Update on SIV remission studies

Recently presented insights on how an antibody used to treat intestinal diseases can suppress Read more

Granulins treasure not trash - potential FTD treatment strategy

Granulins are of interest to neuroscientists because mutations in the granulin gene cause frontotemporal dementia (FTD). However, the functions of granulins were previously Read more

Blood vessels and cardiac muscle cells off the shelf

How to steer induced pluripotent stem cells into becoming endothelial cells, which line blood Read more

Heart

Fragile but potent: RNA delivered by nanoparticle

An intriguing image for November comes from biomedical engineer Mike Davis’ lab, courtesy of BME graduate student Inthirai Somasuntharam.

Each year, thousands of children undergo surgery for congenital heart defects. A child’s heart is more sensitive to injury caused by interrupting blood flow during surgery, and excess reactive oxygen species are a key source of this damage.

Macrophages with blue nuclei and red cytoskeletons, being treated with green nano particles. The particles carry RNA that shut off reactive oxygen species production.

Macrophages with blue nuclei and red cytoskeletons, being treated with green nano particles. The particles carry RNA that shut off reactive oxygen species production.

Davis and his colleagues are able to shut off cheap oakley reactive oxygen species at the source by targeting the NOX (NADPH oxidase*) enzymes that produce them. This photo, from a 2013 Biomaterials paper, shows green fluorescent nanoparticles carrying small interfering RNA. The RNA precisely shuts down one particular gene encoding a NOX enzyme. Eventually, similar nanoparticles may shield the heart from damage during pediatric heart surgery.

In the paper, Somasuntharam used particles made of a slowly dissolving polymer called polyketals. The particles delivered fragile but potent RNA molecules into macrophages, inflammatory cells that swarm into cardiac tissue after a heart attack. Davis and Georgia Tech colleague Niren Murthy previously harnessed this polymer to deliver drugs that can be toxic to the rest of the body.

The polyketal particles are especially well-suited for delivering a payload to macrophages, since those types of cells (as the name implies) are big eaters. Davis reports his lab has been working on customizing the particles so they can deliver RNA molecules into cardiac muscle cells as well.

*While we’re on the topic of NADPH oxidases, Susan Smith and David Lambeth have been looking for and finding potential drugs that inhibit them.

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Dealing with huff-puff? Think HFpEF

For this month’s Current Concept feature, we would like to explain a term from cardiology that is likely to become more prominent:

“Heart failure with preserved ejection fraction” (abbreviated as HFpEF and pronounced “heff-peff”).

Javed Butler, MD, an Emory expert on heart failure and deputy chief science officer for the American Heart Association, laid out in a recent seminar why this category of patients is so important. Look for more from him on this topic in the future.

Three points:

  1. The number of HFpEF patients is growing and they now make up the majority of patients with heart failure in the United States.
  2. No treatments have been proven to benefit them, in terms of reducing mortality.* In clinical studies, medications such as ACE inhibitors, angiotensin receptor blockers and beta-blockers have not helped.
  3. Once hospitalized, HFpEF patients have a high rate of readmission to the hospital within 30 days. The federal Medicare program is penalizing hospitals that have high rates of readmissions and heart failure is one of the largest contributors to readmissions.

The symptoms that drive people with HFpEF to the hospital are mainly fatigue and dyspnea, or shortness of breath, along with fluid in the lungs and swelling of the limbs. Along with heart failure, HFpEF patients often have conditions such as hypertension, anemia, diabetes, kidney disease or sleep apnea. Read more

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Packaging stem cells in capsules for heart therapy

Stem cell therapy for heart disease is happening. Around the world, thousands of heart disease patients have been treated in clinical studies with some form of bone marrow cells or stem cells. But in many of those studies, the actual impact on heart function was modest or inconsistent. One reason is that most of the cells either don’t stay in the heart or die soon after being introduced into the body.

Cardiology researchers at Emory have a solution for this problem. The researchers package stem cells in a capsule made of alginate, a gel-like substance. Once packaged, the cells stay put, releasing their healing factors over time.

Researchers used encapsulated mesenchymal stem cells to form a “patch” that was applied to the hearts of rats after a heart attack. Compared with animals treated with naked cells (or with nothing), rats treated with the capsule patches displayed increased heart function, reduced scar size and more growth of new blood vessels a month later. In addition, many more of the encapsulated cells stayed alive. Read more

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Molecular beacons shine path to cardiac muscle repair

Pure cardiac muscle cells, ready to transplant into a patient affected by heart disease.

That’s a goal for many cardiology researchers working with stem cells. Having a pure population of cardiac muscle cells is essential for avoiding tumor formation after transplantation, but has been technically challenging.

CardioMBs

Fluorescent beacons that distinguish cardiac muscle cells

Researchers at Emory and Georgia Tech have developed a method for Cheap Oakleys purifying cardiac muscle cells from stem cell cultures using molecular beacons.

Molecular beacons are tiny “instruments” that become fluorescent only when they find cells that have turned on certain genes. In this case, they target instructions to make a type of myosin, a protein found in cardiac muscle cells.

Doctors could use purified cardiac muscle cells to heal damaged areas of the heart in patients affected by heart attack and heart failure. In addition, the molecular beacons technique http://www.lependart.com could have broad applications across regenerative medicine, because it could be used with other types of cells produced from stem cell cultures, such as brain cells or insulin-producing islet cells.

The results are published in the journal Circulation.

“Often, we want to generate a particular cell population from stem cells for introduction into patients,” says co-senior author Young-sup Yoon, MD, PhD, professor of medicine (cardiology) and director of stem cell biology at Emory University School of Medicine. “But the desired cells often lack a readily accessible surface marker, or that marker is not specific enough, as is the case for cardiac muscle cells. This technique could allow us to purify almost any type of cell.”

Read more

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Possible diabetes drug/stent interaction

Diabetes and heart disease often intersect. Emory cardiologist Aloke Finn and his colleagues recently had two papers in the Journal of the American College of Cardiology and in Atherosclerosis describing a possible interaction between the widely used diabetes drug metformin and drug-eluting stents, which are used to to treat coronary artery disease. Anwer Habib, MD is the first author of both papers.

The stent props the once-blocked artery open while the drugs in the stents are supposed to prevent the artery from becoming blocked again. The drugs — usually mTOR inhibitors such as http://www.magliettedacalcioit.com everolimus or the newer zotarolimus — slow down cell growth, but this cuts both ways. The drugs slow down the recovery of the lining of the blood vessel and this may contribute to blood clot formation after stent placement.

In cultured human cells and in rabbits with implanted stents, Finn and colleagues showed that metformin augmented the effect of mTOR inhibitors on regrowth of the blood vessel lining. (However — the authors acknowledge that their animal model was not diabetic or atherosclerotic.)

The findings could mean that people taking metformin would need to take medications to prevent blood clotting medications for a longer time after stent placement. The authors say that clinical studies following patients who receive drug-eluting stents should look at metformin’s effects on blood clotting events. A study examining drug eluting stents in diabetic patients is in the works at Emory.

 

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Stress of public speaking mobilizes progenitor cells from bone marrow

The stress of public speaking is enough to drive damage-repairing progenitor cells out of the bone marrow into the blood, a study of patients with heart disease has found.

Public speaking raises the blood pressure -- it also drives progenitor cells out of the bone marrow

Public speaking raises the blood pressure — it also drives progenitor cells out of the bone marrow

Endothelial progenitor cells (EPCs) are found in the bone marrow, and thought to repair damaged blood vessels once mobilized into the blood by injury or stress. Previous research has shown that strenuous exercise can lead to a dramatic increase in blood EPC levels, but the effects of psychological stress on EPCs had not been examined before.

This report emerges Magliette Calcio A Poco Prezzo from a large NHLBI-funded study of mental stress ischemia previously described in Emory Public Health magazine.

The new findings were presented Saturday, March 9 at the American College of Cardiology conference in San Francisco. The presenter was cardiovascular research fellow Ronnie Ramadan, MD. Senior authors are Arshed Quyyumi, MD, professor of medicine and director of the Emory Cardiovascular Research Institute, and Viola Vaccarino, MD, PhD, professor and chair of the Department of Epidemiology, Rollins School of Public Health.

In some patients with coronary artery disease, mental stress may precipitate ischemia– a deficiency in blood flow to the heart – a risk factor for adverse events and death independent of other cardiovascular risk factors such as smoking, cholesterol and diabetes.

Read more

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Editorial on bilateral vs single coronary bypass surgery

John Puskas, chief of cardiac surgery at Emory University Hospital Midtown, recently had an editorial in the journal Circulation on the topic of coronary bypass surgery.

John Puskas, MD

Specifically, he says that many cardiac surgeons are reluctant to employ bilateral internal thoracic artery grafts (as opposed to a single graft), even though there is a long-term benefit, because of perceived risk of infection and suboptimal financial incentives.

Puskas’ key message paragraph was so clear that it demands reposting here:

Why are American surgeons doing so few BITA [bilateral internal thoracic artery] grafts? Fundamentally, U.S. surgeons are responding to their practice environment, especially to a fear of deep sternal wound infection in an increasingly obese, diabetic population of patients. The surgeon pays a large and immediate political price for a deep sternal wound infection and receives relatively little credit for the extra years that BITA grafting adds to a patient’s life in the future. There is also a relative Ray Ban outlet financial disincentive to perform BITA grafting: incremental payment for the second internal thoracic artery graft is small considering the extra time required in the operating room. Moreover, the Centers for Medicare and Medicaid Services no longer reimburse for extra care necessary for treatment of mediastinitis [internal chest inflammation/infection] after cardiac surgery, because this is now deemed a never event. Thus, surgeons, who are increasingly employed by hospitals and hospital systems, are under intense pressure to perform CABG surgery that is safe and cost-effective according to short-term metrics.

Puskas and his colleagues have published an analysis of bilateral vs single grafting at Emory, as well as a proposed metric for when single grafting should be used in the context of patients with diabetes:

Our present practice is generally to use BITA grafting in patients who are <75 years, have suitable coronary artery targets, are not morbidly obese, and whose glycosylated hemoglobin level is <7.0% to 7.5%.

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AHA meeting highlights — an Emory-centric view

Poring over the abundance of information presented at major scientific meetings is like trying to drink from a firehose.  Imposing an Emory-centric filter on this year’s American Heart Association Scientific Sessions meeting in Los Angeles, here are three highlights, with a shoutout to the AHA journal Circulation, which provides a database of meeting abstracts.

Alginate encapsulation, a therapeutic delivery tactic to get stem cells to stay in the heart

Presenter Rebecca Levit, MD, a postdoc in cardiology division chair W. Robert Taylor’s laboratory, was a finalist for an Early Career Investigator Award.

 Stem cell therapies for myocardial repair have shown promise in preclinical trials, but lower than expected retention and viability of transplanted cells. In an effort to improve this, we employed an alginate encapsulation strategy for human mesenchymal stem cells (hMSCs) and attached them to the heart with a biocompatible PEG hydrogel patch in a rat MI model. Encapsulation allows for diffusion of pro-angiogenic cytokines and growth factors made by the hMSCs while maintaining them at the site of implantation…Alginate encapsulated hMSCs attached to the heart with a hydrogel patch resulted in a highly significant improvement in left ventricular function after acute myocardial infarction. The mechanism for this markedly enhanced effect appears to be increased cell survival and retention.

 Note: alginate already has a wide variety of uses, for example in culinary arts and to make dental impressions.

suPAR, a biomarker connected with depression, inflammation and cardiovascular outcomes. Step back, C-reactive protein

Depression, inflammation (Manocha, Vaccarino)

Cardiovascular outcomes (Eapen, Quyyumi)

Coronary microvascular dysfunction (Corban, Samady)

Predicting mental-stress myocardial ischemia via a public speaking test

A study probing myocardial ischemia (a lack of blood flow to the heart) induced by psychological stress, described in this Emory Public Health article. The presentation by Ronnie Ramadan examines physiological responses to a public speaking test as a way of predicting more severe problems.

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FAME 2 clarifies benefits of coronary stents

Who should get stents, the tiny metal tubes designed to keep clogged coronary arteries open? Someone who is having a heart attack certainly should, and the life-prolonging benefits have been demonstrated in several studies. But results have been more ambiguous for patients who have “stable angina”: chest pain that comes with exertion but goes away at rest.

Kreton Mavromatis, MD

A recent study addressing this topic called FAME 2 has received extensive media coverage. It was published in the New England Journal of Medicine and also presented at the European Society of Cardiology meeting in Munich. Kreton Mavromatis, MD, director of cardiac catheterization at the Atlanta VA Medical Center and assistant professor of medicine at Emory, was a co-author on the NEJM paper.

In the new study, researchers used a technique called fractional flow reserve (FFR) to decide if someone with stable angina should get a stent, or receive medical therapy with drugs such as aspirin and statins. Conventionally, X-ray coronary angiography is used to assess the need for a stent.

FFR involves introducing a pressure sensor via guidewire into the coronary artery, to measure how much blood flow is being blocked. FAME 2 was sponsored by St Jude Medical, a company that makes guidewire equipment for use in FFR.

Fractional flow reserve is a way of assessing the effects of blockages in blood flow in a coronary artery.

The clinical trial was stopped early because of clear differences in the rates of hospitalization (4 percent for stents against 13 percent for medical therapy)

“FAME 2 showed that the strategy of treating stable ischemic heart disease with FFR-guided coronary stenting reduces the combination of death, MI and urgent revascularization as compared with strategy of medical therapy alone,” Mavromatis says. “This benefit was specifically due to the reduced need of urgent revascularization due to acute coronary syndrome, a dramatic event for our patients.”

Some cardiologists have criticized the FAME 2 study, noting that the benefits of stenting didn’t come in terms of reducing “hard events” (deaths and heart attacks).

“It is important to recognize that less symptoms of angina and less chance of hospitalization are tremendous benefits that our patients really appreciate,” Mavromatis says. “I think FFR will play a bigger role in evaluating and treating coronary artery disease, as it can direct stenting much more precisely than angiography toward clinically important coronary artery disease, improving patients’ outcomes and saving money.”

The FFR procedure costs several hundred dollars but that is significantly less than the cost of implanting a coronary stent. Habib Samady, MD, director of interventional cardiology at Emory, has also been an advocate for the use of FFR to select who would benefit from a coronary stent. He wrote an article describing its uses in 2009:

We have been using and advocating FFR since pressure guidewire technology first came to the U.S. in 1998. At Emory, we are sometimes asked to reevaluate patients who have been slated for CABG surgery at another hospital where recommendations are made based on angiography alone. When we evaluate these cases using FFR, we are sometimes able to recommend courses of treatment that involve fewer stents or even medical therapy. Occasionally, based on FFR data, we send our patients for an endoscopic or “minimally invasive” bypass and stent the remaining narrowings.

In addition, FFR has helped reduce the number of multi-vessel PCIs performed. Patients who might have received stents in three vessels after angiography alone would likely receive stents in only one or two vessels after FFR-guided analysis. Among patients with single-vessel disease, FFR often has allowed us to recommend medical treatment in lieu of stenting. Implanting fewer stents also means using less contrast agent and fewer materials, which lowers the expenses involved in treatment.

A large, multi-center study called ISCHEMIA is starting that will address the coronary stent vs medical therapy issue in a more definitive way. Both Emory and the Atlanta VA Medical Center are participating. “This is a very important next step in understanding the benefits of invasive therapy of stable ischemic heart disease,” Mavromatis says.

 

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Low vitamin D in people with HIV: links to heart risk, immune function

In people with HIV, low vitamin D levels have been linked to thicker carotid arteries as well as a weaker comeback for the immune system after starting antiretroviral therapy.

These results, published online recently in the journal Antiviral Therapy, are the first to confirm an association between low vitamin D levels and a measure of higher cardiovascular risk in people with HIV. They also suggest that the benefits of vitamin D supplementation for people with HIV should be evaluated in a clinical trial.

Allison Ross, MD, is an infectious disease specialist in the Department of Pediatrics and the Emory-Children's Pediatric Research Center.

The advent of effective antiretroviral therapy against HIV has dramatically improved life expectancies for people with HIV over the last 15 years. The presence of HIV is known to perturb cardiovascular health, even in the absence of an active infection. Since vitamin D levels are known to have an impact on the immune system and cardiovascular disease risk, that drove infectious disease specialist Allison Ross and her colleagues to probe these connections in people living with HIV. The results were also described on the Web sites AidsMeds and NAM/AidsMap.

Ross studied a group of HIV-positive people enrolled in Case Western Reserve University’s HIV clinic in Cleveland. Colleagues from Emory and Case Western were co-authors.

They tested vitamin D levels, immune function and heart health in 149 HIV-positive people and a matched group of 34 HIV-negative people. Vitamin D levels were significantly lower in the HIV-positive group, even when controlling for known factors that affect vitamin D.

The researchers looked at how much the immune system was able to come back after starting retroviral therapy. This involves comparing someone’s lowest ever CD4 T cell count from the current CD4 count. They found that people with the poorest level of immune restoration were the most likely to have the lowest level of vitamin D. In addition, people with the lowest vitamin D levels were more than 10 times as likely to have thickening of the carotid arteries, as measured by ultrasound.

Inflammation can be a driving factor for heart disease, but in the study, low vitamin D was not linked to higher levels of inflammation markers. Additional research could determine whether those who are starting antiretroviral therapy would see better immune recovery if they took a vitamin D supplement.

Researchers at Emory have been investigating several aspects of low Vitamin D levels and their impact on health, including a connection with Parkinson’s disease. Endocrinologist Vin Tangpricha notes that Emory studies are looking at vitamin D in the context of tuberculosis, sepsis, sickle cell disease, cancer, cystic fibrosis and pain sensitivity.

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