Molecular picture of how antiviral drug molnupiravir works

A cryo-EM structure showing how the antiviral drug molnupiravir drug Read more

Straight to the heart: direct reprogramming creates cardiac “tissue” in mice

New avenues for a quest many cardiologists have pursued: repairing the damaged heart like patching a Read more

The future of your face is plastic

An industrial plastic stabilizer becomes a skin Read more

Heart

Straight to the heart: direct reprogramming creates cardiac “tissue” in mice

Bypassing stem cells, Emory scientists can now create engineered heart tissue by directly reprogramming connective tissue cells in mice. The findings could provide new avenues for a quest many cardiologists have pursued: repairing the damaged heart like patching a roof. 

The results were published in Nature Biomedical Engineering

“This is the first study demonstrating direct tissue reprogramming from single adult cells from the body,” says senior author Young-sup Yoon, MD, PhD, professor of medicine at Emory University School of Medicine.

The research could potentially provide therapeutic options for millions of people with heart failure or other conditions. If heart muscle is damaged by a heart attack, the damaged or dead cells do not regenerate. Other scientists have shown they can create human heart tissue from induced pluripotent stem cells (example), but the Emory team showed that it is possible to avoid stem cells and the technologies required to create them, such as viruses. 

“Direct reprogramming into tissues that contain multiple cell types has not previously been reported, and it could open new pathways in the regenerative medicine field,” Yoon says. “It could serve as a platform for cell-based therapy by avoiding the problems of current stem cell-based approaches, and for disease modeling and drug development.”

First author Jaeyeaon Cho, PhD – currently at Yonsei University

Yoon is also part of the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory. First author Jaeyeaon Cho, PhD was a post-doctoral fellow at Emory and is currently a research assistant professor at Yonsei University College of Medicine in South Korea. Emory faculty members Rebecca Levit, MD and Hee Cheol Cho, PhD are co-authors on the paper.

Applying a combination of growth factors, regulatory microRNA and vitamins, the Emory researchers could create tissue that contains cardiac muscle, along with blood vessels containing endothelial cells and smooth muscle cells, and fibroblasts. In culture, the four cell types weave themselves together, bypassing any need to build heart tissue from separate components.

When transplanted onto the damaged heart of a mouse after a simulated heart attack, cells from the engineered tissue can migrate into the host heart, and improve its functioning. 

“In some previous studies, when a tissue patch composed of engineered cells and supportive biomaterials was transplanted to the damaged heart, there was little or no migration of cells from the patch to the host heart,” Yoon says.

From Cho et al. Nature Biomed Eng (2021). Migration of rCVT (reprogrammed cardiovascular tissue) into the host heart, 2 weeks after implantation. The white lines outline the heart muscle wall; only the implanted tissue fluoresces green, because of green fluorescent protein.

The critical elements of the direct reprogramming approach are microRNAs, which are “master keys” that control several genes at once. The researchers discovered the potential of one microRNA fortuitously; a pilot study examined the effect of applying several microRNAs active in the heart to fibroblasts. Unexpectedly, one of them generated endothelial cell and smooth muscle along with cardiac muscle cells.

The Emory researchers say that their engineered tissue does not exactly mimic natural heart tissue. The cardiac muscle cells do spontaneously contract, but they display immature characteristics. But after transplantation, the engrafted cells mature and integrate into the host heart. Over 16 weeks, the engrafted cells become indistinguishable from the host cardiac muscle cells. The researchers checked whether their transplanted tissue induced cardiac arrhythmias in the mice – a danger when introducing immature cells into the damaged heart — and they did not.

Yoon says it took almost 9 years to complete the project; an important next step is to test direct reprogramming with human cells.

This work was supported by grants from the National Heart Lung and Blood Institute (R01HL150877, R61HL 154116, R01HL125391) and a American Heart Association Transformative Project Award.

Posted on by Quinn Eastman in Heart Leave a comment

Regrowing adult heart muscle

In adulthood, our hearts generally can’t grow again in response to injury. Emory cardiology researchers Ahsan Husain and Nawazish Naqvi and their colleagues have been chipping away at this biological edifice in animal models, demonstrating that it is possible to remove constraints that prevent the heart from growing new muscle cells.

Husain and Naqvi’s teams accomplished this by combining the thyroid hormone T3 — already FDA approved — with siRNA-based inhibition of an enzyme called DUSP5. Their latest paper, published in the journal Theranostics, applies the combination in an animal model of drug-induced heart failure.

The anticancer drug doxorubicin is sometimes known as the “red devil”

The anticancer drug doxorubicin is notorious for its cardiotoxicity, yet it is a mainstay of treatment for breast cancer in adults and several types of cancer in children. Cardiotoxicity affects a fraction of breast cancer patients treated with doxorubicin (20 percent in some studies) and severely impacts mortality and quality of life.

In the mouse model, doxorubicin generates severe heart failure, with a 40 percent drop in left ventricular ejection fraction (LVEF), a measure of the heart’s pumping capacity. In response to the combination of T3 and DUSP5 siRNA, a large increase in LVEF is seen. The researchers also report that the treatment has a marked effect on the health of the animals, restoring their activity levels, grooming and posture. See the video for an example of a mouse heart treated with the T3/DUSP5 siRNA combination.

The results are potentially applicable to other situations when doctors would want to regrow or repair cardiac muscle. Husain reports plans for a clinical study in patients with drug-induced or other forms of heart failure, supported by a generous gift from the Atlanta-based ten Broeke Family Foundation.

Read more

Posted on by Quinn Eastman in Cancer, Heart Leave a comment

Simpler, more portable ECGs: Emory experts hosting computing challenge

An electrocardiogram or ECG is a basic non-invasive diagnostic tool for cardiologists, which conventionally uses 12 electrodes to gather information about electrical signals in the heart and its rhythms. Emory biomedical informatics specialists are hosting an international computing contest aimed at reducing that number as low as possible, so that future portable or wearable ECG devices can be smaller, more convenient and lower in cost.

“We are challenging the research community and industry to design algorithms that classify a large range of cardiac abnormalities using ECGs with varying numbers of channels,” says co-organizer Gari Clifford, PhD, chair of biomedical informatics at Emory University School of Medicine. “The aim is to determine how low we can go — that is, how many channels of data do we need to make an accurate diagnosis?”

The devices could aid in diagnosing common conditions such as atrial fibrillation or supraventricular tachycardia.

“Reduced-lead ECGs are more accessible than standard twelve-lead ECGs in many parts of the world, and the development of effective open-source algorithms for reading reduced-lead ECGs is key for tackling the growing problem of cardiac events internationally,” says co-organizer Matthew Reyna, PhD, assistant professor of biomedical informatics and pharmacology and chemical biology.

The 2021 PhysioNet/Computing in Cardiology Challenge is titled “Will Two Do? Varying Dimensions in Electrocardiography” and calls for designers to build an algorithm that can classify cardiac abnormalities based on 12, 6, 3 and 2-lead ECGs.

So that participants can try out their algorithms, contest organizers are sharing the world’s largest and most diverse set of publicly available ECG data: over 45,000 recordings from China, Europe, Russia and the USA. A similar amount of data has been hidden for the organizers to test the competitors’ algorithms, and a separate evaluation metric will reflects errors of misdiagnosis.

This year’s contest builds upon previous years; in 2017, the challenge was to classify atrial fibrillation based on a single lead, and last year’s was a challenge to diagnose a variety of cardiac problems using standard 12 leads. Contest participants are invited to submit an abstract describing their algorithm, open-source code for their algorithm and a paper on their work.

The contest culminates in the Computing in Cardiology conference, scheduled for September 12-15 in Brno, Czech Republic. More information about the contest is available at PhysioNet.org and requirements for entry and the schedule are detailed at the PhysioNet/Computing in Cardiology Challenge 2021 site. The initial deadline for applying to enter the contest is April 9, 2021.

The contest is part of PhysioNet, an archive of biomedical computing resources supported by the National Institute of Biomedical Imaging and Bioengineering (R01EB030362). It is being co-sponsored by the Gordon and Betty Moore Foundation, Google and MathWorks. Complementary MATLAB licenses and Google Cloud Platform credits are being made available for this year’s challenge. The sponsors are also making it possible to offer several prizes worth several thousand dollars.

Posted on by Quinn Eastman in Heart Leave a comment

Dissecting atherosclerosis at the single cell level: tasting each piece of a fruit salad

More than a decade ago, Hanjoong Jo and colleagues developed an elegant animal model allowing the dissection of atherosclerosis. It was the first to definitively show that disturbed patterns of blood flow determine where atherosclerotic plaques will later appear.

In atherosclerosis, arterial walls thicken and harden because of a gradual build-up of lipids, cholesterol and white blood cells, which occurs over the course of years in humans. The Jo lab’s model involves restricting blood flow in the carotid artery of mice, which are fed a high-fat diet and also have mutations in a gene (ApoE) involved in processing fat and cholesterol. The physical intervention causes atherosclerosis to appear within a couple weeks. Inflammation in endothelial cells, which line blood vessels, is visible within 48 hours.

The shear-sensitive gene LMO4 is turned on in the middle boxed region, but not the other two, because of disturbed flow in that area of the aorta

Now Jo’s lab has combined the model with recently developed techniques that permit scientists to see molecular changes in single cells. The results were published Tuesday in Cell Reports.

Jo’s lab is in the Wallace H. Coulter Department of Biomedical Engineering at Emory and Georgia Tech.

Previously, when they saw inflammation in blood vessels, researchers could not distinguish between intrinsic changes in endothelial cells and immune or other cells infiltrating into the blood vessel lining.

A video made by Harvard scientists who developed the single cell techniques describes the difference like this. Looking at the molecules in cells with standard techniques is like making a fruit smoothie – everything is blended together. But single cell techniques allow them to taste and evaluate each piece of fruit individually.

Read more

Posted on by Quinn Eastman in Heart Leave a comment

Elevated troponin after exercise refines cardiac risk prediction

High levels of troponin, a sign of acute stress to the heart, in the blood reveal whether someone recently experienced a heart attack. Advances in testing have made it possible to detect much lower levels of troponin — but still elevated above zero. For example, elevated troponin can be detected after strenuous exercise, even in healthy young athletes.

With that exercise-induced response in mind, Emory Clinical Cardiovascular Research Institute investigators have been studying whether high-sensitivity troponin measurements might be used to replace cardiac stress tests. These procedures are expensive and sometimes involve nuclear imaging, which exposes patients to radiation.

A new paper in American Journal of Cardiology shows how elevated high-sensitivity troponin levels in response to exercise on a treadmill can predict future outcomes in patients with coronary artery disease — better than stress tests with imaging.

Read more

Posted on by Quinn Eastman in Heart Leave a comment

Model of a sticky situation

Here’s an example of how 3D printing can be applied to pediatric cardiology. It’s also an example of how Georgia Tech, Emory and Children’s Healthcare of Atlanta all work together.

Biomedical engineers used a modified form of gelatin to create a model of pulmonary arteries in newborn and adolescent patients with a complex (and serious) congenital heart defect: tetralogy of Fallot with pulmonary atresia. The model allowed the researchers to simulate surgical catheter-based intervention in vitro.

The results were recently published in Journal of the American Heart Association. Biomedical engineer Vahid Serpooshan and his lab collaborated with Sibley Heart Center pediatric cardiologist Holly Bauser-Heaton; both are part of the Children’s Heart Research and Outcomes Center.

“This is a patient-specific platform, created with state-of-the-art 3D bioprinting technology, allowing us to optimize various interventions,” Serpooshan says.

Model of an adolescent patient’s pulmonary arteries, created by 3D printing. From Tomov et al JAHA (2019) via Creative Commons

 

 

Posted on by Quinn Eastman in Heart Leave a comment

Overcoming cardiac pacemaker “source-sink mismatch”

Instead of complication-prone electronic cardiac pacemakers, biomedical engineers at Georgia Tech and Emory envision the creation of “biological pacemakers.” Hee Cheol Cho and colleagues have been taking advantage of his work on a gene called TBX18 that can reprogram heart muscle cells into specialized pacemaker cells.

Graduate student Sandra Grijalva in lab

Every heartbeat originates from a small group of cells in the heart called the sinoatrial node. How these cells drive contractions in the relatively massive, and electrically sturdy, rest of the heart is a problem cardiology researchers call the “source-sink mismatch.” Until Cho’s innovations, it was only possible to isolate a handful of pacemaker cells from animal hearts, and the isolated cells could not be cultured.

Cho and colleagues recently published a paper in Advanced Science describing TBX18-induced pacemaker cell spheroids, a platform for studying source-sink mismatch in culture

Graduate student Sandra Grijalva is the first author of the paper. We first spotted Grijalva’s work when it was presented at the American Heart Association meeting in 2017. Read more

Posted on by Quinn Eastman in Heart Leave a comment

Take heart, Goldilocks — and get more sleep

Sleeping too little or too much increases the risk of cardiovascular events and death in those with coronary artery disease, according to a new paper from Emory Clinical Cardiovascular Research Institute.

Others have observed a similar U-shaped risk curve in the general population, with respect to sleep duration. The new study, published in American Journal of Cardiology, extends the finding to people who were being evaluated for coronary artery disease.

Arshed Quyyumi, MD and colleagues analyzed data from a registry of 2846 patients undergoing cardiac catheterization at Emory. The “sweet spot” appeared to be those who report sleeping between 6.5 and 7.5 hours per night.

39 percent of patients with coronary artery disease reported that they slept fewer than 6.5 hours per night, and 35 percent slept longer than 7.5 hours. For the next few years, both groups had higher risks of all-cause mortality: elevated risk of 45 percent and 41 percent, respectively. Patients were followed for an average of 2.8 years.

The extreme ends of sleep duration both had even higher risk: people who reported less than 4.5 hours per day had almost double mortality risk (96 percent), and those more than 8.5 hours had 84 percent higher mortality risk.

Patients with short sleep durations also had higher cardiovascular mortality (48 percent), but adjusting for cardiovascular risk factors attenuated the association between long sleep duration and CV risk.

A detailed assessment of someone’s sleep can require PSG (polysomnography). In this study,  researchers were able to get information by simply asking about sleep duration.

The participants in the Emory study were simply asked: “How many hours of sleep do you usually get each night (or when you usually sleep)?” This question may not always be answered accurately, since time in bed isn’t necessarily time asleep. Still, the broad strokes show that the sleep-CV health relationship is robust.

“What is most stunning to me are that these data were collected from cardiac patients about to undergo an invasive procedure, who still reported an aspect of their sleep that was meaningful and predictive of future survival,” says Donald Bliwise, PhD, a specialist in sleep and aging research who is a co-author on the Emory study. “Often, epidemiologic studies collect data far away from a clinic setting, where anxiety is less and estimations may be sharper. We have here in this clinical study beautiful evidence that estimates made ‘from the gurney’ may be just as meaningful as those collected in the field.”

Quyyumi says if patients with heart disease are sleeping poorly, it’s important to recognize that they are at higher risk and counsel them regarding getting more sleep, as well as factors that can disrupt sleep, such as caffeine, alcohol and looking at screens late in the day.

More specific treatments may depend what is interfering with high-quality sleep in a given patient. Several conditions can lead to difficulty sleeping, such as sleep apnea, restless leg syndrome, as well as depression, all of which have been linked with heart disease. Physiologically, several mechanisms are probably exerting their effects, such as weakening circadian rhythms and sleep fragmentation with aging, and obesity/metabolic syndrome driving inflammation. Read more

Posted on by Quinn Eastman in Heart Leave a comment

Fetal alcohol cardiac toxicity – in a dish

Alcohol exposure is known to perturb fetal heart development; half of all children with fetal alcohol syndrome have congenital heart defects, such as arrhythmias or structural abnormalities. Chunhui Xu and colleagues recently published a paper in Toxicological Scienceson how human cardiac muscle cells, derived from iPS (induced pluripotent stem cells), can be used as a model for studying the effects of alcohol.

Alcohol-induced cardiac toxicity is usually studied in animal models, but human cells are different, and a cell-culture based approach could make it easier to study the effects of alcohol and possible interventions more easily.

Red shows toxic effects of alcohol on iPS-derived cardiomyocytes

Xu and her colleagues observed that high levels of alcohol damaged cardiac muscle cells and put them under oxidative stress. But even at relatively low concentrations of alcohol, the researchers also saw perturbations in cells’ electrical activity and the ability to contract, which reasonably matches the effects of alcohol on human heart development. The lowest level tested was 17 millimolar – the legal limit for driving in most states (0.08% blood alcohol content). Read more

Posted on by Quinn Eastman in Heart Leave a comment

Nogueira’s trailblazing work on stroke recognized

Neurologist Raul Nogueira’s clinical research on thrombectomy, a life-saving intervention after ischemic stroke, is getting recognition – in non-traditional ways.

A group of Korean neurologists and radiologists recently analyzed the most mentioned neurointervention papers by “altmetrics.” Altmetrics measure the impact a research paper has by looking at online discussion – in international news media, blogs, Wikipedia and social media platforms, as well as attention from post-publication peer-review and patient advocacy groups.

Raul Noguiera, MD

As it turned out, one of Nogueira’s papers was the most mentioned and he was also an author on 12 of the 101 top articles. Nogueira was the first author of a 2018 paper in the New England Journal of Medicine, reporting on results from the DAWN trial. The study was a landmark, extending the time window for thrombectomy to 24 hours. Those treated with thrombectomy in addition to standard care regained significantly more functional independence after 90 days than those who received standard treatment only.

Another recent example that fits within altmetrics: The DAWN study was cited by the American Heart Association as a top research finding in stroke for 2018.

Nogueira is a professor of neurology, neurosurgery and radiology at Emory University School of Medicine and director of endovascular services at Grady Memorial Hospital’s Marcus Stroke & Neuroscience Center. Thrombectomy is the removal of a clot from a blood vessel in the brain – in this case, through a mechanical stent-retriever device.

Posted on by Quinn Eastman in Heart, Neuro Leave a comment
1 2 3 4 5 6 7 8 9 10 11   Next »