The use of low-dose aspirin as a primary prevention strategy in older adults resulted in a significantly higher risk of major hemorrhage and did not result in a significantly lower risk of cardiovascular disease than placebo. (Funded by the National Institute on Aging and others; ASPREE ClinicalTrials.gov number, NCT01038583 .).

Cost-effective strategies to maintain healthy active lifestyle in aging populations are required to address the global burden of age-related diseases. ASPREE will examine whether the potential primary prevention benefits of low dose aspirin outweigh the risks in older healthy individuals. Our primary hypothesis is that daily oral 100 mg enteric-coated aspirin will extend a composite primary endpoint termed ‘disability-free life’ including onset of dementia, total mortality, or persistent disability in at least one of the Katz Activities of Daily Living in 19,000 healthy participants aged 65 years and above (‘US minorities’) and 70 years and above (non ‘US minorities’). ASPREE is a double-blind, randomized, placebo-controlled trial of oral 100 mg enteric-coated acetyl salicylic acid (ASA) or matching placebo being conducted in Australian and US community settings on individuals free of dementia, disability and cardiovascular disease (CVD) events. Secondary endpoints are all-cause and cause specific mortality, fatal and non-fatal cardiovascular events, fatal and non-fatal cancer (excluding non-melanoma skin cancer), dementia, mild cognitive impairment, depression, physical disability, and clinically significant bleeding. To 20 September 2013 14383 participants have been recruited. Recruitment and study completion is anticipated in July 2014 and December 2018 respectively. In contrast to other aspirin trials that have largely focused on cardiovascular endpoints, ASPREE has a unique composite primary endpoint to better capture the overall risk and benefit of aspirin to extend healthy independent lifespan in older adults in the US and Australia.

Rationale: A strong association has emerged between the gut microbiome and atherosclerotic disease. Our recent data suggest L. plantarum 299v (Lp299v) supplementation reduces infarct size in male rats. Limited human data are available on the impact of Lp299v on the vasculature. Objective: To determine whether oral Lp299v supplementation improves vascular endothelial function and reduces systemic inflammation in humans with stable coronary artery disease (CAD). Methods and Results: Twenty men with stable CAD consumed a drink containing Lp299v (20 billion CFU) once daily for six weeks. Following a 4-week washout, subjects were given an option of additionally participating in a 10-day study of oral liquid Vancomycin (250 mg 4x daily). Vascular endothelial function was measured by brachial artery flow-mediated dilation (FMD). Before and following Lp299v, plasma short-chain fatty acids, trimethylamine oxide (TMAO), and adipokine levels were measured. Additional plasma samples underwent unbiased metabolomic analyses using liquid chromatography/mass spectroscopy (UHPLC/MS). 16S rDNA sequencing was used to determine changes of the stool microbiome. Arterioles from CAD patients were obtained and endothelium-dependent vasodilation was measured by video-microscopy following intra-luminal incubation with plasma from Lp299v study subjects. Lp299v supplementation improved brachial FMD (P=0.008) without significant changes in plasma cholesterol profiles, fasting glucose, or body mass index. Vancomycin did not impact FMD. Lp299v supplementation decreased circulating levels of IL-8 (P=0.01), IL-12 (P=0.02), and leptin (P=0.0007) but did not significantly change plasma TMAO concentrations (P=0.27). Plasma propionate (P=0.004) increased while acetate levels decreased (P=0.03). Post-Lp299v plasma improved endothelium-dependent vasodilation in resistance arteries from patients with CAD (P=0.02).16S rRNA analysis the showed Lactobacillus genus was enriched in post-probiotic stool samples without other changes. Conclusions: Lp299v improved vascular endothelial function and decreased systemic inflammation in men with CAD, independent of changes in traditional risk factors and TMAO. Circulating gut-derived metabolites likely account for these improvements and merit further study. Clinical Trial: NCT01952834

We investigated the role of microRNAs (miRNA) in endothelial dysfunction in the setting of cardiometabolic disorders represented by type 2 diabetes mellitus (T2DM). miR‐29 was dysregulated in resistance arterioles obtained by biopsy in T2DM patients. Intraluminal delivery of miR‐29a‐3p or miR‐29b‐3p mimics restored normal endothelium‐dependent vasodilation (EDVD) in T2DM arterioles that otherwise exhibited impaired EDVD. Intraluminal delivery of anti‐miR‐29b‐3p in arterioles from non‐DM human subjects or rats or targeted mutation of Mir29b‐1/a gene in rats led to impaired EDVD and exacerbation of hypertension in the rats. miR‐29b‐3p mimic increased, while anti‐miR‐29b‐3p or Mir29b‐1/a gene mutation decreased, nitric oxide levels in arterioles. The mutation of Mir29b‐1/a gene led to preferential differential expression of genes related to nitric oxide including Lypla1. Lypla1 was a direct target of miR‐29 and could abrogate the effect of miR‐29 in promoting nitric oxide production. Treatment with Lypla1 siRNA improved EDVD in arterioles obtained from T2DM patients or Mir29b‐1/a mutant rats or treated with anti‐miR‐29b‐3p. These findings indicate miR‐29 is required for normal endothelial function in humans and animal models and has therapeutic potential for cardiometabolic disorders.

A risk-stratified screening strategy effectively avoided unnecessary testing in 43.6%. However, the relatively low proportion of screened patients who underwent prophylactic angioplasty or bypass grafting raises the question of whether screening was effective in preventing IHD events.