Tag Archives: Vascular Biology

Fat mice bred to have more muscle give insight, new targets for battling obesity’s cardiovascular risk

Even without losing fat, more muscle appears to go a long way in fighting off the bad cardiovascular effects of obesity.

That emerging evidence has scientists looking hard for new targets to uncouple the unhealthy relationship between fat and cardiovascular disease.

“If you look at the exercise literature, we understand very well that if you exercise, things get better. What we don’t really understand is what about exercise is good; what does it tell us about physiology and how disease starts, and how can you customize it to different populations?” said Dr. David Stepp, vascular biologist in the Vascular Biology Center at the Medical College of Georgia at Georgia Regents University.

Stepp and his colleagues have evidence that an increase in muscle mass – a huge consumer of glucose, a natural energy source that is often elevated in obesity – could mean a healthier ticket for some.

While fat has the unhealthy habit of storing fuel, “muscle is a much more metabolically active tissue, even when it’s just sitting there,” Stepp said. “It burns more oxygen at rest; it burns more energy at rest; so it burns more calories at rest.” Some of things scientists don’t know is if muscles secrete something that improves glucose metabolism or if just having more glucose-consuming muscle is the apparent magic.

A new $2.2 million grant from the National Heart, Lung, and Blood Institute is helping fill in those important blanks as it illuminates new points for intervening in one of the worst consequences of obesity.

“We are trying to establish links between the health of skeletal muscles and the circulatory system,” said Dr. David Fulton, Director of the MCG Vascular Biology Center and Co-Principal Investigator with Stepp on the grant. “When you eat, most of the glucose ends up in your skeletal muscle. When you are young, most of your body mass is skeletal muscle, so that glucose is efficiently distributed in the places where it should go to get used for energy and work.”

Stepp and Fulton were authors on a 2014 study in the Journal of the American Heart Association that showed the benefits of adding muscle when fat is monopolizing the body. They looked at normal mice and mice genetically altered to be obese – mice with voracious appetites that soon doubled their normal weight – as examples of a healthy and unhealthy human. When they deleted myostatin, a natural, negative regulator of muscle growth, from both, both groups developed bigger muscles. The normal mice also had less fat tissue.

But it was the obese-with-muscles mice that truly benefited in the cardiovascular sense: glucose tolerance and blood vessel dilation went up and insulin resistance and superoxide production went down. More muscle didn’t result in these additional changes in the leaner mice.

“If the insulin burner gets bigger and the storage (fat) gets smaller, that’s good,” Stepp said. “What we have demonstrated is that if the burner gets bigger, no matter what the storage does, it’s still good.”

When they looked further at the obese mice, minus the muscles, they also found the superoxide- producing gene Nox1 is a major culprit in obesity-related vascular disease. In fact, the gene is overexpressed in the blood vessels of the fat mice, apparently driven by high glucose levels in the blood.

Obese mice with no muscle added but Nox1 removed also experience cardiovascular improvement, an observation that Postdoctoral Fellow Dr. Jennifer Thompson is pursuing further with a new American Heart Association grant.

Meanwhile, Stepp and Fulton are exploring how elevated blood glucose elevates Nox1, acknowledging that while it makes intuitive sense, the science needs to be clear. Because while the search is on for Nox1 inhibitors, there aren’t any at this moment. Fulton and Stepp hope their studies will further inspire the search and identify additional points of intervention as well.

“We know that high glucose goes to Nox1 goes to superoxide, and superoxide goes to cardiovascular disease. What we don’t know is what is in between glucose and Nox1,” Stepp said. A possibility is galectin-3, a receptor for proteins that get coated with glucose when circulating levels of the sugar get too high. At least in culture, when glucose is added to cells, they produce more Nox1. But when the scientists block galectin-3 and add glucose, Nox1 doesn’t increase.

While it’s known that sugar-coating messes up protein function, the scientists aren’t certain what galectin-3 is doing. Is it clearing the dysfunctional proteins, telling them to die, and/or driving up Nox1? So they are looking at the signaling between all of the above. They are also developing additional mice models, where Nox1 and galectin-3 are removed from already genetically fat mice, to further explore their role in vascular dysfunction. They will also explore the cardiovascular impact, such as blood pressure and how well blood vessels dilate in response to stress, in their fat mice models with added muscle as well as the two new knockouts.

The bottom line: they want to know if they can break “the metabolic connection” between fat and cardiovascular disease. “Where is the key event that causes all these bad things to happen?” Stepp said, and, of course, where and how best to intervene.

Myostatin is part of the yin and yang of muscle growth that enables us, with some effort, to have good, but not excessive, muscle mass. High myostatin levels can produce muscular dystrophy; low ones can mean incredible bulk. Myostatin levels tend to decrease with exercise and increase with aging.

Injectable or infusible myostatin inhibitors are under study for muscular dystrophy and frailty syndrome, where older individuals lose so much muscle mass that they fall frequently. But the drugs are not generally available, even to scientists. While experience with the inhibitors is limited, life with less myostatin appears to be a good thing: Stepp said mice short one copy of the myostatin gene live longer, and humans with documented myostatin deficiency tend to be Olympic athletes.

Major blood vessel constrictor contributes to vision loss in premies

AUGUSTA, Ga. – A gene known to play a major role in constricting blood vessels also appears to be a major player in the aberrant blood vessel growth that can destroy the vision of premature babies.

Endothelin gene expression is greatly increased in the retinal tissue of a mouse model of retinopathy of prematurity, a condition that significantly affects about 1,500 infants annually, resulting in blindness in about half those babies, according to researchers at the Medical College of Georgia at Georgia Regents University.

The finding points toward a new therapy to help prevent the damage as well as a broader role for endothelin, known as a powerful blood pressure regulator, which also appears to have a role in blood vessel formation, said Dr. Chintan Patel, MCG postdoctoral fellow and first author of the study in The American Journal of Pathology.

Despite long-standing strategies to give premature newborns the lowest oxygen therapy possible to protect fragile, immature tissues such as the retina while providing adequate support to vital organs, vision damage remains an ongoing concern in neonatal intensive care units, said Dr. Jatinder Bhatia, Chief of the MCG Section of Neonatology.

In addition to immediate impacts on vision, the condition increases a child’s risk of retinal detachment, nearsightedness, crossed eyes, lazy eye, and glaucoma, according to the National Eye Institute.

The retina is part of the brain and, like the rest of the brain, it continues to develop even after full-term birth, said Dr. Ruth Caldwell, cell biologist at MCG’s Vascular Biology Center and the study’s corresponding author. The soft, three-layered tissue, found at the back of the eye, contains light-sensitive cells, which transform light into a signal for the brain.

The cup-shaped tissue is normally super vascular, but in premature babies, retinas, which are not yet ready to function, likely have not formed blood vessels throughout. Oxygen therapy, necessary to support other organs, further slows blood vessel development so the retina become ischemic. Neurons and supporting cells start secreting proteins and growth factors to try to recuperate from the lack of oxygen and nutrients to these areas, which instead, leads to formation of leaky, malpositioned blood vessels. “There is a dysregulation of growth factors that occurs at a microscopic level,” Patel said.

There are a number of other things happening at the same time, which also are not good. High-oxygen levels also increase levels of oxidative stress, which increases inflammation in the face of decreased production of growth factors needed to produce healthy blood vessels, Patel said.  Blood vessels start growing in every direction, including on top of each other. “We call it pathological neovascularization,” he said.

Protruding blood vessels can create enough stress to actually detach the retina, the main cause of visual impairment and blindness from retinopathy of prematurity, according to the National Eye Institute. Vascular endothelial growth factor, which is essential to neuron growth, is considered a primary culprit in retinopathy of prematurity as well as diabetic retinopathy, in which it contributes to a similar problem with erratic, leaky blood vessel growth that obstructs vision.

In their animal model of retinopathy of prematurity, mice born at term were given high-oxygen levels seven days later, which destroys some of the vessels that have developed and essentially halts the development of new ones as the immature retina continues to develop. They note that even at term, mice eyes remain shut for a few weeks because, as with premature babies, they are not yet ready to function.

Cell sensors that keep up with oxygen exposure, sense too much oxygen and stop growing, so blood vessels don’t form, Caldwell said. The return to normal airs seems like oxygen deprivation by comparison, so, similar to what happens in diabetic retinopathy where retinal blood flow is compromised, mice start growing many, obstructive blood vessels. “In a premature baby, some of the parts of the retina are not fully developed because of high oxygen, so it’s a similar scenario,” Patel said.

When the scientists looked at gene expression in retinal tissue five days after the return to normal air –  considered the peak period of dysregulated blood-vessel growth – they found about a 50-fold increase in the expression of endothelin 2, a potent blood pressure regulator and blood vessel constrictor in normal conditions, and about a three-fold increase in endothelin 1, also a constrictor. There was also a significant increase in endothelin receptors.

Way more vasoconstriction likely translates to far less blood vessel dilation. Endothelin and the equally powerful dilator nitric oxide tend to have a reciprocal relationship, Patel explained. “If you have more endothelin, you have less nitric oxide and vice versa,” he said.

While other genes, including VEGF, had increased expression, endothelin’s was the most dramatic and indicates its role in blood vessel formation. The scientists don’t yet know if it’s a direct effect or secondary to its role in blood pressure regulation. Although the emerging role of endothelin in cancer, where it appears to help tumors survive, indicates a direct one. “We are seeing a lot of the same things here,” Patel said.

Anti-VEGF therapy is often given for diabetic retinopathy and more selectively for retinopathy of prematurity. However, the scientists note that there is increasing evidence that other potential factors may also need regulating.

Endothelin may need to be as well. Because, when they gave endothelin receptor blockers, already used to treat other conditions, to the mice prior to the peak period of dysregulated growth, they helped normalize blood vessel growth.

“What we need is a therapy that does multiple things,” Patel said. Caldwell noted that in diabetic retinopathy, while anti-VEGF therapy is good at stopping dysregulated growth, it doesn’t help spur normal blood vessel growth, which the endothelin receptor blocker did in their studies.

Next steps could include seeing if an endothelin antagonist will also work to correct dysregulated growth after it has occurred and packaging it with anti-VEGF therapy. The research was supported by the National Eye Institute, the Department of Veterans Affairs, the American Heart Association, and the GRU Culver Vision Discovery Institute.

Cancer fighter can help battle pneumonia

AUGUSTA, Ga. – The tip of an immune molecule known for its skill at fighting cancer may also help patients survive pneumonia, scientists report.

A synthesized version of the tip of tumor necrosis factor appears to work like a doorstop to keep sodium channels open inside the air sacs of the lungs so excess fluid can be cleared, according to a study published in the American Journal of Respiratory Critical Care Medicine.

This TIP peptide is attracted to the sugar coating at the mouth of the sodium channel. Once the two connect, they move inside the small but essential number of cells that help keep the lungs clear by taking up sodium, said Dr. Rudolf Lucas, vascular biologist at the Medical College of Georgia at Georgia Regents University and the study’s corresponding author.

Inside these cells, TIP binds to the most critical part of the sodium pump, the alpha subunit, and fluid starts moving again. Sodium comes in the channel, water follows, and the sodium pump pushes the fluid into the body’s natural drainage network, called the lymphatic system.

“The more sodium you take up, the more water will be taken up by these cells,” Lucas said. “That is the way it’s supposed to work.

Fluid in the lungs’ 266 million air sacs interferes with breathing as well as the important transfer of oxygen from air sacs to capillaries so it can be distributed throughout the body. TNF, known for its tumor-killing capacity, actually has been viewed as a “bad guy” in the lungs where it can block the sodium channel. In fact, excessive TNF production can put patients into shock.

“We found that there is another side on the tip of this molecule, which recognizes sugar groups and this side counteracts that side,” Lucas said. “We knew we could stimulate liquid clearance in animal models with this peptide and we also knew we could increase the uptake of sodium. Now we know more about how it works.”

Pneumonia and influenza together are the eighth leading cause of death in the United States with pneumonia overwhelmingly the most deadly, according to the American Lung Association. The elderly, children, and the chronically ill are at highest risk.

Ironically, lung problems can actually worsen with pneumonia treatment. Viruses and bacteria are major causes of pneumonia, with bacteria typically producing the most severe cases. When antibiotics are given to kill the bacteria, the dying organisms release toxins that reduce expression of the sodium channel and help keep it closed at a time when it needs to work even harder. “The natural system is being impaired by an infection,” Lucas said.

TNF weighs in as well. It’s recruited as part of the body’s natural defense against the bacterial infection, producing reactive oxygen species to help destroy the organism but also blocking the sodium pathway. It can even produce more fluid in the lungs by making capillaries leaky.

The TIP peptide appears to help the body do what’s needed at that moment: keep sodium channels open, intact, and safe from bacterial toxins. “You have two opposing sides within the same TNF molecule,” Lucas said. “We give much more of the positive part so we can actually help it function much better than the normal response.”

Mice with less expression of this sugar-loving TIP experience a lot more swelling, or edema, and those missing the alpha subunit of the sodium pump can’t survive.

For the laboratory studies, scientists used the strongest toxin produced by the pneumonia-causing bacteria so next steps include looking at the entire infection. Lucas is also looking at the effect of the TIP peptide in the flu with fellow MCG scientist Dr. Andrew Mellor and in kidney failure with MCG Medicine Chair Dr. Michael Madaio.

His studies in mice and pigs have shown the peptide increases fluid removal fourfold and improves blood oxygen levels.

Recent clinical trials of the peptide at the Medical University of Vienna in patients with pulmonary edema, or swelling, who were at high risk of multiple organ failure and dying, showed that fluid removal occurred earlier and was significantly better in patients receiving the synthesized peptide. It worked best in the sickest patients and no side effects have been reported.

The biotechnology company APEPTICO has a patent on the peptide and funded the clinical studies in which it was given twice daily through the ventilator mask helping support breathing.

In healthy individuals, sodium channels are pretty much always open, people make very little TNF, and there is very little fluid in the lungs.

The research was funded by the National Institutes of Health. GRU Postdoctoral Fellow Istvàn Czikora is first author on the paper. Co-authors include postdoctoral fellow Supriya Sridhar; Dr. Douglas C. Eaton, Chair of Physiology at Emory University; and Dr. Trinad Chakraborty, Dean of the Faculty of Medicine at the University of Giessen, Germany.

Stem cell therapy may help severe congestive heart failure


Dr.Bermanwebfront2
Researchers want to know whether patients with debilitating heart failure can benefit by having their own stem cells injected into their ailing heart muscle.

The severe condition is ischemic dilated cardiomyopathy, a currently incurable condition resulting from significantly compromised blood flow to the heart muscle as well as heart attacks, which leave the muscle bulky and inefficient and patients unable to carry out routine activities.

“We want to know if stem cell therapy is an option for patients who have essentially run out of options,” said Dr. Adam Berman, electrophysiologist at the Medical College of Georgia at Georgia Regents University and Director of Cardiac Arrhythmia Ablation Services at GRHealth. “It’s a very exciting potential therapy, and these studies are designed to see if it works to help these patients.”

Berman is a Principal Investigator on the multi-site study in which stem cells are removed from the bone marrow, their numbers significantly increased by technology developed by Aastrom Biosciences, then injected into multiple weak points in the heart. At GRHealth, the procedure is performed in the Electrophysiology Lab where Berman threads a catheter into an artery from the groin into the heart. Three-dimensional maps of the heart are created to provide a clear picture of its natural geography as well as major sites of damage.

“Everyone’s heart is different, their scar burden is different, everything is different,” Berman said. From that vantage point, small needles – similar in size to those used for skin testing – are used to make about 12 to 20 strategic injections of mesenchymal stem cells, which can differentiate into a variety of cell types. In this case, researchers hope the cells will improve blood flow and function of the heart.

Half of the study participants receive the stem cell treatment called ixmyelocel-T and the remainder a saline placebo. Patients go home the next day but researchers follow all participants for 12 months to assess heart function and quality of life. GRHealth plans to enroll a handful of patients in the clinical trial.

Treatment options for heart failure include front-line therapies such as diuretics to more extreme measures such as implantable ventricular assist devices and heart transplants.

Patients eligible for this trial have explored existing options and must have an internal defibrillator, a standard of care in these patients to help avoid sudden death from an abnormal heart rhythm. Sudden death and progressive heart muscle failure cause most congestive heart failure deaths. Before enrollment, a cardiothoracic surgeon and interventional cardiologist rule out other options to open the patient’s coronary arteries.

While much work remains, Berman hopes stem cell therapy may one day be a part of early intervention to help keep heart failure from progressing to an advanced, debilitating state. “We hope this is the future,” he said.

Laboratory studies at MCG and elsewhere indicate that stem cells injected into the heart typically survive only a week or two. “That has been a very debated point,” said Dr. Neal Weintraub, cardiologist and Associate Director of MCG’s Vascular Biology Center. So while evidence is limited that many stem cells actually turn into new heart cells, good evidence exists that they can help generate new blood vessels to reperfuse the heart and secrete factors that aid survival of existing heart cells, Weintraub said.

The sometimes dramatic change researchers see after injecting stem cells into the heart, at least in the laboratory, likely results from a combination of new and saved tissue, he said.

“What they do is produce a lot of factors that change the environment dramatically and conduce the normal cells in the tissue to work better and potentially help them survive,” Weintraub said. His laboratory studies stem cells endogenous to the heart to learn more about how they work normally and how, in the future, they might be used therapeutically.

“If we can unlock the secrets, we might be able to teach the cells to do this repair on their own,” Weintraub said. In fact, stem cells are found throughout the body, and while evidence suggests they already try to help repair damage, many patients have multiple related conditions, such as high blood pressure and diabetes, that prevent endogenous stem cells from working as well as they should, said Weintraub, who is a Co-Investigator on the new clinical study.

Unlike most clinical trials, Berman notes that if this study results are positive, participants who received placebo can also get ixmyelocel-T.

For more study information, call Carol Smith or Mary Anne Park in the Surgical Research Service at 706-721-0193.

Vascular Biology Research Seminar Series

Dr. Magdalena Chrzanowska-Wodnicka, will present “Small GTPase Rap1 integrates adhesion, chemical and mechanical signals to control cardiovascular functions” on Wednesday, Dec. 18, at 11:30 a.m. in the Sanders Research and Education Building, room CB-3801, on the Health Sciences Campus as part of the Vascular Biology Research Seminar Series.

Chrzanowska-Wodnicka is the Associate Investigator for the Blood Research Institute at the BloodCenter of Wisconsin and Assistant Adjunct Professor of Pharmacology and Toxicology at the Medical College of Wisconsin. For more information, contact Kari Martin at 706-721-6338.

Across Campus

Vascular Biology Seminar

The Vascular Biology Research Seminar Series will feature Dr. Richard J. Roman on Wednesday, Nov. 6, at 12:30 p.m. in the Carl T. Sanders Research and Education Building, room CB-3801, on the Health Sciences Campus. Roman is Professor and Chairman of the Department of Pharmacology, University of Mississippi Medical Center, Jackson, Miss. He will be speaking on “CYP eicosanoids in pathogenesis of hypertension, stroke, kidney disease, and vascular disorders.”

Flu vaccination schedule

Employees can get their flu vaccinations at any of the below events if they present a valid employee ID:

  • Magnolia Room/Terrace Dining, Thursday, Nov. 7, from 11 a.m.-12:30 p.m.
  • Magnolia Room/Terrace Dining, Wednesday, Nov. 13, from 7-8:30 a.m.
  • Flu vaccines are also available in Employee Health, 1515 Pope Avenue, Monday-Friday, 7:30 a.m.-4 p.m.; no appointment is needed.

Zheng Le to present at Vascular Biology Seminar

The Vascular Biology Research Seminar Series will feature Dr. Yun Zheng Le on Wednesday, Nov. 13, at 12:30 p.m. in the Carl T. Sanders Research and Education Building, room CB-3801, on the Health Sciences Campus. Zheng Le is the Choctaw Chair in Diabetes Research at the Harold Hamm Diabetes Center at the University of Oklahoma Health Science Center. He will be speaking on “Pathogenic mechanisms of diabetic retinopathy, perspectives from a cell biologist.”

Paws and Open Enrollment

All enterprise employees are invited to attend the OCM Brown Bag Workshop on Thursday, Nov. 14, from noon to 1 p.m in Lee Auditorium on the Health Sciences Campus. The topic will be “Using PAWS for Open Enrollment,” and we will focus on showing employees how to enroll for benefits using the new employee intranet, PAWS. OCM and HR will be on hand to answer your questions. Snacks, drinks, and fun prizes will be available.

Carnitine supplement may improve survival rates of children with heart defects

Blackwebfront1[3]A common nutritional supplement may be part of the magic in improving the survival rates of babies born with heart defects, researchers report.

Carnitine, a compound that helps transport fat inside the cell powerhouse where it can be used for energy production, is currently used for purposes ranging from weight loss to chest pain.

New research shows it appears to normalize the blood vessel dysfunction that can accompany congenital heart defects and linger even after corrective surgery, said Dr. Stephen M. Black, cell and molecular physiologist at the Vascular Biology Center at the Medical College of Georgia at Georgia Regents University.

“My hope is this is going to have a major, major impact on survival of babies,” Black said.  About half the babies born with heart defects have excessive, continuous high pressure on their lungs from misdirected blood flow. Early surgery can prevent full-blown pulmonary vascular disease, but scientists are finding more subtle disruptions in the signaling inside blood vessels walls that can be problematic – even deadly – up to 72 hours after surgery.

The good news is the changes are reversible and that carnitine speeds recovery and can even prevent the damage in a lamb model of these human heart defects, according to studies published in the journal Pediatric Research.

Normally, most blood flow bypasses the lungs in utero when the placenta provides blood and oxygen for the baby. Baby’s first breaths naturally expand the lungs and blood vessels, activating a process inside the lining of vessels that enables them to accommodate the initial blood surge, then reduce pressure quickly, dramatically and permanently.
This natural transition doesn’t occur when heart defects misdirect blood flow. “It’s kind of like a chronic fetal-to-newborn transition,” said Black, the study’s corresponding author. Lungs get pounded with about three times the normal flow and, even when surgeries are done as early as possible to repair the defect, correct blood flow and protect the lungs, the 20 percent death rates from acute pulmonary hypertension have remained unchanged for a decade. “That’s 1 in 5 kid (with this condition),” Black said.

Left unchecked, the barrage thickens blood vessels, making them unresponsive, much like those of an elderly individual who has lived for years with uncontrolled high blood pressure. The comparatively brief periods of pounding these babies experience impairs the ability of the endothelial cells, which line blood vessels, to produce nitric oxide, a major dilator of blood vessels.

The shear force disrupts carnitine homeostasis, weakens the mitochondria (the cell powerhouse) and impairs nitric oxide production.  To make bad matters worse, the precursor to nitric oxide instead makes more peroxynitrite, prompting endothelial cells to grow and thickening blood vessels.  Black was also corresponding author of a recent study in the Journal of Biological Chemistry that showed peroxynitrite does this by turning on the cell survival protein kinase Akt1.

The new study indicates that even without fixing the heart defect, high daily doses of carnitine in the first four weeks of life can prevent endothelial dysfunction.  In fact, the laboratory lambs’ ability to make nitric oxide is preserved even without the benefit of heart surgery and the responses to the chemical activity that enables blood vessel dilation is normalized, Black said.

Study co-author Dr. Jeffrey Fineman, a whole-animal physiologist and physician at the University of California, San Francisco, developed the model, a lamb whose four-chambered heart is very similar to humans.  In utero surgery that misdirects too much blood to the lungs, means that, like children, the lambs are born with the defect.

Black is now working with Fineman, who is pursuing additional funding to resolve questions such as the optimal dosage and timing for giving carnitine. “Do you want to give it for six weeks when you only have to give it for six hours?” Black said.  The researchers also plan to examine carnitine homeostasis in the blood of children with heart defects to see if it’s disrupted.  If it is, they plan to start clinical trials.

About 1 in 125 babies are born with a heart defect each year in the United States, according to the March of Dimes. The research was funded by the National Institutes of Health, the Foundation Leducq and the American Heart Association.

Carnitine supplement may improve survival rates of children with heart defects

Blackwebfront1[3]A common nutritional supplement may be part of the magic in improving the survival rates of babies born with heart defects, researchers report.

Carnitine, a compound that helps transport fat inside the cell powerhouse where it can be used for energy production, is currently used for purposes ranging from weight loss to chest pain.

New research shows it appears to normalize the blood vessel dysfunction that can accompany congenital heart defects and linger even after corrective surgery, said Dr. Stephen M. Black, cell and molecular physiologist at the Vascular Biology Center at the Medical College of Georgia at Georgia Regents University.

“My hope is this is going to have a major, major impact on survival of babies,” Black said.  About half the babies born with heart defects have excessive, continuous high pressure on their lungs from misdirected blood flow. Early surgery can prevent full-blown pulmonary vascular disease, but scientists are finding more subtle disruptions in the signaling inside blood vessels walls that can be problematic – even deadly – up to 72 hours after surgery.

The good news is the changes are reversible and that carnitine speeds recovery and can even prevent the damage in a lamb model of these human heart defects, according to studies published in the journal Pediatric Research.

Normally, most blood flow bypasses the lungs in utero when the placenta provides blood and oxygen for the baby. Baby’s first breaths naturally expand the lungs and blood vessels, activating a process inside the lining of vessels that enables them to accommodate the initial blood surge, then reduce pressure quickly, dramatically and permanently.
This natural transition doesn’t occur when heart defects misdirect blood flow. “It’s kind of like a chronic fetal-to-newborn transition,” said Black, the study’s corresponding author. Lungs get pounded with about three times the normal flow and, even when surgeries are done as early as possible to repair the defect, correct blood flow and protect the lungs, the 20 percent death rates from acute pulmonary hypertension have remained unchanged for a decade. “That’s 1 in 5 kid (with this condition),” Black said.

Left unchecked, the barrage thickens blood vessels, making them unresponsive, much like those of an elderly individual who has lived for years with uncontrolled high blood pressure. The comparatively brief periods of pounding these babies experience impairs the ability of the endothelial cells, which line blood vessels, to produce nitric oxide, a major dilator of blood vessels.

The shear force disrupts carnitine homeostasis, weakens the mitochondria (the cell powerhouse) and impairs nitric oxide production.  To make bad matters worse, the precursor to nitric oxide instead makes more peroxynitrite, prompting endothelial cells to grow and thickening blood vessels.  Black was also corresponding author of a recent study in the Journal of Biological Chemistry that showed peroxynitrite does this by turning on the cell survival protein kinase Akt1.

The new study indicates that even without fixing the heart defect, high daily doses of carnitine in the first four weeks of life can prevent endothelial dysfunction.  In fact, the laboratory lambs’ ability to make nitric oxide is preserved even without the benefit of heart surgery and the responses to the chemical activity that enables blood vessel dilation is normalized, Black said.

Study co-author Dr. Jeffrey Fineman, a whole-animal physiologist and physician at the University of California, San Francisco, developed the model, a lamb whose four-chambered heart is very similar to humans.  In utero surgery that misdirects too much blood to the lungs, means that, like children, the lambs are born with the defect.

Black is now working with Fineman, who is pursuing additional funding to resolve questions such as the optimal dosage and timing for giving carnitine. “Do you want to give it for six weeks when you only have to give it for six hours?” Black said.  The researchers also plan to examine carnitine homeostasis in the blood of children with heart defects to see if it’s disrupted.  If it is, they plan to start clinical trials.

About 1 in 125 babies are born with a heart defect each year in the United States, according to the March of Dimes. The research was funded by the National Institutes of Health, the Foundation Leducq and the American Heart Association.