New clues found to help protect heart from damage after heart attack

Studying mice, scientists have shown that boosting the activity of specific immune cells in the heart after a heart attack can protect against developing heart failure, an invariably fatal condition. Patients with heart failure tire easily and become breathless from everyday activities because the heart muscle has lost the ability to pump enough blood to the body.

The study, by researchers at Washington University School of Medicine in St. Louis, could lead to new therapies that reduce the risk of developing heart failure after a heart attack, severe viral illness or other cardiac injury. Damage to the heart muscle often causes progressive inflammation, a major driver of heart failure. According to the Centers for Disease Control and Prevention, about 5.7 million American adults have heart failure.

The research is published Nov. 1 in the journal JCI Insight.

“Heart failure remains a major problem, with half of all patients dying within five years of diagnosis,” said senior author and cardiologist Abhinav Diwan, MD, associate professor of medicine. “There are therapies that can relieve symptoms and extend life, but we need to do better. Our research is focused on finding ways to boost the immune system to help the heart heal after injury, which can prevent heart failure from progressing.”

During a heart attack, blood supply to a portion of the heart muscle is cut off, starving the heart muscle of oxygen and leading to the death of cardiac tissue. If the patient survives, the body’s immune cells respond to the heart injury to get rid of dead tissue and begin the healing process.

“These specific immune cells — macrophages — eat up the dead cells damaged during the heart attack and stimulate the heart to repair itself, but if the macrophages stick around too long, they become inflammatory and drive the damage that leads to heart failure,” Diwan said.

In the new study, the researchers, including first author Ali Javaheri, MD, PhD, an instructor in medicine in the Cardiovascular Division, have found a way to supercharge these macrophages, increasing their abilities to digest and dispose of damaged heart tissue left in the wake of a heart attack. The key is in stimulating specialized sacs called lysosomes, which are inside immune cells. Digestion and waste disposal take place inside lysosomes.

The researchers activated a molecule — called TFEB — that spurred heart macrophages to make more lysosomes. In particular, TFEB also helped lysosomes digest lipids, or fat molecules, more effectively.

“Macrophages are the ‘eating cells,’ and lysosomes are like their stomachs,” Diwan said. “When we boosted the number of lysosomes, we enhanced their ability to digest damaged heart cells. Instead of provoking heart failure, this lowered inflammation and helped reduce the development of heart failure in the mice.”

The researchers are planning to investigate various small molecules as potential drug therapies that could activate TFEB and stimulate these important immune cells to improve their capacity to heal the heart following a cardiac injury, whether due to heart attack, viral infection or other forms of heart damage.


This work was supported by the Department of Veterans Affairs, grant number I01BX004235; and the National Institutes of Health (NIH), grant numbers HL107594, 5-T32-HL007081, K08-HL138262, P30DK020579, S10 RR027552 and DDRCC NIH P30DK052574.
Javaheri A, et al. TFEB activation in macrophages attenuates post-myocardial infarction ventricular dysfunction independently of ATG5-mediated autophagy. JCI Insight. Nov. 1, 2019.
Washington University School of Medicine’s 1,500 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is a leader in medical research, teaching and patient care, ranking among the top 10 medical schools in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

Safety-Net Hospitals Fare Better Under New Medicare Reimbursement Rules

New Medicare reimbursement rules provide some relief to safety-net hospitals, shifting the burden of financial penalties toward hospitals serving wealthier patient populations, according to a new study led by Washington University School of Medicine in St. Louis. The new rules also reduce the burden of such penalties on hospitals in states that have more generous Medicaid programs.

The study, conducted by researchers at Washington University, the Missouri Hospital Association and the Henry Ford Health System in Detroit, is published April 15 in JAMA-Internal Medicine.

In an effort to reduce health-care costs, Medicare issues financial penalties via the Hospital Readmissions Reduction Program (HRRP) to hospitals with higher than expected readmission rates. The program — which can cut a hospital’s Medicare reimbursements by up to 3 percent — has been criticized for unfairly penalizing so-called safety-net hospitals that serve the poorest patients, who are more likely to be readmitted for reasons beyond the hospital’s control.

Rather than comparing all hospitals directly, the new rules divide hospitals into five groups according to the proportion of their Medicare patients who are also enrolled in Medicaid, a program intended to help the poorest patients. Hospitals are then only compared to their peers that treat similar proportions of disadvantaged patients. Across the five groups of hospitals, the average proportion of patients dually enrolled in Medicare and Medicaid ranged from a low of 9.5 percent to a high of almost 45 percent.

“The new rules recognize the reality that it is harder to prevent readmissions when people don’t have stable housing or social support,” said Washington University cardiologist Karen Joynt Maddox, MD, the study’s first author and an assistant professor of medicine. “If you have patients who struggle to put food on the table, it’s going to be tougher for them to manage their end-stage heart failure. The old system took money away from hospitals that serve the most vulnerable patients. It created a significant disincentive to provide health care to poor people, and that’s the last thing we want.”

Looking at the most recent data published by the Centers for Medicare & Medicaid Services, the researchers calculated and compared the penalties under the old and new reimbursement rules for just over 3,000 hospitals nationwide. Using the published data, the researchers projected how the penalties will shift by comparing projected penalties under the new rules to what they would have been under the old rules. Under the new rules, penalties for the hospitals serving the fewest poor patients are projected to increase more than $12 million in total. Meanwhile, penalties for the hospitals serving the highest proportion of poor patients are projected to decrease by more than $22 million in total. On an individual hospital level, the changes are projected to range from an increase in penalties of $225,000, to a decrease of $436,000.

Large hospitals and teaching hospitals are the most likely to see reduced penalties. The researchers also found reduced penalties among hospitals serving patients from the most disadvantaged neighborhoods and those serving the most patients with disabilities. Hospitals in states with more generous Medicaid enrollment also fare better than those in states with fewer poor patients enrolled in the Medicaid program.

“States differ widely in the percentage of people living in poverty who are able to enroll in Medicaid,” Joynt Maddox said. “Since the new rules, as written by Congress, only give credit to hospitals for treating patients on Medicaid and not poor patients in general, the states with more people enrolled in Medicaid are going to benefit more from the new system.”

According to Joynt Maddox, the researchers were surprised at the magnitude of the state and regional differences in the shift in penalties, with more penalties for hospitals in the South and Midwest and fewer penalties for hospitals in the West and Northeast. California, which has generous Medicaid enrollment, had the most reduced penalties. Meanwhile, South Dakota and Florida, two states with fewer poor patients enrolled in Medicaid, had the greatest increases. Overall, much of the shift in penalties between states could be explained by differences in state Medicaid enrollment.

“This was a positive change for the HRRP,” Joynt Maddox said. “Making the program more fair doesn’t take away from its goal, which is to use financial incentives to make hospitals think differently about care beyond their walls. Hospitals are increasingly working to provide a soft landing, including discharge planning and communication with outpatient-care providers.”

Still, Joynt Maddox said there is work to be done, even if the new rules more fairly consider the socioeconomic reality of hospitals’ patient populations.

“There are still marked disparities in readmissions related to social determinants of health,” she said. “We need to find innovative solutions to improve outcomes for our most vulnerable patients after they leave the hospital.”


Joynt Maddox reports intermittent contract work for the U.S. Department of Health and Human Services.
This work was supported by the National Institutes of Health (NIH), grant numbers R01MD010243 and RF1AG057784; and by the Washington University School of Medicine Office of Medical Student Research Dean’s Fellowship.
Joynt Maddox KE, Reidhead M, Qi AC, Nerenz DR. Association of stratification by dual enrollment status with financial penalties in the hospital readmission reduction program. JAMA-Internal Medicine. April 15, 2019.

Obese Mouse Mothers Trigger Heart Problems in Offspring

A diet high in fats and sugars is known for its unhealthy effects on the heart. Scientists now have found that a high-fat, high-sugar diet in mouse mothers before and during pregnancy causes problems in the hearts of their offspring, and that such problems are passed down at least three generations, even if the younger generations only eat a standard mouse chow diet.

The study, from Washington University School of Medicine in St. Louis, is published March 22 in the journal AJP-Heart and Circulatory Physiology.

The study also suggests that diet-induced heart changes in offspring are not only transmitted to offspring by their mothers. Obese mothers’ male offspring that mated with healthy females fed a normal diet also passed on the same heart problems. The specific changes to the heart in these offspring were evident in changes to the heart muscle cells’ energy factories, called mitochondria.

“We know that obesity in pregnant mothers raises the risk of future heart problems for her children,” said co-senior author Kelle H. Moley, MD, a professor of obstetrics and gynecology. “But we have shown, at least in mice, that these heart problems don’t stop with a single generation. They are passed down by both the male and female offspring of obese mothers, even when the offspring eat a normal diet. This was a bit of a surprise — problems with heart mitochondria seemed likely to be passed down only through females, through the mitochondrial DNA present in the egg that we inherit only from our mothers.

“Now that we’ve shown that mouse fathers pass this down as well, we have to start studying changes in the DNA of the nucleus in both the egg and the sperm to make sure we understand all the contributing factors,” she said.

Notably, the researchers found multigenerational heart problems, even when the mouse offspring were not obese and ate a normal diet throughout their lives. Though perhaps revealing some effects of a healthy diet, the severity of the heart problems diminished slightly over the generations of mice that ate standard chow diets, the researchers noted.

The heart abnormalities induced by maternal obesity included cardiac mitochondria that appeared small and fragmented and that consumed less oxygen than their normal counterparts. The hearts of most of the offspring, though not all, also showed an increase in the weight of the left ventricle, the main pumping chamber of the heart. In people, increased left ventricle weight is often a marker of poor heart muscle quality that predisposes one to heart failure, a potentially fatal condition in which the heart does not pump blood as well as it should.

“The cardiac abnormalities seem to dissipate somewhat over the generations, which is intriguing,” said co-senior author Abhinav Diwan, MD, an associate professor of medicine. “Problems in echocardiograms and the increase in left ventricle mass were less evident in the females of the youngest generation that we studied. There were also differences in male and female hearts that we can’t explain yet. In many ways, this study presents more questions than it answers, and we plan to continue studying these mice to help answer them.”

The researchers also used in-vitro fertilization to implant fertilized eggs from obese mice into normal-weight mice to carry the pregnancies. These offspring also showed the heart defects, demonstrating that the problems are specific to the original egg from the mother fed the high-fat, high-sugar diet, and not the gestational environment during the pregnancy or nursing afterward.

Moley and her colleagues suspect that the defects in heart mitochondria are likely caused by so-called epigenetic changes in the DNA of the original obese mother’s eggs. The epigenome is an important layer of genetic regulation that governs how DNA instructions are read and executed. And, in theory, these epigenetic changes in the egg would be present in every cell of the offspring, including in their male or female reproductive systems. Indeed, past work by this group confirmed that mitochondrial problems also exist in the skeletal muscle, leading to whole-body metabolic abnormalities, such as insulin resistance, in the offspring of obese mouse mothers and in two subsequent generations.

The researchers plan to study the epigenetic changes in the eggs of obese mothers and tissues of the offspring in an effort to understand what is happening to the mitochondria, but in the meantime emphasize the importance of maintaining a healthy weight before and during pregnancy.

“A big question that people may have is, ‘What can I do if my grandmother or great-grandmother was obese?’” said first author Jeremie L.A. Ferey, PhD, a postdoctoral research scholar. “We need more studies to learn if it’s possible to reverse these mitochondrial defects, but in general, exercise and a healthy diet are always important for heart health.”

This work was supported by the National Institutes of Health (NIH), grant numbers P30DK056341, F32HL140848, R01HD083895 and R01HL143431.

Ferey JLA, Boudoures AL, Reid M, Drury A, Scheaffer Z, Modi Z, Kovacs A, Pietka T, DeBosch BJ, Thompson MD, Diwan A, Moley KH. Maternal high-fat, high-sucrose diet induces transgenerational cardiac mitochondrial dysfunction independent of maternal mitochondrial inheritance. AJP-Heart and Circulatory Physiology. March 22, 2019.

Washington University School of Medicine’s 1,500 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is a leader in medical research, teaching and patient care, ranking among the top 10 medical schools in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

Is Intermittent Fasting the Cure for Diabetes?

(CNN) Three men with Type 2 diabetes used “intermittent fasting” to reverse their dependence on insulin, according to a report published on [October 9th, 2018] — but you shouldn’t try it without medical supervision, experts say.

The new case report says the three patients also lost weight, and their HbA1Cs, a measure of blood sugar levels, improved.

“People are focused on giving drugs to Type 2 diabetes, but it’s a dietary disease,” said study author Dr. Jason Fung, medical director of the Intensive Dietary Management Program in Toronto.

Experts say this clashes with the widely held belief that diabetes is strictly a chronic, irreversible disease — though Fung said that’s been changing in recent years.

“In general, the concept of reversing or curing diabetes … is not well-accepted in the medical field,” said Dr. Abhinav Diwan, associate professor of medicine, cell biology and physiology at the Washington University School of Medicine in St. Louis. “It is not even a therapeutic goal when people start to treat diabetics.”

The US Centers for Disease Control and Prevention estimates that 9.4% of Americans — about 30.3 million people — have diabetes, and nearly a quarter of those are undiagnosed. Ninety to 95% of those cases are Type 2 diabetes. An additional 33.9% of the population, or 84.1 million people, have prediabetes, the agency says.

“Diabetes is the No. 1 cause of kidney failure, lower-limb amputations, and adult-onset blindness,” the CDC says.

In the study, patients followed 24-hour fasts several times a week. They ate only dinner on fasting days but could drink water, coffee and broth throughout. They were all men, ages 40, 52 and 67, who had been diagnosed with diabetes 20, 25 and 10 years prior, respectively.

The participants had been diagnosed with Type 2 diabetes, which has been linked to obesity and develops over years due to a combination of genetics and lifestyle. In this type, the body becomes less responsive to insulin, a hormone it needs to balance glucose in the bloodstream.

This is different from Type 1 diabetes, an autoimmune condition in which the pancreas doesn’t produce much, if any, insulin. Fasting for those with Type 1 diabetes “may be unsafe due to the increased risk for hypoglycemia,” said Diwan, who was not involved in the new study.

However, he has researched fasting and diabetes in mice, looking for important clues at the cellular level about how this might work.

When it comes to this field of research, he said, “these are early days but very exciting.” The new report is not a definitive study, he added; it has a small sample size, no control group and limited followup. Existing research in humans is also difficult to compare because it is largely observational, and how to implement fasting hasn’t been standardized, Diwan said.

“It is very clear that people who can lose weight have better blood sugar control … [and] sometimes can get off insulin if not too advanced in their disease,” said Dr. Robert Gabbay, chief medical officer at the Joslin Diabetes Center, a nonprofit research and care center in Boston affiliated with Harvard Medical School. “The most established example of that are people that have bariatric surgery,” he added. “They lose significant amounts of weight, and some of them get off all medications.”

Gabbay, who was not involved in the new report, calls this a “remission” of diabetes rather than “cure” because, “as far as we know, it’s still worthwhile having a yearly eye exam, having a screening for kidney disease and nerve damage, even in those people that normalize their blood sugars, because they may be at continued risk. Although, honestly, there aren’t enough of those people to know.”

Experts like Fung are calling for more research on this topic, which has not gotten much attention from the broader scientific community. “Intermittent fasting has been in a hinterland for many, many years. There’s been really no data on it,” Fung said, adding that his proposals for larger studies on fasting and diabetes have been denied by two Toronto hospitals.

He said he’s seen thousands of patients in his program, and the new report, which took two years to publish and includes only three patients, is part of an ongoing effort to show early evidence and advocate for larger studies.

The goal of no longer needing insulin is not only a health-related goal, Fung said; it could also mean not having to buy these drugs, which are ever more costly.

But without randomized trials, Diwan said, it’s tough to say how effective intermittent fasting is, what’s the best way to do it and how sustainable it might be in the long run. At the very least, “intermittent fasting has been practiced across various cultures,” Diwan said, citing his own Hindu culture as an example. “So that tells you right off the bat that it’s a doable thing.”

Gabbay said “there’s conflicting data out there” on fasting diets and weight loss, including studies suggesting that fasting is no more effective for weight loss and maintenance than calorie restriction, and other research showing how some people regain weight.

None of the men in the study had episodes in which their blood sugar dropped dangerously low — known as hypoglycemia — but other studies on fasting and diabetes have reported this risk. It could increase if people continue to take their usual dose of insulin while fasting, causing their blood sugar levels to plummet, Fung said.

“Clearly, there is need for caution, because diabetic people are prone to hypoglycemic episodes, and hypoglycemia can be fatal,” Diwan said. “People do not want to put them themselves at risk by fasting without consulting a doctor.”

Experts say there could be other risks to fasting, such as headaches, fatigue, nausea and insomnia. It may also be less safe for some groups of people to fast, including pregnant women and those who take certain medications.

Gabbay said the new paper accomplishes its goal of warranting further study, but on its own, it’s a success story about just three people — and one would be “hard-pressed to draw any conclusions from this kind of work.”

“We always worry when reports of dramatic results are presented, as they may be misinterpreted by people,” he said. “In the world of diet and weight loss, things really catch on quickly.”

Lowering hospitals’ Medicare costs proves difficult

A payment system that provides financial incentives for hospitals that reduce health-care costs for Medicare patients did not lower costs as intended, according to a new study led by Washington University School of Medicine in St. Louis.

The researchers assessed what is called a bundled-payment system, in which hospitals are assigned a target cost for Medicare patients with a given condition. The goal is to keep costs below that target for a patient’s hospitalization plus any care given within 90 days of discharge. The researchers asked whether this bundled-payment strategy would be less expensive than traditional fee-for-service care, which pays health-care providers for every individual service, procedure and doctor visit.

The study, published July 19 in The New England Journal of Medicine, assessed Medicare claims from 2013 through 2015 for more than 100 hospitals that voluntarily participated in the Bundled Payments for Care Improvement initiative, a program run by the Center for Medicare & Medicaid Innovation.

The new study included Medicare patients hospitalized for one of five serious medical conditions: congestive heart failure, pneumonia, chronic obstructive pulmonary disease, sepsis or heart attack. These serious medical conditions are expensive to treat, especially for patients on Medicare, who tend to be older and sicker than the general population.

In the bundled-payment system, hospitals are given a target price for an entire “episode” of care, which includes the hospitalization as well as any health-care services needed in the 90 days following hospitalization, such as readmissions, nursing home stays, or home health visits. The goal is to keep costs below that target for each patient hospitalized with that condition. If the hospital is successful in staying below the target, Medicare returns a portion of the savings to the hospital. If the hospital goes over the target, Medicare bills an additional amount as a penalty.

“The idea behind the program is to give hospitals an incentive to reduce costs and improve care,” said first author Karen E. Joynt Maddox, MD, an assistant professor of medicine at Washington University. “The best way to reduce costs is to reduce complications, reduce hospital readmissions and get people home, if you can, instead of sending them to a nursing home. The hope is that a bundled-payment program would lead to better care at lower cost. But that is not what we saw, at least in this initial analysis.”

The researchers found no differences in cost under the bundled-payment system. On average, the cost per episode of care before the program began was $24,280. The average cost per episode of care under the bundled-payment plan was slightly less, at $23,993. But the difference was not statistically significant. The analysis also showed no differences between the fee-for-service payment system and the bundled payment system in the complexity of the cases, length of stay, emergency room visits, hospital readmissions or deaths.

A past study suggested a bundled-payment system lowered health-care costs for Medicare patients who received total joint-replacement surgeries, which are elective procedures typically performed on otherwise healthy individuals.

“In that situation, bundled payments did save money, so there was a lot of enthusiasm about them,” said Joynt Maddox, who is also a cardiologist who treats patients at Barnes-Jewish Hospital. “In this study, we elected to study costly medical conditions rather than a planned surgical procedure. With joint replacements, doctors see patients ahead of time and decide if they’re healthy enough to undergo the procedure. So the patients in our study were comparatively less healthy than those in the joint-replacement study. If someone shows up at your hospital with heart failure, you take care of them. You don’t get to choose healthier patients.”

Joynt Maddox said another possible reason they found no differences in cost was that the study time frame was relatively short, with an average follow-up time of seven months. She said the researchers will continue to follow patient data to see if cost improvements show up after more time has passed.

Joynt Maddox also pointed out that patients in the study, in addition to being sicker than those in the study of joint replacement, were older, with more than half of participants over age 80.

“These kinds of patients need a lot of home health care and nursing home care and often are readmitted to the hospital when complications arise,” said Joynt Maddox, who is also an assistant professor at Washington University’s Brown School of Social Work. “My sense is that in the costs that we see, there’s not a lot of wasteful spending that’s easy to cut.

“To really bend the cost curve, we’re going to have to do more than just put an incentive at the hospital level,” she added. “Under bundled payments, the hospital is on the hook for any care that takes place within 90 days of discharge. One possible reason the program didn’t work could be that many costs depend more on the home-care service or the nursing home, which are not incentivized to reduce costs like the hospital is. The goal is to get the hospitals to work more closely with these care providers, but that may not be happening. We need a more holistic approach to coordinate care for these complicated patients, which will take time and a lot of new partnerships and collaborations outside the hospital walls.”

In addition to Washington University School of Medicine in St. Louis, the study was conducted by researchers at Brigham and Women’s Hospital and the Harvard T.H. Chan School of Public Health, both in Boston.

This work was supported by the Commonwealth Fund.

Joynt Maddox KE, Orav J, Zheng J, Epstein AM. Evaluation of Medicare’s Bundled Payments Initiative for medical conditions. The New England Journal of Medicine. July 19, 2018.

Scientists ID source of damaging inflammation after heart attack

Scientists have zeroed in on a culprit that spurs damaging inflammation in the heart following a heart attack. The guilty party is a type of immune cell that tries to heal the injured heart but instead triggers inflammation that leads to even more damage.

Further, the researchers have found that an already approved drug effectively tamps down such inflammation in mice, protecting the heart from the progressive damage that often occurs after a heart attack.

The study, from Washington University School of Medicine in St. Louis, is published June 7 in JCI Insight.

Led by senior author Douglas L. Mann, MD, director of the university’s Cardiovascular Division and cardiologist-in-chief at Barnes-Jewish Hospital, the study showed that mice modeling human heart attacks lived longer if then given pirfenidone, a drug already approved to treat an unrelated lung condition. Further, the research showed that the drug works by regulating in the heart the specific response of B cell lymphocytes, the immune cells that the scientists discovered were responsible for the inflammation.

“If we understand how pirfenidone works to reduce inflammation, we can work to modify the drug or make an even better drug that may be able to help a large number of patients,” said Mann, who is also the Tobias and Hortense Lewin Distinguished Professor of Cardiovascular Diseases.

In a heart attack, blood is cut off from an area of the heart that then often dies. If the person survives, the body tries to heal the dead muscle by forming scar tissue — but such tissue can further weaken the heart. Yet another wave of damage can occur when well-intentioned immune cells try to heal the injured heart but instead drive inflammation. Finding ways to prevent progressive inflammatory injury to the heart could help some 1.5 million heart attack patients in the U.S. annually, potentially preventing their progression to heart failure, according to the researchers.

Pirfenidone is approved by the Food and Drug Administration to treat a lung condition called idiopathic pulmonary fibrosis, a scarring of the lungs that has no known cause. The drug also has been known for its heart-protective effects in a number of different animal models of heart attack. Researchers had assumed that pirfenidone’s protective action in the heart paralleled the reason it helps in lung disease. In the lungs, the drug slows the formation of scar tissue.

“That this drug also protects the heart is not new,” said first author Luigi Adamo, MD, PhD, a clinical fellow in cardiology. “But in our studies, pirfenidone didn’t physically reduce scar tissue in the heart. The scar tissue is still there, but somehow the heart works better than expected when exposed to this drug. It wasn’t clear why. So we set out to reverse engineer the drug to pick apart how it may be working. Since scar tissue was still present, we suspected inflammation was the main culprit in poor heart function after a heart attack.”

Adamo said that most immune studies of the heart have focused on other types of immune cells, including macrophages, T cell lymphocytes, neutrophils and monocytes. But he found no differences in the numbers of such immune cells in the injured hearts of mice that received pirfenidone versus those that didn’t. When he serendipitously measured B cells, however, Adamo was surprised to see a huge difference.

“Our results showing B cells driving heart inflammation was quite unexpected,” Adamo said. “We didn’t know that B cells have a role in the type of heart damage we were studying until our data pushed us in that direction. We also found that there isn’t just one type of B cell in the heart, but a whole family of different types that are closely related. And pirfenidone modulates these cells to have a protective effect on heart muscle after a heart attack.”

However, Adamo added that when the researchers removed these cells completely, not only was the heart not protected, the beneficial effect of the drug went away. So the B cells are not exclusively bad, according to the scientists. If they were, removing them completely would protect the heart.

“The protective effects of pirfenidone hinge on the presence of B cells,” Adamo said. “The drug may be working on other cells as well, perhaps directly or perhaps through the B cells. We’re continuing to investigate the details.”

Adamo said that pirfenidone has long been considered safe but that it can have side effects such as nausea and vomiting. He explained that researchers have not tried to improve upon the drug because no one understood precisely how it worked. Now that Adamo, Mann and their colleagues have identified B cell lymphocytes as the drug’s target, they can begin investigating ways to make it better. With the support of Washington University’s Office of Technology Management, the scientists have launched a startup company focused on designing a version of pirfenidone that maintains the drug’s ability to modulate B cell lymphocytes but that may be more tolerable for patients.

This work was supported by the National Institutes of Health (NIH), grant number T32 HL007081.

Adamo L, Staloch L, Rocha-Resende C, Matkovich SJ, Jiang W, Bajpai G, Weinheimer C, Kovacs A, Schilling J, Barger P, Bhattacharya D, Mann DL. Modulation of subsets of cardiac B lymphocytes improves cardiac function after acute injury. JCI Insight. June 7, 2018.

Study of smoking and genetics illuminates complexities of blood pressure

Analyzing the genetics and smoking habits of more than half a million people has shed new light on the complexities of controlling blood pressure, according to a study led by researchers at Washington University School of Medicine in St. Louis.

The research, published Feb. 15 in The American Journal of Human Genetics, stems from an international consortium of institutions tasked with plumbing vast amounts of participant data to uncover how genes interact with lifestyle and influence measures of heart health.

The investigators studied blood pressure because it is a strong indicator of cardiovascular health. While simple to measure, blood pressure is controlled by a complex interplay of genetics and lifestyle, and both must be considered when uncovering what drives high blood pressure. For example, lifelong smokers who have high blood pressure — as might be expected — likely have different genetic backgrounds from lifelong smokers who nevertheless have normal blood pressure. Such differences, which this study sought to uncover, can highlight genes involved in controlling blood pressure that past research may have missed.

“We are trying to identify new reasons why people may have high blood pressure,” said co-senior author Dabeeru C. Rao, a professor and director of the Division of Biostatistics at the School of Medicine. “Blood pressure is extremely complex. We need enormous sample sizes from diverse populations to be able to see what is important in controlling blood pressure.”

The study included more than 600,000 participants from multiple studies that recorded data on smoking status, systolic and diastolic blood pressure, and genetic markers across the genome. It included participants of European, African, Asian, Hispanic and Brazilian ancestries. The analysis uncovered some surprisingly novel results.

“Despite tremendous efforts, we continue to have a lot of difficulty controlling blood pressure in many patients,” said co-first author and cardiologist Lisa de las Fuentes, MD, an associate professor of medicine and of biostatistics. “Even when we try every tool in our arsenal, some patients still don’t respond to medications the way we would expect them to. There are probably biological reasons for this that we haven’t tapped into yet. Our study identified potential genes of interest that we should be investigating for potentially new ways to treat high blood pressure.”

The new study verified many genes already associated with blood pressure and identified new genes in areas that might be expected, including blood vessel structure and kidney function. But the researchers found some surprising genes, as well.  Some of the identified genes are involved with the structure and function of cilia, tiny hairlike extensions on cells that beat rhythmically to clear microbes from the lungs, nose and ears, for example. Because abnormal cilia function also is associated with kidney disease, it may contribute to elevated blood pressure. Another surprise was finding genes governing the length of telomeres, the protective caps on the ends of chromosomes. Telomeres are considered a marker of age, as they shorten slightly with each cell division.

The study also allowed scientists to pinpoint 35 locations in the genome associated with blood pressure that were unique in people of African ancestry. However, the investigators said the sample size was too small to establish an external replication group to validate the findings.

“We are using data from studies that are already available, and historically, these tend to be concentrated on people of European ancestry,” said first author Yun J. Sung, an associate professor of biostatistics. “This emphasizes the need for more studies that include diverse patient populations. There are efforts to change this, but for this study, that data does not yet exist in these non-European populations.”

The researchers found many genes associated with blood pressure that also have been implicated in metabolic problems, including diabetes, obesity and kidney disease. In another interesting finding, the study linked blood pressure to genes associated with addiction, including alcohol and nicotine dependence. In short, the picture emerging in blood pressure control involves central and peripheral systems of the body that span the brain, kidneys, adrenal glands and vasculature, according to the researchers.

“Blood pressure involves everything from how well your heart squeezes, to how well your blood vessels relax, to how well your brain signals your adrenal glands telling your kidneys to hold on to saltwater,” de las Fuentes said. “It’s a sophisticated and elegant system, and we’re still working to understand it so we can better treat our patients.”

Deadly heart rhythm halted by noninvasive radiation therapy

Radiation therapy often is used to treat cancer patients. Now, doctors at Washington University School of Medicine in St. Louis have shown that radiation therapy — aimed directly at the heart — can be used to treat patients with a life-threatening heart rhythm. They treated five patients who had irregular heart rhythms, called ventricular tachycardia, at the School of Medicine.

The patients had not responded to standard treatments and collectively experienced more than 6,500 episodes of ventricular tachycardia in the three months before they were treated with radiation therapy. In ventricular tachycardia, the heart beats exceedingly fast and its chambers often fall out of sync, interfering with blood flow and placing patients at risk of sudden cardiac death. When delivered directly to problematic areas of the heart muscle, the radiation therapy resulted in a dramatic reduction in the number of ventricular arrhythmia events in these patients, as measured by their implanted defibrillators.

An analysis of the patients’ experiences is reported Dec. 14 in The New England Journal of Medicine. There have been two previous cases reported of treating ventricular tachycardia with radiation therapy, but this is the first to do so in an entirely noninvasive process, from imaging to treatment.

“As a radiation oncologist who specializes in treating lung cancer, I’ve spent most of my career trying to avoid irradiating the heart,” said senior author Clifford G. Robinson, MD, an associate professor of radiation oncology. “But I also have been exploring new uses for stereotactic body radiation therapy that we use almost exclusively for cancer.”

At the same time, cardiologist and first author Phillip S. Cuculich, MD, an associate professor of medicine, was looking for new ways to treat ventricular tachycardia in patients who did not respond to conventional treatments. Ventricular tachycardia is estimated to cause 300,000 deaths per year in the U.S. and is the leading cause of sudden cardiac death. Standard therapy includes medication and invasive procedures that involve threading a catheter through a vein into the heart and selectively burning the tissue that causes the electrical circuits of the heart to misfire.

“These patients have defibrillators implanted to act like a paramedic and save their lives if a bad heart rhythm starts up,” Cuculich said. “The device recognizes a dangerous arrhythmia and can deliver a life-saving electrical shock. While it’s wonderful that we can stop people from dying in that situation, the shock can be a traumatic event. Patients understand that they have just avoided death. And when this happens repetitively, often without warning, it can be devastating for patients.”

PHILLIP CUCULICH
A noninvasive cardiac map shows the electrical signals of a single beat. The gray area is a scar from a prior heart attack. The electrical signals that cause ventricular tachycardia enter the scar at the blue area, follow the yellow arrow along the border of the scar and exit the scar at the red area.
Ventricular tachycardia often develops after injury to the heart, commonly following a heart attack. As the heart muscle attempts to heal, the resulting scars interrupt the proper flow of electrical impulses. Traditional catheter ablation essentially kills off the tissue that triggers the electrical misfires. But the procedure is too risky for many patients with additional medical problems, and the arrhythmia often returns after a period of time.

The five patients in the study had undergone catheter ablation procedures and their ventricular tachycardia returned, or they were unable to go through the procedure because of other high-risk medical conditions. One patient was on the waiting list for a heart transplant. Four of the patients were in their 60s; one patient was over age 80.

In the three months before treatment with noninvasive radiation therapy, the five patients together experienced more than 6,500 ventricular tachycardia events. The average number of events per patient during this time was 1,315, with a range of five to 4,312. During the first six weeks following radiation therapy, as the patients were recovering, they experienced a total of 680 episodes. In the one year the patients continued to be followed, they collectively had four events. Two patients didn’t experience any episodes at all. The investigators are cautious, saying they are still monitoring for long-term side effects of radiation therapy, such as lung scarring and further damage to the heart itself. They emphasized that their use of external radiation to the heart only included very ill patients in end-stage disease who had run out of options. More research is required before doctors might consider this approach for younger, healthier patients or as a possible addition to standard therapies.

“A lot of my work is focused on reducing toxicity of radiation therapy using modern technology,” Robinson said. “These patients have done quite well in the first 12 months after therapy, which is enough time to see the early toxicities. But we’re continuing to monitor patients for long-term side effects.”

The single dose of radiation these patients received is on par with what might be given to a patient with an early-stage lung tumor. Doctors can target such tumors with a large dose of radiation given once or up to five times.

The preparation and mapping of the anatomy and electrical circuits of the heart is time-intensive, but the treatment itself takes 10-15 minutes, the researchers said.

“A traditional catheter ablation procedure can take six hours or more and requires general anesthesia,” Cuculich said. “This new process is entirely noninvasive. We take pictures of the heart with various imaging methods — MRI, CT, PET scans. But the unique piece is the noninvasive electrical mapping called electrocardiographic imaging. This allows us to pinpoint where the arrhythmias are coming from. When we overlay the scar mapping with the electrical mapping, we get a beautiful model of heart function that lets us see not only where the arrhythmia comes from, but where it might progress.

“Based on these maps, Dr. Robinson is then able to deliver the energy entirely noninvasively,” Cuculich added. “It’s simply amazing to see a ventricular tachycardia patient get an ablation therapy for a few minutes and then get up off the table and walk out the door.”

Electrocardiographic imaging (ECGI) was developed by co-author and Washington University biomedical engineer Yoram Rudy, PhD, the Fred Saigh Distinguished Professor of Engineering.

The radiation therapy does not take effect immediately. The number of arrhythmia events went down but did not disappear in the first six weeks after treatment, which the doctors characterize as a recovery period. After that six-week period, however, the number of events dropped to almost zero. Patients were able to slowly come off medications used to control the arrhythmia.

Of the five patients, one patient died in the first month after treatment of causes unlikely to be related to treatment. This patient, who was over age 80, had other heart conditions in addition to ventricular tachycardia. The remaining four, who are all in their 60s, are alive two years after radiation therapy. The patient on the transplant list went on to receive a new heart. One whose arrhythmia continues to be controlled also is dealing with gradual heart failure, meaning the heart muscle is weakening over time, and has received a left ventricular assist device. Two patients continue to live unassisted without ventricular tachycardia.

The researchers currently are enrolling patients in a clinical trial to further evaluate this approach and, to date, have performed the procedure on 23 patients.

Aggressive testing provides no benefit to patients in ER with chest pain

Patients who go to the emergency room (ER) with chest pain often receive unnecessary tests to evaluate whether they are having a heart attack, a practice that provides no clinical benefit and adds hundreds of dollars in health-care costs, according to a new study from researchers at Washington University School of Medicine in St. Louis.

Specifically, computed tomography (CT) scans and cardiac stress tests are overused in the ER for patients with chest pain and provide no information to determine whether a patient is in the midst of a heart attack, the researchers found.

The study appears Nov. 14 in JAMA Internal Medicine, which coincides with a presentation of the study at the American Heart Association’s Scientific Sessions in Anaheim, Calif.

A typical clinical evaluation includes a medical history, physical exam, electrocardiogram and blood test for a protein that becomes elevated after the heart is damaged. In addition, many patients also are given a CT scan of the arteries that deliver blood to the heart or a cardiac stress test. A stress test measures heart function during exercise.

“Our study suggests that in the emergency room, stress testing and CT scans are unnecessary for evaluating chest pain in possible heart attack patients,” said cardiologist and senior author David L. Brown, MD, a professor of medicine. “Patients don’t do any better when given these additional tests. Our study is not a definitive randomized clinical trial, but it does suggest that we are over-testing and over-treating these patients.”

In recent years, Brown said doctors can more accurately diagnose heart attacks largely because of advances in the blood test that measures levels of a protein called troponin. High troponin levels signal injury to the heart.

“This troponin test is super-sensitive,” Brown said. “But earlier blood tests were much less accurate. A patient could be having a heart attack and these older tests often would come back normal. Doctors didn’t trust the tests, so they looked for other ways to evaluate the patient. CT scans and stress tests were among the methods used. But now that the blood testing method is so much better, there is less reason to continue doing these screening tests in the emergency room.”

The investigators evaluated data from 1,000 patients treated at nine medical centers across the country, including Washington University School of Medicine, that were a part of the Rule Out Myocardial Ischemia/Infarction by Computer Assisted Tomography (ROMICAT-II) clinical trial. The current study revisited data from that trial, looking for any differences in outcomes for patients who received a clinical evaluation alone (118 patients) compared with those who received a clinical evaluation plus either a CT scan or a stress test (882 patients). In the study, 88 percent of patients received the extra testing. Nationwide, the overwhelming majority of patients evaluated for chest pain in the ER get such extra tests, Brown said.

During the nearly month-long follow-up period, there were no differences between the two groups in the percentages of patients that had a stent placed to open an artery, underwent coronary artery bypass surgery, returned to the emergency room or experienced a major cardiac event, such as heart attack.

While providing no clear health benefit to emergency room patients, the extra tests also led patients to stay in the hospital longer than may have been necessary and exposed them to radiation from testing that was not required to diagnose a heart attack. Length-of-stay for patients who received less testing was, on average, 20 hours compared with 28 hours for those who did receive either of the two additional tests.

The analysis also showed that, on average, a patient receiving more testing accrued $500 more in health-care costs during the ER visit. Patients who received more testing during the initial ER visit also received more follow-up tests, leading to $300 more in health-care costs for this group during the 28-day follow-up period. With 10 million patients coming to the ER for chest pain each year in the United States, these extra costs add up, according to the investigators.

“It’s important to keep in mind that CT scans and stress tests are used to diagnose coronary disease — whether someone has plaque in the arteries,” Brown said. “Many people have coronary plaque but are not having a heart attack.

“The goal of evaluating patients with chest pain in the ER is not to screen for coronary artery disease,” he said. “Anyone who goes to the ER for chest pain and gets sent home should make an appointment to see their primary care doctor to talk about their recent hospital visit. It’s important to follow up to see if additional testing is warranted because screening tests are not appropriate in this specific emergency situation.”

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Drug trial shows promise for deadly neurological disorder

Results of a small clinical trial show promise for treating a rare neurodegenerative condition that typically kills those afflicted before they reach age 20. The disease, called Niemann-Pick type C (NPC), causes cholesterol to build up in neurons, leading to a gradual loss of brain function. In the drug trial, researchers have shown that treatment with a type of sugar molecule called cyclodextrin slows progression of the disease.

The study, led by researchers at Washington University School of Medicine in St. Louis and the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (NIH), is published Aug. 10 in The Lancet.

“We were surprised to see evidence that this therapy could slow progression of the disease and, in some cases, get back some function — speech in particular,” said first author Daniel S. Ory, MD, the Alan A. and Edith L. Wolff Professor of Cardiology at Washington University School of Medicine in St. Louis. “In a neurodegenerative disease, therapies can’t recover neurons that have died. But if some brain cells are dysfunctional rather than dead, it seems this drug can recover some of that function.”

The findings are a result of efforts by the National Center for Advancing Translational Sciences of the NIH to find new treatments for rare and neglected diseases. NPC affects about one in 100,000 births, though Ory noted the disease is underdiagnosed and genetic studies suggest a true incidence of closer to one in 40,000 births.

The cholesterol buildup characteristic of NPC can affect organs other than the brain, such as the liver and spleen, but neurological symptoms often first suggest something is amiss. Age of onset varies considerably, but learning delays and clumsiness may emerge in early childhood, followed by progressive loss of brain function, including loss of motor control, hearing, speech and cognition. Most patients with the condition die 10 to 15 years after the onset of symptoms.

In the combined phase one/two clinical trial, 14 NPC patients who were ages 4 to 23 years and showing neurological symptoms were given cyclodextrin, administered into the spinal column once per month for 12 to 18 months. Another three patients were given cyclodextrin in the spinal column every two weeks for 18 months. Since cyclodextrin does not cross into the brain from the bloodstream, the drug must be in injected into the spinal column by lumbar puncture, an outpatient procedure often referred to as a spinal tap. The study did not have a control group that received a placebo, so researchers compared the patients’ progression with historical data collected from past NPC patients.

Doctors used a specialized scoring system to measure disease progression. Called the NPC Neurological Severity Score, it helps assess eye movement, gait, speech, swallowing, fine motor skills, cognition, hearing, memory, and presence and severity of seizures. In each category, patients can score zero to five points, with zero indicating normal function and five indicating severe disability or loss of that category of function.

The historical data from past NPC patients showed that patients’ scores increased — meaning the disease worsened — an average of 2.9 points per year. In contrast, the scores of patients in the trial increased an average of 1.2 points per year, a difference that is statistically significant. The improvements compared with the historical data were seen most in gait, cognition and speech.

“Some of the patients began this trial without the ability to speak, and now they speak,” Ory said. “There is a slowing of the decline, but we were surprised to see trends toward improvement in a few categories. Compared with the historical data, half of the patients in this study saw an improvement or no worsening in the neurological severity score.”

Seven of the 14 patients saw one-point improvements in their own scores in one or two categories compared with their own baseline scores in those categories over the course of the trial. The remaining seven either remained unchanged or experienced worsening scores. Though, on average, their scores worsened less than patients in the historical comparison group.

However, hearing loss, a symptom of NPC, was also a major adverse effect of the drug.

“Cyclodextrin therapy accelerates the hearing loss that is already a part of the natural progression of this disease,” said Ory, adding that the researchers expected to see hearing loss as a side effect, based on testing of the drug in animals.

“Before beginning the trial, we discussed this issue extensively with patients and families in the NPC community, as well as with the Food and Drug Administration (FDA),” Ory said. “A therapy that causes hearing loss is not ideal. But since the disease itself causes hearing loss, we felt that this side effect may be a reasonable trade-off, given the alternative decline and death that the disease also causes.”

Ory added that the patients were able to use hearing aids to maintain quality of life.

Cyclodextrin is a sugar molecule that long has been used as a minor ingredient in many other pharmaceuticals because it helps drug compounds dissolve in water. It is also the active ingredient in Febreze, a household air-freshening product that eliminates odors. In NPC, cholesterol becomes trapped in cellular compartments called lysosomes. Cyclodextrin appears to release the trapped cholesterol, allowing it to be metabolized and removed from the cell. A different drug called miglustat also shows evidence of slowing NPC progression. Though miglustat is approved for treating NPC in Europe, Canada and a few other countries, the FDA — citing a need for more data — has declined to approve it for treating NPC in the United States.

In addition to demonstrating that disease progression slowed with cyclodextrin, Ory and his colleagues assessed biomarker measurements in the blood that showed evidence that the drug was removing cholesterol from the brain. Such biomarkers raise the possibility of early diagnosis, since levels of certain compounds differ between healthy people and patients with NPC, even before the onset of symptoms. With early diagnosis in mind, the researchers are continuing work on a newborn screening test using standard blood spots sampled from newborns in New York.

But before such a screening test can be widely adopted, the researchers must demonstrate that effective treatments exist for newborns identified as having the condition. Based on the results of this trial and past work, Ory said a larger phase three clinical trial — that is both randomized and controlled — is already underway investigating cyclodextrin for patients with NPC.

 

Type of sugar may treat atherosclerosis, mouse study shows

Researchers have long sought ways to harness the body’s immune system to treat disease, especially cancer. Now, scientists have found that the immune system may be triggered to treat atherosclerosis and possibly other metabolic conditions, including fatty liver disease and type 2 diabetes.

Studying mice, researchers at Washington University School of Medicine in St. Louis have shown that a natural sugar called trehalose revs up the immune system’s cellular housekeeping abilities. These souped-up housecleaners then are able to reduce atherosclerotic plaque that has built up inside arteries. Such plaques are a hallmark of cardiovascular disease and lead to an increased risk of heart attack.

The study is published June 7 in Nature Communications.

“We are interested in enhancing the ability of these immune cells, called macrophages, to degrade cellular garbage — making them super-macrophages,” said senior author Babak Razani, MD, PhD, an assistant professor of medicine.

Macrophages are immune cells responsible for cleaning up many types of cellular waste, including misshapen proteins, excess fat droplets and dysfunctional organelles — specialized structures within cells.

“In atherosclerosis, macrophages try to fix damage to the artery by cleaning up the area, but they get overwhelmed by the inflammatory nature of the plaques,” Razani explained. “Their housekeeping process gets gummed up. So their friends rush in to try to clean up the bigger mess and also become part of the problem. A soup starts building up — dying cells, more lipids. The plaque grows and grows.”

In the study, Razani and his colleagues showed that mice prone to atherosclerosis had reduced plaque in their arteries after being injected with trehalose. The sizes of the plaques measured in the aortic root were variable, but on average, the plaques measured 0.35 square millimeters in control mice compared with 0.25 square millimeters in the mice receiving trehalose, which translated into a roughly 30 percent decrease in plaque size. The difference was statistically significant, according to the study.

The effect disappeared when the mice were given trehalose orally or when they were injected with other types of sugar, even those with similar structures.

Found in plants and insects, trehalose is a natural sugar that consists of two glucose molecules bound together. It is approved by the Food and Drug Administration for human consumption and often is used as an ingredient in pharmaceuticals. Past work by many research groups has shown trehalose triggers an important cellular process called autophagy, or self-eating. But just how it boosts autophagy has been unknown.

In this study, Razani and his colleagues show that trehalose operates by activating a molecule called TFEB. Activated TFEB goes into the nucleus of macrophages and binds to DNA. That binding turns on specific genes, setting off a chain of events that results in the assembly of additional housekeeping machinery — more of the organelles that function as garbage collectors and incinerators.

“Trehalose is not just enhancing the housekeeping machinery that’s already there,” Razani said. “It’s triggering the cell to make new machinery. This results in more autophagy — the cell starts a degradation fest. Is this the only way that trehalose works to enhance autophagy by macrophages? We can’t say that for sure — we’re still testing that. But is it a predominant process? Yes.”

The researchers are continuing to study trehalose as a potential therapy for atherosclerosis, especially since it is not only safe for human consumption but is also a mild sweetener. One obstacle the scientists would like to overcome, however, is the need for injections. Trehalose likely loses its effectiveness when taken orally because of an enzyme in the digestive tract that breaks trehalose into its constituent glucose molecules. Razani said the research team is looking for ways to block that enzyme so that trehalose retains its structure, and presumably its function, when taken by mouth.

 

BJC, School of Medicine establish Health Systems Innovation Lab

Improving patients’ health while reducing costs has become a mantra in health care, but this requires new ways of thinking about patients’ medical needs and delivering care more efficiently. At the same time, the pace of scientific discovery continues to accelerate, particularly in understanding how genes, behaviors and environments affect one’s health. These developments are propelling health care toward a future of “personalized health,” in which the delivery of care increasingly will be tailored to better meet an individual’s needs.

In this context, BJC HealthCare and Washington University School of Medicine are partnering to launch the Health Systems Innovation Lab, an effort aimed at developing innovative ways to deliver care and improve people’s health. Cross-disciplinary in nature, the lab will bring together clinicians, patients, researchers, public health experts and private industry to find solutions to problems that prevent patients from receiving optimal care.

BJC HealthCare will provide $20 million over the next 10 years to support the lab.

Among the lab’s goals are investigating how new technology can best be used, and determining how to streamline care to make it more efficient.

“We are excited to begin this bold initiative to find solutions to real-world health-care problems and improve care for patients,” said Clay Dunagan, MD, senior vice president and chief clinical officer of BJC HealthCare. “The Health Systems Innovation Lab is going to be a great asset in helping us identify innovative care approaches and integrating them across BJC HealthCare hospitals and Washington University clinics, the broader St. Louis community and beyond.”

The lab’s 14-member governing board will be chaired by David H. Perlmutter, MD, executive vice chancellor for medical affairs and dean of Washington University School of Medicine, and by Steve Lipstein, CEO of BJC HealthCare.

Washington University and BJC HealthCare have chosen Thomas M. Maddox, MD, to lead the lab. A search committee selected Maddox because of his background as the national director for the Veterans Affairs Health System’s Clinical Assessment, Reporting and Tracking Cardiac Quality Program, which oversees quality, safety and value for all 79 cardiac catheterization laboratories in the VA health-care system, and his research expertise in cardiology.

Maddox began his new position June 1.

“We are thrilled to welcome Tom Maddox in this position,” said Bradley Evanoff, MD, director of the Institute of Clinical and Translational Sciences and the Richard A. and Elizabeth Henby Sutter Professor of Occupational Industrial and Environmental Medicine at the School of Medicine. “We believe he has the knowledge, leadership skills and passion for innovation to help all campus and health-system partners work together to identify, develop and implement clinical changes that will benefit patients.”

Maddox said he is looking forward to leading the lab. “Health care is in the midst of a remarkable and rapid transformation,” he said. “The Health Systems Innovation Lab is in a unique position to capitalize on this by leveraging the resources of BJC HealthCare and the intellectual talent of Washington University to provide truly innovative health and health-care solutions that benefit patients and the greater St. Louis community.”

The lab’s partners will include the BJC HealthCare Center for Clinical Excellence and Washington University’s Center for Biomedical Informatics, the Institute of Clinical and Translational Sciences, and the Institute for Public Health.

William Powderly, MD, the Dr. J. William Campbell Professor of Medicine at the School of Medicine and the Larry J. Shapiro Director of the Institute for Public Health, said the institute looks forward to a close partnership with the new lab. “This effort is important because innovation in the hospital and outpatient settings can lead to overall improvement in our region’s population health, particularly among our most vulnerable communities with high burdens of chronic disease.”

Although he will devote most of his time and energy to the lab, Maddox also will serve as a professor of medicine in the Cardiovascular Division at the School of Medicine and will see patients at Barnes-Jewish Hospital.

He earned a medical degree from Emory University School of Medicine, a master’s degree from the Harvard University School of Public Health and a bachelor’s degree cum laude in economics and history from Rice University.

In addition to serving as national director of the VA Clinical Assessment, Reporting, and Tracking Cardiac Quality Program, Maddox most recently has served as an associate professor of cardiology at the University of Colorado, Denver, with a clinical appointment as a cardiologist for the Veterans Affairs (VA) Eastern Colorado Health System.

His research has focused on “learning health-care systems” that use real-time clinical data to shape cardiology clinical practice and research. He has authored more than 150 peer-reviewed publications and received multiple grants to study the best strategies to prevent and reduce cardiac risk among patients with coronary artery disease.

“As we take on this new initiative, we need to understand how the multiple characteristics of a health system interact, and how new technologies, knowledge and procedures can best be introduced to improve the health and care of patients,” Evanoff said. “This is a wonderful opportunity that will engage WU researchers and BJC staff toward an important goal.”

 

Genetic errors associated with heart health may guide drug development

One family with rare gene mutation gives clues to preventing heart attacks.

Natural genetic changes can put some people at high risk of certain conditions, such as breast cancer, Alzheimer’s disease or high blood pressure. But in rare cases, genetic errors also can have the opposite effect, protecting individuals with these helpful genetic mistakes from developing common diseases.

A new study of such “beneficial” genetic mutations, led by Washington University School of Medicine in St. Louis, may provide guidance on the design of new therapies intended to reduce the risk of heart attacks.

The study is published March 29 in the Journal of the American College of Cardiology.

The researchers studied members of a family with rare mutations in a gene called ANGPTL3. The gene is known to play important roles in processing lipoproteins, molecules that package and transport fat and cholesterol through the bloodstream. Partial or complete loss of this gene was known to cause low cholesterol and triglyceride levels in the bloodstream. But whether it affects risk of heart attack was unclear.

Three of these family members — those with a complete loss of this gene — showed extremely low blood cholesterol and no evidence of plaque in their coronary arteries. According to the study authors, it was noteworthy that one of these patients showed no evidence of atherosclerosis despite having high risk factors for it, including high blood pressure and a history of type 2 diabetes and tobacco use.

“The family members with complete loss of ANGPTL3 have extraordinarily low cholesterol,” said first author Nathan O. Stitziel, MD, PhD, an assistant professor of medicine and of genetics. “The interesting thing about this family is the individuals with total loss of this gene had siblings with normal copies of the same gene. So we could compare people with differences in the function of this gene who are otherwise closely related genetically and share similar environments. It’s an anecdotal study of one family, but we felt it might provide some insight into the effects of blocking ANGPTL3.”

While the individuals with nonfunctional copies of the gene showed no coronary plaque, their siblings with working copies of the gene showed evidence of plaque in the coronary arteries, though it was not yet causing symptoms — a situation that is common in the general population, according to Stitziel.

To study the gene beyond the experience of a single family, the scientists also analyzed data available from large population studies. In data from one study of about 20,000 patients, the researchers found those with a partial loss of this gene had, on average, 11 percent lower total cholesterol, 12 percent lower LDL cholesterol, and 17 percent lower triglycerides, measured in the blood, than individuals with full gene function.

Analysis of data from other large population studies showed a link between partial loss of the gene and a lower risk of coronary artery disease and an association between lower circulating levels of ANGPTL3 protein and a lower risk of heart attack.

Taken together, these findings provide support for efforts to develop drugs that inhibit ANGPTL3 in order to reduce the risk of coronary artery disease and heart attack. The same reasoning led to the development of a class of drugs known as PCSK9 inhibitors, which have recently been shown to be effective at reducing the risk of heart attack in a large clinical trial of more than 27,000 men and women.

Several years ago, researchers found natural beneficial mutations in the PCSK9 gene that lowered people’s cholesterol levels and protected them from coronary artery disease, much as mutations in ANGPTL3 seem to do. Both PCSK9 and ANGPTL3 are important in the body’s processing of cholesterol from the diet. Any drugs that inhibit them, then, work differently than commonly prescribed statins, which reduce cholesterol levels in the blood by blocking the body’s internal cholesterol manufacturing.

While reducing cholesterol levels in the blood typically is thought to be good for the heart, Stitziel pointed out that there may be dangers to inhibiting the normal function of a gene. Not all genetic mutations that result in low cholesterol in the bloodstream are healthy. For example, there is one genetic disorder in which cholesterol levels in the blood are low because cholesterol gets stuck in the liver, resulting in fatty liver disease.

“We need a better understanding of how cholesterol is processed in individuals with complete loss of ANGPTL3 function before we can fully say what effect inhibiting ANGPTL3 is going to have,” Stitziel said. “Studies of people with mutations that completely knock out a gene’s function are important because they can provide insight into the potential effects — both good and bad — of drugs inhibiting that gene’s function.”

Along with Washington University School of Medicine, other institutions that played key roles in the study included the Broad Institute of MIT and Harvard and the Perelman School of Medicine at the University of Pennsylvania.

The study is published March 29, 2017, in the Journal of the American College of Cardiology.

Study reveals ways to improve outcomes, reduce costs for common heart procedure

Hospitals can improve patient care and reduce costs associated with coronary angioplasty if cardiologists perform more of these procedures through an artery in the wrist and if they take steps to discharge such patients on the same day, according to a new study led by Washington University School of Medicine in St. Louis.

Coronary angioplasty is a procedure in which arteries are opened to increase blood flow to the heart.

The research, published Feb. 20 in the Journal of the American College of Cardiology, suggests that the lower costs of the wrist approach largely are due to the fact that patients experience fewer complications and can be discharged earlier, compared with procedures that access the heart through the larger, deeper artery in the groin. The researchers estimated that shifting standard practice by 30 percent to the wrist approach, along with same-day discharge, could save the United States $300 million per year.

“We have unequivocal evidence and data that show better outcomes when we access the heart’s coronary arteries and perform angioplasty through a blood vessel in the wrist rather than through the femoral artery in the groin,” said first author Amit P. Amin, MD, an assistant professor of medicine. “The femoral artery is the traditional route, but when we go in through a vessel in the wrist, we see less bleeding, fewer complications, less pain and discomfort, higher patient satisfaction, shorter hospital stays, and lower costs.”

Patients may undergo coronary angioplasty — also called percutaneous coronary intervention (PCI) — to alleviate chest pain or shortness of breath. Such symptoms suggest the coronary arteries that deliver blood to the heart are blocked or narrowed and oxygen delivery to the heart muscle is reduced. Interventional cardiologists insert a small tube into an artery in the wrist or the groin, which can be used to view the narrowed heart artery, deliver an inflatable balloon to open up the narrowed section, and possibly deliver a stent to hold the vessel open.

Using the National Cardiovascular Data Registry CathPCI Registry, the researchers analyzed data from almost 280,000 Medicare patients who underwent PCI and were eligible for same-day discharge. Despite the fact that all of these patients were capable of leaving the hospital the same day as their procedures, only about 5 percent of these patients actually were discharged without having stayed overnight.

Read more on Washington University School of Medicine’s site »

This research was published February 20, 2017, in the Journal of the American College of Cardiology.

Genetic error that increases risk of aortic rupture identified

A study led by Washington University School of Medicine in St. Louis, in collaboration with Brigham and Women’s Hospital in Boston, has identified a genetic error that weakens the aorta, placing patients with this and similar errors at high risk of aortic aneurysms and ruptures. The findings will help diagnose, monitor and treat patients with aortic disease not caused by well-known conditions, such as Marfan syndrome and other genetic mutations known to disrupt connective tissues.

The study appears July 18, 2016 in the Proceedings of the National Academy of Sciences.

Read more at Medicine.wustl.edu »

New Guidelines Open Competitive Sports to Some Athletes with Heart Conditions

New guidelines from the American Heart Association and the American College of Cardiology have loosened some restrictions placed on competitive athletes with certain heart conditions.

Cardiologists at Washington University School of Medicine in St. Louis led two of the task forces responsible for updating the guidelines that help doctors decide when it is safe for a heart patient to participate in competitive sports, from high school athletics to Olympic or professional-level competitions.

“We want people to be active, but we also want them to be safe,” said cardiologist Alan C. Braverman, MD, the Alumni Endowed Professor in Cardiovascular Diseases in the Department of Medicine, and a co-author of the guidelines. “The good news is sudden death in athletes is thankfully very rare. But there are certain types of cardiovascular diseases associated with that risk. The goal of these guidelines is to help doctors recognize when someone has an increased risk of sudden cardiac death and help change activity levels to lower that risk.”

Read more on medicine.wustl.edu »

Genetic Study Finds New Gene and Pathway that Prevent Heart Attacks

A new study of genetic data from more than 190,000 people has identified genes that, when altered in specific ways, reduce the risk of heart disease. The findings may help guide efforts to design new preventive drugs, similar to the way statins are now prescribed to lower LDL-cholesterol, that are focused on reducing the risk of heart disease.

The results of the research study, led by Nathan Stitziel, MD, PhD, a Washington University cardiologist and Assistant Professor of Medicine and Genetics, appeared online this week in the New England Journal of Medicine.

“We identified genetic variation in several genes that associated with protection from coronary heart disease,” said Stitziel. “Our findings support the idea that therapies focused on a major pathway regulating triglycerides should help prevent the buildup of plaque in the heart’s coronary arteries and protect against heart attacks.”

After conducting a search across the genomes of 190,000 participants, Stitziel and his colleagues identified genetic changes in two genes, ANGPTL4 and SVEP1, that were definitively associated with heart attack. The genetic change in SVEP1 associated with higher risk of heart attack while the change in ANGPTL4 associated with protection from heart disease. The investigators sequenced ANGPTL4 and found that loss of function mutations were associated with both lower levels of triglycerides and a reduction in risk of heart attack.ANGPTL4 is a member of the lipoprotein lipase pathway which is also highlighted by this study.

In summarizing the translational potential, Stitziel said “our findings support the idea that therapies focused on modulating the lipoprotein lipase pathway should not only reduce levels of circulating triglyceride-rich lipoproteins but also protect against heart attacks.”

Read more on Washington University School of Medicine’s site »

The research was published online March 2, 2016 in the New England Journal of Medicine.

Dietary Nitrate Increases Muscle Speed and Power in Patients with Heart Failure

Washington University researchers have demonstrated that beetroot juice, which is rich in nitrate (NO3), can increase muscle function in heart failure patients. This may enhance their ability to perform activities of daily living and hence improve their quality of life.

Although heart failure starts out as a disease of the heart, it ultimately becomes a systemic whole-body problem. “Heart failure patients are weaker, slower, and their muscles are less powerful than healthy persons, even when accounting for differences in muscle size and physical activity,” said lead and corresponding author Andrew Coggan, PhD, an exercise physiologist at Washington University. “This may be partially due to decreased nitric oxide (NO) bioavailability. We therefore hypothesized that dietary NO3, which can be converted to NO would improve muscle function in such patients.”

The authors tested this by measuring the contractile performance of the knee extensor muscles of 13 HF patients several hours after they had drunk a commercial BRJ supplement. They found that, compared to ingestion of a NO3-depleted beetroot juice placebo, ingestion of beetroot juice containing NO3 resulted in a 13% increase in maximal muscle power. This was enough to acutely erase ~1/3rd of the patients’ deficit compared to normal individuals.

“It’s a small study,” said Linda Peterson, MD, a Washington University cardiologist and co-principal investigator on the project, “but if we can improve the ability of HF patients to perform power-based activities such as climbing stairs or getting up out of a chair, we could have a significant impact on their quality of life.” The study was published September 15th in Circulation: Heart Failure.

Genetic Study Identifies Individuals Who Benefit Most From Statins

Researchers at Washington University have shown that a panel of genetic markers can identify individuals at increased risk for heart attack. Those same individuals appear to benefit most from statin therapy (read more). The research appears online March 5th in the Lancet.

For patients at risk of heart disease, doctors routinely prescribe statins, known for their cholesterol-lowering effect. “Current clinical guidelines base treatment indications, in part, on the estimated 10-year risk of having an event,” said Nathan Stitziel, MD, PhD, a Washington University cardiologist and human geneticist who co-authored the report. “In estimating risk of coronary heart disease, a panel of genetic markers appears to identify individuals at higher risk who derive greater benefit from statin therapy.” By combining genetic data on nearly 50,000 individuals enrolled across five studies, the study authors demonstrated that a panel of genetic markers could identify individuals at increased risk for coronary heart disease. They then went on to examine the clinical benefit of statin therapy in groups at different genetic risk. The authors found that individuals with the highest genetic risk derived both greater absolute and relative risk reductions from treatment. “We need more research to confirm these results,” Stitziel said. “Regardless, it appears that individuals with high genetic risk appear to benefit more from statin therapy because they start at a higher baseline risk, even after adjusting for all of the current clinical measures we routinely examine.” The research is published in the Lancet.

Multiple Rare Gene Mutations Associated With Increased Risk of Heart Attack

Research performed at Washington University and other leading biomedical research institutions found that multiple rare mutations in two genes increase an individual’s risk of heart attack. The research appears online this week in the journal Nature.

Nathan Stitziel, MD, PhD, a cardiologist at Washington University School of Medicine and co-first author of the report, helped to lead the analysis team. The study involved sequencing the entire protein-coding portion of the genome-also called the exome-in approximately 10,000 individuals, half of whom had heart attack at an early age and half who had not had any heart attack. After the research team examined the exomes to detect significant differences between heart attack victims and controls, they found two genes, LDLR and APOA5, in which mutations increase an individual’s risk of disease.

Specifically, they found that multiple rare mutations in LDLR were associated with higher levels of LDL cholesterol and increased risk of heart attack, while multiple rare mutations in APOA5 increased blood triglycerides in addition to raising heart attack risk. “For over 40 years elevated LDL cholesterol has been known as one of the major risk beyond LDL cholesterol,” said Stitziel. “Large genetic studies like this one are an amazing resource for providing insight into the biology of human disease and pointing toward new therapeutic targets.”

The research was published online December 10, 2014 in Nature.

New Treatment For Marfan’s Syndrome Shows Promise

An investigational treatment for Marfan’s syndrome is as effective as the standard therapy at slowing enlargment of the aorta, new research shows (read more). The findings indicate a second treatment option for Marfan’s patients, who are at high risk of sudden death from aortic dissection. “For years, standard medical therapy for Marfan’s syndrome consisted of giving patients beta blockers, which lower heart rate and blood pressure, reducing stress on the wall of the aorta,” said study co-author Alan C. Braverman, MD, a cardiologist at Washington University School of Medicine in St. Louis. “The new study suggests that we have a second option for patients that appears to be as effective as standard treatment.”

The second option is Losartan, an angiotensin receptor blocker. Past research in mice and smaller clinical trials suggested that this class of drugs might actually be superior to beta blocker treatment for Marfan’s syndrome. Angiotensin receptor blockers commonly are prescripted to treat high blood pressure. Investigators in the Pediatric Heart Network of the National Institutes of Health (NIH), including Braverman and senior author Ronald V. Lacro, MD, a cardiologist at Harvard Medical School and Boston Children’s Hospital, conducted a clinical trial comparing the beta blocker Atenolol with Losartan. After following participants for three years, the invetigators reported no differences between the two gropus in the rate of dilation of aorta, and observed similar rates of dissection in the aorta, and no difference in the number of deaths between the two groups. “This trial demonstrated that Marfan’s patients treated with either Atenolol or Losartan had very slow rates of aortic grown, and each group tolerated their medications well,” said Braverman, who treats patients at Barnes-Jewish Hospital. “While beta blockers may be the gold standard for this condition, these results suggest we must use effective doses. This is also an important alternative therapy for the smaller number of patients who are intolerant to beta blockers.”

The study appeared online in the New England Journal of Medicine.

Gene Mutations in NPC1L1, the Target of the Drug Ezetimibe, Found to Reduce Cholesterol and Protect Against Heart Attack

Researchers at Washington University have shown that mutations in the gene NPC1L1 are associated with lower cholesterol and about 50% reduction in risk of heart attack. The research was led by Washington University Cardiologist Dr. Nathan Stitziel and appears online November 12th in the New England Journal of Medicine.

Ezetimibe, a drug commonly prescribed to lower LDL cholesterol, functions by inhibiting the protein product of the NPC1L1 gene. It is unknown if treatment with ezetimibe also lowers risk of heart attack. The research team performed a genetic analysis on more than 113,000 individuals to identify people who carried mutations that inactivated one copy of NPC1L1. “Inactivating mutations in gene encoding a drug target can mimic the action of an inhibitory drug can provide insight into the potential efficacy of that drug,” said the study’s lead author Nathan Stitziel, MD, PhD, Instructor in Medicine at Washington University School of Medicine. These individuals who carried inactivating mutations in NPC1L1 had 12 mg/dL lower LDL cholesterol and 53% reduced risk of heart attack compared with non-carriers. “These data suggest that pharmacologic therapies targeting NPC1L1, such as ezetimibe, should reduce the risk of heart attack,” Stitziel said. “More generally, this work demonstrates the potential of protective mutations in revealing insights into human disease and the ability to point toward important drug targets.” The research is published in the New England Journal of Medicine.

 

The Heart’s Own Immune Cells Can Help It Heal

Researchers at Washington University have found the heart holds its own pool of immune cells capable of helping it heal after injury, according to a new study in mice at Washington University School of Medicine in St Louis. Research led by cardiologist Dr. Kory Levine, showed that the injured pediatric and adult heart contains two types of macrophages with different developmental origins, a finding that may explain why the failing pediatric heart has a greater capacity for cardiac recover.

“Researchers have known for some time that the neonatal mouse heart can completely recover from injury, and in some cases can even regenerate,” said the first author Kory J. Lavine, MD, PhD, instructor in medicine. “If you cut off the tip of the neonatal heart, it forms scar tissue.” Dr. Lavine hypothesized that differences in the innate immune system might explain the disparity in healing capacity between the neonatal and adult heart.

Macrophages are a central component of the innate immune system and are required for clearance of pathogens, inflammatory responses, and wound healing. How these immune cells perform such diverse functions is not well understood. Using a mouse model of cardiac injury to simulate heart failure, the injured pediatric heart contained macrophages of embryonic origin that stimulated tissue repair, while the injured adult heart contained macrophages recruited from the bone marrow that generated inflammation and imparted additional damage to the heart. “The same macrophages that promote healing after injury in the neonatal heart also are present in the adult heart, however they disappear following injury.” The research team additionally found that by blocking recruitment of macrophages from the bone marrow to the injured adult heart, they were able to preserve the pool of beneficial embryonic macrophages and improve the reparative capacity of the adult heart. Their findings implicate a new potential therapeutic approach for treating patients with heart failure. This article appeared online November 10th, on the National Institutes of Health site.

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New Experimental Drug Reduces Tissue Damage Following Myocardial Infarction and Minimizes the Risk of Bleeding

Researchers at Washington University and St. Louis based APT Therapeutics Inc., show that a novel drug known as APT102 significantly reduced tissue damage to heart muscle following experimental myocardial infarction and minimized the risk of bleeding during follow-up treatments. The research team at Washington University was led by Dr. Dana Abendschein.

Myocardial infarction causes damage to heart muscle. Once the blood clot that causes a heart attack is removed from the artery, molecules from dead and dying cells mix with blood coursing through the reperfused artery. One of these molecules, adenosine triphosphate (ATP), is inflammatory; while another, adenosine diphosphate (ADP), triggers more clotting. APT102 is a genetically engineered version of the human protein apyrase, which transforms ATP and ADP into adenosine monophosphante, which is a benign molecule. Another enzyme changes this molecule into adenosine, which is beneficial for the heart.

“APT102, has the potential to change the paradigm for how heart attack patients initially are treated,” said senior author Dana Abendschein, PhD, associate professor of medicine and of cell biology and physiology at Washington Universtiy. “This also may be a better way to treat strokes caused by or associated with a blood clot.”

The study, which was funded by a National Institutes of Health (NIH) Small Business Innovation Research Grant and by APT Therapeutics, Inc., the developer of APT102, is available online in Science Translational Medicine (online Aug. 6, 2014).

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Regions of the Genome Once Mislabled as ‘Junk’ are Linked to Pathogenesis of Heart Failure

Dr. Jeanne Nerbonne and a team of Washington University researchers from the Center of Cardiovascular Research (CCR) reported results from a comprehensive analysis of different families of RNA molecules expressed in the human heart. The researchers studied non-failing hearts and failing hearts before and after patients received mechanical pump support from left ventricular assist devices (LVAD). The LVADs increased each heart’s pumping capacity while patients waited for heart transplants.

In the new study, the investigators found that unlike other RNA species, the expression patterns of long noncoding RNAs could distinguish between two major types of heart failure and between failing hearts before and after they received LVAD support. Long noncoding RNA has often been referred to as dark matter or junk RNA because the function of the long noncoding RNA is not known. “We don’t know whether these changes in long noncoding RNAs are a cause or an effect of heart failure,” Nerbonne said. “But it seems likely they play some role in coordinating the regulation of multiple genes involved in heart function.” The research is published in the American Heart Association journal Circulation (2014; 129: 1009-1021).

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Nanoparticles Treat Muscular Dystrophy in Mice

A team of researchers at Washington University School of Medicine in St. Louis have demonstrated a new approach to treating muscular dystrophy. (Read more) Mice with a form of this muscle weakening disease showed improved strength and heart function when treated with nanoparticles loaded with rapamycin, an immunosuppressive drug recently found to improve recycling of cellular waste.

The investigators, led by Dr. Sam Wickline, studied a mouse model of Duchenne muscular dystrophy, which is an inherited disease that exclusively affects boys, who become wheelchair bound by age 12 and die from heart or respiratory failure in their 20’s. The faulty gene that causes the disease prevents the body from producing dystrophin, a protein crucial for maintaining muscle cell integrity and function. The new study demonstrated that mice with muscular dystrophy, in addition to missing dystrophin, also can’t recycle cellular waste, a process known as autophagy, or self-eating. “Autophagy plays a major role in disposing of cellular debris,” said Samuel A. Wickline, MD, the James R. Hornsby Family Professor of Medicine. “If it doesn’t happen, you might say the cell chokes on its own refuse. In muscular dystrophy, defective autophagy is not necessarily a primary source of muscle weakness, but it clearly becomes a problem over time. If you solve that, you can help the situation by maintaining more normal cellular function.” The research is published in the American journal FASEB (2014:28, 2047-61).

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New Insights Into How Immune Cells Heal Injured Hearts

The immune system plays an important role in the heart’s response to injury. But until recently, conflicting data made it difficult to distinguish the immune factors that encourage the heart to heal following a heart attack, versus those factors that can lead to further damage. (Read more)

Now, research performed by Dr. Slava Epelman and colleagues at Washington University School of Medicine in St. Louis have shown that two major pools of immune cells are at work in the heart. Both belong to a class of cells known as macrophages. One appears to promote healing, while the other likely drives inflammation, which is detrimental to long-term heart function. “Macrophages have long been thought of as a single type of cell,” said first author Slava Epelman, instructor in medicine. “Our study shows there actually are many different types of macrophages that originate in different places in the body. Some are protective and can help blood vessels grow and regenerate tissue. Others are inflammatory and can contribute to damage.” The research is published in the Cell Press journal Immunity (2014; 40: 90-104).

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2nd Annual CV Research Day

The Cardiovascular Division held its Second Annual Cardiovascular Research Day on December 5, 2013. The event drew more than 150 participants, and focused on a wide variety of basic, clinical and translational cardiovascular research efforts. Junior faculty presented on current research and both graduate students and postdoctoral research fellows offered poster presentations. The event was highlighted by the first Burton E Sobel lecture that was given by Dr. Eric N. Olson, who is Professor and Chairman of the Department of Molecular Biology at the University of Texas Southwest Medical Center.

New Study from Washington University Investigators Shows that Black Patients Undergo Aortic Valve Replacement Less Frequently

In a study, published online in the American Journal of Cardiology, Drs. Michael Yeung (Division of Cardiology, University of North Carolina, Chapel Hill, USA) and Alan Zajarias (Division of Cardiology, Washington University School of Medicine, St. Louis, USA) noted that although prior studies have shown that Black patients undergo interventions for acute myocardial infarction less frequently than do white patients, the role of race in aortic valve replacement had not been previously investigated. Accordingly, the Washington University School of Medicine investigators conducted a study to determine (1) if African Americans with severe aortic stenosis underwent aortic valve replacement less frequently than Caucasians with severe aortic stenosis and (2) to identify the possible reasons for any disparity that was present.

Using data from patients cared for at Barnes-Jewish Hospital, the investigators identified patients with severe aortic stenosis. Of 880 patients who were identified with severe aortic stenosis and known treatment status, 791 (90%) were Caucasian and 89 were African American (10%). Although the rates of symptomatic aortic stenosis were similar between racial groups, Caucasians complained more frequently of dyspnea and African Americans had evidence of worse disease severity on echocardiogram. Overall, 51% of patients with severe aortic stenosis underwent aortic valve replacement. However, significantly fewer African Americans underwent surgery than Caucasians (39% vs. 53%, respectively; p=0.019). The reasons for not undergoing surgery (ranging from advanced age to lack of symptoms) were mostly similar between groups, but African Americans more frequently declined aortic valve surgery than did Caucasians. Zajarias and colleagues reported that previous studies have suggested that cultural preferences influence the decision-making process in cardiac surgery, and that cultural preferences may explain why more African Americans declined surgery in their retrospective study. Zajarias told Cardiovascular News: “Socioeconomic status may influence the ability of patients to fully understand a disease process, treatment options and their implications. This may be one of the reasons leading to the treatment differences seen in the previous studies.”

First Annual Cardiovascular Research Day

The Cardiovascular Division held its First Cardiovascular Research Day and Alumni Celebration on December 7, 2012. The event was the highlight of the division’s 65th anniversary year. Junior faculty presented on current research and both graduate students and postdoctoral research fellows offered poster presentations. The plenary session lecturer was Eugene Braunwald, MD, Distinguished Hersey Professor of Medicine at Harvard Medical School and founding chairman of the TIMI Study Group at Brigham and Women’s Hospital.

Over-Use of Drug-Eluting Stents Found

A review of more than 1.5 million percutaneous coronary intervention (PCI) procedures documented in the National Cardiovascular Data Registry has found that cardiologists are “routinely over-using” drug-eluting stents versus bare-metal stents for patients at low risk for repeat blockages of arteries. The study, published online in the Archives of Internal Medicine found that DES use was high whether the patient was at high or low risk for restenosis. Drug-eluting stents are more costly than bare-metal stents and require patients to take blood thinners or aspirin after the procedure. Reducing DES use by 50 percent, say the researchers, could lower healthcare costs in the United States by as much as $205 million annually while at the same time, increasing the overall risk for vessel revascularization by only .05 percent. Lead author for the study is Amit P. Amin, MD, assistant professor in the Cardiovascular Division at Washington University School of Medicine. His research was conducted a fellow at Saint Luke’s Mid-America Heart Institute in Kansas City.

Noninvasive Imaging Technique May Help Kids with Heart Transplants

Washington University cardiologists have developed a noninvasive imaging technique that may help determine whether children who have had heart transplants are showing early signs of rejection. The technique could reduce the need for these patients to undergo invasive imaging tests every one to two years.

The noninvasive technique, which involves the use of gadolinium contrast-enhanced cardiac MRI. Gadolinium is not radioactive and makes areas of inflamed arteries and heart muscle appear brighter on images. Researchers found that the brightness corresponds to evidence of coronary artery disease.

If larger studies confirm the results, the noninvasive test could reduce the number of coronary angiograms, which require the use of a catheter to look for dangerous plaque on arterial walls.

The study involved 29 pediatric heart transplant patients. Samuel A. Wickline, MD, professor of medicine in the cardiovascular division, is the senior author of the study. Colleagues include Charles E. Canter, MD, professor of pediatrics; and medical student Mohammad H. Madani, a Doris Duke Clinical Fellow.

Researchers do note that gadolium is sometimes toxic to the kidney, so the technique is not appropriate for patients with poor kidney function. They also note that clear contrast-enhanced MRIs are difficult to obtain in very young children because of their high heart rates.

The new method is described in the July 2, 2012 online publication of the Journal of Heart and Lung Transplantation. The investigators are now in the process of developing a larger study to confirm and refine the results.

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Heart Disease and Diabetes

Researchers at Washington University School of Medicine have received a $4.7 million grant from the National Heart, Lung and Blood Institute to study heart disease in patients with diabetes. The study is led by Jean Schaffer, MD, the Virginia Minnich Distinguished Professor of Medicine and Director of the Diabetic Cardiovascular Disease Center and Diabetes Research Center.

“We’re particularly interested in why people with diabetes suffer from unusually severe forms of heart disease” says Schaffer.

Schaffer and her colleagues suspect a likely culprit is abnormal metabolism of lipids, a class of molecules that include fats, such as fatty acids and triglycerides. The research will include a clinical trial for patients with Type 2 diabetes to examine whether a drug that lowers blood lipids improves heart function.

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Calorie-restricted diet keeps heart young

A research team led by Dr. Phyllis Stein has found that a key measure of the heart’s ability to adapt to physical activity, stress, sleep and other factors that influence the rate at which the heart pumps blood, doesn’t decline nearly as rapidly in people who have significantly restricted their caloric intake for an average of seven years. They found that people who restrict their caloric intake in an effort to live longer have hearts that function more like those in people who are 20 years younger. The study is available online in the journal Aging Cell.

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Genetic Study Shows Racial Differences to be Factor in Mortality in Heart Attack Patients Receiving Anti-Platelet Therapy

Dr. Sharon Cresci and a team of Washington University researchers have identified the first genetic variations linked to race that begin to explain a higher risk of death among some African-American and Caucasian patients taking the clopidogrel (Plavix) after a heart attack.

These variants increased patients’ risk of dying in the year following a first heart attack, but they appeared to do so for different reasons depending on race, according to a recently published study in Circulation: Cardiovascular Genetics. In particular, the team found that two DNA variants common in African Americans were associated with an increased risk of both bleeding and death. In Caucasians, a different variant was linked to additional heart attacks and a higher risk of death. “The research is proactive”, said the study’s first author, cardiologist Sharon Cresci, MD, assistant professor of medicine and of genetics. “Knowing about potential genetic differences based on race can help physicians tailor drugs to patients based on their genetic makeup.” The research is published in the American Heart Association journal Circulation: Cardiovascular Genetics.

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