U-shaped relationship between apolipoprotein A1 levels and mortality risk in men and women.

BACKGROUND: Apolipoprotein A1 (ApoA1) is the principal protein component of high-density lipoprotein (HDL). Although low HDL cholesterol (HDL-C) levels are known to be associated with greater cardiovascular risk, recent studies have also shown heightened mortality risk at very high HDL-C levels. AIMS: To investigate the sex-specific association between elevated ApoA1 levels and adverse outcomes, and their genetic basis. METHODS: A prospective cohort study of United Kingdom Biobank participants without coronary artery disease at enrollment was performed. The primary exposure was serum ApoA1 levels. The primary and secondary outcome measures were cardiovascular and all-cause death, respectively. RESULTS: In 402 783 participants followed for a median of 12.1 years, there was a U-shaped relationship between ApoA1 levels and both cardiovascular as well as all-cause mortality, after adjustment for traditional cardiovascular risk factors. Individuals in the highest decile of ApoA1 levels (1.91-2.50 g/L) demonstrated higher cardiovascular (HR 1.21, 95% CI 1.07-1.37, P < 0.0022) and all-cause mortality (HR 1.14, 95% CI 1.07-1.21, P < 0.0001) compared with those within the lowest risk eighth decile (1.67-1.75 g/L). The U-shaped relationship was present in both sexes, though more pronounced in men. Sensitivity analyses showed that cardiovascular mortality rates were higher in those with greater alcohol intake (P < 0.004). Adjustment for polygenic variation associated with higher ApoA1 levels did not attenuate the effect of very high ApoA1 levels on mortality. In the sub-group with very elevated HDL-C levels (> 80 mg/dL in men, > 100 mg/dL in women), there was no association between ApoA1 levels and mortality. CONCLUSION: Both very low and very elevated ApoA1 levels are associated with higher cardiovascular and all-cause mortality.

Bone marrow mobilization with granulocyte macrophage colony-stimulating factor improves endothelial dysfunction and exercise capacity in patients with peripheral arterial disease.

BACKGROUND: We hypothesized that granulocyte macrophage colony-stimulating factor (GM-CSF) administration will be safe and will improve endothelial dysfunction and exercise capacity by mobilizing progenitor cells in patients with peripheral arterial disease (PAD). METHODS: Forty-five patients with PAD received thrice-weekly injections for 2 weeks of 3, 6, or 10 microg/kg per day of GM-CSF or placebo in successive cohorts of 15 subjects randomized 2:1 to drug or placebo. CD34+ mononuclear cell subsets and colony formation assay, endothelial function, ankle-brachial index, and walking capacity were measured. RESULTS: Granulocyte macrophage colony-stimulating factor administration was safe. After pooling data from GM-CSF cohorts, at 2 weeks, there was a significant increase in total leukocytes (43%, P < .0001), CD34+ cells (46%, P = .035), and colony-forming units (31%, P = .026, week 1). At 12 weeks, endothelial function improved with GM-CSF (flow-mediated vasodilation increased by 59%, P < .01) as did pain-free treadmill walking time (38 seconds, P = .008) and total treadmill walking time (55 seconds, P = .016). Corresponding changes were not observed in the placebo group. CONCLUSIONS: Granulocyte macrophage colony-stimulating factor therapy in patients with PAD was associated with mobilization of progenitor cells, improvement of endothelial dysfunction, and exercise capacity. The efficacy of strategies designed to mobilize bone marrow progenitors warrants further study in patients with PAD.

Debulking for in-stent restenosis in the brachytherapy era: does it still have a role?

Despite the advent of intracoronary brachytherapy, treatment of in-stent restenosis, particularly diffuse in-stent restenosis, remains problematic. Adjunctive debulking prior to brachytherapy may improve long-term outcomes. We review the literature and report our results of a series of patients treated with excimer laser coronary atherectomy along with balloon angioplasty and brachytherapy for in-stent restenosis. We conclude that adjunctive debulking may improve the long-term clinical outcomes of patients with diffuse in-stent restenosis treated with angioplasty and intracoronary radiation. A randomized controlled trial is warranted.