Left ventricular remodeling in swine after myocardial infarction: a transcriptional genomics approach

Despite the apparent appropriateness of left ventricular (LV) remodeling following myocardial infarction (MI), it poses an independent risk factor for development of heart failure. There is a paucity of studies into the molecular mechanisms of LV remodeling in large animal species. We took an unbiased molecular approach to identify candidate transcription factors (TFs) mediating the genetic reprogramming involved in post-MI LV remodeling in swine. Left ventricular tissue was collected from remote, non-infarcted myocardium, 3 weeks after MI-induction or sham-surgery. Microarray analysis identified 285 upregulated and 278 downregulated genes (FDR < 0.05). Of these differentially expressed genes, the promoter regions of the human homologs were searched for common TF binding sites (TFBS). Eighteen TFBS were overrepresented >two-fold (p < 0.01) in upregulated and 13 in downregulated genes. Left ventricular nuclear protein extracts were assayed for DNA-binding activity by protein/DNA array. Out of 345 DNA probes, 30 showed signal intensity changes >two-fold. Five TFs were identified in both TFBS and protein/DNA array analyses, which showed matching changes for COUP-TFII and glucocorticoid receptor (GR) only. Treatment of swine with the GR antagonist mifepristone after MI reduced the post-MI increase in LV mass, but LV dilation remained unaffected. Thus, using an unbiased approach to study post-MI LV remodeling in a physiologically relevant large animal model, we identified COUP-TFII and GR as potential key mediators of post-MI remodeling

Predictors of Diet-Induced Weight Loss in Overweight Adults with Type 2 Diabetes.

A very low calorie diet improves the metabolic regulation of obesity related type 2 diabetes, but not for all patients, which leads to frustration in patients and professionals alike. The aim of this study was to develop a prediction model of diet-induced weight loss in type 2 diabetes.192 patients with type 2 diabetes and BMI>27 kg/m2 from the outpatient diabetes clinic of the Erasmus Medical Center underwent an 8-week very low calorie diet. Baseline demographic, psychological and physiological parameters were measured and the C-index was calculated of the model with the largest explained variance of relative weight loss using backward linear regression analysis. The model was internally validated using bootstrapping techniques.Weight loss after the diet was 7.8±4.6 kg (95%CI 7.2-8.5; p<0.001) and was independently associated with the baseline variables fasting glucose (B = -0.33 (95%CI -0.49, -0.18), p = 0.001), anxiety (HADS; B = -0.22 (95%CI -0.34, -0.11), p = 0.001), numb feeling in extremities (B = 1.86 (95%CI 0.85, 2.87), p = 0.002), insulin dose (B = 0.01 (95%CI 0.00, 0.02), p = 0.014) and waist-to-hip ratio (B = 6.79 (95%CI 2.10, 11.78), p = 0.003). This model explained 25% of the variance in weight loss. The C-index of this model to predict successful (≥5%) weight loss was 0.74 (95%CI 0.67-0.82), with a sensitivity of 0.93 (95% CI 0.89-0.97) and specificity of 0.29 (95% CI 0.16-0.42). When only the obese T2D patients (BMI≥30 kg/m2; n = 181) were considered, age also contributed to the model (B = 0.06 (95%CI 0.02, 0.11), p = 0.008), whereas waist-to-hip ratio did not.Diet-induced weight loss in overweight adults with T2D was predicted by five baseline parameters, which were predominantly diabetes related. However, failure seems difficult to predict. We propose to test this prediction model in future prospective diet intervention studies in patients with type 2 diabetes

Sphingolipids in Cerebrospinal Fluid and Plasma Lipoproteins of APOE4 Homozygotes and Non-APOE4 Carriers with Mild Cognitive Impairment versus Subjective Cognitive Decline

BACKGROUND: Alzheimer's disease (AD) patients display alterations in cerebrospinal fluid (CSF) and plasma sphingolipids. The APOE4 genotype increases the risk of developing AD. OBJECTIVE: To test the hypothesis that the APOE4 genotype affects common sphingolipids in CSF and in plasma of patients with early stages of AD. METHODS: Patients homozygous for APOE4 and non-APOE4 carriers with mild cognitive impairment (MCI; n = 20 versus 20) were compared to patients with subjective cognitive decline (SCD; n = 18 versus 20). Sphingolipids in CSF and plasma lipoproteins were determined by liquid-chromatography-tandem mass spectrometry. Aβ42 levels in CSF were determined by immunoassay. RESULTS: APOE4 homozygotes displayed lower levels of sphingomyelin (SM; p = 0.042), SM(d18:1/18:0) (p = 0.026), and Aβ42 (p  0.49; p < 0.032) and with Cer(d18:1/24:1) in non-APOE4 carriers (r = 0.50; p = 0.025). CSF-Aβ42 correlated positively with Cer(d18:1/24:0) in MCI (p = 0.028), but negatively in SCD patients (p = 0.019). Levels of Cer(d18:1/22:0) and long-chain SMs were inversely correlated with Mini-Mental State Examination score among MCI patients, independent of APOE4 genotype (r< -0.47; p < 0.039). Nevertheless, age and sex are stronger determinants of individual sphingolipid levels in CSF than either the APOE genotype or the cognitive state. In HDL, ratios of Cer(d18:1/18:0) and Cer(d18:1/22:0) to cholesterol were higher in APOE4 homozygotes than in non-APOE4 carriers (p = 0.048 and 0.047, respectively). CONCLUSION: The APOE4 genotype affects sphingolipid profiles of CSF and plasma lipoproteins already at early stages of AD. ApoE4 may contribute to the early development of AD through modulation of sphingolipid metabolism