No abstract

Background-Targeted therapies to stabilize the clinical manifestations and prolong pregnancy in preeclampsia do not exist. Soluble fms-like tyrosine kinase 1 (sFlt-1), an alternatively spliced variant of the vascular endothelial growth factor receptor 1, induces a preeclampsia-like phenotype in experimental models and circulates at elevated levels in human preeclampsia. Removing sFlt-1 may benefit women with very preterm (Ͻ32 weeks) preeclampsia. Methods and Results-We first show that negatively charged dextran sulfate cellulose columns adsorb sFlt-1 in vitro. In 5 women with very preterm preeclampsia and elevated circulating sFlt-1 levels, we next demonstrate that a single dextran sulfate cellulose apheresis treatment reduces circulating sFlt-1 levels in a dose-dependent fashion. Finally, we performed multiple apheresis treatments in 3 additional women with very preterm (gestational age at admission 28, 30, and 27ϩ4 weeks) preeclampsia and elevated circulating sFlt-1 levels. Dextran sulfate apheresis lowered circulating sFlt-1, reduced proteinuria, and stabilized blood pressure without apparent adverse events to mother and fetus. Pregnancy lasted for 15 and 19 days in women treated twice and 23 days in a woman treated 4 times. In each, there was evidence of fetal growth. Conclusions-This pilot study supports the hypothesis that extracorporeal apheresis can lower circulating sFlt-1 in very preterm preeclampsia. Further studies are warranted to determine whether this intervention safely and effectively prolongs pregnancy and improves maternal and fetal outcomes in this setting. (Circulation. 2011;124:940-950.)Key Words: angiogenic factor Ⅲ apheresis Ⅲ preeclampsia P reeclampsia is a devastating medical complication of pregnancy associated with significant maternal and fetal morbidity and mortality. 1 The risk is highest in very preterm (Ͻ32 weeks) preeclampsia when the infant mortality rate is 70 times higher than at term. 2,3 Delivery of the placenta remains the only effective means to treat preeclampsia. Randomized trials have tested nonspecific interventions including antihypertensive agents; however, the ability of these and other interventions to prevent or stabilize the clinical manifestations and prolong pregnancy in preterm preeclampsia is limited. 4 -6 The underlying pathogenesis of preeclampsia has remained elusive, hampering successful development of targeted interventions for the condition. Clinical Perspective on p 950The prevailing hypothesis suggests that preeclampsia involves a placental factor that circulates to distal organs and causes damage to the vasculature. 7 We and others have suggested that excess placental derived soluble fms-like tyrosine kinase 1 (sFlt-1) or the soluble vascular endothelial growth factor (VEGF) receptor 1, an alternatively spliced variant of VEGF receptor 1, mediates the signs and symptoms of preeclampsia, and elevated circulating levels are associated with clinical preeclampsia. 8 -11 Circulating sFlt-1 levels in very preterm preeclampsia are among the highest obs...

These results indicate that triglyceride-rich lipoproteins and cholesterol-rich lipoproteins have a differential effect on mild/moderate and severe lesion progression, respectively. These results add to the growing evidence of the importance of triglyceride-rich lipoproteins as a risk factor for coronary artery disease and the need for treatment in the progression of atherosclerosis.

Background Cardiovascular disease burden and treatment patterns among patients with familial hypercholesterolemia (FH) in the United States remain poorly described. In 2013, the FH Foundation launched the Cascade Screening for Awareness and Detection (CASCADE) of FH Registry to address this knowledge gap. Methods and Results We conducted a cross-sectional analysis of 1295 adults with heterozygous FH enrolled in the CASCADE-FH Registry from 11 US lipid clinics. Median age at initiation of lipid-lowering therapy was 39 years, and median age at FH diagnosis was 47 years. Prevalent coronary heart disease was reported in 36% of patients, and 61% exhibited 1 or more modifiable risk factors. Median untreated low-density lipoprotein cholesterol (LDL-C) was 239 mg/dL. At enrollment, median LDL-C was 141 mg/dL; 42% of patients were taking high-intensity statin therapy and 45% received >1 LDL-lowering medication. Among FH patients receiving LDL-lowering medication(s), 25% achieved an LDL-C <100 mg/dL and 41% achieved a ≥50% LDL-C reduction. Factors associated with prevalent coronary heart disease included diabetes mellitus (adjusted odds ratio 1.74; 95% confidence interval 1.08–2.82) and hypertension (2.48; 1.92–3.21). Factors associated with a ≥50% LDL-C reduction from untreated levels included high-intensity statin use (7.33; 1.86–28.86) and use of >1 LDL-lowering medication (1.80; 1.34–2.41). Conclusions FH patients in the CASCADE-FH Registry are diagnosed late in life and often do not achieve adequate LDL-C lowering, despite a high prevalence of coronary heart disease and risk factors. These findings highlight the need for earlier diagnosis of FH and initiation of lipid-lowering therapy, more consistent use of guideline-recommended LDL-lowering therapy, and comprehensive management of traditional coronary heart disease risk factors.

Little is known regarding cardiovascular disease risk indices in HIV-infected women. This study investigated cardiovascular disease risk indices in 100 consecutively recruited HIV-infected women and 75 healthy female control subjects. Subjects were recruited from hospital- and community-based health care providers. C-reactive protein (CRP), interleukin-6 (IL-6), adiponectin, lipid, and glucose levels were the main outcome measures. CT scan, dual-energy x-ray absorptiometry (DXA), and anthropometry were used to assess body composition. Although similar in age, weight, and racial composition, HIV-infected women demonstrated higher CRP (4.6 +/- 0.7 vs. 2.3 +/- 0.4 mg/L, P = 0.007), IL-6 (2.7 +/- 0.2 vs. 1.8 +/- 0.1 pg/mL, P = 0.02), triglyceride (1.84 +/- 0.21 vs. 0.85 +/- 0.05 mM, P = 0.0002), 2-hour glucose after oral glucose challenge (6.88 +/- 0.22 vs. 5.72 +/- 0.17 mM, P = 0.0003), and fasting insulin (81 +/- 8 vs. 45 +/- 2 pM, P = 0.0002) and lower high-density lipoprotein cholesterol (1.17 +/- 0.03 vs. 1.45 +/- 0.05 mM, P < 0.0001) and adiponectin (5.4 +/- 0.3 vs. 7.6 +/- 0.5 mg/L, P = 0.0001) levels compared with the control population. HIV-infected women had more abdominal visceral fat and less extremity fat by CT and DXA scan and demonstrated a higher waist-to-hip ratio (WHR) than the control population. Within the HIV group, CRP and other indices were significantly related to body composition in stepwise regression models. Among all subjects, WHR, but not HIV status, was significantly related to CRP and other cardiovascular disease risk indices. HIV-infected women demonstrate significantly increased risk factors for cardiovascular disease in association with abnormal fat distribution.

Objective Metabolic abnormalities including diabetes, dyslipidemia, hypertension, and abdominal obesity occur commonly in HIV patients, are associated with increased coronary artery calcification (CAC), and contribute to increased cardiovascular disease (CVD) in this population. We hypothesized that lifestyle modification (LSM) and metformin would improve CVD indices in HIV patients with metabolic syndrome. Design A randomized, placebo controlled trial to investigate LSM and metformin, alone and in combination, over one year, among 50 HIV-infected patients with metabolic syndrome. Methods We assessed CAC, cardiovascular and metabolic indices. Results Among the participants, duration of HIV-infection was 14±1 yr and duration of antiretroviral therapy was 6±1 yr. Metformin-treated subjects demonstrated significantly less progression of CAC (−1±2 vs. 33±17, P=0.004, metformin vs. placebo) whereas the effect of LSM on CAC progression was not significant (8±6 vs. 21±14, P=0.82, LSM vs. no LSM). Metformin had a significantly greater effect on CAC than LSM (P=0.01). Metformin-treated subjects also demonstrated less progression in calcified plaque volume (−0.4±1.9 vs. 27.6±13.8 mm3, P=0.008) and improved HOMA-IR (P=0.05) compared to placebo. Subjects randomized to LSM vs. no LSM showed significant improvement in HDL (P=0.03), hsCRP (P=0.05), and cardiorespiratory fitness. Changes in CAC among the 4 groups: 1) no LSM, placebo (43±30); 2) LSM, placebo (19±7); 3) no LSM, metformin (1±1); and 4) LSM, metformin (−4±6) were different (P=0.03 for ANOVA and linear trend across groups), the majority of this effect was mediated by metformin. Results are mean ± SEM. Conclusion Metformin prevents plaque progression in HIV-infected patients with the metabolic syndrome.

No abstract

No abstract