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

Objective To determine whether moderate obesity (BMI ≥ 30 kg/m2) is associated with impaired conduit and microvascular endothelial function, and whether men or women are more susceptible to impairment of endothelial function related to moderate obesity. Design and Methods 41 middle aged, non-diabetic moderately obese (BMI 34.7±4.0 kg/m2) and non obese (BMI 24.3±2.6 kg/m2) subjects of both sexes underwent noninvasive studies of endothelial function (brachial reactivity) and measurements of endothelial dependent vasodilation of gluteal subcutaneous arterioles to acetylcholine (Ach). Results Endothelium dependent vasodilation to Ach was decreased in the moderately obese compared to the non-obese (P<0.001). Stratified analysis based on sex showed impairment of arteriolar endothelial function in women BMI ≥ 30 kg/m2 (P=0.02), but not men. There was no difference between in vivo endothelial function (FMD%, FMD mm) by BMI category. Sex specific analysis showed FMD% was lower in women with BMI ≥ 30 kg/m2 compared to those with BMI < 30 kg/m2 (P=0.02). No differences were seen in men based on BMI category (P=0.18). In women, high sensitivity C-reactive protein (hsCRP) correlated with BMI (ρ=0.68, P=0.006). Conclusion Moderate obesity is associated with impaired resistance arteriolar endothelial function. This is more prominent in women than men and is associated with systemic inflammation.

The novel COVID-19 has had an unprecedented and devastating spread internationally. COVID-19 infection can lead to a number of cardiovascular sequelae, including heart failure, which may portend worse clinical outcomes. Here, we report a rare case of a 57-year-old woman who developed acute left ventricular systolic dysfunction with apical ballooning consistent with takotsubo cardiomyopathy (TCM), and mixed cardiogenic and septic shock in the setting of COVID-19 disease. We briefly review the pathophysiology and diagnosis of TCM (also described as apical ballooning syndrome and stress-induced cardiomyopathy). Additionally, this case highlights the importance of a multidisciplinary approach to clinical decision-making and resource allocation in diagnosis and management of critical illness in the setting of the ongoing international COVID-19 pandemic.

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.

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