Multiple myeloma patients display weakened antibody responses to mRNA COVID vaccines

Weakened antibody responses to COVID-19 mRNA vaccines among most patients with multiple Read more

Precision medicine with multiple myeloma

“Precision medicine” is an anti-cancer treatment strategy in which doctors use genetic or other tests to identify vulnerabilities in an individual’s cancer subtype. Winship Cancer Institute researchers have been figuring out how to apply this strategy to multiple myeloma, with respect to one promising drug called venetoclax, in a way that can benefit the most patients. Known commercially as Venclexta, venetoclax is already FDA-approved for some forms of leukemia and lymphoma. Researchers had observed that multiple Read more

Promiscuous protein droplets regulate immune gene activity

Biochemists at Emory are achieving insights into how an important regulator of the immune system switches its function, based on its orientation and local environment. New research demonstrates that the glucocorticoid receptor (or GR) forms droplets or “condensates” that change form, depending on its available partners. The inside of a cell is like a crowded nightclub or party, with enzymes and other proteins searching out prospective partners. The GR is particularly well-connected and promiscuous, and Read more

cardiology

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.

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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.

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Detecting heart failure via wearable devices

Cardiology researchers have been eagerly taking up consumer electronic devices that include pulse oximeters. Being able to conveniently measure the level of oxygen in someone’s blood is a useful tool, whether one is interested in sleep apnea or COVID-19.

The news that the new Apple Watch includes a pulse oximeter prompted Lab Land to check in with Amit Shah, an Emory cardiologist who has been experimenting with similar devices to discriminate patients with heart failure from those with other conditions.

Shah, together with Shamim Nemati, now at UCSD, and bioinformatics chair Gari Clifford recently published a pilot study on detecting heart failure using the Samsung Simband. The Simband was a prototype device that didn’t make it to the consumer market, but it carried sensors for optical detection of blood volume changes (photoplethysmography), like on the Apple Watch. 

Heart failure causes symptoms such as shortness of breath and leg swelling, but other conditions such as anemia or lung diseases can appear similarly. The idea was to help discriminate people who might need an examination by echocardiogram (cardiac ultrasound).

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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.

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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

 

 

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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

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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

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Mapping shear stress in coronary arteries can help predict heart attacks

A heart attack is like an earthquake. When a patient is having a heart attack, it’s easy for cardiologists to look at a coronary artery and identify the blockages that are causing trouble. However, predicting exactly where and when a seismic fault will rupture in the future is a scientific challenge – in both geology and cardiology.

In a recent paper in Journal of the American College of Cardiology, Habib Samady, MD, and colleagues at Emory and Georgia Tech show that the goal is achievable, in principle. Calculating and mapping how hard the blood’s flow is tugging on the coronary artery wall – known as “wall shear stress” – could allow cardiologists to predict heart attacks, the results show.

Map of wall shear stress (WSS) in a coronary artery from someone who had a heart attack

“We’ve made a lot of progress on defining and identifying ‘vulnerable plaque’,” says Samady, director of interventional cardiology/cardiac catheterization at Emory University Hospital. “The techniques we’re using are now fast enough that they could help guide clinical decision-making.”

Here’s where the analogy to geography comes in. By vulnerable plaque, Samady means a spot in a coronary artery that is likely to burst and cause a clot nearby, obstructing blood flow. The researchers’ approach, based on fluid dynamics, involves seeing a coronary artery like a meandering river, in which sediment (atherosclerotic plaque) builds up in some places and erodes in others. Samady says it has become possible to condense complicated fluid dynamics calculations, so that what once took months now might take a half hour.

Previous research from Emory showed that high levels of wall shear stress correlate with changes in the physical/imaging characteristics of the plaque over time. It gave hints where bad things might happen, in patients with relatively mild heart disease. In contrast, the current results show that where bad things actually did happen, the shear stress was significantly higher.

“This is the most clinically relevant work we have done,” says Parham Eshtehardi, MD, a cardiovascular research fellow, looking back on the team’s previous research, published in Circulation in 2011.  Read more

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Mini-monsters of cardiac regeneration

After a heart attack, cardiac muscle cells die because they are deprived of blood and oxygen. In an adult human, those cells represent a dead end. They can’t change their minds about what kind of cell they’ve become.

In newborn babies, as well as in adult fish, the heart can regenerate after injury. Why can’t the human heart be more fishy? At Emory, researcher Jinhu Wang is seeking answers, which could guide the development of regenerative therapies.

“If we want to understand cardiac regeneration in mammals, we can look at it from the viewpoint of the fish,” he says.

A lot of research in regenerative medicine focuses on the potential of stem cells, which have not committed to become one type of tissue, such as brain, skin or muscle. Wang stresses that the ability of zebrafish hearts to regenerate does not originate from stem cells. It comes from the regular tissues. The cells are induced to go back in time and multiply, although their capacity to regenerate may vary with the age of the animal, he says.

Jinhu Wang, PhD manages an impressive set of fish tanks

Zebrafish hearts are simpler than mammals’: theirs have just two chambers, while ours have four. Nobel Prize winner Christiane Nusslein-Vollhard has promoted the use of zebrafish as a genetic model in developmental biology. Its embryos are transparent, making it easy to spot abnormalities.

Wang’s fish room in the basement of Emory’s Rollins Research Center contains more than 1000 fish tanks, with different sizes of cage for various ages and an elaborate water recycling system. The adult fish eat brine shrimp that are stored in vats in one corner of the lab. Read more

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Racial disparities in a CV biomarker

Because circulating progenitor cells repair blood vessels, they are a measure of regenerative capacity in the cardiovascular system. Cardiologist Arshed Quyyumi, MD and his colleagues at Emory Clinical Cardiovascular Research Institute have intensively studied this cell type as a marker of vulnerability or resilience.

A recent paper from Quyyumi’s team in Circulation Research examines circulating progenitor cells (CPCs) through the lens of racial disparity. The authors find that African-Americans tend to have lower levels of this regenerative biomarker:

In a large well-characterized biracial cohort, we demonstrate that black participants had significantly lower CPC counts compared with whites, even after adjustment for differences in demographic factors and CVD risk factors. These results were validated in an independent cohort. Thus, on average, after adjustment for sex and other CVD risk factors, blacks have CPC levels that are ≈15% to 30% lower compared with whites, even in subjects free of risk factors. CPC levels decline with age, reaching on average half the levels at age 80 compared with age 20. We found that blacks have CPC counts equivalent to those in whites who are 14 years older. CPC levels are higher after AMI as a result of mobilization because of injury. We show for first time that blacks have 30% to 35% lower CPC mobilization in the setting of AMI.

This is a tricky area to study. How many socioeconomic and environmental factors go into the racial disparities of cardiovascular disease risk? Diet. Exercise. Geography, education, access to healthcare. Air pollution. Psychological stress and inflammation associated with discrimination. It is possible to view CPCs as summing up many of these influences, analogous to the way hemoglobin A1C measurements integrate someone’s blood sugar levels over time as a marker of diabetes. Read more

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