4 haploinsufficient mice (GPx4+/−) and in samples of human myocardium.MethodsWild-type (WT) and GPx4+/− mice were fed either a standard chow (CNTL) or HFHS diet for 24 weeks, with metabolic and cardiovascular parameters measured throughout. Biochemical and immuno-histological analysis was performed in heart and liver at termination of study, and mitochondrial function was analyzed in heart. Biochemical analysis was also performed on samples of human atrial myocardium from a cohort of 103 patients undergoing elective heart surgery.ResultsFollowing HFHS diet, WT mice displayed moderate increases in 4-hydroxynonenal (HNE)-adducts and carbonyl stress, and a 1.5-fold increase in GPx4 enzyme in both liver and heart, while gpx4 haploinsufficient (GPx4+/−) mice had marked carbonyl stress in these organs accompanied by exacerbated glucose intolerance, dyslipidemia, and liver steatosis. Although normotensive, cardiac hypertrophy was evident with obesity, and cardiac fibrosis more pronounced in obese GPx4+/− mice. Mitochondrial dysfunction manifesting as decreased fat oxidation capacity and increased reactive oxygen species was also present in obese GPx4+/− but not WT hearts, along with up-regulation of pro-inflammatory and pro-fibrotic genes. Patients with diabetes and hyperglycemia exhibited significantly less GPx4 enzyme and greater HNE-adducts in their hearts, compared with age-matched non-diabetic patients.ConclusionThese findings suggest LPPs are key factors underlying cardio-metabolic derangements that occur with obesity and that GPx4 serves a critical role as an adaptive countermeasure.

Obesity has been identified as a risk factor for postoperative atrial fibrillation (POAF) following coronary artery bypass grafting (CABG). However, no studies have addressed the influence of race on this association. A total of 13,594 patients undergoing first-time, isolated CABG without preoperative atrial fibrillation between 1992 and 2011 were included in our study. The association between body mass index (BMI) and POAF was compared by race. Relative risk and 95% confidence intervals were computed using maximum likelihood log-binomial regression. Increasing levels of BMI were associated with higher POAF risk following CABG among black but not white patients (Pinteraction=0.0009).

Background and Objective Following coronary artery bypass graft (CABG) surgery, mortality rates are significantly higher among black patients who experience postoperative atrial fibrillation (POAF). Perioperative inotropic therapy (PINOT) was associated with POAF in previous reports, but the extent to which race influences this association is unknown. In the present study, the relationship between PINOT, race, and POAF was examined in patients undergoing CABG surgery. Methods and Setting Clinical records were examined from a prospectively maintained cohort of 11,855 patients (median age 64 yrs; 70% male; 16% black) undergoing primary isolated CABG at a large cardiovascular institute in the southeastern region of the United States. Relative risk (RR) and 95% confidence intervals (CIs) were computed using log-binomial regression. Main Results The association between PINOT and POAF was significantly increased among black patients (adjusted RR 1.7, CI 1.4–2.0) compared with white patients (adjusted RR 1.3, CI 1.2–1.4) (pinteraction = 0.013). Conclusions These findings suggest that PINOT may be disproportionately associated with POAF among black patients undergoing CABG surgery. Additional studies are needed to examine further the potential underlying mechanisms of this association.

[This corrects the article DOI: 10.1016/j.molmet.2015.04.001.].