Stage fright: don't get over it, get used to it

Many can feel empathy with the situation Banerjee describes: facing “a room full of scientists, who for whatever reason, did not look very happy that Read more

Beyond birthmarks and beta blockers, to cancer prevention

Ahead of this week’s Morningside Center conference on repurposing drugs, we wanted to highlight a recent paper in NPJ Precision Oncology by dermatologist Jack Arbiser. It may represent a new chapter in the story of the beta-blocker propranolol. Several years ago, doctors in France accidentally discovered that propranolol is effective against hemangiomas: bright red birthmarks made of extra blood vessels, which appear in infancy. Hemangiomas often don’t need treatment and regress naturally, but some can lead Read more

Drying up the HIV reservoir

Wnt is one of those funky developmental signaling pathways that gets re-used over and over again, whether it’s in the early embryo, the brain or the Read more

cardiology

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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Stem cells driven into selective suicide

The term “stem cell” is increasingly stretchy. Orthopedic specialists have been using it when referring to bone marrow concentrate or platelet rich plasma, which are marketed as treatments for joint pain. At Lab Land, we have an interest in pluripotent stem cells, which can differentiate into many types of tissues.

For many applications, the stem cells are actually impurities that need to be removed, because pluripotent stem cells are capable of becoming teratomas, a type of tumor. For quality control, researchers want to figure out how to ensure that the stem-cell-derived cardiac muscle or neural progenitor or pancreas cells (or whatever) are as pure as possible.

Cardiologist and stem cell expert Chunhui Xu has been continuing a line of investigation on this topic. In a recent paper in ACS Chemical Biology, her team showed that “suicide-inducing molecules” can eliminate undifferentiated stem cells from a mixture of cells. This stem-cell-derived mixture was mostly cardiac muscle cells or their progenitors, which Xu’s team wants to use for therapeutic purposes.

Other labs have used metabolic selection – depriving cells of glucose and giving them only lactate –as a selective method for eliminating stem cells from cardiac muscle cultures. This paper shows that the “selective suicide” method works for early-stage differentiation cultures, containing cardiac progenitors, while the metabolic method works only for late-stage cultures contains beating cardiomyocytes.

Read more

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Blue plate special: express delivery to the heart

The anti-arrhythmia drug amiodarone is often prescribed for control of atrial fibrillation, but can have toxic effects upon the lungs, eyes, thyroid and liver. Emory and Georgia Tech scientists have developed a method for delivering amiodarone directly to the heart in an extended release gel to reduce off-target effects.

The results were published in Circulation: Arrhythmia and Electrophysiology.

The senior author is Rebecca Levit, MD, assistant professor of medicine (cardiology) at Emory University School of Medicine and adjunct in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory. Graduate student Jose Garcia – part of co-author Andres Garcia’s lab at Georgia Tech — and Peter Campbell, MD are the first authors.

An amiodarone-containing gel was applied to the outside of the heart by a minimally invasive procedure. After a one-time delivery, the gel could reduce the duration of atrial fibrillation and the likelihood of its development for a month in a pig model. The researchers were also able to show that amiodarone did not have toxic effects on the pigs’ lungs.

As noted in the book Off-label prescribing – Justifying unapproved medicine, amiodarone is “one of the very few drugs approved by the FDA in modern times without rigorous randomized clinical trials.” Read more

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For nanomedicine, cell sex matters

The biological differences between male and female cells may influence their uptake of nanoparticles, which have been much discussed as specific delivery vehicles for medicines.

Biomedical engineer Vahid Serpooshan, PhD

New Emory/Georgia Tech BME faculty member Vahid Serpooshan has a recent paper published in ACS Nano making this point. He and his colleagues from Brigham and Women’s Hospital and Stanford/McGill/UC Berkeley tested amniotic stem cells, derived from placental tissue. They found that female amniotic cells had significantly higher uptake of nanoparticles (quantum dots) than male cells. The effect of cell sex on nanoparticle uptake was reversed in fibroblasts. The researchers also found out that female versus male amniotic stem cells exhibited different responses to reprogramming into induced pluripotent stem cells (iPSCs).

Female human amniotic stem cells with nanoparticles .Green: quantum dots/ nanoparticles; red: cell staining; blue: nuclei.

“We believe this is a substantial discovery and a game changer in the field of nanomedicine, in taking safer and more effective and accurate steps towards successful clinical applications,” says Serpooshan, who is part of the Department of Pediatrics and the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory.

Serpooshan’s interests lie in the realm of pediatric cardiology. His K99 grant indicates that he is planning to develop techniques for recruiting and activating cardiomyoblasts, via “a bioengineered cardiac patch delivery of small molecules.” Here at Emory, he joins labs with overlapping interests such as those of Mike Davis, Hee Cheol Cho and Nawazish Naqvi. Welcome!

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Elevated (but still low) troponin as a long term cardio biomarker

This weekend (March 10) at the American College of Cardiology meeting, data will emerge on whether expensive and much-discussed PCSK9 inhibitors can lower the risk of heart disease as much as they reduce LDL cholesterol.

To help doctors decide who should take cholesterol-lowering drugs that cost thousands of dollars a year, the focus of discussion could fall on risk models, such as the Framingham score and its successors, or other biomarkers besides various forms of cholesterol. What a coincidence! We have experts on those topics at Emory Clinical Cardiovascular Research Institute: ECCRI co-director Arshed Quyyumi, MD and Laurence Sperling, MD, Director of Preventive Cardiology at the Emory Clinic.

Cardiologists led by Quyyumi have a recent paper in Journal of the American Heart Association looking at troponin as a long-term cardiovascular disease biomarker. Troponin is familiar to cardiologists because it is a sign of acute damage to the heart muscle. If someone with chest pain goes to the emergency department of a hospital, a test for troponin in the blood can say whether a heart attack occurred.

However, as clinical tests for troponin have become more sensitive in the last decade, interpretation has moved past just a “yes/no” question. The levels of troponin now detectable are much smaller than those used to confirm a heart attack. Elevated troponin can be detected in all sorts of situations where the heart is under stress, including after strenuous exercise in healthy individuals. The “optimal cutoff” the Emory authors use in some of their statistical analyses is 5.2 picograms per milliliter. This graph, derived from a 2011 Circulation paper, illustrates just how low that is. Read more

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When circulating ambulances disappear

Someone driving around a city on a regular basis will see ambulances. At times they’re going somewhere fast; sometimes they’re just driving. What if, on a given day, fewer ambulances are visible?

One possible conclusion might be: the ambulances are away responding to a group of people who need help. This effect resembles what Arshed Quyyumi and colleagues from Emory Clinical Cardiovascular Research Institute observed in a recent paper, published in the Journal of the American Heart Association.

Arshed Quyyumi, MD

Quyyumi’s team looked at progenitor cells, which circulate in the blood and are attracted to sites of injury.  In a group of 356 patients with stable coronary artery disease, the researchers saw that some (31 percent) had “ExMI” – exercise-mediated myocardial ischemia. That means impairments in blood flow were visible via cardiac imaging under the stress of exercise. This is a relatively mild impairment; participants did not report chest pain. This paper emerges from the MIPS (Mental Stress Ischemia Prognosis) study, 2011-2014.

The ambulance-progenitor cell analogy isn’t perfect; exercise, generally a good thing, increases progenitor cell levels in the blood, says co-first author and cardiology fellow Muhammad Hammadah. The study supports the idea that patients with coronary artery disease may benefit from cardiac rehab programs, which drive the progenitor cells into the ischemic tissue, so they can contribute into vascular repair and regeneration. Read more

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