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.

The concept of dry weight (DW) is central to dialysis therapy. The most commonly used definition of DW is the weight below which patients become hypotensive on dialysis. However, this definition is dependent on patient symptoms. A more rigorous definition of DW is the body weight at a physiological extracellular volume (ECV) state. Overhydration is an excess in ECV above that found in healthy subjects. In healthy subjects, within extremes of salt intake, ECV may vary between 280 and 340 mL/kg lean body mass. Sodium accumulation is one of the many consequences of renal failure; it results in increased water intake and an increase in ECV, and an accompanying rise in blood pressure with its clinical sequelae, most prominently cardiovascular and cerebrovascular diseases. Recently characterized endogenous digitalis-like factors which are released in response to ECV expansion have extended this traditional picture. Efforts to reduce a positive sodium balance include dietary counseling and avoidance of iatrogenic intradialytic sodium loading, such as dialysate sodium exceeding serum levels, sodium profiling, and intravenous saline. Excess ECV is predominantly located in the interstitial compartment and must be removed during dialysis therapy by ultrafiltration. During this process, interstitial fluid redistributes to the intravascular space via uptake in the capillary bed. In addition to that mechanism, we propose that increased lymphatic flow into the venous system contributes to plasma refilling. Both clinical and technical means are used to assess the presence of DW. Continuous segmental calf bioimpedance is a promising new technology for intradialytic DW diagnosis.

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Cell culture and animal work indicate that dipeptidyl peptidase-4 (DPP-4) inhibition may exert cardiovascular benefits through favorable effects on the vascular endothelium. Prior human studies evaluating DPP-4 inhibition have shown conflicting results that may in part be related to heterogeneity of background anti-diabetes therapies. No study has evaluated the acute response of the vasculature to DPP-4 inhibition in humans. We recruited 38 patients with type 2 diabetes on stable background metformin therapy for a randomized, double-blind, placebo-controlled crossover trial of DPP-4 inhibition with sitagliptin (100 mg/day). Each treatment period was eight weeks long separated by four weeks of washout. Endothelial function and plasma markers of endothelial activation (ICAM-1 and VCAM-1) were measured prior to and two hours following acute dosing of sitagliptin or placebo, as well as following eight weeks of intervention with each pill. Thirty subjects completed the study and were included in analyses. Neither acute nor chronic sitagliptin therapy resulted in significant changes in vascular endothelial function. While post-acute sitagliptin ICAM-1 levels were lower than that post-chronic sitagliptin, the ICAM-1 concentration was not significantly different than pre-acute sitagliptin levels or levels measured in relationship to placebo. There were no significant changes in plasma VCAM-1 levels at any time point. Acute and chronic sitagliptin therapies have neutral effects on the vascular endothelium in the setting of metformin background therapy. Our findings suggest DPP-4 inhibition has a neutral effect on cardiovascular risk in patients without a history of heart failure or renal insufficiency.