Effect of Aspirin on Cardiovascular Events and Bleeding in the Healthy Elderly.

BACKGROUND: Aspirin is a well-established therapy for the secondary prevention of cardiovascular events. However, its role in the primary prevention of cardiovascular disease is unclear, especially in older persons, who have an increased risk. METHODS: From 2010 through 2014, we enrolled community-dwelling men and women in Australia and the United States who were 70 years of age or older (or ≥65 years of age among blacks and Hispanics in the United States) and did not have cardiovascular disease, dementia, or disability. Participants were randomly assigned to receive 100 mg of enteric-coated aspirin or placebo. The primary end point was a composite of death, dementia, or persistent physical disability; results for this end point are reported in another article in the Journal. Secondary end points included major hemorrhage and cardiovascular disease (defined as fatal coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal stroke, or hospitalization for heart failure). RESULTS: Of the 19,114 persons who were enrolled in the trial, 9525 were assigned to receive aspirin and 9589 to receive placebo. After a median of 4.7 years of follow-up, the rate of cardiovascular disease was 10.7 events per 1000 person-years in the aspirin group and 11.3 events per 1000 person-years in the placebo group (hazard ratio, 0.95; 95% confidence interval [CI], 0.83 to 1.08). The rate of major hemorrhage was 8.6 events per 1000 person-years and 6.2 events per 1000 person-years, respectively (hazard ratio, 1.38; 95% CI, 1.18 to 1.62; P<0.001). CONCLUSIONS: 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 .).

Lactobacillus plantarum 299v Supplementation Improves Vascular Endothelial Function and Reduces Inflammatory Biomarkers in Men With Stable Coronary Artery Disease.

RATIONALE: A strong association has emerged between the gut microbiome and atherosclerotic disease. Our recent data suggest Lactobacillus 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 6 weeks. After a 4-week washout, subjects were given an option of additionally participating in a 10-day study of oral liquid vancomycin (250 mg QID). Vascular endothelial function was measured by brachial artery flow-mediated dilation. Before and after Lp299v, plasma short-chain fatty acids, trimethylamine oxide, and adipokine levels were measured. Additional plasma samples underwent unbiased metabolomic analyses using liquid chromatography/mass spectroscopy. 16S rRNA sequencing was used to determine changes of the stool microbiome. Arterioles from patients with CAD were obtained, and endothelium-dependent vasodilation was measured by video microscopy after intraluminal incubation with plasma from Lp299v study subjects. Lp299v supplementation improved brachial flow-mediated dilation ( P=0.008) without significant changes in plasma cholesterol profiles, fasting glucose, or body mass index. Vancomycin did not impact flow-mediated dilation. Lp299v supplementation decreased circulating levels of IL (interleukin)-8 ( P=0.01), IL-12 ( P=0.02), and leptin ( P=0.0007) but did not significantly change plasma trimethylamine oxide concentrations ( P=0.27). Plasma propionate ( P=0.004) increased, whereas 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 showed the Lactobacillus genus was enriched in postprobiotic 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 trimethylamine oxide. Circulating gut-derived metabolites likely account for these improvements and merit further study. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01952834.

Dynamin-related protein 1 mediates low glucose-induced endothelial dysfunction in human arterioles.

Intensive glycemic regulation has resulted in an increased incidence of hypoglycemia. Hypoglycemic burden correlates with adverse cardiovascular complications and contributes acutely and chronically to endothelial dysfunction. Prior data indicate that mitochondrial dysfunction contributes to hypoglycemia-induced endothelial dysfunction, but the mechanisms behind this linkage remain unknown. We attempt to determine whether clinically relevant low-glucose (LG) exposures acutely induce endothelial dysfunction through activation of the mitochondrial fission process. Characterization of mitochondrial morphology was carried out in cultured endothelial cells by using confocal microscopy. Isolated human arterioles were used to explore the effect LG-induced mitochondrial fission has on the formation of detrimental reactive oxygen species (ROS), bioavailability of nitric oxide (NO), and endothelial-dependent vascular relaxation. Fluorescence microscopy was employed to visualize changes in mitochondrial ROS and NO levels and videomicroscopy applied to measure vasodilation response. Pharmacological disruption of the profission protein Drp1 with Mdivi-1 during LG exposure reduced mitochondrial fragmentation among vascular endothelial cells (LG: 0.469; LG+Mdivi-1: 0.276; P = 0.003), prevented formation of vascular ROS (LG: 2.036; LG+Mdivi-1: 1.774; P = 0.005), increased the presence of NO (LG: 1.352; LG+Mdivi-1: 1.502; P = 0.048), and improved vascular dilation response to acetylcholine (LG: 31.6%; LG+Mdivi-1; 78.5% at maximum dose; P < 0.001). Additionally, decreased expression of Drp1 via siRNA knockdown during LG conditions also improved vascular relaxation. Exposure to LG imparts endothelial dysfunction coupled with altered mitochondrial phenotypes among isolated human arterioles. Disruption of Drp1 and subsequent mitochondrial fragmentation events prevents impaired vascular dilation, restores mitochondrial phenotype, and implicates mitochondrial fission as a primary mediator of LG-induced endothelial dysfunction.NEW & NOTEWORTHY Acute low-glucose exposure induces mitochondrial fragmentation in endothelial cells via Drp1 and is associated with impaired endothelial function in human arterioles. Targeting of Drp1 prevents fragmentation, improves vasofunction, and may provide a therapeutic target for improving cardiovascular complications among diabetics.Listen to this article's corresponding podcast @ http://ajpheart.podbean.com/e/mitochondrial-dynamics-impact-endothelial-function/.

Impact of DPP-4 inhibition on acute and chronic endothelial function in humans with type 2 diabetes on background metformin therapy.

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 8 weeks long separated by 4 weeks of washout. Endothelial function and plasma markers of endothelial activation (intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1)) were measured prior to and 2 hours following acute dosing of sitagliptin or placebo, as well as following 8 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. In conclusion, our findings suggest DPP-4 inhibition has a neutral effect on cardiovascular risk in patients without a history of heart failure or renal insufficiency. TRIAL REGISTRATION: NCT01859793.

Mineralocorticoid exposure and receptor activity modulate microvascular endothelial function in African Americans with and without hypertension.

Prior work suggests blood pressure in African Americans is more sensitive to the effects of aldosterone than in Caucasians. This mechanism may relate to a negative response of the vascular endothelium to aldosterone, including reduced glucose-6-phosphate dehydrogenase (G6PD) activity. Thirty-three African Americans (11 hypertensives, 22 controls) without evidence of diabetes or metabolic syndrome completed the protocol. The protocol included measurement of in vivo microvascular endothelial function by digital pulse arterial tonometry and ex vivo measurement of endothelial function by videomicroscopy of arterioles obtained from these same subjects with and without exposure to aldosterone or spironolactone. Systemic and arteriolar G6PD activities were also measured. In vivo and ex vivo microvascular endothelial function were impaired in African Americans with hypertension. One-hour exposure with aldosterone impaired endothelium-dependent vasodilation in arterioles from normotensive subjects, while 1 hour of spironolactone exposure reversed endothelial dysfunction in arterioles from hypertensive subjects. G6PD activity was impaired in hypertensive arterioles. Aldosterone-related endothelial dysfunction may be responsible for at least a portion of the greater blood pressure sensitivity to aldosterone in African Americans. This may be in part related to vascular suppression of G6PD activity.

miR-29 contributes to normal endothelial function and can restore it in cardiometabolic disorders.

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.

Associations of Reducing Sedentary Time With Vascular Function and Insulin Sensitivity in Older Sedentary Adults.

BACKGROUND: We previously reported increased moderate-intensity (3-6 metabolic equivalents (METs)) physical activity (PA) reverses aging-associated vascular endothelial dysfunction, a surrogate marker of cardiovascular risk. Whether reductions in sedentary time alone contribute to this improvement is unknown. METHODS: Data from 96 adults (aged ≥50 years) enrolled in a randomized control trial evaluating a 12-week intervention to increase PA in sedentary individuals were analyzed. Amount and intensity of activity were measured pre- and post-intervention by step count and accelerometry. Subjects were divided into 3 categories based on change in sedentary activity (<1. 5 METs): (i) ≥5% reduction in sedentary time, (ii) 0-4.99% reduction, and (iii) increase sedentary time. Vascular endothelial function was measured by brachial artery flow-mediated dilation (FMD%) pre- and post-intervention. RESULTS: Sedentary time decreased overall (P = 0.001), with a 101-minute decrease in category 1 (N = 27, P < 0.001), a 42-minute decrease in category 2 (N = 29, P = 0.003), and a 44-minute increase in category 3 (N = 40, P = 0.02). While FMD% increased in the entire study population (P = 0.008) over 12 weeks, no differences were observed between the categories (P = 0.73). In category 1, FMD% improvement was associated achievement of ≥20 minutes/day of moderate intensity PA in bouts ≥ 10 minutes in length. CONCLUSIONS: Reductions of up to 100 minutes of sedentary time per day over 12 weeks was not significantly associated with improved vascular endothelial function in older adults. FMD% was significantly higher among those with lower sedentary behavior and concomitant moderate-intensity PA of ≥20 minutes/day in bouts.

Risk-stratified screening for ischemic heart disease in kidney transplant candidates.

BACKGROUND: Few studies have examined the effectiveness of a risk-stratified approach to screening kidney transplantation candidates for ischemic heart disease (IHD). METHODS: We retrospectively reviewed records from all adult patients (n = 514) placed on the deceased donor kidney transplantation waiting list at a single center between January 1992 and June 2000. During this time there was a consistent policy for high-risk patients to undergo noninvasive stress testing and/or coronary angiography. We examined screening tests, the resulting interventions, and the incidence of subsequent IHD events (myocardial infarction, angioplasty, bypass surgery, or IHD death) among those screened and not screened. RESULTS: For 224 (43.6%) low-risk patients who were not screened, the actuarial incidence of an IHD event after listing (before or after transplantation) was only 0.5% at 1 year, 3.5% at 3 years, and 5.3% at 5 years. Screening 290 (56.4%) high-risk patients resulted in prophylactic angioplasty in 18 (6.2%), and bypass surgery in 8 (2.8%) before listing. After listing, 61 patients were screened, resulting in angioplasty in 6 (9.8%) and bypass surgery in 1 (1.6%). Of the 68 patients who ultimately had an IHD event after being placed on the waiting list, only 13 (19.4%) had not been screened. CONCLUSIONS: 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.

The Impact of Moderate Intensity Physical Activity on Cardiac Structure and Performance in Older Sedentary Adults.

BACKGROUND: Sedentary aging leads to adverse changes in vascular function and cardiac performance. We published improvements in vascular function with moderate intensity physical activity (PA) in continuous bouts. Whether moderate intensity PA also impacts cardiac structure and cardiovascular performance of the aging left ventricle (LV) is unknown. METHODS: We recruited and analyzed results from 102 sedentary older adults ages ≥ 50 from a randomized controlled trial with 3 study groups: control (group 1), a pedometer-only intervention (group 2), or a pedometer with an interactive website employing strategies to increase habitual physical activity (PA, group 3) for 12 weeks. Transthoracic echocardiograms were performed prior to and following the 12 week intervention period to assess cardiac morphology, left ventricular (LV) systolic performance, LV diastolic function, arterial and LV ventricular elastance. Step count and PA intensity/distribution were measured by pedometer and accelerometer. RESULTS: We found no significant changes in cardiac morphology. Further, we found no improvement in the aforementioned cardiac functional parameters. Comparing those who achieved the following benchmarks to those who did not showed no significant changes in cardiac structure or performance: 1)10,000 steps/day, 2) ≥ 30 minutes/day of moderate intensity physical activity, or 3) moderate intensity PA in bouts ≥ 10 minutes for ≥ 20 minutes/day. CONCLUSIONS: In sedentary older adults, increasing moderate intensity PA to currently recommend levels does not result in favorable changes in LV morphology or performance over 12 weeks. More prolonged exposure, higher PA intensity, or earlier initiation of PA may be necessary to see benefits.

Simultaneous treatment to attain blood pressure and lipid goals and reduced CV risk burden using amlodipine/atorvastatin single-pill therapy in treated hypertensive participants in a randomized controlled trial.

TOGETHER investigated whether targeting multiple cardiovascular (CV) risk factors using single-pill amlodipine/atorvastatin (AML/ATO) and therapeutic lifestyle changes (TLC) results in greater blood pressure (BP)/lipid control and additional reduction in estimated cardiovascular disease (CVD) risk compared with blood pressure intervention only using amlodipine (AML) + TLC. TOGETHER was a 6-week, randomized, double-blind, double-dummy trial using hypertensive participants with additional CV risk factors without CVD/diabetes. Participants were randomized to either AML/ATO (5 to 10/20 mg) + TLC or AML (5 to 10 mg) + TLC. The primary end point was the difference in proportion of participants attaining both BP (<140/90 mm Hg) and low-density lipoprotein cholesterol (LDL-C) (<100 mg/dL) goals at week 6. At week 6, 67.8% of participants receiving AML/ATO + TLC attained the combined BP/LDL-C goal versus 9.6% with AML + TLC (RD [A-B]: 58.2; 95% CI [48.1 to 68.4] P < 0.001; OR: 19.0; 95% CI 9.1 to 39.6; P < 0.001). Significant reductions from baseline in LDL-C, total cholesterol and triglycerides and estimated 10-year Framingham risk were also observed. Treatment with AML/ATO was well tolerated. In conclusion, a multifactorial CV management approach is more effective in achieving combined BP/LDL-C targets as well as CV risk reduction compared with BP intervention only in this patient population.