Dislipidemia e Disfunção Endotelial: Apo CIII

Circulation. 2008;118:731-742.)
Apolipoprotein CIII Links Hyperlipidemia With Vascular Endothelial Cell Dysfunction

Akio Kawakami, MD; Mizuko Osaka, BS; Mariko Tani, PhD; Hiroshi Azuma, PhD; Frank M. Sacks, MD; Kentaro Shimokado, MD; Masayuki Yoshida, MD
. E-mail kawakami.vasc@tmd.ac.jp
Background— Apolipoprotein CIII (apoCIII) is a component of some triglyceride-rich very-low-density and low-density lipoprotein and is elevated in dyslipidemia with insulin resistance and the metabolic syndrome. We previously reported that apoCIII directly activates proinflammatory and atherogenic signaling in vascular endothelial cells through protein kinase C-β (PKCβ). Because PKCβ impairs the response of vascular endothelial cells to insulin, we tested the hypothesis that apoCIII affects insulin signaling in vascular endothelial cells and its function in vitro and in vivo.
Methods and Results— ApoCIII inhibited insulin-induced tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1), decreasing phosphatidylinositol 3-kinase (PI3K)/Akt activation in human umbilical vein endothelial cells. These effects of apoCIII led to reduced endothelial nitric oxide synthase (eNOS) activation and NO release into the media. ApoCIII activated PKCβ in human umbilical vein endothelial cells, resulting in IRS-1 dysfunction via serine phosphorylation. ApoCIII also activated mitogen-activated protein kinase through PKCβ. The impaired insulin signaling was restored by PKCβ inhibitor or MEK1 inhibitor. ApoCIII-rich very-low-density lipoprotein and apoCIII impaired insulin signaling in the aorta of C57BL/6J mice and in human umbilical vein endothelial cells, which was recovered by PKCβ inhibitor. They also inhibited endothelium-dependent relaxation of the aortas of C57BL/6J mice. In summary, apoCIII in very-low-density lipoprotein impaired insulin stimulation of NO production by vascular endothelium and induced endothelial dysfunction in vivo. This adverse effect of apoCIII was mediated by its activation of PKCβ, which inhibits the IRS-1/PI3K/Akt/eNOS pathway.
Conclusion— Our results suggest that apoCIII is a crucial link between dyslipidemia and insulin resistance in vascular endothelial cells with consequential deleterious effects on their atheroprotective functions.

Impacto da Prevenção na Redução da Doença Cardiovascular

(Circulation. 2008;118:576-585) coraçaodobrasil/estrategiasdeprevençao

The Impact of Prevention on Reducing the Burden of Cardiovascular Disease.

Richard Kahn, PhD; Rose Marie Robertson, MD, FAHA; Robert Smith, PhD; David Eddy, MD, PhD
E-mail rkahn@diabetes.org
Objective— Cardiovascular disease (CVD) is prevalent and expensive. While many interventions are recommended to prevent CVD, the potential effects of a comprehensive set of prevention activities on CVD morbidity, mortality, and costs have never been evaluated. We therefore determined the effects of 11 nationally recommended prevention activities on CVD-related morbidity, mortality, and costs in the United States.
Research Design and Methods— We used person-specific data from a representative sample of the US population (National Health and Nutrition Education Survey IV) to determine the number and characteristics of adults aged 20-80 years in the United States today who are candidates for different prevention activities related to CVD. We used the Archimedes model to create a simulated population that matched the real US population, person by person. We then used the model to simulate a series of clinical trials that examined the effects over the next 30 years of applying each prevention activity one by one, or altogether, to those who are candidates for the various activities and compared the health outcomes, quality of life, and direct medical costs to current levels of prevention and care. We did this under two sets of assumptions about performance and compliance: 100% success for each activity and lower levels of success considered aggressive but still feasible.
Results— Approximately 78% of adults aged 20-80 years alive today in the United States are candidates for at least one prevention activity. If everyone received the activities for which they are eligible, myocardial infarctions and strokes would be reduced by 63% and 31%, respectively. If more feasible levels of performance are assumed, myocardial infarctions and strokes would be reduced 36% and 20%, respectively. Implementation of all prevention activities would add 221 million life-years and 244 million quality-adjusted life-years to the US adult population over the coming 30 years, or an average of 1.3 years of life expectancy for all adults. Of the specific prevention activities, the greatest benefits to the US population come from providing aspirin to high-risk individuals, controlling pre-diabetes, weight reduction in obese individuals, lowering blood pressure in people with diabetes, and lowering LDL cholesterol in people with existing coronary artery disease (CAD). As currently delivered and at current prices, most prevention activities are expensive when considering direct medical costs; smoking cessation is the only prevention strategy that is cost-saving over 30 years.
Conclusions— Aggressive application of nationally recommended prevention activities could prevent a high proportion of the CAD events and strokes that are otherwise expected to occur in adults in the United States today. However, as they are currently delivered, most of the prevention activities will substantially increase costs. If preventive strategies are to achieve their full potential, ways must be found to reduce the costs and deliver prevention activities more efficiently