Statin therapy and long-term adverse limb outcomes in patients with peripheral artery disease: insights from the REACH registry

Aims Due to a high burden of systemic cardiovascular events, current guidelines recommend the use of statins in all patients with peripheral artery disease (PAD). We sought to study the impact of statin use on limb prognosis in patients with symptomatic PAD enrolled in the international REACH registry. Methods Statin use was assessed at study enrolment, as well as a time-varying covariate. Rates of the primary adverse limb outcome (worsening claudication/new episode of critical limb ischaemia, new percutaneous/surgical revascularization, or amputation) at 4 years and the composite of cardiovascular death/myocardial infarction/stroke were compared among statin users vs. non-users. Results A total of 5861 patients with symptomatic PAD were included. Statin use at baseline was 62.2%. Patients who were on statins had a significantly lower risk of the primary adverse limb outcome at 4 years when compared with those who were not taking statins [22.0 vs. 26.2%; hazard ratio (HR), 0.82; 95% confidence interval (CI), 0.72-0.92; P = 0.0013]. Results were similar when statin use was considered as a time-dependent variable (P = 0.018) and on propensity analysis (P < 0.0001). The composite of cardiovascular death/myocardial infarction/stroke was similarly reduced (HR, 0.83; 95% CI, 0.73-0.96; P = 0.01). Conclusion Among patients with PAD in the REACH registry, statin use was associated with an ∼18% lower rate of adverse limb outcomes, including worsening symptoms, peripheral revascularization, and ischaemic amputations. These findings suggest that statin therapy not only reduces the risk of adverse cardiovascular events, but also favourably affects limb prognosis in patients with PA

New-onset atrial fibrillation in chronic coronary syndrome: the CLARIFY registry

Background and Aims: Data on new-onset atrial fibrillation (NOAF) in patients with chronic coronary syndromes (CCS) are scarce. This study aims to describe the incidence, predictors and impact on cardiovascular outcomes of NOAF in CCS patients. Methods: Data from the international (45 countries) CLARIFY registry (prospeCtive observational LongitudinAl RegIstry oF patients with stable coronary arterY disease) were used. Among 29,001 CCS outpatients without previously reported AF at baseline, patients with at least one episode of AF/flutter diagnosed during 5-year follow-up were compared with patients in sinus rhythm throughout the study. Results: The incidence rate of NOAF was 1.12 [95% confidence interval (CI) 1.06-1.18] per 100 patient-years (cumulative incidence at 5 years: 5.0%). Independent predictors of NOAF were increasing age, increasing body mass index, low estimated glomerular filtration rate, Caucasian ethnicity, alcohol intake and low left ventricular ejection fraction, while high triglycerides were associated with lower incidence. NOAF was associated with a substantial increase in the risk of adverse outcomes, with adjusted hazard ratios of 2.01 (95% CI 1.61-2.52) for the composite of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke, 2.61 (95% CI 2.04-3.34) for cardiovascular death, 1.64 (95% CI 1.07-2.50) for non-fatal myocardial infarction, 2.27 (95% CI 1.85-2.78) for all-cause death, 8.44 (95% CI 7.05-10.10) for hospitalization for heart failure and 4.46 (95% CI 2.85-6.99) for major bleeding. Conclusions: Among CCS patients, NOAF is common and is strongly associated with worse outcomes. Whether more intensive preventive measures and more systematic screening for AF would improve prognosis in this population deserves further investigation

Optimal or standard control of systolic and diastolic blood pressure across risk factor categories in patients with chronic coronary syndromes

Aims: Guidelines have lowered blood pressure (BP) targets to &lt;130/80 mmHg. We examined the benefit of intensive control for each BP component, versus the burden of other modifiable risk factors, in patients with chronic coronary syndromes (CCS). Methods and results: The CLARIFY registry (ISRCTN43070564) enrolled 32 703 CCS patients, from 2009−2010, with a 5-year follow-up. Patients with either BP component below European guideline safety boundaries (120/70 mmHg) were excluded, leaving 19 167 patients (mean age 63.8 ± 10.1 years, 78% men) in the present analysis. A multivariable-adjusted Cox proportional hazards model showed a gradual increase in cardiovascular risk (cardiovascular death, myocardial infarction, or stroke) when the number of uncontrolled risk factors (active smoking, no physical activity, low-density lipoprotein cholesterol ≥100 mg/dL, and diabetes with glycated haemoglobin ≥7%) increased [adjusted hazard ratio (HR): 1.34; 95% confidence interval (CI): 1.17−1.52, 1.65 (1.40−1.94), and 2.47 (1.90−3.21) for 1, 2, and 3 or 4 uncontrolled risk factors, respectively, versus 0], without significant interaction with BP. Although uncontrolled systolic (≥140 mmHg) and diastolic (≥90 mmHg) BP were both associated with higher risk than standard BP, standard BP was associated with higher risk than optimal control for only the diastolic component (adjusted HR: 1.08; 95% CI: 0.94−1.25 for systolic BP 130−139 versus 120−129 mmHg and 1.43; 95% CI: 1.27−1.62 for diastolic BP 80−89 versus 70−79 mmHg). Conclusions: Our results suggest that optimal BP target in CCS may be ≤139/79 mmHg, and that optimizing the burden of other risk factors should be prioritized over further reduction of systolic BP

A Comparison of the Effects of Random and Selective Mass Extinctions on Erosion of Evolutionary History in Communities of Digital Organisms

The effect of mass extinctions on phylogenetic diversity and branching history of clades remains poorly understood in paleobiology. We examined the phylogenies of communities of digital organisms undergoing open-ended evolution as we subjected them to instantaneous “pulse” extinctions, choosing survivors at random, and to prolonged “press” extinctions involving a period of low resource availability. We measured age of the phylogenetic root and tree stemminess, and evaluated how branching history of the phylogenetic trees was affected by the extinction treatments. We found that strong random (pulse) and strong selective extinction (press) both left clear long-term signatures in root age distribution and tree stemminess, and eroded deep branching history to a greater degree than did weak extinction and control treatments. The widely-used Pybus-Harvey gamma statistic showed a clear short-term response to extinction and recovery, but differences between treatments diminished over time and did not show a long-term signature. The characteristics of post-extinction phylogenies were often affected as much by the recovery interval as by the extinction episode itself

External applicability of the Effect of ticagrelor on Health Outcomes in diabEtes Mellitus patients Intervention Study (THEMIS) trial: An analysis of patients with diabetes and coronary artery disease in the REduction of Atherothrombosis for Continued Health (REACH) registry.

THEMIS is a double-blind, randomized trial of 19,220 patients with diabetes mellitus and stable coronary artery disease (CAD) comparing ticagrelor to placebo, in addition to aspirin. The present study aimed to describe the proportion of patients eligible and reasons for ineligibility for THEMIS within a population of patients with diabetes and CAD included in the Reduction of Atherothrombosis for Continued Health (REACH) registry. The THEMIS eligibility criteria were applied to REACH patients. THEMIS included patients ≥50 years with type 2 diabetes and stable CAD as determined by either a history of previous percutaneous coronary intervention, coronary artery bypass grafting, or documentation of angiographic stenosis of ≥50% of at least one coronary artery. Patients with prior myocardial infarction or stroke were excluded. In REACH, 10,156 patients had stable CAD and diabetes. Of these, 6515 (64.1%) patients had at least one exclusion criteria. From the remaining population, 784 patients did not meet inclusion criteria (7.7%) mainly due to absence of aspirin treatment (7.2%), yielding a 'THEMIS-eligible population' of 2857 patients (28.1% of patients with diabetes and stable CAD). The main reasons for exclusion were a history of myocardial infarction (53.1%), use of oral anticoagulation (14.5%), or history of stroke (12.9%). Among the 4208 patients with diabetes and a previous PCI, 1196 patients (28.4%) were eligible for inclusion in the THEMIS-PCI substudy. In a population of patients with diabetes and stable coronary artery disease, a sizeable proportion appear to be 'THEMIS eligible.' http://www. gov identifier: NCT01991795.The THEMIS trial was funded by AstraZeneca. The REACH registry was sponsored by Sanofi, Bristol-Myers Squibb, and the Waksman Foundation (Tokyo, Japan) and is endorsed by the World Heart Federation.S

The effects of low-impact mutations in digital organisms

<p>Abstract</p> <p>Background</p> <p>Avida is a computer program that performs evolution experiments with digital organisms. Previous work has used the program to study the evolutionary origin of complex features, namely logic operations, but has consistently used extremely large mutational fitness effects. The present study uses Avida to better understand the role of low-impact mutations in evolution.</p> <p>Results</p> <p>When mutational fitness effects were approximately 0.075 or less, no new logic operations evolved, and those that had previously evolved were lost. When fitness effects were approximately 0.2, only half of the operations evolved, reflecting a threshold for selection breakdown. In contrast, when Avida's default fitness effects were used, all operations routinely evolved to high frequencies and fitness increased by an average of 20 million in only 10,000 generations.</p> <p>Conclusions</p> <p>Avidian organisms evolve new logic operations only when mutations producing them are assigned high-impact fitness effects. Furthermore, purifying selection cannot protect operations with low-impact benefits from mutational deterioration. These results suggest that selection breaks down for low-impact mutations below a certain fitness effect, the <it>selection threshold</it>. Experiments using biologically relevant parameter settings show the tendency for increasing genetic load to lead to loss of biological functionality. An understanding of such genetic deterioration is relevant to human disease, and may be applicable to the control of pathogens by use of lethal mutagenesis.</p

Changing a bit at a time : patterns and mechanisms of microevolution and macroevolution in an electronic microcosm

While the use of microbial model systems in experimental evolution has made great contributions to our understanding of evolutionary processes, technological limitations and the problems of transparency they cause continue to inhibit their use in understanding even the most basic evolutionary phenomena. Conventional mathematical models are too constraining in that the range of genotypes and fitnesses must be designated at the outset, and so such models cannot be used to describe truly open-ended systems. In this thesis, I use Artificial Life technology to investigate patterns and mechanisms of evolution over short and long periods of time in a simulated chemostat-type system. The system may be rendered completely transparent, and is "open" in that genotypes with unique sequences and fitness arise unpredictably through mutation and selection.The results demonstrate that Artificial Life technology is an open-ended, yet tractable system that may be used satisfactorily to investigate problems that he beyond the reach of current theory and biotechnology. (Abstract shortened by UMI.

Data from: The tree balance signature of mass extinction is erased by continued evolution in clades of constrained size with trait-dependent speciation

The kind and duration of phylogenetic topological “signatures” left in the wake of macroevolutionary events remain poorly understood. To this end, we examined a broad range of simulated phylogenies generated using trait-biased, heritable speciation probabilities and mass extinction that could be either random or selective on trait value, but also using background extinction and diversity-dependence to constrain clade sizes. In keeping with prior results, random mass extinction increased imbalance of clades that recovered to pre-extinction size, but was a relatively weak effect. Mass extinction that was selective on trait values tended to produce clades of similar or greater balance compared to random extinction or controls. Allowing evolution to continue past the point of clade-size recovery resulted in erosion and eventual erasure of this signal, with all treatments converging on similar values of imbalance, except for very intense extinction regimes targeted at taxa with high speciation rates. Return to a more balanced state with extended post-extinction evolution was also associated with loss of the previous phylogenetic root in most treatments. These results further demonstrate that while a mass extinction event can produce a recognizable phylogenetic signal, its effects become increasingly obscured the further an evolving clade gets from that event, with any sharp imbalance due to unrelated evolutionary factors

SOD0.5_OUTPUTFILES

R-processed output files for SOD extinction, intensity = 0.