Scientific Breakthrough May Limit Damage Caused by Heart Attacks

Research identifies master controller of blood vessel growth in the heart

Paramedic Brett Schneider uses iTREAT to consult with Andrew Southerland, MD, a stroke expert at the University of Virginia Health System.

Newswise, July 1, 2016— A research advance from the Sanford Burnham Prebys Medical Discovery Institute (SBP) and Stanford University could lead to new drugs that minimize the damage caused by heart attacks.

The discovery, published today in Nature Communications, reveals a key control point in the formation of new blood vessels in the heart, and offers a novel approach to treat heart disease patients.

“We found that a protein called RBPJ serves as the master controller of genes that regulate blood vessel growth in the adult heart,” said Mark Mercola, Ph.D., professor in SBP’s Development, Aging, and Regeneration Program and jointly appointed as professor of medicine at Stanford University, senior author of the study.

“RBPJ acts as a brake on the formation of new blood vessels. Our findings suggest that drugs designed to block RBPJ may promote new blood supplies and improve heart attack outcomes.”

In the US, someone has a heart attack every 34 seconds. The ensuing loss of heart muscle, if it affects a large enough area, can severely reduce the heart’s pumping capacity, which causes labored breathing and makes day-to-day tasks difficult. This condition, called heart failure, arises within five years in at least one in four heart attack patients.

The reason heart muscle dies in a heart attack is that it becomes starved of oxygen—a heart attack is caused by blockage of an artery supplying the heart. If heart muscle had an alternative blood supply, more muscle would remain intact, and heart function would be preserved.

Many researchers have therefore been searching for ways to promote the formation of additional blood vessels in the heart.

“Studies in animals have shown that having more blood vessels in the heart reduces the damage caused by ischemic injuries, but clinical trials of previous therapies haven’t succeeded,” said Ramon Díaz-Trelles, Ph.D., staff scientist at SBP and lead author of the study.

“The likely reason they have failed is that these studies have evaluated single growth factors, but in fact building blood vessels requires the coordinated activity of numerous factors. Our data show that RBPJ controls the production of these factors in response to the demand for oxygen.

“We used mice that lack RBPJ to show that it plays a novel role in myocardial blood vessel formation (angiogenesis)—it acts as a master controller, repressing the genes needed to create new vessels,” added Diaz-Trelles.

“What’s remarkable is that removing RBPJ in the heart muscle did not cause adverse effects—the heart remained structurally and functionally normal in mice without it, even into old age.”

“RBPJ is a promising therapeutic target. It’s druggable, and our findings suggest that blocking it could benefit patients with cardiovascular disease at risk of a heart attack. It may also be relevant to other diseases,” commented Pilar Ruiz-Lozano, Ph.D., associate professor of pediatrics at Stanford and adjunct professor at SBP, co-senior author.

“Inhibitors of RBPJ might also be used to treat peripheral artery disease, and activators might be beneficial in cancer by inhibiting tumor angiogenesis.”

This research was performed in collaboration with scientists at Stanford University, Washington University in St. Louis, and the University of California, San Diego. Funding was provided by the National Institutes of Health, the Sanford Children’s Health Center, the American Heart Association, the Burroughs Wellcome Fund, the California Institute for Regenerative Medicine, the Italian Ministry of Research and Education, and the Italian Society of Cardiology.

About SBP
Sanford Burnham Prebys Medical Discovery Institute (SBP) is an independent nonprofit medical research organization that conducts world-class, collaborative, biological research and translates its discoveries for the benefit of patients. SBP focuses its research on cancer, immunity, neurodegeneration, metabolic disorders and rare children’s diseases. The Institute invests in talent, technology and partnerships to accelerate the translation of laboratory discoveries that will have the greatest impact on patients. Recognized for its world-class NCI-designated Cancer Center and the Conrad Prebys Center for Chemical Genomics, SBP employs about 1,100 scientists and staff in San Diego (La Jolla), Calif., and Orlando (Lake Nona), Fla. For more information, visit us at SBPdiscovery.org or on Facebook at facebook.com/SBPdiscovery and on Twitter @SBPdiscovery.

About Stanford
The Stanford University School of Medicine consistently ranks among the nation’s top medical schools, integrating research, medical education, patient care and community service. For more news about the school, please visithttp://www.med.stanford.edu/school.html. The medical school is part of Stanford Medicine, which includes Stanford Health Care and Lucile Packard Children’s Hospital Stanford. For information about all three, please visithttp://www.med.stanford.edu.

Both Limited and Excess Sleep May Raise Diabetes Risk in Men

Study is the first to show opposite effects of lost sleep in healthy men and women

Newswise, June 30, 2016—Men who sleep either fewer or more hours than average may face a greater risk of developing diabetes, according to a new study published in the Endocrine Society’s Journal of Clinical Endocrinology & Metabolism.

More than 29 million people nationwide have diabetes, according to the Endocrine Society’sEndocrine Facts and Figures Report. 

During the last 50 years, the average self-reported sleep duration for individuals has decreased by 1.5 to 2 hours, according to the study’s senior author, Femke Rutters, PhD, of the VU Medical Centre in Amsterdam, The Netherlands. The prevalence of diabetes has doubled in the same time period.

“In a group of nearly 800 healthy people, we observed sex-specific relationships between sleep duration and glucose metabolism,” said Rutters.

“In men, sleeping too much or too little was related to less responsiveness of the cells in the body to insulin, reducing glucose uptake and thus increasing the risk of developing diabetes in the future. In women, no such association was observed.”

The cross-sectional study examined the sleep duration and diabetes risk factors in 788 people. The researchers analyzed a subset of participants in the European Relationship between Insulin Sensitivity and Cardiovascular Disease (EGIR-RISC) study, who were healthy adults ranging in age from 30 to 60 years old. Study participants were recruited from 19 study centers in 14 European countries.

Researchers measured the participants’ sleep and physical activity using a single-axis accelerometer, a device to track movement.

To assess the risk for diabetes, researchers used a device called a hyperinsulinemic-euglycemic clamp to measure how effectively the body used the hormone insulin, which processes sugar in the bloodstream.

The study found that men who slept the least and the most were more likely to have an impaired ability to process sugar compared to men who slept an average amount, about seven hours. The men at either end of the spectrum had higher blood sugar levels than men who got the average amount of sleep.

Women who slept less or more than average, however, were more responsive to the hormone insulin than women who slept the average amount.

They also had enhanced function of beta cells – the cells in the pancreas that produce the hormone insulin. This suggests lost sleep may not put women at increased risk of developing diabetes.

The study is the first to show opposite effects of lost sleep on diabetes risk in men and women.

The authors theorized this may be a result of the study population being made up of healthy individuals, rather than those at risk of developing diabetes. The researchers also measured insulin sensitivity and sleep with more sensitive devices than past studies.

“Even when you are healthy, sleeping too much or too little can have detrimental effects on your health,” Rutters said. “This research shows how important sleep is to a key aspect of health – glucose metabolism.”

Key to Chronic Fatigue Syndrome Is in Your Gut, Not Head

Newswise, June 30, 2016— Physicians have been mystified by chronic fatigue syndrome, a condition where normal exertion leads to debilitating fatigue that isn’t alleviated by rest. There are no known triggers, and diagnosis requires lengthy tests administered by an expert.

Now, for the first time, Cornell University researchers report they have identified biological markers of the disease in gut bacteria and inflammatory microbial agents in the blood.

In a study published June 23 in the journalMicrobiome, the team describes how they correctly diagnosed myalgic encephalomyeletis/chronic fatigue syndrome (ME/CFS) in 83 percent of patients through stool samples and blood work, offering a noninvasive diagnosis and a step toward understanding the cause of the disease.

“Our work demonstrates that the gut bacterial microbiome in chronic fatigue syndrome patients isn’t normal, perhaps leading to gastrointestinal and inflammatory symptoms in victims of the disease,” said Maureen Hanson, the Liberty Hyde Bailey Professor in the Department of Molecular Biology and Genetics at Cornell and the paper’s senior author.

“Furthermore, our detection of a biological abnormality provides further evidence against the ridiculous concept that the disease is psychological in origin.”

“In the future, we could see this technique as a complement to other noninvasive diagnoses, but if we have a better idea of what is going on with these gut microbes and patients, maybe clinicians could consider changing diets, using prebiotics such as dietary fibers or probiotics to help treat the disease,” said Ludovic Giloteaux, a postdoctoral researcher and first author of the study.

In the study, Ithaca campus researchers collaborated with Dr. Susan Levine, an ME/CFS specialist in New York City, who recruited 48 people diagnosed with ME/CFS and 39 healthy controls to provide stool and blood samples.

The researchers sequenced regions of microbial DNA from the stool samples to identify different types of bacteria.

Overall, the diversity of types of bacteria was greatly reduced and there were fewer bacterial species known to be anti-inflammatory in ME/CFS patients compared with healthy people, an observation also seen in people with Crohn’s disease and ulcerative colitis.

At the same time, the researchers discovered specific markers of inflammation in the blood, likely due to a leaky gut from intestinal problems that allow bacteria to enter the blood, Giloteaux said.

Bacteria in the blood will trigger an immune response, which could worsen symptoms.

The researchers have no evidence to distinguish whether the altered gut microbiome is a cause or a whether it is a consequence of disease, Giloteaux added.

In the future, the research team will look for evidence of viruses and fungi in the gut, to see whether one of these or an association of these along with bacteria may be causing or contributing to the illness.

The study was funded by the National Institutes of Health.

New Pathway to Treat Heart Failure

 Researchers discover a new way to keep the heart pumping, which could lead to new drugs for heart disease

Newswise, June 30, 2016 — (PHILADELPHIA) -- About 5.7 million Americans have heart failure, half of whom will die from the disease within 5 years, according to the Centers for Disease Control and Prevention (CDC).

Two processes help drive the disease: a weakened heart muscle that is less able to pump, and the death of heart cells that irreparably damage the heart. Beta-blockers, commonly used to treat heart disease, work by blocking the beta-adrenergic receptors in the heart, saving heart cells from cell death. But beta-adrenergic receptors also help keep the heart pumping, a function that this medication also blocks.

Now, Jefferson researchers have discovered how to bypass this problem by tapping an alternate pathway that both blocks damage to the heart and helps it keep pumping.

The research, published online this week in theProceedings of the National Academy of Sciences USA (PNAS) offers the possibility of developing a new, and potentially more effective, class of heart-failure medications.

“There’s much more work to be done before this is ready for patients, but this is an excellent example of how a little curiosity in the basic research laboratory can lead to discoveries that have the potential to change the way we treat a very common and very deadly illness,” said senior author Jeffrey Benovic, Ph.D., Thomas Eakins Professor and Chair of the Department of Biochemistry and Molecular Biology at the Sidney Kimmel Medical College and Associate Director at the Sidney Kimmel Cancer Center at Thomas Jefferson University.

Of the beta-adrenergic receptors present in the heart, it is the beta1-adrenergic receptors that are primarily responsible for the heart’s contraction, or pumping action, and that are targeted by traditional beta-blockers.

 Dr. Benovic’s lab, however, had developed a series of molecules called pepducins that were derived from pieces of the beta2-adrenergic receptor, and which, they discovered, could selectively activate the very receptor they came from.

It was while former graduate student Richard Carr, in Dr. Benovic’s lab, was characterizing the properties of these pepducins that he noticed that the molecule shared similar characteristics to a common heart-failure medication called carvedilol.

They sent the pepducin to their colleague Dr. Douglas Tilley, Ph.D., at Temple University who tested how heart cells responded to the molecule. “He was blown away by what he saw,” said Dr. Benovic.

When Dr. Tilley pulsed the heart cells with the pepducin, the cells started to beat more forcefully.

“We didn’t expect that this would happen,” said Dr. Benovic.

The pepducin they were using was specific for the beta2-adrenergic receptor pathway, and didn’t have any effect on the beta1 receptors. The researchers had demonstrated for the first time that contraction of heart muscle cells could be triggered via the beta2-adrenergic receptor, using this novel pepducin.

Through further biochemical analysis the researchers showed that the pepducin activated the ability of the beta2-adrenergic receptor to interact with a secondary signaling molecule called beta-arrestin and that it was this interaction that promoted the heart cells to beat.

In addition, the pepducin only activated the beta2 receptor to 40 or 50 percent. By tinkering with the pepducin molecules, said Benovic, “we think we can get full activation.”

The next steps, said Dr. Benovic, are to design a better version of the pepducin. In addition, Dr. Benovic and colleagues plan to screen existing small molecules, or drugs, to see if one can mimic the action of the pepducin.

They also plan to study the structure of the pepducin and the beta2 receptors to gain better insight into the design of more effective pepducin-like molecules.

“If we find or design a compound that works like this pepducin, it wouldn’t necessarily cure heart disease, but it would give doctors another tool to help bolster a failing heart,” says Benovic.

This research was supported by National Institutes of Health awards R37 GM047417, R01 GM068857, P01 HL114471, R01 HL105414, RO1 HL074854, P01 HL075443, P01 HL091799 and T32 GM100836. The authors report no conflicts of interest.

Two-in-One Approach Could Help Keep Brain Cancer in Check

Newswise, June 30, 2016 — A “combined therapy” approach to treating the most common form of brain cancer could prove promising, scientists say.

Glioblastoma is not only the most common form of brain cancer, it’s also the most deadly. It affects people from around 40 years of age, and most people live for less than 2 years after aggressive therapy. “This is a devastating disease,” says Simona Parrinello of the MRC’s Clinical Sciences Centre, who led the research.

New treatments are urgently needed, and in a study published today in eLife, the team shows that targetting just one protein has two effects, it both halts the division of the cancer cells, and stops these cells from spreading through normal tissue, a two-in-one approach.

“Current treatments often fail because the tumours spread throughout the brain, and so can’t be fully removed by surgery. If we can target this spread, it may be possible to make therapies more effective. When we target this one protein we block two key features of the tumour: its ability to divide and its ability to invade. It could be a combined therapy in one,” says Parrinello.

Scientists are not clear exactly how the cancer cells invade the brain in patients with this condition, though they know that one key route is through the space that surrounds blood vessels.

It is also known that it’s a critical subset of cancer cells that appears to favour this route. These are called “glioblastoma stem-like cells”, or GSCs, because they behave in a similar way to stem cells in the developing and adult brain.

GSCs are particularly resistant to chemotherapy and radiotherapy. Scientists believe that this, and their ability to invade, could mean it’s these cells that are responsible for the regular recurrence of glioblastoma after initial treatment.

In this study, Parrinello’s team used a cutting-edge technique called intravital imaging, to watch GSC invasion within the normal brain in real time.

Using this technique, the team discovered that when healthy cells first develop non-cancerous mutations, blood vessels within the brain keep them in a compartment so that they cannot spread and cause damage.

They found that the vessels do this by producing a protein, called ephrin-B2, which appears to immobilise the cells and hold them in place. However, when cells become cancerous GSCs, they are able to override this anti-invasion signal, and escape the compartment.

Crucially, Parrinello showed that the GSCs do this by producing their own ephrin-B2, which makes them insensitive to the ephrin-B2 already on the blood vessels.

The study also shows that a positive feedback effect comes into play along with the raised levels of ephrin-B2. At high levels, the protein appears to act as a signal, telling the GSCs to divide.

The team tried blocking ephrin-B2 using mouse models created with tumour cells from patients with the condition, a “gold standard” test for potential treatments in people.

They found that the tumour cells were unable to divide and spread through the brain. This resulted in tumours shrinking in size and the mice outliving those that did not receive the treatment, with some tumours disappearing completely. 

Parrinello says it is exciting that one treatment targets two key traits of a tumour.

“The ephrin-B2 system is complex, but in this case it works in our favour. By blocking one molecule we affect two key aspects of the tumour,” says Parrinello.

“In addition, because ephrin-B2 levels are much higher in tumour cells relative to normal cells, blocking this protein should have minimal side-effects”.

Whilst an important discovery, the scientists expect that it will be many years before this treatment is ready to be tested in people.

 In this study, they explored one particular sub-type of glioblastoma. Parrinello now plans to investigate how other subtypes respond, and whether other signalling molecules play a similar role to ephrin-B2.

Earlier this year, Parrinello won a ‘Programme Foundation Award’ grant from Cancer Research UK worth £1.5 million. Her Cell Interactions and Cancer group has also been awarded a grant from MRC Technology, which will allow the team to explore how this treatment might be used alongside existing approaches such as chemotherapy and surgery.

In this study, the CSC scientists worked with colleague Vincenzo De Paola to set up the technique for intravital imaging of the tumour cells, with Steven Pollard from the MRC Centre for Regenerative Medicine in Edinburgh, who supplied patient cells, and with Jorge Martinez-Torrecuadrada from the Centro Nacional de Investigaciones Oncologicas in Madrid who developed the molecule that blocks ephrin-B2. Federico Roncaroli of the University of Manchester provided and analysed human tumour material. Paul Bertone from the European Bioinformatics Institute in Cambridge assisted with the bioinformatics analysis of the results. 

Soaring Temperatures Pose Threat to Children, Elderly

Newswise, June 24, 2016 — The searing, record-setting temperatures in the West and Southwest United States flared a warning that extreme heat could be commonplace across much of the country this summer.

“Any extremes in weather can be inherently dangerous, but the initial heat waves every summer can be particularly perilous to those who are most vulnerable to heat-related illnesses, including children, the elderly and those with chronic medical conditions,” said Dr. Jennifer Caudle, a family physician and an assistant professor at the Rowan UniversitySchool of Osteopathic Medicine.

Most individuals can adjust to changes in temperature, a process called acclimatization, within five to seven days, but for some the process can take up to two weeks, Dr. Caudle explained.

“When the weather changes quickly, such as with a sudden heat wave, our bodies race to help maintain a normal body temperature by adjusting blood flow and sweating,” she said.

“The bodies of infants and the elderly aren’t able to make those changes as easily as healthy adults, leaving them at higher risk for serious illness and even death.”

A study by the U.S. Centers for Disease Control and Prevention (CDC) found that hot weather causes, on average, 658 deaths in the United States each year.

Interestingly, the results of the study indicated that most of the deaths occurred in the home and the vast majority of times those homes had no air conditioning. Already this year a number of deaths have been attributed to the heat in the West and Southwest United States.

“Many older individuals have medical conditions or live in situations that make them more likely to succumb to the heat,” Dr. Caudle noted.

 “Aside from their bodies’ inability to adjust quickly to changing temperatures, older individuals are less likely to sense and respond to changes in temperature and can have a diminished thirst reflex that keeps them from drinking adequate amounts of liquid. They may also have safety and financial concerns that keep them behind closed windows without fans or air conditioners.”

Dr. Caudle also emphasized that it is never o.k. to leave a child alone in a parked car, not even for a minute. Temperatures inside a parked car increase rapidly, as much as 20 degrees in just 10 minutes and can rise nearly 30 degrees within 20 minutes. Tragically, at least 15 children across the country have died already this year from the heat when left in parked cars.

“If you find a child asleep in a parked car, don’t assume that child is merely napping,” she said.

“Lethargy and confusion are signs of heat exhaustion or heat stroke, and are urgent medical conditions. Remove the child from the car and call 911 immediately. A high body temperature in a child could lead to permanent brain and organ damage.”

Dr. Caudle offered these hot-weather safety tips:

Children
• Never leave children unattended in a parked vehicle or near any pool or body of water for any amount of time.
• Avoid outdoor activities during the hours (10 a.m. to 3 p.m.) when the sun is hottest.
• Wear and re-apply sunscreen frequently.
• Children dehydrate faster than adults and should drink plenty of water during hot weather.

Elderly
• Check on elderly relatives and neighbors twice daily during hot weather.
• Make sure older individuals are appropriately dressed in loose, lightweight clothing.
• Encourage non-caffeine fluids and make sure they are within easy reach. Avoid overly sugary drinks or alcoholic drinks because these can make dehydration worse.
• If safety or finances keep older individuals behind closed doors without air conditioning, offer to take them to an air-conditioned environment like a mall or library.

Heat-related illnesses
• Heat cramps are spasms of the large muscles of the abdomen or legs accompanied by excessive perspiration. Move this person to a cool area to rest and to drink plenty of caffeine free, non alcoholic liquids.
• Heat exhaustion causes heavy perspiration, dizziness, weakness and nausea. Treat heat exhaustion with rest, drinks of cool water every 10 or 15 minutes and by applying cool, wet cloths directly to the skin. Seek immediate medical help if symptoms don’t improve quickly or if they suddenly worsen.
• Heat stroke causes many of the symptoms of heat exhaustion, without the perspiration. In fact, skin is often red and hot. Other symptoms include fainting, staggering or acting in a strange or confused manner. Heat stroke is a life threatening condition. Call 911 or emergency services for immediate help.

About Rowan University
Rowan University offers bachelor’s through doctoral programs to 16,100 students through its campuses in Glassboro, Camden and Stratford, New Jersey. In the past four years, Rowan created a School of Biomedical Sciences & Health Professions; opened the Camden-based Cooper Medical School of Rowan University; and incorporated the School of Osteopathic Medicine and the Graduate School of Biomedical Sciences, making Rowan only the second university in the nation to grant both M.D. and D.O. medical degrees. Rowan is collaborating with Rutgers-Camden to create degree programs to meet the growing need for medical services in the City of Camden. One of only three state-designated public research institutions in New Jersey, Rowan comprises the University's William G. Rohrer College of Business, the Henry M. Rowan College of Engineering and colleges of Communication & Creative Arts, Education, Humanities & Social Sciences, Performing Arts, and Science & Mathematics and the Division of Global Learning & Partnerships, as well as the medical schools.

Diabetes Raises Risk of Heart Attack Death by 50 Percent

Newswise, June 24, 2016 — Having diabetes increases the risk of dying from the effects of a heart attack by around 50 per cent, according to a widespread study.

Researchers at the University of Leeds tracked 700,000 people who had been admitted to hospital with a heart attack between January 2003 and June 2013.

Of these, 121,000 had diabetes.

After stripping out the effects of age, sex, any other illnesses and differences in the emergency medical treatment received, the team found stark differences in survival rates.

People with diabetes were 56 per cent more likely to have died if they had experienced a ST elevation myocardial infarction (STEMI) heart attack - in which the coronary artery is completely blocked - than those without the condition.

They were 39 per cent more likely to have died if they had a non-ST elevation myocardial infarction (NSTEMI) heart attack - in which the artery is partially blocked - than those without diabetes.

Lead researcher Dr Chris Gale, Consultant Cardiologist and Associate Professor in the university's School of Medicine, said: "These results provide robust evidence that diabetes is a significant long-term population burden among patients who have had a heart attack.

"Although these days people are more likely than ever to survive a heart attack, we need to place greater focus on the long-term effects of diabetes in heart attack survivors.

"The partnership between cardiologists, GPs and diabetologists needs to be strengthened and we need to make sure we are using established medications as effectively as possible among high-risk individuals."

He added that the next step in their research would be finding out exactly what it is about having diabetes that increases the risk of death following heart attack.

Dr Mike Knapton, Associate Medical Director at the British Heart Foundation, which funded the study said: "We knew that following a heart attack, you are less likely to survive if you also have diabetes.

"However, we did not know if this observation was due to having diabetes or having other conditions which are commonly seen in people with diabetes.

"This paper is the first to conclusively show that the adverse effect on survival is linked to having diabetes, rather than other conditions people with diabetes may suffer from.

"This research highlights the need to find new ways to prevent coronary heart disease in people with diabetes and develop new treatments to improve survival after a heart attack.

"The British Heart Foundation is committed to funding research in this area.

"We are currently funding researchers in Leeds to find new ways of keeping blood vessels healthy in people with diabetes in the fight for every heartbeat."

Dr Anna Morris, Head of Research Funding at Diabetes UK, said: "While researchers tackle this issue, we know that managing diabetes effectively can reduce the risk of developing cardiovascular disease.

"This includes eating healthily, keeping active and taking medications as prescribed by your doctor.

"It's essential that people with diabetes get the support they need to do this effectively, and that we continue to fund research across the UK aimed at preventing the onset of complications in the first place."

The study is published in the Journal of Epidemiology and Community Health.