For Babies With Heart Defects, Death Risk Is Far Lower At Most Experienced Hospitals

Each year, thousands of babies are born with severe heart defects that must be operated on within days or weeks of their birth. And though the odds for these infants are much better now than they were even 10 years ago, a new study suggests that there may be a way to give them an even better chance at living: Get them to the hospitals that are the most experienced at handling such cases.

In the first national study of this issue, a team of University of Michigan researchers found that infants with specific complex heart defects are much less likely to die before leaving the hospital if they are treated at the centers that treat the largest numbers of these patients. This relationship between hospital volume and mortality has been seen in adult heart operations, but the new study suggests it holds true for infants as well.

“A generation ago, we were just happy when these patients lived, but that’s not good enough anymore,” says lead author Jennifer Hirsch, M.D., a U-M pediatric cardiac surgeon and member of the Michigan Congenital Heart Center. “Although mortality rates are much lower, there is still a significant variation between centers. This study indicates that it may be time to selectively regionalize these patients’ care, to give them the best chance at a good outcome.”

The study is published online in the journal Pediatric Cardiology. Hirsch and her colleagues based their study on data from the 2003 Kids’ Inpatient Database, a national database sponsored by the Agency for Healthcare Research and Quality that includes information on children hospitalized in 36 states.

They analyzed data for two of the most severe congenital heart defects: transposition of the great arteries (TGA), in which the major blood vessels leading between the heart and lungs are switched, and hypoplastic left heart syndrome (HLHS), in which the left side of the heart does not develop properly.

Both defects are lethal if not treated within a few weeks of birth, with operations called the arterial switch operation for TGA and the Norwood procedure for HLHS. Infants may need additional operations later in life, but these initial open-heart procedures are critical for their survival.

The study shows that an infant’s risk of dying in the hospital during or after their operation varied greatly depending on the number of each procedure performed that year at the hospital where they were treated. Mortality rates ranged from more than 10 percent to less than 1 percent for the arterial switch operation, and from more than 35 percent to around 10 percent for the Norwood procedure.

“The relationship between hospital volume and risk of dying was significant across the spectrum for both defects, though in the case of arterial switch operations the difference dwindled among hospitals that performed about 15 or more in a year,” says Hirsch, a Lecturer in the Section of Cardiac Surgery at the U-M Medical School who performs operations at the U-M C.S. Mott Children’s Hospital. “For the Norwood, the trend to decreased mortality did not level off.”

The researchers chose the two conditions for their study not because the operations themselves vary in difficulty — both require skilled surgeons and operating room teams — but because of differences in the difficulty of pre- and post-surgical care. TGA care is considered somewhat less tricky than HLHS care. Even after the Norwood operation, babies with HLHS will still need at least two more operations in their first years of life to palliate their defect.

“All of the surgeons who operate on congenital heart defects are incredibly well trained,” says Hirsch, noting that pediatric cardiac surgeons must complete more than 10 years of surgical training after four years of college and four years of medical school to operate on the tiny hearts of infants and children. “It’s a matter of exposure to these complex cases not just for the surgeon, but also for the anesthesiologist, the surgical nurses and perfusionists, the intensive care unit staff, and the social workers and floor nurses who help prepare parents to take care of these children at home.”

The new results suggest that for these most rare and complex of cases, infants have the best outcomes when treated at hospitals whose teams are accustomed to caring for TGA and HLHS babies. The Michigan Congenital Heart Center, for example, handles more than 60 Norwood cases and 20 arterial switch cases each year, along with hundreds of other children with lesser defects.

Selectively regionalizing the care of these more severely ill infants, the researchers conclude, may be warranted based on the difference in mortality seen in the new study. But making sure that babies get to the most experienced centers in time for their operation will require commitments of resources and logistics, and a commitment by smaller congenital heart programs to refer the most complex patients early.

More research is also needed on the factors that influence a baby’s likelihood of dying after being discharged from the hospital following a Norwood procedure, but before he or she has the second- or third-stage operations for HLHS. Currently, this inter-stage mortality is estimated at 15 percent. The U-M has launched a new effort — the Michigan Congenital Heart Outcomes Research & Discovery program — that will allow researchers to collect and analyze much more detailed data about U-M congenital heart patients than ever before, to help answer these questions and more.

The newly published study differs in several major ways from previous studies that examined the relationship between in-hospital mortality and hospital volume for congenital heart patients. Other United States studies, performed in the 1990s when congenital heart operations and post-surgical care were still evolving at a rapid pace, used data for all heart conditions in one or two states.

Although these studies found a relationship between the number of infants treated and their risk of dying, the major thresholds were seen at the 100- to 200-patient level. Hirsch and her colleagues note that these studies included data from patients with much less severe heart defects, who had operations that carry a much lower risk of death during and after surgery.

“For the more routine congenital heart surgery, outcomes are excellent everywhere,” says Hirsch. “But when it comes to a child with a complex defect, it’s important to send him or her to a center of excellence. And the parents of these children are often so overwhelmed by their sudden situation, it will be important to develop the systems and support that will help them get to the right place.”

In addition to Hirsch, the paper’s authors are pediatric heart surgeon Richard G. Ohye, M.D., and James Gurney, Ph.D. and Janet Donohue, MPH of the U-M Child Health Evaluation and Research Unit.

Adapted from materials provided by University of Michigan Health System.

Scientists Overcome Major Obstacles To Stem Cell Heart Repair

Scientists at Imperial College London have overcome two significant obstacles on the road to harnessing stem cells to build patches for damaged hearts. Presenting the research at a UK Stem Cell Initiative conference December 13 in Coventry, research leader Professor Sian Harding has explained how her group have made significant progress in maturing beating heart cells (cardiomyocytes) derived from embryonic stem cells and in developing the physical scaffolding that would be needed to hold the patch in place in the heart in any future clinical application.

From the outset the Imperial College researchers have been aiming to solve two problems in the development of a stem cell heart patch. The first is undesirable side effects, such as arrhythmia, that can result from immature and undeveloped cardiomyocytes being introduced to the heart. The second is the need for a scaffold that is biocompatible with the heart and able to hold the new cardiomyocytes in place while they integrate into the existing heart tissue. Matching the material to human heart muscle is also hoped to prevent deterioration of heart function before the cells take over.

The stem cell team, led by Dr Nadire Ali, co-investigator on the grant*, have managed to follow beating embryonic stem cell-derived cardiomyocytes for up to seven months in the laboratory and demonstrate that these cells do mature. In this period the cells have coordinated beating activity, and they adopt the mature controls found in the adult heart by approximately four months after their generation from embryonic stem cells. These developed cardiomyocytes will then be more compatible with adult heart and less likely to cause arrhythmias.

The team have also overcome hurdles in the development of a biocompatible scaffold. Working closely with a group of biomaterial engineers, led by Dr Aldo Boccaccini and Dr Qizhi Chen, co-investigators on the grant, in the Department of Materials, Imperial College London, they have developed a new biomaterial with high level of biocompatibility with human tissue, tailored elasticity and programmable degradation. The latter quality is important as any application in the heart needs to be able to hold cells in place long enough for them to integrate with the organ but then degrade safely away. The researchers have found that their material, which shares the elastic characteristics of heart tissue, can be programmed to degrade in anything from two weeks upwards depending on the temperatures used during synthesis.

Professor Harding said: “Although we are still some way from having a treatment in the clinic we have made excellent progress on solving some of the basic problems with stem cell heart therapies. The work we have done represents a step forward in both understanding how stem cell-derived developing heart cells can be matured in the laboratory and how materials could be synthesised to form a patch to deliver them to damaged areas of the heart.

“A significant amount of hard work and research remains to be done before we will see this being used in patients but the heart is an area where stem cell therapies offer promise. We know that the stem cell-derived cardiomyocytes will grow on these materials, and the next step is to see how the material and cell combination behave in the long term.”

Professor Nigel Brown, BBSRC Director of Science and Technology, commented: “This research shows that although embryonic stem cell therapies are still some way away from the clinic, progress is being made on the basic biological developments. As with all new biomedical applications, an understanding of the underpinning fundamental science is essential to successfully moving forward.”

*This research was funded by the Biotechnology and Biological Sciences Research Council.

Carbon balls could help fight allergies

Soccer ball-shaped nanoparticles known as buckyballs may one day help to offer relief for allergy sufferers. Adapted buckyballs are capable of blocking the pathway mediating allergic responses in human immune cells, new research has revealed.

Buckminsterfullerenes—spherical cages about 1-10 nanometres in size made up of 60 carbon atoms—have for years attracted interest from material scientists for their ability to make strong, lightweight materials with interesting electrical properties. But they could have medical uses too.

It is known that buckyballs have a talent for mopping up reactive oxygen species called ‘free radicals’, which can play havoc with biological systems. “C60 has a very high electron affinity. It grabs electrons easily, so it can act to neutralise free radicals,” explains James Cross, a chemist researching fullerenes at Yale University in New Haven, Connecticut.

Previous studies have shown that buckyballs can be used to protect nerve cells, for example, from damaging oxygen species1.

Chris Kepley, an immunologist at Virginia Commonwealth University in Richmond, wondered if the carbon balls could also help out the immune system. Kepley’s team, working with a Virginia-based nanomaterials company, tested modified versions of the nanospheres in human cells and mice. Although the specifics of their formulations remain are under wraps, they say they were able to enhance the fullerenes’ functionality by adding side groups that increase their solubility. While some studies have hinted that buckyballs might be toxic, these modified versions have no apparent ill effects, says Kepley.

The group put human immune cells called mast cells in a dish—some with buckyballs, and some without—and then challenged them with a particle that is commonly used to mimic allergens such as pollen. Those with buckyballs released 50 times less histamine, one of the chemicals responsible for inflammation and tightening of the airways in asthma, and inhibited 30-40 other mediators involved in the allergic response.

Exactly how the buckyballs prevent mast cells from releasing histamine is unclear.

Dark chocolate lowers blood pressure

Dark chocolate can reduce blood pressure but over-indulgence in it can cause harm, suggests a new study by researchers in Germany. Chocolates are made from cocoa – the dried and partially fermented fatty seed of the cacao tree.

Cocoa contains flavonoid, a type of chemical that researchers say has been shown to improve blood flow and reduce blood pressure.

Researchers at the University Hospital of Cologne studied 44 people with raised blood pressure, putting them into two groups. One ate six grams of dark chocolate daily, the other the same amount of white chocolate.

The people were between 56 to 73 years with either upper-range pre hypertension (blood pressure between 130/85 and 139/89) or stage 1 hypertension (blood pressure between 140/90 and 160/100).

None of those eating dark chocolate registered changes in body weight or their levels of glucose and lipids, the researchers wrote in the Journal of American Medicine (JAMA).

Their systolic blood pressure – the upper reading which measures the force of blood as the heart beats – fell by 2.9 mm and their diastolic blood pressure – the lower figure taken as the heart relaxes – reduced by 1.9 mm.

The suggestion that cocoa is beneficial for health is not new and previous research had also suggested it could bring down blood pressure.

However, it had been thought that large quantities were needed to achieve the desired effect and that the benefits would then be offset by the consequences of consuming the high levels of fat and sugar associated with cocoa products.

But the researchers said they have now shown that benefits can be achieved with a small amount – 30 calories worth of chocolate.

They noted that the blood pressure reduction was small but stressed that the effects were clinically noteworthy.

A 3 mm reduction in blood pressure could “reduce the relative risk of stroke mortality by 8 percent, of coronary artery disease by 5 percent, and of all cause mortality by 4 percent,” the researchers said.

They also stressed that asking people to consume a couple of chunks of chocolate a day was far easier than encouraging “complex behavioural changes” to help them reduce their blood pressure.

However, the British Heart Foundation’s nutritionist Sara Stanner warned that it was “important to remember that chocolate is also high in fat and calories so over-indulgence is not good for your heart.”