POSE : A mathematical and visual modelling tool to guide energy aware code optimisation

Performance engineers are beginning to explore software-level optimisation as a means to reduce the energy consumed when running their codes. This paper presents POSE, a mathematical and visual modelling tool which highlights the relationship between runtime and power consumption. POSE allows developers to assess whether power optimisation is worth pursuing for their codes. We demonstrate POSE by studying the power optimisation characteristics of applications from the Mantevo and Rodinia benchmark suites. We show that LavaMD has the most scope for CPU power optimisation, with improvements in Energy Delay Squared Product (ED2P) of up to 30.59%. Conversely, MiniMD offers the least scope, with improvements to the same metric limited to 7.60%. We also show that no power optimised version of MiniMD operating below 2.3 GHz can match the ED2P performance of the original code running at 3.2 GHz. For LavaMD this limit is marginally less restrictive at 2.2 GHz

Atrial fibrillation and heart failure: Factors influencing the choice of oral anticoagulant.

Atrial fibrillation (AF) and heart failure (HF) frequently coexist. AF is identified in approximately one third of patients with HF and is linked to increased morbidity and mortality than from either condition alone. AF is relatively more common in HF with preserved ejection fraction (HFpEF) than with reduced ejection fraction (HFrEF). Nevertheless, the risk of stroke and systemic embolism (SSE) is significantly increased with both HF types and the absolute risk is heavily influenced by the presence and severity of associated additional stroke risk factors. The European Society of Cardiology has very recently introduced a third HF subtype entitled HF with mid-range ejection fraction (HFmrEF). At present oral anticoagulation is recommended for all patients with AF and HF, independent of HF type. In addition to warfarin there are currently four non-vitamin K oral anticoagulants (NOACs, previously called novel oral anticoagulants) that have been approved for the prevention of SSE. They consist of one direct thrombin inhibitor, dabigatran and three factor Xa inhibitors: rivaroxaban, apixaban and, most recently, edoxaban. In this review article we present an overview of the evidence to support the use of NOACs for the prevention of SSE in patients with AF and HF and review the influence of HF subtype and co-morbidities on the potential choice of oral anticoagulant

Arrhythmogenic actions of the Ca2+ channel agonist FPL-64716 in Langendorff-perfused murine hearts

The experiments explored the extent to which alterations in L-type Ca2+ channel-mediated Ca2+ entry triggers Ca2+-mediated arrhythmogenesis in Langendorff-perfused murine hearts through use of the specific L-type Ca2+ channel modulator FPL-64716 (FPL). Introduction of FPL (1 μm) resulted in a gradual development (>10 min) of diastolic electrical events and alternans in spontaneously beating hearts from which monophasic action potentials were recorded. In regularly paced hearts, they additionally led to non-sustained and sustained ventricular tachycardia (nsVT and sVT). Programmed electrical stimulation (PES) resulted in nsVT and sVT after 5–10 and >10 min perfusion, respectively. Pretreatments with nifedipine, diltiazem and cyclopiazonic acid abolished arrhythmogenic tendency induced by subsequent introduction of FPL, consistent with its dependence upon both extracellular Ca2+ entry and the degree of filling of the sarcoplasmic reticular Ca2+ store. Values for action potential duration at 90% repolarization when any of these agents were applied to FPL-treated hearts became indistinguishable from those shown by untreated control hearts, in contrast to earlier reports of their altering in long QT syndrome type 3 and hypokalaemic murine models for re-entrant arrhythmogenesis. These arrhythmic effects instead correlated with alterations in Ca2+ homeostasis at the single-cell level found in investigations of the effects of both FPL and the same agents in regularly stimulated fluo−3 loaded myocytes. These findings are compatible with a prolonged extracellular Ca2+ entry that potentially results in an intracellular Ca2+ overload and produces the cardiac arrhythmogenecity following addition of FPL

The contribution of refractoriness to arrhythmic substrate in hypokalemic Langendorff-perfused murine hearts

The clinical effects of hypokalemia including action potential prolongation and arrhythmogenicity suppressible by lidocaine were reproduced in hypokalemic (3.0 mM K(+)) Langendorff-perfused murine hearts before and after exposure to lidocaine (10 μM). Novel limiting criteria for local and transmural, epicardial, and endocardial re-excitation involving action potential duration (at 90% repolarization, APD(90)), ventricular effective refractory period (VERP), and transmural conduction time (Δlatency), where appropriate, were applied to normokalemic (5.2 mM K(+)) and hypokalemic hearts. Hypokalemia increased epicardial APD(90) from 46.6 ± 1.2 to 53.1 ± 0.7 ms yet decreased epicardial VERP from 41 ± 4 to 29 ± 1 ms, left endocardial APD(90) unchanged (58.2 ± 3.7 to 56.9 ± 4.0 ms) yet decreased endocardial VERP from 48 ± 4 to 29 ± 2 ms, and left Δlatency unchanged (1.6 ± 1.4 to 1.1 ± 1.1 ms; eight normokalemic and five hypokalemic hearts). These findings precisely matched computational predictions based on previous reports of altered ion channel gating and membrane hyperpolarization. Hypokalemia thus shifted all re-excitation criteria in the positive direction. In contrast, hypokalemia spared epicardial APD(90) (54.8 ± 2.7 to 60.6 ± 2.7 ms), epicardial VERP (84 ± 5 to 81 ± 7 ms), endocardial APD(90) (56.6 ± 4.2 to 63.7 ± 6.4 ms), endocardial VERP (80 ± 2 to 84 ± 4 ms), and Δlatency (12.5 ± 6.2 to 7.6 ± 3.4 ms; five hearts in each case) in lidocaine-treated hearts. Exposure to lidocaine thus consistently shifted all re-excitation criteria in the negative direction, again precisely agreeing with the arrhythmogenic findings. In contrast, established analyses invoking transmural dispersion of repolarization failed to account for any of these findings. We thus establish novel, more general, criteria predictive of arrhythmogenicity that may be particularly useful where APD(90) might diverge sharply from VERP

Gastrointestinal Bleeding in Patients With Atrial Fibrillation Treated With Rivaroxaban or Warfarin:ROCKET AF Trial

AbstractBackgroundGastrointestinal (GI) bleeding is a common complication of oral anticoagulation.ObjectivesThis study evaluated GI bleeding in patients who received at least 1 dose of the study drug in the on-treatment arm of the ROCKET AF (Rivaroxaban Once-daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) trial.MethodsThe primary outcome was adjudicated GI bleeding reported from first to last drug dose + 2 days. Multivariable modeling was performed with pre-specified candidate predictors.ResultsOf 14,236 patients, 684 experienced GI bleeding during follow-up. These patients were older (median age 75 years vs. 73 years) and less often female. GI bleeding events occurred in the upper GI tract (48%), lower GI tract (23%), and rectum (29%) without differences between treatment arms. There was a significantly higher rate of major or nonmajor clinical GI bleeding in rivaroxaban- versus warfarin-treated patients (3.61 events/100 patient-years vs. 2.60 events/100 patient-years; hazard ratio: 1.42; 95% confidence interval: 1.22 to 1.66). Severe GI bleeding rates were similar between treatment arms (0.47 events/100 patient-years vs. 0.41 events/100 patient-years; p = 0.39; 0.01 events/100 patient-years vs. 0.04 events/100 patient-years; p = 0.15, respectively), and fatal GI bleeding events were rare (0.01 events/100 patient-years vs. 0.04 events/100 patient-years; 1 fatal events vs. 5 fatal events total). Independent clinical factors most strongly associated with GI bleeding were baseline anemia, history of GI bleeding, and long-term aspirin use.ConclusionsIn the ROCKET AF trial, rivaroxaban increased GI bleeding compared with warfarin. The absolute fatality rate from GI bleeding was low and similar in both treatment arms. Our results further illustrate the need for minimizing modifiable risk factors for GI bleeding in patients on oral anticoagulation

Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation

Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death. Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups. To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery