Brigitte M. Sondermeijer

Monocyte Gene Expression Signature of Patients with Early Onset Coronary Artery Disease

The burden of cardiovascular disease (CVD) cannot be fully addressed by therapy targeting known pathophysiological pathways. Even with stringent control of all risk factors CVD events are only diminished by half. A number of additional pathways probably play a role in the development of CVD and might serve as novel therapeutic targets. Genome wide expression studies represent a powerful tool to identify such novel pathways. We compared the expression profiles in monocytes from twenty two young male patients with premature familial CAD with those from controls matched for age, sex and smoking status, without a family history of CVD. Since all patients were on statins and aspirin treatment, potentially affecting the expression of genes in monocytes, twelve controls were subsequently treated with simvastatin and aspirin for 6 and 2 weeks, respectively. By whole genome expression arrays six genes were identified to have differential expression in the monocytes of patients versus controls; ABCA1, ABCG1 and RGS1 were downregulated in patients, whereas ADRB2, FOLR3 and GSTM1 were upregulated. Differential expression of all genes, apart from GSTM1, was confirmed by qPCR. Aspirin and statins altered gene expression of ABCG1 and ADBR2. All finding were validated in a second group of twenty four patients and controls. Differential expression of ABCA1, RSG1 and ADBR2 was replicated. In conclusion, we identified these 3 genes to be expressed differently in CAD cases which might play a role in the pathogenesis of atherosclerotic vascular disease.

Non-HDL cholesterol vs. apo B for risk of coronary heart disease in healthy individuals: the EPIC-Norfolk prospective population study.

There is an ongoing debate about the performance of non–high‐density lipoprotein cholesterol (non‐HDL‐C) compared with apolipoprotein B (apo B) in the prediction of coronary heart disease (CHD) risk. Therefore, we compared the associations between non‐HDL‐C and apo B in regard to CHD among apparently healthy Western European individuals.

Clinical implications of JUPITER in a contemporary European population: the EPIC-Norfolk prospective population study.

AIMS Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) has raised several points of debate. We quantified the proportion of individuals meeting the JUPITER criteria, determined their risk profile, and their risk of coronary heart disease (CHD) events during a long-term follow-up in a contemporary European cohort. METHODS AND RESULTS A total of 25 639 participants aged between 45 and 79 years were followed for 11.4 ± 2.8 years in EPIC-Norfolk population cohort. A total of 8397 individuals with complete data available were considered potentially eligible for primary prevention. A total of 846 (10.1%) individuals fulfilled the JUPITER criteria [low-density lipoprotein cholesterol-C (LDL-C) <3.4 mmol/L/C-reactive protein ≥ 2 mg]. This group had a 10-person-year event rate of 14.6% compared with 7.0% for those with LDL-C <3.4 mmol/L/C-reactive protein <2 mg (P = 0.001); the corresponding adjusted hazard ratio for future CHD was 1.70 (95% CI: 1.31-2.21). The group fulfilling JUPITER criteria had significantly higher CHD risk compared with those with LDL-C ≥ 3.4 mmol/L and C-reactive protein <2 mg/L. Among individuals who did not qualify for statin therapy based on the Society of Cardiology Systematic COronary Risk Evaluation (SCORE) (n = 4652) or ATP III criteria (n = 4466), 18.1 and 18.9%, respectively, would have qualified using the JUPITER criteria. CONCLUSION In this European cohort, JUPITER-eligible individuals had significantly higher event rates compared with those with LDL-C <3.4 mmol/L/C-reactive protein <2 mg and LDL-C ≥ 3.4 mmol/L/C-reactive protein <2 mg/L. Application of the JUPITER criteria qualified almost one-fifth of the population for statin therapy that otherwise would not have qualified based on SCORE or ATP III criteria.

Infusion of a lipid emulsion in healthy men decreases the serotonergic response.

Subjects with obesity and insulin resistance display a low response to a serotonergic challenge test. One of the hallmarks of obesity and insulin resistance is elevated plasma free fatty acids (FFAs). We hypothesize that increasing plasma FFA by infusion of a lipid emulsion, may be a contributing component leading to decreased serotonergic responsivity in healthy young men. Ten lean healthy men, 23.6 ± 5.0 years and BMI 22.6 ± 1.9 kg/m2, were included. Serotonergic responsivity was assessed using the prolactin response to infusion with citalopram, a selective serotonin reuptake inhibitor, which is a validated tool to assess serotonergic tone. All participants received a lipid/heparin emulsion (Intralipid) infusion during 6 h. Saline infusion was used as a control. To evaluate a possible effect of heparin per se on prolactin, four out of the ten subjects also received heparin only during 6 h without the serotonergic challenge test. Plasma prolactin increased by 74.3 ± 15.5% during saline infusion. Intralipid infusion increased plasma FFA from 0.5 ± 0.05 to 2.3 ± 0.2 mmol/l (p < 0.001). The increase in plasma prolactin during Intralipid infusion was significantly lower (39.3 ± 10%; p < 0.001 compared to saline infusion). Heparin infusion per se increased plasma prolactin by 14.0 ± 1.9%. We found that during the Intralipid infusion with concomitant high plasma FFA levels the serotonergic response was decreased in healthy young men. Higher FFA levels may be the mediator of the decreased serotonergic response reported in patients with insulin resistance and obesity.

Subthalamic nucleus stimulation does not influence basal glucose metabolism or insulin sensitivity in patients with Parkinson's disease

Animal studies have shown that central dopamine signaling influences glucose metabolism. As a first step to show this association in an experimental setting in humans, we studied whether deep brain stimulation (DBS) of the subthalamic nucleus (STN), which modulates the basal ganglia circuitry, alters basal endogenous glucose production (EGP) or insulin sensitivity in patients with Parkinsons disease (PD). We studied 8 patients with PD treated with DBS STN, in the basal state and during a hyperinsulinemic euglycemic clamp using a stable glucose isotope, in the stimulated and non-stimulated condition. We measured EGP, hepatic insulin sensitivity, peripheral insulin sensitivity (Rd), resting energy expenditure (REE), glucoregulatory hormones, and Parkinson symptoms, using the Unified Parkinsons Disease Rating Scale (UPDRS). Basal plasma glucose and EGP did not differ between the stimulated and non-stimulated condition. Hepatic insulin sensitivity was similar in both conditions and there were no significant differences in Rd and plasma glucoregulatory hormones between DBS on and DBS off. UPDRS was significantly higher in the non-stimulated condition. DBS of the STN in patients with PD does not influence basal EGP or insulin sensitivity. These results suggest that acute modulation of the motor basal ganglia circuitry does not affect glucose metabolism in humans.

Contents Vol. 95, 2012

D.H. Abbott, Madison, Wisc. H. Ahlman, Gothenburg E. Arzt, Buenos Aires T. Bartness, Atlanta, Ga. C.L. Bethea, Beaverton, Oreg. D.W. Brann, Augusta, Ga. B. Canny, Monash, Vic. M. Caplin, London K. Catt, Bethesda, Md. A. Chodobski, Providence, R.I. W. de Herder, Rotterdam S.L. Dickson, Gothenburg J. Drouin, Montreal, Que. P.J. Enriori, Monash, Vic. W. Farrell, Keele M. Freeman, Tallahasse, Fla. A.C. Gore, Austin, Tex. K. Grove, Beaverton, Oreg. T. Harmar, Edinburgh A. Herbison, Dunedin J. Herman, Cincinnati, Ohio J.J. Hirst, Callaghan, N.S.W. T. Hökfelt, Stockholm U. Kaiser, Boston, Mass. A. Kauff man, La Jolla, Calif. K. Kim, Seoul J.Z. Kiss, Geneva A.C. Latronico, São Paulo G. Leng, Edinburgh J. Levine, Evanston, Ill. C. Libertun, Buenos Aires C. Llorens-Cortes, Paris A. Loudon, Manchester Z.-L. Lu, Edinburgh G. Martinez de la Escalera, Querétaro R. Melcangi, Milano I. Modlin, New Haven, Conn. Z. Naor, Tel Aviv M. Palkovits, Budapest I. Parhar, Kuala Lumpur D.W. Pfaff , New York, N.Y. T.M. Plant, Pittsburgh, Pa. J. Reul, Bristol R. Reynolds, Edinburgh E. Rissman, Charlottesville, Va. J.L. Roberts, San Antonio, Tex. I. Robinson, London P. Ruszniewski, Clichy W. Schlegel, Geneva D. Skinner, Laramie, Wyo. E. Spinedi, La Plata R. Steiner, Seattle, Wash. E. Terasawa, Madison, Wisc. A. Tilbrook, Roseworthy, S.A. B. Walker, Edinburgh H. Watanobe, Chiba M. Wierman, Denver, Colo. J. Wingfi eld, Seattle, Wash. S. Wray, Bethesda, Md. International Journal for Basic and Clinical Studies on Neuroendocrine Relationships