Researchers examine role of inflammatory mechanisms in a healing heart

ScienceDaily (Nov. 30, 2011) — Virginia Commonwealth University researchers have found that an inflammatory mechanism known as inflammasome may lead to more damage in the heart following injury such as a heart attack, pointing researchers toward developing more targeted strategies to block the inflammatory mechanisms involved.

Following a heart attack, an inflammatory process occurs in the heart due to the lack of oxygen and nutrients. This process helps the heart to heal, but may also promote further damage to the heart. The mechanisms by which the heart responds to injury are not fully understood, so researchers have been examining the cellular pathways involved to gain further insight.

In a study published online the week of Nov. 21 in the Proceedings of the National Academy of Sciences, researchers addressed the role of a specific inflammatory mechanism, called inflammasome, during the process of healing in the heart. Using an animal model, the team found that inflammasome amplifies the response by generating the production of a key inflammatory mediator known as Interleukin-1ß. Further, they described that pharmacologic inhibition of the formation of inflammasome prevents heart enlargement and dysfunction.

"Defining the role of the inflammasome in the response to injury in the heart and the possibility to intervene opens a new area of investigation for the prevention and treatment of heart failure following a heart attack," said Antonio Abbate, M.D., assistant professor of medicine in the VCU Department of Internal Medicine and Division of Cardiology.

According to Abbate, who serves as the interim director for the cardiac intensive care unit at the VCU Pauley Heart Center, this study supports the team's previous findings that showed that Interleukin-1ß affects the heart, and blocking Interleukin-1ß benefits patients of heart attack and heart failure.

"Based on the findings of the current study we are even more convinced that blocking Interleukin-1ß may be safe and beneficial, and we are now exploring novel ways to do so," he said.

Abbate said there are four ongoing clinical trials at the VCU Pauley Heart Center in patients with various heart conditions treated with a drug called anakinra which blocks Interleukin-1ß.

Abbate and his team continue to examine the molecular mechanisms of inflammasome formation and heart injury, and hope to determine new ways to intervene with potentially more targeted strategies in the future.

The study was conducted in the Victoria W. Johnson Center for Research at VCU, which is directed by Norbert Voelkel, M.D, professor of medicine in the Pulmonary and Critical Care Division.

Abbate led with a multidisciplinary team of VCU researchers biologists, physicians, and pharmacists including Eleonora Mezzaroma, Ph.D., and Stefano Toldo, Ph.D., post-doctoral associates in the VCU Pauley Heart Center; Daniela Farkas, B.S., research specialist in the Victoria Johnson Research Laboratory; Benjamin Van Tassell, Pharm.D., assistant professor of pharmacology and outcome sciences; and Fadi Salloum, Ph.D., assistant professor of medicine and physiology in the VCU Pauley Heart Center.

This study was supported by a grant from the American Heart Association.

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E. Mezzaroma, S. Toldo, D. Farkas, I. M. Seropian, B. W. Van Tassell, F. N. Salloum, H. R. Kannan, A. C. Menna, N. F. Voelkel, A. Abbate. The inflammasome promotes adverse cardiac remodeling following acute myocardial infarction in the mouse. Proceedings of the National Academy of Sciences, 2011; DOI: 10.1073/pnas.1108586108

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Snakes with big hearts may help yours: Fatty acids involved in python heart growth could benefit diseased human heart

ScienceDaily (Oct. 27, 2011) — Identification of three fatty acids involved in the extreme growth of Burmese pythons' hearts following large meals could prove beneficial in treating diseased human hearts, according to research co-authored by a University of Alabama scientist and publishing in the Oct. 28 issue of Science.

Growth of the human heart can be beneficial when resulting from exercise -- a type of growth known as physiological cardiac hypertrophy -- but damaging when triggered by disease -- growth known as pathological hypertrophy. The new research shows a potential avenue by which to make the unhealthy heart growth more like the healthy version.

"We may later be able to turn the tables, in a sense, in the processes involved in pathological hypertrophy by administering a combination of fatty acids that occur in very high concentrations in the blood of digesting pythons," said Dr. Stephen Secor, associate professor of biological sciences at UA and one of the paper's co-authors. "This could trigger, perhaps, something more akin to the physiological form of hypertrophy."

The research, conducted in collaboration with multiple researchers at the University of Colorado working in the lab of Dr. Leslie Leinwand, identified three fatty acids, myristic acid, palmitic acid and palmitoleic acid, for their roles in the snakes' healthy heart growths following a meal.

Researchers took these fatty acids from feasting pythons and infused them into fasting pythons. Afterward, those fasting pythons underwent heart-rate growths similar to that of the feasting pythons. In a similar fashion, the researchers were able to induce comparable heart-rate growths in rats, indicating that the fatty acids have a similar effect on the mammalian heart.

The paper, whose lead author was Dr. Cecilia Riquelme of the University of Colorado, also showed that the pythons' heart growth was a result of the individual heart cells growing in size, rather than multiplying in number.

By studying gene expression in the python hearts -- which genes are turned on following feasting -- the research, Secor said, shows that the changes the pythons' hearts undergo is more like the positive changes seen in a marathon runner rather than the types of changes seen in a diseased, or genetically altered, heart.

"Cyclists, marathon runners, rowers, swimmers, they tend to have larger hearts," Secor said. "It's the heart working harder to move blood through it. The term is 'volume overload,' in reference to more blood being pumped to tissues. In response, the heart's chambers get larger, and more blood is pushed out with every contraction, resulting in increased cardiac performance."

However, the time-frame of this increased heart performance of a python blows away even the most physically-fit distance runner, Secor said.

"Instead of experiencing elevated cardiac performance for several hours with running, the Burmese python is maintaining heightened cardiac output for five to six days, non-stop, while digesting their large meal."

Another interesting finding of the research, Secor said, is even with the increased volume of triglycerides circulating in the snakes after feeding, those lipids are not remaining within the snakes' hearts or vascular systems after the completion of digestion.

"The python hearts are using the circulating lipids to fuel the increase in performance."

Traditionally, mice have been the preferred animal model used to study the genetic heart disease known as hypertrophic cardiomyopathy, characterized by heart growth and contractile dysfunction. However, the snakes' unusual physiological responses render them more insightful models, in some cases, Secor said.

Pythons are infrequent feeders, sometimes eating only once or twice a year in the wild. When they do eat, they undergo extreme physiologic and metabolic changes that include increases in the size of the heart, along with the liver, pancreas, small intestine and kidney. Three days after a feeding, a python's heart mass can increase as much as 40 percent, before reverting to its pre-meal size once digestion is completed, Secor said.

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The above story is reprinted from materials provided by University of Alabama in Tuscaloosa.

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Cecilia A. Riquelme, Jason A. Magida, Brooke C. Harrison, Christopher E. Wall, Thomas G. Marr, Stephen M. Secor, Leslie A. Leinwand. Fatty Acids Identified in the Burmese Python Promote Beneficial Cardiac Growth. Science, 2011; 334 (6055): 528-531 DOI: 10.1126/science.1210558

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Python study may have implications for human heart health

ScienceDaily (Oct. 27, 2011) — A surprising new University of Colorado Boulder study shows that huge amounts of fatty acids circulating in the bloodstreams of feeding pythons promote healthy heart growth, results that may have implications for treating human heart disease.

CU-Boulder Professor Leslie Leinwand and her research team found the amount of triglycerides -- the main constituent of natural fats and oils -- in the blood of Burmese pythons one day after eating increased by more than fiftyfold. Despite the massive amount of fatty acids in the python bloodstream there was no evidence of fat deposition in the heart, and the researchers also saw an increase in the activity of a key enzyme known to protect the heart from damage.

After identifying the chemical make-up of blood plasma in fed pythons, the CU-Boulder researchers injected fasting pythons with either "fed python" blood plasma or a reconstituted fatty acid mixture they developed to mimic such plasma. In both cases, the pythons showed increased heart growth and indicators of cardiac health. The team took the experiments a step further by injecting mice with either fed python plasma or the fatty acid mixture, with the same results.

"We found that a combination of fatty acids can induce beneficial heart growth in living organisms," said CU-Boulder postdoctoral researcher Cecilia Riquelme, first author on the Science paper. "Now we are trying to understand the molecular mechanisms behind the process in hopes that the results might lead to new therapies to improve heart disease conditions in humans."

The paper is being published in the Oct. 28 issue of the journal Science. In addition to Leinwand and Riquelme, the authors include CU postdoctoral researcher Brooke Harrison, CU graduate student Jason Magida, CU undergraduate Christopher Wall, Hiberna Corp. researcher Thomas Marr and University of Alabama Tuscaloosa Professor Stephen Secor.

Previous studies have shown that the hearts of Burmese pythons can grow in mass by 40 percent within 24 to 72 hours after a large meal, and that metabolism immediately after swallowing prey can shoot up by fortyfold. As big around as telephone poles, adult Burmese pythons can swallow prey as large as deer, have been known to reach a length of 27 feet and are able to fast for up to a year with few ill effects.

There are good and bad types of heart growth, said Leinwand, who is an expert in genetic heart diseases including hypertrophic cardiomyopathy, the leading cause of sudden death in young athletes. While cardiac diseases can cause human heart muscle to thicken and decrease the size of heart chambers and heart function because the organ is working harder to pump blood, heart enlargement from exercise is beneficial.

"Well-conditioned athletes like Olympic swimmer Michael Phelps and cyclist Lance Armstrong have huge hearts," said Leinwand, a professor in the molecular, cellular and developmental biology department and chief scientific officer of CU's Biofrontiers Institute. "But there are many people who are unable to exercise because of existing heart disease, so it would be nice to develop some kind of a treatment to promote the beneficial growth of heart cells."

Riquelme said once the CU team confirmed that something in the blood plasma of pythons was inducing positive cardiac growth, they began looking for the right "signal" by analyzing proteins, lipids, nucleic acids and peptides present in the fed plasma. The team used a technique known as gas chromatography to analyze both fasted and fed python plasma blood, eventually identifying a highly complex composition of circulating fatty acids with distinct patterns of abundance over the course of the digestive process.

In the mouse experiments led by Harrison, the animals were hooked up to "mini-pumps" that delivered low doses of the fatty acid mixture over a period of a week. Not only did the mouse hearts show significant growth in the major part of the heart that pumps blood, the heart muscle cell size increased, there was no increase in heart fibrosis -- which makes the heart muscle more stiff and can be a sign of disease -- and there were no alterations in the liver or in the skeletal muscles, he said.

"It was remarkable that the fatty acids identified in the plasma-fed pythons could actually stimulate healthy heart growth in mice," said Harrison. The team also tested the fed python plasma and the fatty acid mixture on cultured rat heart cells, with the same positive results, Harrison said.

The CU-led team also identified the activation of signaling pathways in the cells of fed python plasma, which serve as traffic lights of sorts, said Leinwand. "We are trying to understand how to make those signals tell individual heart cells whether they are going down a road that has pathological consequences, like disease, or beneficial consequences, like exercise," she said.

The prey of Burmese pythons can be up to 100 percent of the constricting snake's body mass, said Leinwand, who holds a Marsico Endowed Chair of Excellence at CU-Boulder. "When a python eats, something extraordinary happens. Its metabolism increases by more than fortyfold and the size of its organs increase significantly in mass by building new tissue, which is broken back down during the digestion process."

The three key fatty acids in the fed python plasma turned out to be myristic acid, palmitic acid and palmitoleic acid. The enzyme that showed increased activity in the python hearts during feeding episodes, known as superoxide dismutase, is a well-known "cardio-protective" enzyme in many organisms, including humans, said Leinwand.

The new Science study grew out of a project Leinwand began in 2006 when she was named a Howard Hughes Medical Institute Professor and awarded a four-year, $1 million undergraduate education grant from the Chevy Chase, Md.-based institute. As part of the award Leinwand initiated the Python Project, an undergraduate laboratory research program designed to focus on the heart biology of constricting snakes like pythons thought to have relevance to human disease.

Undergraduates contributed substantially to the underpinnings of the new python study both by their genetic studies and by caring for the lab pythons, said Leinwand. While scientists know a great deal about the genomes of standard lab animal models like fruit flies, worms and mice, relatively little was known about pythons. "We have had to do a lot of difficult groundwork using molecular genetics tools in order to undertake this research," said Leinwand.

CU-Boulder already had a laboratory snake facility in place, which contributed to the success of the project, she said.

"The fact that the python study involved faculty, postdoctoral researchers, a graduate student and an undergraduate, Christopher Wall, shows the project was a team effort," said Leinwand. "Chris is a good example of how the University of Colorado provides an incredible educational research environment for undergraduates." Wall is now a graduate student at the University of California, San Diego.

Hiberna Corp., a Boulder-based company developing drugs based on natural models of extreme metabolic regulation, signed an exclusive agreement with CU's Technology Transfer Office in 2008, licensing technology developed by Leinwand based on the natural ability of pythons to dramatically increase their heart size and metabolism.

Directed by Nobel laureate and CU Distinguished Professor Tom Cech, the Biofrontiers Institute was formed to advance human health and welfare by exploring critical areas of biology and translating new knowledge into practical applications. The institute is educating a new generation of interdisciplinary scientists to work together on solutions to complex biomedical challenges and to expand Colorado's leadership in biotechnology. For more information on the Biofrontiers Institute visit cimb.colorado.edu .

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Cecilia A. Riquelme, Jason A. Magida, Brooke C. Harrison, Christopher E. Wall, Thomas G. Marr, Stephen M. Secor, Leslie A. Leinwand. Fatty Acids Identified in the Burmese Python Promote Beneficial Cardiac Growth. Science, 2011; 334 (6055): 528-531 DOI: 10.1126/science.1210558

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To diagnose heart disease, visualization experts recommend a simpler approach

ScienceDaily (Oct. 27, 2011) — A team of computer scientists, physicists, and physicians at Harvard has developed a simple yet powerful method of visualizing human arteries that may result in more accurate diagnoses of atherosclerosis and heart disease.

The prototype tool, called "HemoVis," creates a 2D diagram of arteries that performs better than the traditional 3D, rainbow-colored model. In a clinical setting, the tool has been shown to increase diagnostic accuracy from 39% to 91%.

Presented Oct. 27 at the IEEE Information Visualization Conference(InfoVis 2011), the new visualization methodoffers insight to clinicians, imaging specialists, engineers, and others in a wide range of fields who need to explore and evaluate complex, branching structures.

"Our goal was to design a visual representation of the data that was as accurate and efficient for patient diagnosis as possible," says lead author Michelle Borkin, a doctoral candidate at the Harvard School of Engineering and Applied Sciences (SEAS). "What we found is that the prettiest, most popular visualization is not always the most effective."

HemoVis takes data from patient-specific blood flow simulations, combined with traditional imaging data, and visually displays a tree diagram of the arteries with areas of disease highlighted to assist in diagnosis.

Tools for artery visualization in both clinical and research settings commonly use 3D models that portray the shape and spatial arrangement of vessels of interest. These complex tools require users to rotate the models to get a complete perspective of spatial orientation.

By contrast, the new visualization requires no such rotation or interaction. The tool utilizes 2D, circumference-adjusted cylindrical cross sections arranged in tree diagrams.

Though this visualization method may seem less high-tech, the team demonstrated through quantitative evaluation with medical experts that the 2D model is actually more accurate and efficient for patient diagnosis.

"In the 3D case, the more complex and branched the arteries were, the longer it took to complete the patient diagnosis, and the lower the accuracy was," Borkin reflects. "In the 2D representation, it didn't matter how many branches we had or how complex they were -- we got consistently fast, accurate results. We weren't expecting that."

Tree diagrams are hardly new, as evolutionary biologists will attest, but scientists in many fields are using them to solve a range of very modern and complex problems. In fact, Borkin applied her own experience in astronomy and physics to transform the concept of visualization for SEAS' Multiscale Hemodynamics research group. In prior work, she had used a very similar type of tree diagram to determine the structure of nebulae in outer space.

"With the consultation and cooperation of clinicians, we were able to draw on fairly well known visualization techniques and principles from computer science to solve a practical clinical problem," says Hanspeter Pfister, Gordon McKay Professor of the Practice of Computer Science at SEAS.

Borkin, Pfister, and their colleagues relied on the input of physicians and others with clinical or laboratory imaging experience throughout the process. Through extensive surveys and interviews, they identified the most popular options for display, accurate layout, and coloring of these arterial projections.

However, Borkin drew on well supported research that is less well known outside the visualization community:

"For years, visualization, computer science, and psychology researchers have identified that color is critical for conveying the value of data, but that the rainbow coloring is not well-attuned to the human visual system."

Accordingly, HemoVis departs from the traditional practice of rainbow color-coding in favor of a graded single-color scheme (red to black) that can represent placement along a continuum.

In tests, diagnostic accuracy, as measured by the proportion of diseased areas identified, increased dramatically with the new color scheme.

Widespread adoption of visual representations like those in HemoVis could have the effect of not only optimizing tasks that are critical for doctors, but also changing long-entrenched mindsets and making scientists "think twice" about their assumptions in data visualization, Borkin says.

"This approach to visualization design and validation is broadly applicable in medicine, engineering, and science," notes Pfister. "We hope that people will use this process as a template for transforming their own visualizations."

Borkin and Pfister acknowledged that while HemoVis represents an important step forward, traditional 3D artery models still play a role, particularly in providing a spatially intuitive tool for surgical planning.

With this in mind, the next steps for this research include further development and optimization of the 2D tool and investigation into how it might complement, rather than replace, its 3D counterpart.

A paper about this work will be published later this year in the journal IEEE Transactions on Visualization and Computer Graphics.

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The above story is reprinted from materials provided by Harvard University. The original article was written by Mureji Fatunde.

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