Personalized absolute benefit of statin treatment for primary or secondary prevention of vascular disease in individual elderly patients

Objective: To estimate the absolute treatment effect of statin therapy on major adverse cardiovascular events (MACE; myocardial infarction, stroke and vascular death) for the individual patient aged C70 years. Methods: Prediction models for MACE were derived in patients aged C70 years with (n = 2550) and without (n = 3253) vascular disease from the ‘‘PROspective Study of Pravastatin in Elderly at Risk’’ (PROSPER) trial and validated in the ‘‘Secondary Manifestations of ARTerial disease’’ (SMART) cohort study (n = 1442) and the ‘‘Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm’’ (ASCOT-LLA) trial (n = 1893), respectively, using competing risk analysis. Prespecified predictors were various clinical characteristics including statin treatment. Individual absolute risk reductions (ARRs) for MACE in 5 and 10 years were estimated by subtracting ontreatment from off-treatment risk. Results: Individual ARRs were higher in elderly patients with vascular disease [5-year ARRs: median 5.1 %, interquartile range (IQR) 4.0–6.2 %, 10-year ARRs: median 7.8 %, IQR 6.8–8.6 %] than in patients without vascular disease (5-year ARRs: median 1.7 %, IQR 1.3–2.1 %, 10-year ARRs: 2.9 %, IQR 2.3–3.6 %). Ninetyeight percent of patients with vascular disease had a 5-year ARR C2.0 %, compared to 31 % of patients without vascular disease. Conclusions: With a multivariable prediction model the absolute treatment effect of a statin on MACE for individual elderly patients with and without vascular disease can be quantified. Because of high ARRs, treating all patients is more beneficial than prediction-based treatment for secondary prevention of MACE. For primary prevention of MACE, the prediction model can be used to identify those patients who benefit meaningfully from statin therapy.

Cardiopulmonary bypass down-regulates NOD signaling and inflammatory response in children with congenital heart disease

In the present study, we aimed to examine the impact of cardiopulmonary bypass (CPB) on expression and function of NOD1 and NOD2 in children with congenital heart disease (CHD), in an attempt to clarify whether NOD1 and NOD2 signaling is involved in the modulation of host innate immunity against postoperative infection in pediatric CHD patients. Peripheral blood samples were collected from pediatric CHD patients at five different time points: before CPB, immediately after CPB, and 1, 3, and 7 days after CPB. Real-time PCR, Western blot, and ELISA were performed to measure the expression of NOD1 and NOD2, their downstream signaling pathways, and inflammatory cytokines at various time points. Proinflammatorycytokine IL-6 and TNF-α levels in response to stimulation with either the NOD1 agonist Tri-DAP or the NOD2 agonist MDP were significantly reduced after CPB compared with those before CPB, which is consistent with a suppressed inflammatory response postoperatively. The expression of phosphorylated RIP2 and activation of the downstream signaling pathways NF-κB p65 and MAPK p38 upon Tri-DAP or MDP stimulation in PBMCs were substantially inhibited after CPB. The mRNA level of NOD1 and protein levels of NOD1 and NOD2 were also markedly decreased after CPB. Our results demonstrated that NOD-mediated signaling pathways were substantially inhibited after CPB, which correlates with the suppressed inflammatory response and may account, at least in part, for the increased risk of postoperative infection in pediatric CHD patients.

A small molecule activator of p300/CBP histone acetyltransferase promotes survival and neurite growth in a cellular model of Parkinson’s disease

Parkinson’s disease (PD) is a progressive neurodegenerative disease characterised by motor and non-motor symptoms, resulting from the degeneration of nigrostriatal dopaminergic neurons and peripheral autonomic neurons. Given the limited success of neurotrophic factors in clinical trials, there is a need to identify new small molecule drugs and drug targets to develop novel therapeutic strategies to protect all neurons that degenerate in PD. Epigenetic dysregulation has been implicated in neurodegenerative disorders, while targeting histone acetylation is a promising therapeutic avenue for PD. We and others have demonstrated that histone deacetylase inhibitors have neurotrophic effects in experimental models of PD. Activators of histone acetyltransferases (HAT) provide an alternative approach for the selective activation of gene expression, however little is known about the potential of HAT activators as drug therapies for PD. To explore this potential, the present study investigated the neurotrophic effects of CTPB (N-(4-chloro-3-trifluoromethyl-phenyl)-2-ethoxy-6-pentadecyl-benzamide), which is a potent small molecule activator of the histone acetyltransferase p300/CBP, in the SH-SY5Y neuronal cell line. We report that CTPB promoted the survival and neurite growth of the SH-SY5Y cells, and also protected these cells from cell death induced by the neurotoxin 6-hydroxydopamine. This study is the first to investigate the phenotypic effects of the HAT activator CTPB, and to demonstrate that p300/CBP HAT activation has neurotrophic effects in a cellular model of PD.