'Master key' microRNA has links to both ASD and schizophrenia

Recent studies of complex brain disorders such as schizophrenia and autism spectrum disorder (ASD) have identified a few "master keys," risk genes that sit at the center of a network of genes important for brain function. Researchers at Emory and the Chinese Academy of Sciences have created mice partially lacking one of those master keys, called MIR-137, and have used them to identify an angle on potential treatments for ASD. The results were published this Read more

Shape-shifting RNA regulates viral sensor

OAS senses double-stranded RNA: the form that viral genetic material often takes. Its regulator is also Read more

Mapping shear stress in coronary arteries can help predict heart attacks

Predicting exactly where and when a future seismic fault will rupture is a scientific challenge – in both geology and Read more

Department of Medicine

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

Posted on by Quinn Eastman in Heart Leave a comment

Clues to lupus’s autoimmune origins in precursor cells

In the autoimmune disease systemic lupus erythematosus or SLE, the immune system produces antibodies against parts of the body itself. How cells that produce those antibodies escape the normal “checks and balances” has been unclear, but recent research from Emory University School of Medicine provides information about a missing link.

Investigators led by Ignacio (Iñaki) Sanz, MD, studied blood samples from 90 people living with SLE, focusing on a particular type of B cells. These “DN2” B cells are relatively scarce in healthy people but substantially increased in people with SLE.

The results were published in the journal Immunity.

People with lupus can experience a variety of symptoms, such as fatigue, joint pain, skin rashes and kidney problems. Levels of the DN2 cells were higher in people with more severe disease or kidney problems. DN2 B cells are thought to be “extra-follicular,” which means they are outside the B cell follicles, regions of the lymph nodes where B cells are activated in an immune response.

“Overall, our model is that a lot of lupus auto-antibodies come from a continuous churning out of new responses,” says postdoctoral fellow Scott Jenks, PhD, co-first author of the paper. “There is good evidence that DN2 cells are part of the early B cell activation pathway happening outside B cells’ normal homes in lymph nodes.”

Previous research at Emory has shown that African American women have significantly higher rates of lupus than white women. In the current study, the researchers observed that the frequency of DN2 cells was greater in African American patients. Participants in the study were recruited by Emory, University of Rochester and Johns Hopkins. Read more

Posted on by Quinn Eastman in Immunology Leave a comment

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

Posted on by Quinn Eastman in Heart Leave a comment

Probiotics for bone health study heads into clinic

Probiotic supplements can protect female mice from the loss of bone density that occurs after having their ovaries removed, researchers at Emory and Georgia State reported a couple years ago.

Roberto Pacifici, MD

This finding, published in Journal of Clinical Investigation, had clear implications for the treatment of osteoporosis in post-menopausal women. Prompted by external emails, Lab Land learned that the Emory investigators are now continuing their research in the clinic.

Endocrinologist/osteoimmunologist Roberto Pacifici and colleague Jessica Alvarez are conducting a double-blind study for women aged 50-65, using VSL3, a widely available and inexpensive dietary supplement. Participants would take the supplement or placebo for a year. More information is available here.

In mice, the loss of estrogen increases gut permeability, which allows bacterial products to activate immune cells in the intestine. In turn, immune cells release signals that break down bone. It appears that probiotics both tighten up the permeability of the gut and dampen inflammatory signals that drive the immune cells. Read more

Posted on by Quinn Eastman in Immunology Leave a comment

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

Posted on by Quinn Eastman in Heart Leave a comment

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

Posted on by Quinn Eastman in Heart Leave a comment

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

Posted on by Quinn Eastman in Heart Leave a comment

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

Posted on by Quinn Eastman in Heart Leave a comment

FMT microbial transplant for C diff gaining acceptance

In February, the Infectious Diseases Society of America issued new guidelines for fighting Clostridium difficile, the hardy bacterium that can cause life-threatening diarrhea and whose dominance is sometimes a consequence of antibiotic treatment. The guidelines recommend for the first time that FMT (fecal microbiota transplant) be considered for individuals who have repeatedly failed standard antibiotics.

In a nice coincidence, Emory FMT specialists Colleen Kraft and Tanvi Dhere recently published a look at their clinical outcomes with C diff going back to 2012, in Clinical Infectious Diseases. They report 95 percent of patients (122/128) indicated they would undergo FMT again and 70 percent of the 122 said they would prefer FMT to antibiotics as initial treatment if they were to have a recurrence. Read more

Posted on by Quinn Eastman in Immunology Leave a comment

Nox-ious link to cancer Warburg effect

At Emory, Kathy Griendling’s group is well known for studying NADPH oxidases (also known as Nox), enzymes which generate reactive oxygen species. In 2009, they published a paper on a regulator of Nox enzymes called Poldip2. Griendling’s former postdoc, now assistant professor, Alejandra San Martin has taken up Poldip2.

Griendling first came to Nox enzymes from a cardiology/vascular biology perspective, but they have links to cancer. Nox enzymes are multifarious and it appears that Poldip2 is too. As its full name suggests, Poldip2 (polymerase delta interacting protein 2) was first identified as interacting with DNA replication enzymes.  Poldip2 also appears in mitochondria, indirectly regulating the process of lipoylation — attachment of a fatty acid to proteins anchoring them in membranes. That’s where a recent PNAS paper from San Martin, Griendling and colleagues comes in. It identifies Poldip2 as playing a role in hypoxia and cancer cell metabolic adaptation.

Part of the PNAS paper focuses on Poldip2 in triple-negative breast cancer, more difficult to treat. In TNBC cells, Poldip2’s absence appears to be part of the warped cancer cell metabolism known as the Warburg effect. Lab Land has explored the Warburg effect with Winship’s Jing Chen.

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