Exercise training improved FMD and exercise capacity in stable CAD patients independent of the changes in inflammation, oxidative stress, or endothelial progenitor cells. The beneficial effects of exercise training on FMD and exercise capacity are inter-related, and more pronounced in those with baseline impaired exercise capacity.

BackgroundAtrial fibrillation is associated with higher mortality. Identification of causes of death and contemporary risk factors for all‐cause mortality may guide interventions.Methods and ResultsIn the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study, patients with nonvalvular atrial fibrillation were randomized to rivaroxaban or dose‐adjusted warfarin. Cox proportional hazards regression with backward elimination identified factors at randomization that were independently associated with all‐cause mortality in the 14 171 participants in the intention‐to‐treat population. The median age was 73 years, and the mean CHADS 2 score was 3.5. Over 1.9 years of median follow‐up, 1214 (8.6%) patients died. Kaplan–Meier mortality rates were 4.2% at 1 year and 8.9% at 2 years. The majority of classified deaths (1081) were cardiovascular (72%), whereas only 6% were nonhemorrhagic stroke or systemic embolism. No significant difference in all‐cause mortality was observed between the rivaroxaban and warfarin arms (P=0.15). Heart failure (hazard ratio 1.51, 95% CI 1.33–1.70, P<0.0001) and age ≥75 years (hazard ratio 1.69, 95% CI 1.51–1.90, P<0.0001) were associated with higher all‐cause mortality. Multiple additional characteristics were independently associated with higher mortality, with decreasing creatinine clearance, chronic obstructive pulmonary disease, male sex, peripheral vascular disease, and diabetes being among the most strongly associated (model C‐index 0.677).ConclusionsIn a large population of patients anticoagulated for nonvalvular atrial fibrillation, ≈7 in 10 deaths were cardiovascular, whereas <1 in 10 deaths were caused by nonhemorrhagic stroke or systemic embolism. Optimal prevention and treatment of heart failure, renal impairment, chronic obstructive pulmonary disease, and diabetes may improve survival.Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00403767.

Background-Endothelial damage and dysfunction are crucial mediators that link diabetes mellitus with atherosclerotic cardiovascular disease. AMP-activated kinase (AMPK) has been implicated in regulation of both energy metabolism and vascular homeostasis. The present study investigated whether endothelium-selective activation of AMPK prevents diabetes mellitus-induced endothelial damage and vascular dysfunction by improving reendothelialization in mice. Methods and Results-Transgenic mice with endothelium-selective expression of a constitutively active (CA) AMPK were generated and rendered diabetic by the injection of streptozotocin. Relaxation and reendothelialization of carotid arteries and circulating numbers of endothelial progenitor cells (EPCs) were examined after wire-induced denudation. Bone marrow-derived EPCs were isolated to monitor their in vivo and in vitro function. Compared with wild-type littermates, the CA-AMPK transgenic mice were resistant to diabetes mellitus-induced impairment in endotheliumdependent relaxation and reendothelialization of their injured carotid arteries. These changes in the transgenic mice were accompanied by increased mobilization of EPCs and enhanced incorporation of EPCs into injured blood vessels. Furthermore, EPCs from the transgenic mice exhibited augmented adhesion, migration, and tube formation capacities. At the molecular level, the expression of heme oxygenase (HO)-1 and the secretion of stromal cell-derived factor (SDF)-1␣ were upregulated in EPCs derived from the transgenic mice, whereas AMPK-mediated elevation of serum SDF-1␣ levels and improvements of EPC function and reendothelialization were all abrogated by pharmacological inhibition of heme oxygenase-1. Conclusions-Endothelium-specific AMPK activation is sufficient to protect against diabetes mellitus-induced aggravation of vascular injury by promoting EPC function and reendothelialization via upregulation of heme oxygenase-1 and

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