MSCs: what’s in a name?

Whether they are "stem" or "stromal", from adult tissues or from umbilical cord blood, MSCs are being used for a lot of clinical trials. Read more

Mopping up immune troublemakers after transplant

Memory CD8+ T cells play an important role in kidney transplant rejection, and they resist drugs that would otherwise improve Read more

Tracking a frameshift through the ribosome

Ribosomal frameshifting, visualized through X-ray Read more

Heart

Bits from HIV + Aging conference

What conferences like the HIV + Aging meeting recently held by Emory in Decatur offer the visiting writer: anecdotes that illustrate issues of clinical care.

To illustrate her point that assumptions about who is likely to develop a new HIV infection may lead doctors to miss possible diagnoses, keynote speaker Amy Justice from Yale described a patient who was seen last year at Yale-New Haven Hospital.

A 60 year old man reported fatigue and had lost 40 pounds over the course of a year. Despite those symptoms, and the discovery of fungal and viral infections commonly linked to HIV/AIDS, it took nine months before a HIV test was performed on the patient, a delay Justice deplored.

Sex and substance abuse do not end at age 50, she said, citing data showing that the risk of HIV transmission can be greater among older adults, and that substance abuse is more likely among adults who are HIV positive compared to those who are HIV negative.

Justice also highlighted the issue of polypharmacy (interactions between prescription drugs at the same time), a concern even in people who are not living with HIV. Common blood pressure medications taken by older adults to prevent heart disease have been suspected of increasing the risk for falls. That’s a problem especially for people living with HIV, because HIV infection has been linked to weakened bone. Read more

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

The age of blood

Nature Medicine has a nice feature from Jeanne Erdmann highlighting the debate over how long donated blood can be stored. It sets the stage for two prospective clinical trials (RECESS and ABLE), which recently concluded but are still being analyzed. The trials were looking at how the age of stored blood affects patients undergoing cardiac surgery or in intensive care, respectively. Erdmann also mentions that the NIH’s Clinical Center already has tightened its standards for blood storage time.

Emory Blood Bank director John Roback and cardiologist Arshed Quyyumi have been participants in this debate, both theoretically and experimentally. In 2011, they proposed that depletion of the messenger molecule nitric oxide limits the benefits donated blood can provide to patients. In addition to nitric oxide depletion, the “storage lesion” is likely to include several changes, such as lysis of red blood cells, mechanical alterations in the remaining cells, and other chemical changes.

Since then, Emory research has shown that transfusion of donated blood more than three weeks old results in impaired blood vessel function in hospitalized patients, but in contrast, not in healthy volunteers. This information could allow doctors to prioritize fresher blood for patients with cardiovascular diseases.

Posted on by Quinn Eastman in Heart Leave a comment

What are exosomes?

Biomedical engineer Mike Davis reports he has obtained NHLBI funding to look into therapeutic applications of exosomes in cardiology. But wait. What are exosomes? Time for an explainer!

Exosomes are tiny membrane-wrapped bags, which form inside cells and are then spat out. They’re about 100 or 150 nanometers in diameter. That’s smaller than the smallest bacteria, and about as large as a single influenza or HIV virion. They’re not visible under a light microscope, but are detectable with an electron microscope.

Scientific interest in exosomes shot up after it was discovered that they can contain RNA, specifically microRNAs, which inhibit the activity of other genes. This could be another way in which cells talk to each other long-distance, besides secreting proteins or hormones. Exosomes are thus something like viruses, without the infectivity.

Since researchers are finding that microRNAs have potential as therapeutic agents, why not harness the vehicles that cells use to send microRNAs to each other? Similarly, if so much evidence points toward the main effect of cell therapy coming from what the cells make rather than the cells themselves, why not simply harvest what the cells make? Read more

Posted on by Quinn Eastman in Heart Leave a comment

Making cardiac progenitor cells feel at home

One lab uses goopy alginate, another uses peptides that self-assemble into hydrogels. The objective is the same: protecting cells that are injected into the heart and making them feel like they’re at home.

Around the world, thousands of heart disease patients have been treated in clinical studies with some kind of cell-based therapy aimed at regenerating the heart muscle or at least promoting its healing. This approach is widely considered promising, but its effectiveness is limited in that most of the cells don’t stay in the heart or die soon after being introduced. [UPDATE: Nice overview of cardiac cell therapy controversy in July 18 Science]

Biomedical engineer Mike Davis and his colleagues recently published a paper in Biomaterials describing hydrogels that can encourage cardiac progenitor cells injected into the heart to stay in place. The first author is former graduate student Archana Boopathy, who recently started her postdoctoral work at MIT. Davis has been working with these self-assembling peptides for some time: see this 2005 Circulation paper he published during his own postdoctoral work with Richard Lee at Harvard.DavisDiagram

How do these hydrogels keep cells from washing away? We don’t have to go much beyond the name: think Jello. Researchers design snippets of proteins (peptides) that, like Jello*, form semisolid gels under the right conditions in solution. Helpfully, they also are customized with molecular tools for making cardiac progenitor cells happy. Read more

Posted on by Quinn Eastman in Heart 1 Comment

Evaluating a different way to measure LDL

What is the most important measurement of cholesterol or lipids in the blood, when it comes to cardiovascular disease risk? LDL-C [low density lipoprotein cholesterol], is often called “bad cholesterol” because it is linked to atherosclerosis, but the landscape is always shifting. Even as cardiologists across the country get used to the new AHA/ACC guidelines, which call for changes in how physicians and patients view LDL-C, new research is focusing attention on other related markers. For example, a recent pair of studies in the New England Journal of Medicine identify gene mutations that lower both triglycerides and heart disease risk, suggesting that drugs that target that gene pathway could be beneficial. A new paper in Atherosclerosis, coauthored by Emory’s Terry Jacobson, looks at LDL-P, a different way of looking at LDL that has been proposed to be a better measure of cardiovascular disease risk. Jacobson is director of the Office of Health Promotion and Disease Prevention at Grady Health Systems. Read more

Posted on by Quinn Eastman in Heart Leave a comment

Epigenetic changes in atherosclerosis

If someone living in America and eating a typical diet and leading a sedentary lifestyle lets a few years go by, we can expect plaques of cholesterol and inflammatory cells to build up in his or her arteries. We’re not talking “Super-size Me” here, we’re just talking average American. But then let’s say that same person decides: “OK, I’m going to shape up. I’m going to eat healthier and exercise more.”

claimtoken-53a9ba0b1a476

Let’s leave aside whether low-carb or low-fat is best, and let’s say that person succeeds in sticking to his or her declared goals. How “locked in” are the changes in the blood vessels when someone has healthy or unhealthy blood flow patterns?

Biomedical engineer Hanjoong Jo and his colleagues published a paper in Journal of Clinical Investigation that touches on this issue. They have an animal model where disturbed blood flow triggers the accumulation of atherosclerosis. They show that the gene expression changes in endothelial cells, which line blood vessels, have an epigenetic component. Specifically, the durable DNA modification known as methylation is involved, and blocking DNA methylation with a drug used for treating some forms of cancer can prevent atherosclerosis in their model. This suggests that blood vessels retain an epigenetic imprint reflecting the blood flow patterns they see.

Although treating atherosclerosis with the drug decitabine is not a viable option clinically, Jo’s team was able to find several genes that are silenced by disturbed blood flow and that need DNA methylation to stay shut off. A handful of those genes have a common mechanism of regulation and may be good therapeutic targets for drug discovery.

Posted on by Quinn Eastman in Heart Leave a comment

Thyroid makes young mouse hearts grow

The entire heart muscle in young children may hold untapped potential for regeneration, new research suggests.

For decades, scientists believed that after a child’s first few days of life, cardiac muscle cells did not divide. Instead, the assumption was that the heart could only grow by having the muscle cells become larger.

Cracks were already appearing in that theory. But new findings in mice, published May 8 in Cell, provide a dramatic counterexample — with implications for the treatment of congenital heart disorders in humans. Read more

Posted on by Quinn Eastman in Heart Leave a comment

Blood vessels aren’t straight tubes

For years, scientists like Hanjoong Jo have been telling us that blood vessels are like rivers and streams. Fluid dynamics are important; the patterns of curvature and current influence where sediment — or atherosclerosis — builds up.

One of the biggest possible perturbations of fluid dynamics in a blood vessel would be to stick a metal tube into it. Of course, cardiologists do this all the time. During percutaneous coronary intervention (PCI), doctors place a stent, basically a metal tube, inside a blood vessel to relieve an obstruction and restore blood flow to the heart muscle.

Habib Samady, Emory Healthcare’s director of interventional cardiology, is leading a clinical trial looking at the effects of stent introduction on blood vessels that are not straight, but curved or angulated. To be eligible for the study, the patient’s blocked vessel has to bend more than 30 degrees. The study will look at patients who have undergone PCI for a heart attack and follow them over the course of a year. Less “disturbed flow” should mean better heart healing for the patient down the road. The study uses OCT (optical coherence tomography) and IVUS (intravascular ultrasound) to monitor the blood vessel and see how healing is affected by fluid dynamics after stent placement. Read more

Posted on by Quinn Eastman in Heart Leave a comment

Targeting naked DNA in the heart

Hoechst-Structure-300px

The first thing that comes up in a Google search for “Hoechst” is the family of fluorescent dyes used to stain DNA in cells before microscopy. The Hoechst dyes derive their names from their manufacturer: a company, now part of Sanofi, named after the town where it was founded, which is now part of Frankfurt, Germany. The word itself means “highest [spot].”

Although DNA runs the show in every cell, it’s usually well-hidden inside the nucleus or the mitochondria. Extracellular DNA’s presence is a signal that injury is happening and cells are dying.

Biomedical engineer Mike Davis and collaborator Niren Murthy have been exploiting the properties of a DNA-binding dye called Hoechst 33342, often used to stain DNA in cells before microscopy. The dye can only bind DNA if it can get to the DNA – that is, if membranes are broken. This property makes the dye a good way to target injured tissue, either as an imaging agent or for therapy.

At the recent Pediatric Healthcare Innovation retreat, Davis discussed the potential use of such Hoechst derivatives to diagnose myocarditis (inflammation of the heart muscle) in children.

In addition, in a recent paper published in Scientific Reports, Davis and his colleagues attach the Hoechst dye to the cardioprotective growth factor IGF-1, creating a version of IGF-1 that is targeted to injured heart muscle. The first author of the paper is cardiology fellow Raffay Khan, MD. Screen Shot 2014-04-24 at 1.18.35 PM

IGF-1 has shown a lot of potential for treating heart disease, but it’s not the most cooperative as a drug, because it doesn’t last long in the body and doesn’t stick around in the heart. Linked up to the dye, IGF-1 behaves better. When used to treat mouse hearts after a heart attack, the Hoechst-IGF-1 treated-hearts have better function and less scar tissue (seen here as red).

The authors conclude:

With the broad chemistry surrounding functionalized PEG used to create Hoechst derivatives, it may be possible to target other therapies such as cells, small molecules, and even nanoparticles. We believe that the use of DNA binding agents such as Hoechst can be used to target exposed DNA in other diseases where necrotic cell death plays a critical role and could be used as a platform therapy.

 

 

Posted on by Quinn Eastman in Heart Leave a comment

Addendum on CRISPR

An excellent example of the use of CRISPR gene editing technology came up at the Emory-Children’s Pediatric Research Center’s Innovation Conference this week.

Marcela Preininger, who is working with cardiomyocyte stem cell specialist Chunhui Xu, described her work (poster abstract 108) on cells derived from a 12 year old patient with an inherited cardiac arrhythmia syndrome: catecholaminergic polymorphic ventricular tachycardia or CPVT. Her team has obtained skin fibroblasts from the patient, and converted those cells into induced pluripotent stem cells, which can then be differentiated into cardiac muscle cells or cardiomyocytes.

Working with TJ Cradick, director of the Protein Engineering Facility at Georgia Tech, Preininger is testing out CRISPR gene editing as a means of correcting the defect in this patient’s cells, outside the body. Cradick says that while easy and efficient, RNA-directed CRISPR can be lower in specificity compared to the protein-directed TALEN technology.

From Preininger’s abstract:

Once the mutation has been corrected at the stem cell level, we will investigate whether the repaired (mutation-free) iPS cells can be differentiated into functional cardiomyocytes with normal Ca2+ handling properties, while closely monitoring the cells for mutagenic events. Pharmacological restoration of the normal myocardial phenotype will also be optimized and explored in our model.

Posted on by Quinn Eastman in Heart Leave a comment