The ENVISAGE-TAVI AF trial is the largest to investigate an edoxaban-based strategy in this patient population compared with warfarin, which is currently the standard of care. It demonstrates that edoxaban is non-inferior to warfarin. The results, which could lead to an alternative treatment strategy, were announced Saturday, August 28, as a late-breaking clinical trial at the ESC Congress 2021 from the European Society of Cardiology and simultaneously published in The New England Journal of Medicine.

“Atrial fibrillation after transcatheter aortic valve replacement is common, especially among older patients, but there has been little research on the optimal treatment strategies, and this has resulted in heterogeneous use of anticoagulants in clinical practice. TAVR patients are typically very elderly and possess numerous comorbidities; therefore they are at high risk for all sorts of adverse events, both ischemic and bleeding. It is important to further understand what treatment is most effective to prevent devastating complications,” says lead investigator George Dangas, MD, PhD, Professor of Medicine (Cardiology) and Director of Cardiovascular Innovation at the Zena and Michael A. Wiener Cardiovascular Institute at the Icahn School of Medicine at Mount Sinai. “Based on these results, the trial met its primary endpoint of non-inferiority and edoxaban may be a plausible alternative to warfarin, albeit with attention to increased bleeding with this agent in this study population.”

Cardiologists prescribe antithrombotic agents — specifically warfarin, a vitamin K antagonist — to prevent thromboembolic complications in patients who have TAVR, a minimally invasive heart procedure to replace the aortic valve. Choosing the optimal antithrombotic regimen remains challenging, especially in patients with an underlying condition like AF — irregular rapid heartbeat that impacts blood flow — that requires the use of anticoagulants. Past studies have shown anywhere between 20-40 percent of TAVR patients have AF and a large proportion of them are frail, so a main challenge in managing their care involves balancing the risks of bleeding and stroke.

Until now, there has been minimal research into the optimal oral anticoagulation therapy in TAVR patients.

Mount Sinai researchers led an international trial across 173 centers in 14 countries to compare the safety and efficacy of edoxaban versus warfarin in AF patients who need oral anticoagulation. To determine efficacy, they looked at combined adverse clinical events including all-cause death, thromboembolic events, and major bleeding. For safety they looked at serious bleeding events. Investigators randomized 1,426 patients 5 to 12 days after TAVR to either warfarin (with or without antiplatelet therapy) or 60 mg daily oral edoxaban (with or without antiplatelet therapy). They followed up with patients for up to three years following TAVR (average of 18 months). The study findings showed that edoxaban was noninferior to warfarin for efficacy as assessed by a composite set of ischemic and bleeding adverse events. At the same time, edoxaban led to some higher bleeding complications (mainly gastrointestinal) when compared to warfarin (or its analogs as available in each country).

Interestingly, patients who received a lower dose of edoxaban (30 mg instead of 60 mg) due to poor kidney function or low body weight appeared to have similar rates of adverse thromboembolic and bleeding events to those on warfarin.

“The next step would be to establish in large randomized trials the optimal anticoagulant dose according to different bleeding-ischemic risk profiles,” adds Dr. Dangas. “It seems that lowering the edoxaban dosage when indicated and avoiding patients with mandatory antiplatelet therapy because of their elevated bleeding risk is reasonable safety advice from the clinical point of view. We will be conducting a detailed analysis on various types of bleeding in the near future. ENVISAGE-TAVI AF suggests that treatment with edoxaban can be valuable in the management of this high-risk population of AF patients after TAVI.”

ENVISAGE-TAVI AF was sponsored by Daiichi Sankyo Inc. with a scientific collaboration between scientists of Icahn Mount Sinai and Global Specialty Medical Affairs of Daiichi Sankyo.

Animals as small and soft as tardigrades seldom have legs and almost never bother walking. For example, round worms of similar size and body type thrash about, slithering their doughy forms over unpredictable substrates. Yet the water bear, a micro-animal so distinct that scientists were forced to assign it to its own phylum, uses eight stubby legs to improbably propel itself through marine and freshwater sediment, across desert dunes, and beneath the soil.

Now, a new study in PNAS analyzes tardigrade gaits and finds that water bears walk in a manner most closely resembling that of insects 500,000 times their size. The discovery implies the existence of either a common ancestor or an evolutionary advantage that explains why one of the smallest and squishiest creatures evolved to walk just like larger, hard-bodied insects.

“Tardigrades have a robust and clear way of moving — they’re not these clumsy things stumbling around in the desert or in leaf litter,” says Jasmine Nirody, a fellow in Rockefeller’s Center for Studies in Physics and Biology. “The similarities between their locomotive strategy and that of much larger insects and arthropods opens up several very interesting evolutionary questions.”

Smooth runners

Nirody and colleagues first determined how water bears walk and run. “If you watch tardigrades under a light microscope for long enough, you can capture a wide range of behavior,” Nirody says. “We didn’t force them to do anything. Sometimes they would be really chill and just want to stroll around the substrate. Other times, they’d see something they like and run towards it.”

Nirody found that, at their most leisurely, water bears lumber about half a body length per second. At full throttle, their loping strides carried them two body lengths in the same amount of time. But the surprise came when she observed how a water bear’s feet contact the ground as it gains momentum. Unlike vertebrates, which have distinct gaits for each speed — picture a horse’s hooves as it transitions from a walk to a gallop — tardigrades run more like insects, scurrying at increasing speeds without ever changing their basic stepping patterns.

“When vertebrates switch from walking to running, there is a discontinuity,” Nirody says. “With arthropods, all stepping patterns exist along the same continuum.”

Ancient coordination

Why do tardigrades share a locomotive strategy with much larger, hard-bodied insects?

One possible explanation is that tardigrades, long assumed to fit neatly into no existing taxonomy, may share common ancestors — and even a common neural circuit — with insects such as fruit flies, ants, and other segmented scurrying creatures. In fact, some scientists advocate classifying tardigrades within the proposed panarthropod clade, a catchall group that would assign common shelf space to insects, crustaceans, velvet worms, and water bears.

Another possibility is that there is no ancestral connection between tardigrades and arthropods, but that the unrelated groups of organisms independently arrived at the same walking and running strategies because they were evolutionarily advantageous. Perhaps the best way to navigate unpredictable terrain with a microscopic body is to plod like a water bear.

Nirody is equally fascinated by both possibilities. “If there is some ancestral neural system that controls all of panarthropod walking, we have a lot to learn,” she says. “On the other hand, if arthropods and tardigrades converged upon this strategy independently, then there’s much to be said about what makes this strategy so palatable for species in different environments.”

Beyond the implications for evolutionary biology and the study of animal locomotion, the findings may have ramifications for the burgeoning fields of soft and microscale robotics.

By studying how small animals evolved to move across challenging environments, scientists may be able to design robots that can more efficiently squeeze into small spaces or operate at the microscale. “We don’t know much about what happens at the extremes of locomotion — how to make an efficient small walker, or how soft-bodied things should move,” Nirody says.

“Tardigrades are an important porthole into soft-bodied, microscale locomotion.”

Researchers discovered that chlorpyrifos, which is banned for use on foods in Canada but widely sprayed on fruits and vegetables in many other parts of the world, slows down the burning of calories in the brown adipose tissue of mice. Reducing this burning of calories, a process known as diet-induced thermogenesis, causes the body to store these extra calories, promoting obesity.

Scientists made the discovery after studying 34 commonly used pesticides and herbicides in brown fat cells and testing the effects of chlorpyrifos in mice fed high calorie diets. Their findings were published in Nature Communications and could have important implications for public health.

“Brown fat is the metabolic furnace in our body, burning calories, unlike normal fat that is used to store them. This generates heat and prevents calories from being deposited on our bodies as normal white fat. We know brown fat is activated during cold and when we eat,” said senior author Gregory Steinberg, professor of medicine and co-director of the Centre for Metabolism, Obesity, and Diabetes Research at McMaster.

“Lifestyle changes around diet and exercise rarely lead to sustained weight loss. We think part of the problem may be this intrinsic dialling back of the metabolic furnace by chlorpyrifos.”

Steinberg said chlorpyrifos would only need to inhibit energy use in brown fat by 40 calories every day to trigger obesity in adults, which would translate to an extra five lbs of weight gain per year.

He said that while several environmental toxins including chlorpyrifos have been linked to rising obesity rates in both humans and animals, most of these studies have attributed weight gain to increases in food intake and not the burning of calories.

While the use of chlorpyrifos on foods is banned in Canada, imported produce may still be treated with it.

“Although the findings have yet to be confirmed in humans, an important consideration, is that whenever possible consume fruits and vegetables from local Canadian sources and if consuming imported produce, make sure it is thoroughly washed,” said Steinberg.

External funding for the study was provided by the Canadian Institutes of Health Research.

Story Source:

Materials provided by McMaster University. Note: Content may be edited for style and length.