Fragile X: preclinical portfolio for PI3k drug strategy

An alternative drug strategy for fragile X is gathering strength. Lots of data on behavior and biochemistry from mouse Read more

Stem cells driven into selective suicide

The term “stem cell” is increasingly stretchy. This is one way to get rid of a particular Read more

The blue spot: where seeds of destruction begin

Learn more about the locus coeruleus, a "canary in the coal Read more

cardiology

When cardiac risk biomarkers will become really useful (and save money?)

The news is awash in studies of cholesterol-lowering statins and a much-anticipated (and expensive) class of drugs called PCSK9 inhibitors. Clinical trials show that now-generic (and cheap) statins reduce the risk of heart attack and stroke, although some patients report they can’t tolerate them. The data is still to come showing whether PCSK9 inhibitors have the same risk-lowering effect, as opposed to their effects on LDL cholesterol, which are robust.

When /if doctors have to start deciding who should take drugs that cost thousands of dollars a year and who shouldn’t, biomarkers may come in handy. How about a panel of markers like the one studied by Emory cardiologist Arshed Quyyumi, MD and colleagues?

At the recent American College of Cardiology meeting in Chicago, research fellow Salim Hayek, MD reported on a five-marker panel and how it could predict the risk of cardiovascular events (that is: death, heart attack, hospitalization for heart failure) in a group of patients who underwent cardiac catheterization at Emory hospitals.

The five biomarkers are: C-reactive protein (CRP, measures inflammation), suPAR (soluble urokinase-type plasminogen activator receptor or suPAR, predicts kidney disease), fibrin degradation products (FDP: blood coagulation), heat-shock protein-70 (HSP70, cellular stress) and troponin (hs-TnI, cardiac muscle damage). Data on three of these were published in 2013.

The Emory team keeps adding more biomarkers, and the ability of the accumulated information to add to what doctors can figure out easily — the Framingham score and its successors — becomes stronger.

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ACC 2016: Stem cell study sees improved heart failure outcomes

Patients with heart failure who received an experimental stem cell therapy experienced a reduced rate of death, hospitalization and unplanned clinic visits over the next year compared to a placebo group, according to results presented Monday at the American College of Cardiology meeting in Chicago.

The results of the ixCELL-DCM study were published online Monday by The Lancet. It was reportedly the largest cell therapy study done in patients with heart failure so far (58 treated vs 51 placebo).

Emory University School of Medicine investigators led by Arshed Quyyumi, MD, and their patients participated in the study, and Emory was one of the largest enrolling sites. Lead authors were Timothy Henry, MD of Cedars-Sinai Heart Institute in Los Angeles and Amit Patel, MD of the University of Utah.

“For the first time, a clinical trial has shown that administration of a cellular therapeutic results in an improvement in cardiac outcomes based on a prespecified analysis,” an editorial accompanying the paper in The Lancet says.

This study, which was sponsored by Vericel Corporation, was phase II, meaning that a larger phase III study will be needed before FDA approval. Read more

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ACC 2016: Elevated troponin linked to mental stress ischemia

Some people with heart disease experience a restriction of blood flow to the heart in response to psychological stress. Usually silent (not painful), the temporary restriction in blood flow, called ischemia, is an indicator of greater mortality risk.

Cardiologists at Emory University School of Medicine have discovered that people in this group tend to have higher levels of troponin — a protein whose increased presence in the blood that is a sign of recent damage or stress to the heart muscle– all the time, independently of whether they are experiencing stress or chest pain at that moment.

The results were presented Sunday by cardiology research fellow Muhammad Hammadah, MD at the American College of Cardiology meeting in Chicago, as part of the Young Investigator Awards competition. Hammadah works with Arshed Quyyumi, MD, and Viola Vaccarino, MD, PhD, and colleagues at the Emory Clinical Cardiovascular Research Institute.

“Elevated troponin levels in patients with coronary artery disease may be a sign that they are experiencing repeated ischemic events in everyday life, with either psychological or physical triggers,” Hammadah says.

Doctors test for troponin in the blood to tell whether someone has recently had a heart attack. But the levels seen in this study were lower than those used to diagnose a heart attack: less than a standard cutoff of 26 picograms per milliliter, in a range that only a high-sensitivity test for troponin could detect.

In a separate study, Emory investigators have shown that elevated troponin levels (especially: more than 10 pg/mL)  predict mortality risk over the next few years in patients undergoing cardiac catheterization, even in those without apparent coronary artery disease.

There is already a lot of information available for doctors about the significance of elevated troponin. It has even been detected at elevated levels after strenuous exercise in healthy individuals. One recent study suggested that low levels of troponin could be used to rule out heart attack for patients in the emergency department.

More information about the mental stress ischemia study: Read more

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Emory labs on LabTV

This summer, video producers from the web site LabTV came to two laboratories at Emory. We are pleased to highlight the first crop of documentary-style videos.

LabTV features hundreds of young researchers from universities and institutes around the United States, who tell the public about themselves and their research. The videos include childhood photos and explanations from the scientists about what they do and what motivates them. Screen Shot 2015-12-18 at 9.14.51 AM

The two Emory labs are: Malu Tansey’s lab in the Department of Physiology, which studies the intersection of neuroscience and immunology, focusing on neurodegenerative disease, and Mike Davis’ lab in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory, which is developing regenerative approaches and technologies for heart disease in adults and children. Read more

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CV cell therapy: bridge between nurse and building block

In the field of cell therapy for cardiovascular diseases, researchers see two main ways that the cells can provide benefits:

*As building blocks – actually replacing dead cells in damaged tissues

*As nurses — supplying growth factors and other supportive signals, but not becoming part of damaged tissues

Tension between these two roles arises partly from the source of the cells.

Many clinical trials have used bone marrow-derived cells, and the benefits here appear to come mostly from the “paracrine” nurse function. A more ambitious approach is to use progenitor-type cells, which may have to come from iPS cells or cardiac stem cells isolated via biopsy-like procedures. These cells may have a better chance of actually becoming part of the damaged tissue’s muscles or blood vessels, but they are more difficult to obtain and engineer.

A related concern: available evidence suggests introduced cells – no matter if they are primarily serving as nurses or building blocks — don’t survive or even stay in their target tissue for long.

Transplanted cells were labeled with a red dye, while a perfused green dye shows the extent of functional blood vessels. Blue is DAPI, staining nuclear DNA. Yellow arrows indicate where red cells appear to contribute to blood vessels.

Transplanted cells were labeled with a red dye, while a perfused green dye shows the extent of functional blood vessels. Blue is DAPI, staining nuclear DNA. Yellow arrows indicate where red cells appear to contribute to green blood vessels. Courtesy of Sangho Lee.

Stem cell biologist Young-sup Yoon and colleagues recently published a paper in Biomaterials in which the authors use chitosan, a gel-like carbohydrate material obtained by processing crustacean shells, to aid in cell retention and survival. Ravi Bellamkonda’s lab at Georgia Tech contributed to the paper.

More refinement of these approaches are necessary before clinical use,  but it illustrates how engineered mixtures of progenitor cells and supportive materials are becoming increasingly sophisticated and complicated.

The chitosan gel resembles the alginate material used to encapsulate cells by the Taylor lab. Yoon’s team was testing efficacy in a hindlimb ischemia model, in which a mouse’s leg is deprived of blood. This situation is analogous to peripheral artery disease, and the readout of success is the ability of experimental treatments to regrow capillaries in the damaged leg.

The current paper builds a bridge between the nurse and building block approaches, because the researchers mix two complementary types of cells: an angiogenic one derived from bone marrow cells that expands existing blood vessels, and a vasculogenic one derived from embryonic stem cells that drives formation of new blood vessels. Note: embryonic stem cells were of mouse origin, not human. Read more

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There will be microparticles (in stored blood)

More than 9 million people donate blood in the United States every year, according to the American Red Cross. Current guidelines say that blood can be stored for up to six weeks before use.

What happens to red blood cells while they are in storage, which transfusion experts call the “storage lesion”? Multiple studies have shown that older blood may have sub-optimal benefits for patients receiving a transfusion. The reasons include: depletion of the messenger molecule nitric oxide, lysis of red blood cells and alterations in the remaining cells’ stiffness.

To that list, we could add the accumulation of microparticles, tiny membrane-clothed bags that contain proteins and RNA, which have effects on blood vessels and the immune system upon transfusion. Note: microparticles are similar to exosomes but larger – the dividing line for size is about 100 nanometers. Both are much smaller than red blood cells.

EUH blood bank director John Roback recently gave a talk on the blood storage issue, and afterwards, cardiologist Charles Searles and research fellow Adam Mitchell were discussing their work on microparticles that come from red blood cells (RBCs). They have been examining the effects RBC-derived microparticles have on endothelial cells, which line blood vessels, and on immune cells’ stickiness.Red blood cell microparticles280

Mitchell mentioned that he had some striking electron microscope images of microparticles and some of the particles looked like worms. With the aim of maintaining Lab Land’s “Cool Image” feature, I resolved to obtain a few of his photos, and Mitchell generously provided several.

“Those worms definitely had me mesmerized for a while,” he says.

In his talk, Roback described some of the metabolomics research he has been pursuing with Dean Jones. Instead of focusing only on how long blood should be stored, Roback’s team is examining how much differences between donors may affect donated blood’s capacity to retain its freshness. Read more

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Deliver, but not to the liver

The potential of a gene-silencing technique called RNA interference has long enticed biotechnology researchers. It’s used routinely in the laboratory to shut down specific genes in cells. Still, the challenge of delivery has held back RNA-based drugs in treating human disease.

RNA is unstable and cumbersome, and just getting it into the body without having it break down is difficult. One that hurdle is met, there is another: the vast majority of the drug is taken up by the liver. Many current RNA-based approaches turn this apparent bug into a strength, because they seek to treat liver diseases. See these articles in The Scientist and in Technology Review for more.

But what if you need to deliver RNA somewhere besides the liver?

Biomedical engineer Hanjoong Jo’s lab at Emory/Georgia Tech, working with Katherine Ferrara’s group at UC Davis, has developed technology to broaden the liver-dominant properties of RNA-based drugs.

Hanjoong Jo, PhD

The results were recently published in ACS Nano. The researchers show they can selectively target an anti-microRNA agent to inflamed blood vessels in mice while avoiding other tissues.

“We have solved a major obstacle of using anti-miRNA as a therapeutic by being able to do a targeted delivery to only inflamed endothelial cells while all other tissues examined, including liver, lung, kidney, blood cells, spleen, etc showed no detectable side-effects,” Jo says. Read more

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How white blood cells limit muscle regeneration

A paper from cardiologist Aloke Finn and colleagues (published Wednesday, Aug. 5 in Nature Communications) describes how the protein CD163, produced by macrophages, puts the brakes on muscle repair after ischemic injury in mice. Here’s why we think this paper is interesting.

*Speculatively, there are connections to the recent wave of “young blood cures old body” parabiosis research. Increased CD163 is a marker of aging in humans. Maybe low levels of CD163 are part of how young blood is restorative.

*Translational potential — it wouldn’t be too hard to make an antibody against human CD163. Something that blocks CD163 could possibly be used to treat muscle breakdown, which occurs in response to injury, inactivity and in diseases such as cancer and diabetes.

*Finn says his team was surprised to find that mice lacking CD163, tested in experiments where blood flow is restricted in one leg, showed increased blood vessel and muscle growth in the other leg. It looks like part of CD163’s role is to limit muscle regeneration to the site of injury. Read more

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Really? I had a heart attack?

A recent Harvard study, published in Circulation, found a surprising level of inconsistency between what medical records say about whether people had a heart attack and what they report themselves in surveys.

About a quarter of Medicare patients who said in a survey that they previously had a heart attack have no record of having any heart-related hospital admission. Conversely, about one-third of patients who, according to Medicare, experienced a heart attack said they hadn’t.

This finding is consistent with an Emory study from cardiologists Neal Dickert and Habib Samady, in which participants in a clinical trial were interviewed just a couple days after the initial procedure. The trial was testing a “post-conditioning” modification of angioplasty+stenting performed during treatment for a heart attack. Just over half (55 percent) of the participants initially remembered being asked to participate when asked. Read more

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Leslee Shaw explains coronary artery calcium scoring

On Thursday, cardiology researcher Leslee Shaw, PhD joined an exclusive club at Emory with her 2015 Dean’s Distinguished Faculty Lecture and Award.* Shaw is the co-director of Emory’s Clinical Cardiovascular Research Institute and research director of Emory Women’s Heart Center. Her lecture focused on the utility of coronary artery calcium (CAC) scoring in predicting cardiovascular disease.

Much cardiovascular risk research has focused on finding imaging or biomarker tests that can provide doctors with cost-effective decision-making power. One prominent question: should the patient take cholesterol-reducing statins? These tests should provide information above and beyond the Framingham Risk Score or its ACC/AHA update, which incorporates information about a patient’s age, sex, cholesterol/HDL, blood pressure and diabetes status.

CAC scoring is a good place to start, Shaw said, since it is a standardized, relatively inexpensive test that measures the buildup of calcium in atherosclerotic plaque, and the radiation dose is low compared with other cardiac imaging techniques. Read more

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