SciCombinator

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Concept: Atherosclerosis

299

To determine whether dietary pattern assessed by a simple self-administered food frequency questionnaire is associated with major adverse cardiovascular events (MACE) in high-risk patients with stable coronary artery disease.

Concepts: Atherosclerosis, Coronary artery disease, Heart, Blood vessel, Heart disease, Artery, Coronary circulation, Cardiovascular system

298

Background We evaluated whether rivaroxaban alone or in combination with aspirin would be more effective than aspirin alone for secondary cardiovascular prevention. Methods In this double-blind trial, we randomly assigned 27,395 participants with stable atherosclerotic vascular disease to receive rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily), rivaroxaban (5 mg twice daily), or aspirin (100 mg once daily). The primary outcome was a composite of cardiovascular death, stroke, or myocardial infarction. The study was stopped for superiority of the rivaroxaban-plus-aspirin group after a mean follow-up of 23 months. Results The primary outcome occurred in fewer patients in the rivaroxaban-plus-aspirin group than in the aspirin-alone group (379 patients [4.1%] vs. 496 patients [5.4%]; hazard ratio, 0.76; 95% confidence interval [CI], 0.66 to 0.86; P<0.001; z=-4.126), but major bleeding events occurred in more patients in the rivaroxaban-plus-aspirin group (288 patients [3.1%] vs. 170 patients [1.9%]; hazard ratio, 1.70; 95% CI, 1.40 to 2.05; P<0.001). There was no significant difference in intracranial or fatal bleeding between these two groups. There were 313 deaths (3.4%) in the rivaroxaban-plus-aspirin group as compared with 378 (4.1%) in the aspirin-alone group (hazard ratio, 0.82; 95% CI, 0.71 to 0.96; P=0.01; threshold P value for significance, 0.0025). The primary outcome did not occur in significantly fewer patients in the rivaroxaban-alone group than in the aspirin-alone group, but major bleeding events occurred in more patients in the rivaroxaban-alone group. Conclusions Among patients with stable atherosclerotic vascular disease, those assigned to rivaroxaban (2.5 mg twice daily) plus aspirin had better cardiovascular outcomes and more major bleeding events than those assigned to aspirin alone. Rivaroxaban (5 mg twice daily) alone did not result in better cardiovascular outcomes than aspirin alone and resulted in more major bleeding events. (Funded by Bayer; COMPASS ClinicalTrials.gov number, NCT01776424 .).

Concepts: Myocardial infarction, Atherosclerosis, Cardiovascular disease, Stroke, Low-density lipoprotein, Statistical significance, Infarction

291

Elevated levels of blood cholesterol are associated with cardiovascular disease, a leading cause of morbidity and mortality worldwide. Current therapies for addressing elevated blood cholesterol can be inadequate, ineffective or associated with side effects; therefore, the search for additional therapies is ongoing. This study evaluated Daily Body Restore (DBR), a proprietary blend of 9 probiotic organisms of the genera Lactobacillus and Bifidobacterium, and 10 digestive enzymes, for its effects on cholesterol metabolism using an in vitro system and a mouse model.

Concepts: Cell, Bacteria, Metabolism, Nutrition, Atherosclerosis, Low-density lipoprotein, Steroid, Hypercholesterolemia

279

Statins reduce LDL cholesterol and prevent vascular events, but their net effects in people at low risk of vascular events remain uncertain.

Concepts: Cholesterol, Myocardial infarction, Atherosclerosis, Low-density lipoprotein, Statin, Mevalonate pathway

269

Background The clinical effect of routine oxygen therapy in patients with suspected acute myocardial infarction who do not have hypoxemia at baseline is uncertain. Methods In this registry-based randomized clinical trial, we used nationwide Swedish registries for patient enrollment and data collection. Patients with suspected myocardial infarction and an oxygen saturation of 90% or higher were randomly assigned to receive either supplemental oxygen (6 liters per minute for 6 to 12 hours, delivered through an open face mask) or ambient air. Results A total of 6629 patients were enrolled. The median duration of oxygen therapy was 11.6 hours, and the median oxygen saturation at the end of the treatment period was 99% among patients assigned to oxygen and 97% among patients assigned to ambient air. Hypoxemia developed in 62 patients (1.9%) in the oxygen group, as compared with 254 patients (7.7%) in the ambient-air group. The median of the highest troponin level during hospitalization was 946.5 ng per liter in the oxygen group and 983.0 ng per liter in the ambient-air group. The primary end point of death from any cause within 1 year after randomization occurred in 5.0% of patients (166 of 3311) assigned to oxygen and in 5.1% of patients (168 of 3318) assigned to ambient air (hazard ratio, 0.97; 95% confidence interval [CI], 0.79 to 1.21; P=0.80). Rehospitalization with myocardial infarction within 1 year occurred in 126 patients (3.8%) assigned to oxygen and in 111 patients (3.3%) assigned to ambient air (hazard ratio, 1.13; 95% CI, 0.88 to 1.46; P=0.33). The results were consistent across all predefined subgroups. Conclusions Routine use of supplemental oxygen in patients with suspected myocardial infarction who did not have hypoxemia was not found to reduce 1-year all-cause mortality. (Funded by the Swedish Heart-Lung Foundation and others; DETO2X-AMI ClinicalTrials.gov number, NCT01787110 .).

Concepts: Oxygen, Epidemiology, Clinical trial, Myocardial infarction, Atherosclerosis, Randomness, Troponin, Oxygen therapy

263

The healthspan of mice is enhanced by killing senescent cells using a transgenic suicide gene. Achieving the same using small molecules would have a tremendous impact on quality of life and burden of age-related chronic diseases. Here, we describe the rationale for identification and validation of a new class of drugs termed senolytics, which selectively kill senescent cells. By transcript analysis, we discovered increased expression of pro-survival networks in senescent cells, consistent with their established resistance to apoptosis. Using siRNA to silence expression of key nodes of this network, including ephrins (EFNB1 or 3), PI3Kδ, p21, BCL-xL, or plasminogen activated inhibitor-2, killed senescent cells, but not proliferating or quiescent, differentiated cells. Drugs targeting these factors selectively killed senescent cells. Dasatinib eliminated senescent human fat cell progenitors, while quercetin was more effective against senescent human endothelial cells and mouse BM-MSCs. The combination of dasatinib and quercetin was effective in eliminating senescent MEFs. In vivo, this combination reduced senescent cell burden in chronologically aged, radiation-exposed, and progeroid Ercc1(-/Δ) mice. In old mice, cardiac function and carotid vascular reactivity were improved 5 days after a single dose. Following irradiation of one limb in mice, a single dose led to improved exercise capacity for at least 7 months following drug treatment. Periodic drug administration extended healthspan in Ercc1(-/∆) mice, delaying age-related symptoms and pathology, osteoporosis and loss of intervertebral disc proteoglycans. These results demonstrate the feasibility of selectively ablating senescent cells and the efficacy of senolytics for alleviating symptoms of frailty and extending healthspan. This article is protected by copyright. All rights reserved.

Concepts: DNA, Protein, Gene, Gene expression, Atherosclerosis, Organism, Copyright, KILL

262

Regular exercise training improves maximal oxygen uptake (VO2max), but the optimal intensity and volume necessary to obtain maximal benefit remains to be defined. A growing body of evidence suggests that exercise training with low-volume but high-intensity may be a time-efficient means to achieve health benefits. In the present study, we measured changes in VO2max and traditional cardiovascular risk factors after a 10 wk. training protocol that involved three weekly high-intensity interval sessions. One group followed a protocol which consisted of 4×4 min at 90% of maximal heart rate (HRmax) interspersed with 3 min active recovery at 70% HRmax (4-AIT), the other group performed a single bout protocol that consisted of 1×4 min at 90% HRmax (1-AIT). Twenty-six inactive but otherwise healthy overweight men (BMI: 25-30, age: 35-45 y) were randomized to either 1-AIT (n = 11) or 4-AIT (n = 13). After training, VO2max increased by 10% (∼5.0 mL⋅kg(-1)⋅min(-1)) and 13% (∼6.5 mL⋅kg(-1)⋅min(-1)) after 1-AIT and 4-AIT, respectively (group difference, p = 0.08). Oxygen cost during running at a sub-maximal workload was reduced by 14% and 13% after 1-AIT and 4-AIT, respectively. Systolic blood pressure decreased by 7.1 and 2.6 mmHg after 1-AIT and 4-AIT respectively, while diastolic pressure decreased by 7.7 and 6.1 mmHg (group difference, p = 0.84). Both groups had a similar ∼5% decrease in fasting glucose. Body fat, total cholesterol, LDL-cholesterol, and ox-LDL cholesterol only were significantly reduced after 4-AIT. Our data suggest that a single bout of AIT performed three times per week may be a time-efficient strategy to improve VO2max and reduce blood pressure and fasting glucose in previously inactive but otherwise healthy middle-aged individuals. The 1-AIT type of exercise training may be readily implemented as part of activities of daily living and could easily be translated into programs designed to improve public health.

Concepts: Blood, Myocardial infarction, Atherosclerosis, Blood pressure, Artery, Pulse, Cardiac cycle, Systole

254

Certain non-steroidal anti-inflammatory drugs (NSAIDs) (e.g., rofecoxib [Vioxx]) increase the risk of heart attack and stroke and should be avoided in patients at high risk of cardiovascular events. Rates of cardiovascular disease are high and rising in many low- and middle-income countries. We studied the extent to which evidence on cardiovascular risk with NSAIDs has translated into guidance and sales in 15 countries.

Concepts: Myocardial infarction, Atherosclerosis, Cardiovascular disease, Cyclooxygenase, Non-steroidal anti-inflammatory drug, Diclofenac, Celecoxib, Etoricoxib

253

We developed a new statistical framework to find genetic variants associated with extreme longevity. The method, informed GWAS (iGWAS), takes advantage of knowledge from large studies of age-related disease in order to narrow the search for SNPs associated with longevity. To gain support for our approach, we first show there is an overlap between loci involved in disease and loci associated with extreme longevity. These results indicate that several disease variants may be depleted in centenarians versus the general population. Next, we used iGWAS to harness information from 14 meta-analyses of disease and trait GWAS to identify longevity loci in two studies of long-lived humans. In a standard GWAS analysis, only one locus in these studies is significant (APOE/TOMM40) when controlling the false discovery rate (FDR) at 10%. With iGWAS, we identify eight genetic loci to associate significantly with exceptional human longevity at FDR < 10%. We followed up the eight lead SNPs in independent cohorts, and found replication evidence of four loci and suggestive evidence for one more with exceptional longevity. The loci that replicated (FDR < 5%) included APOE/TOMM40 (associated with Alzheimer's disease), CDKN2B/ANRIL (implicated in the regulation of cellular senescence), ABO (tags the O blood group), and SH2B3/ATXN2 (a signaling gene that extends lifespan in Drosophila and a gene involved in neurological disease). Our results implicate new loci in longevity and reveal a genetic overlap between longevity and age-related diseases and traits, including coronary artery disease and Alzheimer's disease. iGWAS provides a new analytical strategy for uncovering SNPs that influence extreme longevity, and can be applied more broadly to boost power in other studies of complex phenotypes.

Concepts: Alzheimer's disease, Gene, Cancer, Senescence, Atherosclerosis, Coronary artery disease, Gerontology, Aging-associated diseases

245

Background To assess potentially elevated cardiovascular risk related to new antihyperglycemic drugs in patients with type 2 diabetes, regulatory agencies require a comprehensive evaluation of the cardiovascular safety profile of new antidiabetic therapies. We assessed cardiovascular outcomes with alogliptin, a new inhibitor of dipeptidyl peptidase 4 (DPP-4), as compared with placebo in patients with type 2 diabetes who had had a recent acute coronary syndrome. Methods We randomly assigned patients with type 2 diabetes and either an acute myocardial infarction or unstable angina requiring hospitalization within the previous 15 to 90 days to receive alogliptin or placebo in addition to existing antihyperglycemic and cardiovascular drug therapy. The study design was a double-blind, noninferiority trial with a prespecified noninferiority margin of 1.3 for the hazard ratio for the primary end point of a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Results A total of 5380 patients underwent randomization and were followed for up to 40 months (median, 18 months). A primary end-point event occurred in 305 patients assigned to alogliptin (11.3%) and in 316 patients assigned to placebo (11.8%) (hazard ratio, 0.96; upper boundary of the one-sided repeated confidence interval, 1.16; P<0.001 for noninferiority). Glycated hemoglobin levels were significantly lower with alogliptin than with placebo (mean difference, -0.36 percentage points; P<0.001). Incidences of hypoglycemia, cancer, pancreatitis, and initiation of dialysis were similar with alogliptin and placebo. Conclusions Among patients with type 2 diabetes who had had a recent acute coronary syndrome, the rates of major adverse cardiovascular events were not increased with the DPP-4 inhibitor alogliptin as compared with placebo. (Funded by Takeda Development Center Americas; EXAMINE ClinicalTrials.gov number, NCT00968708 .).

Concepts: Myocardial infarction, Atherosclerosis, Hypertension, Angina pectoris, Diabetes mellitus, Obesity, Cardiovascular disease, Acute coronary syndrome